Canadian Journal of Chemistry · 114 oxadiazolines 39a-i are obtained by oxidation with lead tetraacetate or PIDA.17 The acetate 115 group of each of those oxadiazoline can be replaced

Draft

Synthesis of carotol using a formal (4 + 1)-cycloaddition of

chiral dialkoxycarbenes

Journal: Canadian Journal of Chemistry

Manuscript ID cjc-2017-0594.R1

Manuscript Type: Article

Date Submitted by the Author: 08-Nov-2017

Complete List of Authors: Gund, Machhindra; Université de Sherbrooke, Chimie Déry, Martin; Paraza Pharma, Chemistry Spino, Claude; Universite de Sherbrooke,

Is the invited manuscript for consideration in a Special

Issue?: N/A

Keyword: [4+1]-cycloaddition, carotol, sesquiterpene, dialkoxycarbene

https://mc06.manuscriptcentral.com/cjc-pubs

Canadian Journal of Chemistry

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1

Synthesis of carotol using a formal (4 + 1)-cycloaddition of chiral dialkoxycarbenes. 1

Machhindra Gund, Martin Déry, and Claude Spino* 2

Université de Sherbrooke, Département de chimie, 2500 Boul. Université, Sherbrooke, QC, J1K 3

2R1, Canada 4

5

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Abstract: We report formal intramolecular (4+1)-cycloadditions of dialkoxycarbenes used in the 6

synthesis of the daucane-type sesquiterpene carotol. We found a chiral dialkoxycarbene capable 7

of diastereoselective formation of a key oxabicyclo[3.3.0]octene adduct. Carotol was synthesized 8

in 14 linear steps from simple starting materials. 9

Key words: [4+1]-cycloaddition, carotol, sesquiterpene, dialkoxycarbene. 10

11

Introduction 12

Carotol (1) is a daucene-type sesquiterpene first isolated by Asahina et al. (1925) from seeds and 13

roots of many plants of the Apiaceae (carrots) and Zingiberaceae (ginger) families.1 It has a 14

strong larvicidal and antimicrobial activity. It also acts as a potent olfactive attractant to the black 15

bean aphid (Aphis fabae). Its core bicyclo[5.3.0]decane skeleton presents a synthetic challenge in 16

the form of two adjacent adjacent quaternary carbons, including an all-carbon quaternary center, 17

and it is part of many other natural sesquiterpenes (Figure 1). The absolute configuration of 18

natural (+)-carotol was established in 1964.2 19

20

Figure 1. Biologically important natural products exhibiting a bicyclo[5.3.0]decane core. 21

22

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Prior to our synthesis,3 only one total synthesis of carotol was achieved in 15 steps starting from 23

(+)-dihydrocarvone 4 in low overall yield (Scheme 1).4 In this synthesis, the 5,7-fused rings 24

system was installed using a ring-expansion/ring-contraction strategy. Installation of the 25

endocyclic double bond led to a mixture of many products, among which were carotol (1), 26

daucene (8) and five other alcohols. 27

Stoltz’ group made ∆11

-carotol (14) in 11 steps from cycloheptenone derivative 9, which was 28

obtained from the Pd-catalyzed asymmetric allylation of isobutyloxycycloheptenone (Scheme 29

2).5 They also made (-)-epoxydaucenal B (11) from a common intermediate 10. Interestingly, 30

reduction of ketone 10 gave a small amount of the retro-aldol product 12, in contrast to one of 31

our first approaches where one intermediate underwent a spontaneous and irreversible aldol 32

reaction (vide infra). Fortunately, compound 12 could be made to undergo the forward reaction 33

and was recycled. 34

35

Scheme 1. Synthesis of carotol by Levisalles and coworkers. 36

37

38

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39

Scheme 2. Synthesis of ∆11

-carotol and epoxydaucenal B (11) by Stoltz and coworkers. 40

41

42

Other syntheses of daucane-type terpenes have been reported, the vast majority of them starting 43

with a monoterpene obtained from the chiral pool.6 The first synthesis of daucene by Yamasaki 44

started with (+)-limonene but the acid-catalyzed final step yielded a mixture of five products 45

from which (-)-daucene 8 was isolated in 42% yield (Scheme 3).7 Vandewalle and his coworkers 46

started from (-)-piperitone and in ten steps derived into (+)-daucene. Two of their key steps 47

include a [2+2]-cycloaddition and a thermal cycloreversion, but the subsequent conversion to 48

daucene proved a bit tedious.8 A third example is the synthesis of racemic lasidiol 23 using an 49

intramolecular [4+3]-cycloaddition between a furan and a dibromoketone 21. That key reaction 50

gave a mixture of six diastereomers and by-products from which cycloadduct 22 was isolated in 51

28% yield. Finally, the group of Anita Maguire has recently developed an approach to the 52

daucane skeleton based on an intramolecular Buchner cyclisation of α-diazoketones (not 53

shown).9 54

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The bicyclo[5.3.0]decane is well suited to showcase our method based on the intramolecular 55

(4+1)-cycloaddition between dialkoxycarbenes and electron-poor dienes. Dialkoxycarbenes10

are 56

nucleophilic species and take part in many reactions with carbonyls, alkenes, alkynes,10

57

isocyanates,11

vinyl isocyanates,12

and electron-poor dienes.13

They can be generated easily using 58

Warkentin’s oxadiazoline method, but despite this fact, only a handful of applications of 59

dialkoxycarbenes to the synthesis of natural products have been reported.14

We herein wish to 60

report a short and efficient synthesis of carotol using a diastereoselective formal (4+1)-61

cycloaddition as the key step and by doing so, demonstrate the convenience and effectiveness of 62

Warkentin’s oxadiazolines as dialkoxycarbene precursors in synthesis. 63

64

65

Scheme 3 : Approaches to the bicyclo[5,3,0]decane core of daucane-type terpenes. 66

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67

68

Our initial approach to the natural product is depicted in Scheme 4. We are able to control the 69

stereochemical outcome of the key reaction (27 � 25) by controlling the number of atoms 70

tethering the diene and the carbene in 27 (three atoms in this case).13a

However, we did not know 71

if controlling the absolute configuration of the adduct by introducing a chiral auxiliary would be 72

possible (28 � 26). 73

The precursor to dialkoxycarbene 27 is oxadiazoline 29, the synthesis of which is only three 74

steps as shown in Scheme 5. 3-Butyn-1-ol (31) was subjected to Negishi’s carboalumination 75

protocol to give vinyliodide 32. The latter was efficiently coupled to methylvinylketone via a 76

Heck reaction to give diene 33 as a single E,E-geometrical isomer. Note that the geometries of 77

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the alkenes do not determine the C2-C5 relative configuration in the subsequent [4+1]-78

cycloaddition (vide infra).13a

Submitting alcohol 33 to a catalytic amount of camphorsulfonic 79

acid and Warkentin’s oxadiazoline 3415

gave an excellent yield of the dialkoxycarbene precursor 80

29. The acetate in oxadiazoline 34 can be replaced by alcohols, thiols, and amines making the 81

generation of the corresponding carbene a simple matter.10

82

83

Scheme 4. Retrosynthetic analysis of carotol 1. 84

85

86

We felt that diastereoselectivity in the intramolecular formal (4+1)-cycloaddition might be 87

possible but we were concerned by the apparent lack of rigidity (free rotation) around the C–O 88

bonds of the carbene. Moreover, in our experience, NHCs or aminoalkoxycarbenes, which may 89

have allowed the construction of a more rigid chiral carbene system, do not undergo the (4+1)-90

annulation efficiently.13

Dialkoxycarbenes can adopt two different conformations (W-28 and S-91

28) with a difference in energy expected to be less than 2 kcal/mol and a barrier to 92

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interconversion of approximately 16 kcal/mol, based on calculation for dimethoxycarbene 93

(Figure 2).16

The third one (U-28) is too high in energy and its concentration would be small. We 94

have established the mechanism of the intramolecular (4+1)-cycloaddition to consist of an initial 95

concerted cyclopropanation reaction followed by ring-opening to a zwitterionic intermediate, 96

free bond-rotation, and collapse to the (4+1)-cycloadduct.13a

Therefore, the stereochemically 97

defining event is expected to be the concerted cyclopropanation, as it fixes the stereochemistry at 98

C5 while the stereochemistry at C2 is controlled by the length of the tether as alluded to earlier. 99

The preferred orientation of the chiral appendage at transition states (e.g. W-TS-26 and S-TS-100

26) would determine the sense and level of asymmetric induction. 101

102

Scheme 5: Synthesis of oxadiazoline 29. 103

104

105

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106

Figure 2: Conformations of the dialkoxycarbenes and transition states (TS) leading to the 107

intermediate cyclopropanes. 108

109

We therefore made several chiral oxadiazolines from chiral alcohols, some commercially 110

available, others made in a few steps (Scheme 6). Starting from chiral alcohols 35a-i, mixed 111

carbonates 36a-i are fabricated and reacted with hydrazine to give the carbamates 37a-i. 112

Following Warkentin’s procedure, acetone is condensed to the hydrazones 38a-i and the 113

oxadiazolines 39a-i are obtained by oxidation with lead tetraacetate or PIDA.17

The acetate 114

group of each of those oxadiazoline can be replaced by the primary alcohol 33 to give the 115

corresponding oxadiazoline 30a-i ready to undergo the (4+1)-cycloaddition. 116

We first investigated the key reaction on the racemic oxadiazoline 29 and obtained a 89% yield 117

of a mixture of oxabicyclo [3.3.0]-octaenes 25 and 40 in 93:7 ratio, easily separable by normal 118

silica gel column chromatography (Scheme 7, top). This diastereomeric ratio was perfectly in 119

line with what was expected considering the three-atom tether leading to the 5,5-fused 120

cycloadduct ring system.13a

It is of note that this ratio remained the same for all (4+1)-121

cycloaddition regardless of the nature of the substituent R on oxadiazolines 30a-i. 122

123

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Scheme 6: Synthesis of chiral oxadiazolines 30a-i. 124

125

126

Scheme 7: (4+1)-cycloaddition of oxadiazoline 29 and 30a-i. 127

128

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We then examined the asymmetric induction of the chiral appendages on oxadiazolines 30a-i, 129

which translates into the diastereomeric ratio of cycloadducts 26:41 (Scheme 7, bottom). One of 130

the simplest chiral alcohols that we could find was 3,3-dimethyl-2-butanol (35a). The 131

corresponding oxadiazoline 30a was thermolyzed under the same conditions as per oxadiazoline 132

29 and the ratio of cycloadducts was measured by 1H NMR. A disappointing ratio of 55:45 of 133

26a:41a (or 41a:26a) was obtained. The sense of asymmetric induction was not determined at 134

this point. Thinking that perhaps polar effects, and not only steric volumes, should help 135

differentiate the two groups flanking the carbinol, we tried the trifluoromethyl homologue 35b, 136

only to realize that such polar effects are virtually absent (57:43 ratio of 26b:41b). We looked to 137

introduce a second stereogenic carbon in the form of oxadiazolines 30c and 30d, with a 138

noticeable improvement on the ratio when 30d was thermolysed (67:33). In all likeliness, this 139

result has to do with the size and orientation of the second substituent (OBn), not its polarity, as 140

demonstrated by the identical ratio of cycloadducts 26e and 41e obtained upon thermolysis of 141

oxadiazoline 30e. 142

Convinced that the size and orientation of the substituents were major factors in controlling the 143

asymmetric induction of the chiral appendage, we examined the ratios of cycloadducts formed 144

during the thermolysis of oxadiazolines 30f-h. We were happy to obtain an acceptable ratio of 145

85:15 when the oxadiazoline derivative of the commercially available cyclohexanol auxiliary 146

35h was utilized. This level of induction is slightly lower than those obtained by Rigby and 147

coworkers in their intermolecular cycloadditions with vinylisocyanates.18

Still, given the fact that 148

we cannot use a cyclic, rigid framework derived from a chiral diol or aminoalcohol because of 149

the intramolecular nature of our reaction, we were satisfied at the level of diastereoselectivity 150

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attained in this reaction. All isomeric cycloadducts were separable by normal silica gel column 151

chromatography. 152

As mentioned earlier, the mechanism of the reaction proceeds via the formation of a 153

cyclopropane,13a

which is the stereo-determining step, followed by rearrangement to the final 154

adduct. Two W-TS and two S-TS conformations (c.f. Figure 2) in competition are depicted in 155

Scheme 8. The two B conformations and the two D conformations on the right of the Scheme 156

should be the ones with the larger difference in energy because the R group is closest to the rest 157

of the molecule. The ‘W’ conformers should be favored and the average of W-TS-26-A and W-158

TS-26-B should be lower in energy than the average of W-TS-41-C and W-TS-41-D. The role 159

of the second substituent (R’) is not understood and may simply add bulk to the auxiliary or 160

produce subtle conformational change. 161

162

Scheme 8: Transition states (TS) for the cycloadditions of dialkoxycarbenes derived from 26f-h. 163

W-TS-26-A W-TS-26-B

O

O Me

E

R

O

O Me

E

R

O

OMe

E

R

O

OMe

E

R

R'R'

R' R'

S-TS-26-B

O

O Me

E

R

R'

O

OMe

E

R

R'

W-TS-41-C W-TS-41-D S-TS-41-D

S-TS-26-A

O

O Me

E

R

O

OMe

E

R

R'

R'

S-TS-41-C 164

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It seemed to us that a pseudo C2-symmetrical auxiliary should fare better, making conformations 165

A nearly identical to conformations B (and C near identical to D) decreasing the need for 166

rigidity. We thus submitted oxadiazoline 30i, derived from alcohol 35i, to the same reaction 167

conditions but a rather surprising ratio of nearly 1:1 was obtained. Clearly, the methyl groups 168

were not voluminous enough. Though more elaborate chiral alcohols with pseudo C2-symmetry 169

like 35i bearing sufficiently large groups could be envisaged, they would take several steps to 170

prepare, rendering such a chiral auxiliary less appealing. We decided not to pursue this avenue. 171

Ketone 42 is a key intermediate in the synthesis of carotol (Scheme 9). It was prepared in a 172

straightforward manner by converting cycloadduct 25 into a diene with the Petasis reagent 173

(79%). Both double bonds were hydrogenated over PtO2 (98%) and the resulting acetal was 174

hydrolyzed to ketone (±)-42 with amberlyst-15 resin (92%). Other acidic hydrolysis conditions 175

favoured epimerization at C2. Starting with pure 26f, we repeated the sequence and obtained the 176

non-racemic (-)-42.19

This compound had been made by Srikrishna and coworkers in 8 steps 177

from (+)-limonene.20

We have made it in 7 steps from 3-butyn-1-ol. The optical rotation of (-)-42 178

was compared with the one obtained by Srikrishna. In addition, the minor diastereomer 41f was 179

also transformed into the corresponding diastereomer of (+)-42 (not shown). An X-ray 180

diffraction analysis of the intermediate after the hydrogenation also confirmed the relative 181

configuration as depicted.3 182

183

184

185

186

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Scheme 9: Synthesis of hydroxy-ketone (±)-42 and (-)-42. 187

O

Me

O

O

Me

R

2526f

Me

Me

Me

HO O

(±)-42(-)-42

1. Petasis2. PtO2, H2

3. Amb.-15

Me

Me

Me

HO OH

43

M

188

189

Unfortunately, the addition of alkylmetalson ketone 42 proved impossible in our hands. 190

Protecting or not the primary alcohol in 42 made no difference. This was unfortunate as the 191

synthesis would have been more convergent this way and carotol might have been, in principle, 3 192

steps away from intermediate 43. We were not the only ones having trouble with similarly 193

congested cyclopentanones.21

Only alkynylmetals successfully added to ketone 42. The 194

alkynylcerium derivative of 3-benzyloxy-1-butyne 44 was added diastereoselectively to the 195

hindered ketone (±)-42 giving the propargyl alcohol 45 in 82% yield (Scheme 10). We then 196

attempted to hydrogenate the triple bond and hydrogenolyse the benzyl group in one step using 197

Pd/C/H2 to get the saturated triol 48. In the event, the propargylic C-O bond proved susceptible 198

to hydrogenolysis leading to the undesired diol 46 in quantitative yield. We attempted to halt the 199

hydrogenolysis of the propargyl alcohol by lowering the catalyst loading and reducing the 200

reaction time to 3h. The alkyne was only partially reduced but still we observed the formation of 201

the hydrogenolysis product 46. The diastereomeric mixture of allylic alcohols 47a and 47b 202

obtained were separable by normal silica gel column chromatography. A single crystal X-ray 203

analysis for 47b confirmed the structure and the relative configuration of the tertiary alcohol. 204

The two allylic alcohols were converted into the required triol 48 using PtO2/H2 in 35% yield 205

along with the hydrogenolysis product 46 in large quantity. It did not bode well for the alkyne-206

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to-alkane strategy and yet we could not add nucleophiles other than sp-hybridized carbons to 207

ketone 42. 208

In our minds, the best way to avoid the propargylic C-O bond fission during hydrogenation was 209

to oxidize this carbon at the level of a carbonyl. To that end, we deprotected the propargylic 210

alcohol (Scheme 11, 50 � 51) and chemoselectively oxidized it with MnO2. We were a little 211

surprised to isolate none of the desired compound 52 but instead, a mixture of products which 212

seemed to contain the cyclized product 53 (not fully characterized). While it is always possible to 213

catalyze such cyclisations, this one was spontaneous. No doubt, a strong Thorpe-Ingold effect 214

was at play here. 215

216

Scheme 10: Problem of hydrogenolysis of the propargylic functions. 217

218

219

220

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Scheme 11: Problem with an unexpectedly fast cyclisation in the synthesis. 221

Me

Me

MeHO

OHTBSO

Me

Me

OTBS

a) n-BuLi, THF

-78 oC to 0 oC

b) CeCl3, THF, 0oC

c) (±)-42, 81%5049 51

TBAF, THF Me

Me

MeHO

OHHO

Me

MnO2

52

Me

Me

MeHO

OHO

Me

O

Me

OHMe

O

MeMe

53222 223

Undaunted, we simply protected the primary alcohol as an acetate before oxidizing the propargyl 224

alcohol (Scheme 12, 50 � 54), well aware that the synthesis was taking a turn for the worse with 225

extra, unproductive steps. In any case, while this plan successfully solved the hydrogenolysis 226

problem, for some reason, the tertiary alcohol eliminated during hydrogenation of ketone 55 to 227

give keto-alkene 56, regardless of what precaution we took to avoid it. This side reaction had not 228

been observed before (though it will come up again later). Note that many terpenoids of the 229

daucane family do have an alkene at that position (e.g. daucene, daucenal). 230

We were looking for a solution that would not only lead to the desired product, but reduce the 231

number of steps in the process. We very nearly achieved that when we decided to oxidize diol 51 232

to the ketoaldehyde 57. Hydrogenation of the alkyne was not accompanied by elimination of 233

water as per the hydrogenation of the alkyne 55. Instead, it gave way to a spontaneous 234

intramolecular and stereoselective aldol reaction to give 59 in 48% yield. No doubt, the strong 235

Thorpe-Ingold effect was interfering again. Hoping this aldol product might give back 236

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ketoaldehyde 58 under the basic conditions of the Wittig reaction, we did try to transform 59 to 237

the bis-alkene 24 (c.f. Scheme 4) but to no avail. 238

239

Scheme 12: Problem with an unruly alcohol. 240

241

242

Scheme 13: Problem with a spontaneous aldol reaction. 243

244 245

As is often the case, a solution to these problems lied with a compound that had been prepared 246

for a different purpose. It turns out that the TBS-protected propargyl alcohol 50 undergoes triple 247

bond hydrogenation with only little concomitant hydrogenolysis. Indeed, treating this compound 248

with palladium on alumina gave 80% yield of the desired diol 60 along with small amounts of 249

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the partially reduced diols 61 and hydrogenolysis product 46 (Scheme 14). The steric bulk of the 250

TBS protecting group must help in preventing the hydrogenolysis of the propargyl ether. 251

The primary hydroxyl in compound 60 was oxidized quantitatively with IBX and the resulting 252

aldehyde was subjected to olefination using methylphosphonium ylide to give 62 in 84% yield. 253

When a freshly prepared Petasis reagent was used instead, the terminal alkene migrated to give 254

the corresponding internal olefin (62b not shown) in 63% yield, with no trace of the desired 255

terminal olefin 62. Then, the secondary alcohol obtained after removal of the TBS protecting 256

group in 62 was subjected to the Ley-Griffith22

oxidation to give ketone 63 in 75% yield. 257

Deprotection of 62 and subsequent oxidation using Swern or IBX gave a complex mixture of 258

products. The crude mixture from its oxidation with TPAP/NMO contained as the major 259

compound what we eventually identified as cyclic enolether 64. However, upon standing or after 260

chromatography on silica gel, ketone 63 would become the sole product. We believe that the 261

molecular sieve in the oxidation medium gave rise to the dehydration of ketone 63 to enol 64 and 262

the latter slowly reverted back to ketone 63 upon handling. This is yet another demonstration of 263

the large Thorpe-Ingold effect present in these systems. 264

With ketone (±)-63 in hand, it was easy to complete the synthesis of carotol. We performed a 265

Wittig reaction with ketone 63 and isolated bis-alkene 24 in 56% yield. Grubbs’ first generation 266

catalyst23

was able to convert the latter to racemic carotol.24

A substantial amount of dehydration 267

occurred on ketone 63 to give keto-alkene 65, analogous to keto-alkene 56 (c.f. Scheme 12), 268

making this last step somewhat unsatisfactory. 269

270

271

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Scheme 14: A solution, but not the solution. 272

273

274

Scheme 15: Synthesis of carotol. 275

276

We thought we could yet improve on the current synthesis. Starting back from ketone 42, we 277

added the alkylnylcerium 66 to give 67 (Scheme 16).25

Its increased bulk should help in 278

preventing the hydrogenolysis of the propargyl ether. Indeed, we saw no trace of such product 279

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upon hydrogenation with palladium on alumina. Oxidation of the primary alcohol and olefination 280

gave compound 69 from which the tertiary alcohol could be deprotected and eliminated in 64% 281

yield to bis-alkene 24 along with a small amount of spiro-tetrahydrofuran compound 70 (<5%). 282

We thus retracted 2 linear steps from the previous synthesis, produced fewer side products, and 283

improved on the overall yield of the synthesis. Since we have made enantiomerically pure ketone 284

(-)-42, this also constitutes a formal synthesis of non-racemic (-)-carotol. Our synthesis has a 285

total of 14 linear steps from the structurally very simple 3-butyn-1-ol, a global yield of 5.6% 286

(counting the non-racemic route) for an average of 82% yield per step. 287

288

Scheme 16: Improved synthesis of carotol. 289

290 291

EXPERIMENTAL SECTION: 292

General Considerations 293

Unless otherwise noted all reactions were performed under an argon atmosphere. Anhydrous 294

acetone was purchased. Other solvents were distilled from potassium/benzophenone ketyl (THF, 295

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Et2O), from calcium hydride (DCM, toluene, DMF, Et3N). Proton nuclear magnetic resonance 296

(1H NMR) spectra were recorded on a 300 MHz or 400 MHz spectrometer. Carbon nuclear 297

magnetic resonance (13C NMR) spectra were recorded on the same spectrometer. NMR samples 298

were dissolved in chloroform-d (unless specified otherwise) and chemical shifts are reported in 299

ppm (δ units) relative to the residual undeuterated solvent. Multiplicities are reported as follows: 300

s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, 301

ddd = doublet of doublet of doublets, m = multiplet. LRMS analyses were performed on a GC 302

system spectrometer (30 m length, 25µ OD, DB-5 ms column) coupled with a mass 303

spectrometer. High-resolution mass spectrometry was performed by electrospray time-of-flight. 304

All reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm silica gel coated 305

glass plate visualized under UV (254 nm) and TLC stains such as vanillin, KMnO4, PMA, 306

Dragen Dorff, or by 1H NMR and GCMS analysis. Silica gel (230-400 mesh) was used for flash 307

chromatography. 308

(E)-4-Iodo-3-methylbut-3-en-1-ol (32) 309

To a stirred solution of 3-butyn-1-ol (31) (4.52 g, 64.5 mmol) in dichloromethane (50 mL) at 0 310

ºC under argon was added AlMe3 (1.44 g, 20.0 mmol, 10 mL of 2M/toluene). To another flask, 311

containing a stirred suspension of zirconocene dichloride (4.15 g, 14.2 mmol) in 312

dichloromethane (240 mL) at -20 ºC under argon was added dropwise AlMe3 solution (14.41 g, 313

200.0 mmol, 99.94 mL of 2M/toluene) and continued stirring for 15 min. when water (1.80 mL, 314

20.0 mmol) was added dropwise (caution: exothermic!!) and the resulting yellow colored slurry 315

was stirred vigorously for 20 min. The solution of 3-butyn-1-ol pretreated with AlMe3 was then 316

cannulated to above the slurry at -20 ºC, the mixture was allowed to warm to rt and the mixture 317

was stirred for 2.5 h. A solution of iodine (19.64 g, 77.39 mmol) in diethyl ether (130 mL) was 318

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added slowly to the above reaction mixture at -20 ºC and continued stirring at rt for 2 h. Contents 319

of the flask were slowly poured into 2L conical flask containing stirred saturated solution of 320

potassium sodium tartrate (500 mL) at 0 ºC under argon flush (caution : exothermic!!) The 321

resulting biphasic mixture was stirred for 2 h, filtered through celite, washed with ether (100 mL) 322

and the layers were separated. The aqueous layer was extracted with ether and the combined 323

organic extracts were washed successively with satd. Na2S2O3 solution, water, brine, dried over 324

anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude mixture was 325

purified by silica gel flash chromatography using 20% ethyl acetate in hexanes to afford the 326

alkenyl iodide 32 as colorless oil. (12.0 g, 88%). 1H NMR (300 MHz, CDCl3) δ 6.02 (d, J = 0.9 327

Hz, 1H), 3.72 (t, J = 6.3 Hz, 2H), 2.48 (t, J = 6.3 Hz, 2H), 1.88 (d, J = 0.6 Hz, 3H), 1.41 (bs, 1H, 328

-OH). 13C NMR (75.5 MHz, CDCl3): δ 144.6, 76.9, 60.1, 42.3, 23.9. 329

(3E,5E)-8-Hydroxy-6-methylocta-3,5-dien-2-one (33) 330

To a stirred solution of alkenyl iodide 32 (12.0 g, 56.6 mmol) in anhydrous DMF (100 mL) at rt 331

under argon was added palladium(II)acetate (0.64 g, 2.83 mmol) followed by NaHCO3 (16.64 g, 332

198.1 mmol), Bu4NCl (15.73 g, 56.59 mmol) and methylvinylketone (7.93 g, 113 mmol). The 333

reaction mixture was stirred at rt for 5 days and quenched by addition of ice-cold water (1 L) and 334

ethyl acetate (300 mL). The contents of the flask were stirred for 15 min. and filtered through 335

celite. Layers were separated, the aqueous layer was extracted with ethyl acetate (2 x 150 mL). 336

The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, 337

filtered and concentrated under reduced pressure. The crude product was purified by silica gel 338

flash chromatography using 30% ethyl acetate/hexanes to afford the desired product 33 as 339

colorless oil. (6.85g, 78%). 1H NMR (300 MHz, CDCl3): δ 7.42 (dd, J = 11.7, 11.4 Hz, 1H), 340

6.05–6.13 (m, 2H), 3.78 (t, J = 6.3 Hz, 2H), 2.42 (t, J = 6.3 Hz, 2H), 2.27 (s, 3H), 1.95 (d, J = 1.5 341

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Hz, 3H), 1.53 (bs, 1H, -OH). 13C NMR (100.7 MHz, CDCl3): δ 199.4, 148.0, 139.5, 128.7, 342

125.3, 60.1, 43.2, 27.3, 17.5. IR (neat): ν (cm-1) 3620–3129 (br), 3045, 2941, 2878, 1631, 1264, 343

1048. LRMS (m/z, relative intensity): 177 ((M+Na)+, 100). HRMS m/z: [M+Na]

+ Calcd for 344

C9H14NaO2: 177.0886, found: 177.0887. 345

(3E,5E)-8-(2-Methoxy-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-346

dien-2-one (29) 347

To a stirred solution of crude oxadiazoline 34 (11.71 g, 62.25 mmol) in dichloromethane (35 348

mL) was added a solution of alcohol 33 (6.40 g, 41.5 mmol) in dichloromethane (30 mL) 349

followed by camphorsulfonic acid (0.39 g, 1.66 mmol). The reaction mixture was stirred at rt for 350

7 h, diluted with dichloromethane (40 mL) and washed with satd. NaHCO3 solution, water, and 351

brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated 352

under reduced pressure. The crude product was purified by silica gel flash chromatography using 353

10% ethyl acetate in hexanes to afford the desired product 29 as colorless oil (10.31 g, 88%). 1H 354

NMR (300 MHz, CDCl3): δ 7.36, 7.41 (dd, J = 11.4 Hz, 1H), 6.01-6.10 (m, 2H), 3.75-3.96 (m, 355

2H), 3.41 (s, 3H), 2.46 (t, J = 6.6 Hz, 2H), 2.26 (s, 3H), 1.92 (d, J = 0.9 Hz, 3H), 1.54 (s, 3H), 356

1.50 (s, 3H). 13C NMR (100.7 MHz, CDCl3): δ (ppm) 198.5, 146.6, 138.8, 136.8, 128.9, 125.3, 357

119.0, 62.4, 51.7, 39.9, 27.4, 24.0, 23.8, 17.4. IR (neat): ν (cm-1) 3050, 2988, 2949, 1633, 1259, 358

1160. LRMS (m/z, relative intensity): 305 ((M+Na)+, 100), 235 (30). HRMS m/z : [M+Na]

+ 359

calcd for: C14H22N2NaO4: 305.1472, found: 305.1476. 360

General procedures for the synthesis of mixed phenyl carbonates 36a-i 361

To a stirred solution of chiral alcohol 35 (1.0 equiv.) in dry dichloromethane at 0 ºC was added 362

pyridine (4.0 equiv.)equiv.) followed by dropwise addition of phenyl chloroformate (1.1 363

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equiv.)equiv.). The reaction mixture was then stirred at rt for 12 h, diluted with dichloromethane, 364

washed with 1N HCl, water, brine, dried over anhydrous MgSO4, filtered and concentrated under 365

reduced pressure to afford the desired carbonate as colorless oil. (70-97%). In most of the cases 366

the crude carbonate 36 was pure enough and used in the next step without any purification. 367

3,3-dimethylbutan-2-yl phenyl carbonate (36a) 368

Colorless oil, 4.50 g, 88% yield. 1H NMR (300 MHz, CDCl3): δ 7.45-7.36 (m, 2H), 7.30-7.27 369

(m, 2H), 7.16–7.19 (m, 1H), 4.63 (q, J = 6.3 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H), 0.98 (s, 9H). 370

HRMS m/z : [M+Na]+ calcd for: C13H18NaO3: 245.1153, found: 245.1164. 371

Phenyl-1,1,1-trifluoro-3-methylbutan-2-yl carbonate (36b) 372

Colorless oil, 1.90 g, quantitative. 1H NMR (300 MHz, CDCl3) δ 7.43–7.40 (m, 2H), 7.30–7.26 373

(m, 2H), 7.22 (m, 1H), 5.05–4.97 (m, 1H), 2.26 (dt, J = 13.5, 6.8 Hz, 1H), 1.11 (dd, J = 6.9, 0.9 374

Hz, 6H). HRMS m/z : [M+Na]+ calcd for: C12H13F3NaO3: 285.0714, found: 285.0719. 375

(1S,2S)-2-(benzyloxy)cyclopentyl phenyl carbonate (36c) 376

Colorless oil, 1.13 g, 70% yield. 1H NMR (300 MHz, CDCl3): δ 7.43–7.36 (m, 2H), 7.35-7.34 377

(m, 4H), 7.31–7.22 (m, 2H), 7.21–7.17 (m, 2H), 5.16–5.12 (m, 1H), 4.62 (q, J = 11.3 Hz, 2H), 378

4.08–4.05 (m, 1H), 2.19–2.03 (m, 2H), 1.88–1.76 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 153.2, 379

151.2, 138.4, 129.6, 128.5, 127.7, 126.1, 121.1, 83.9, 83.7, 71.4, 30.5, 30.3, 21.7. HRMS m/z : 380

[M+Na]+ calcd for: C19H20NaO4: 335.1259, found: 335.1266. 381

(1S,2S)-2-(benzyloxy)cyclohexyl phenyl carbonate (36d) 382

Colorless oil, 1.90 g, 92% yield. 1H NMR (300 MHz, CDCl3) δ 7.33–7.25 (m, 1H), 7.24–7.11 383

(m, 1H), 7.09–7.04 (m, 1H), 4.72 (ddd, J = 10.1, 8.4, 4.5 Hz, 1H), 4.62 (d, J = 11.9 Hz, 1H), 4.54 384

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(d, J = 11.9 Hz, 1H), 3.42 (ddd, J = 9.9, 8.4, 4.4 Hz, 1H), 2.13–2.00 (m, 1H), 1.66 (dd, J = 11.8, 385

3.5 Hz, 1H), 1.48–1.15 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 153.4, 151.3, 138.8, 129.7, 386

129.5, 128.5, 127.6, 127.5, 125.9, 121.2, 121.0, 80.3, 79.2, 71.6, 29.9, 23.4. HRMS m/z : 387

[M+Na]+ calcd for: C20H22NaO4: 349.1416, found: 349.1418. 388

Phenyl (1S,2R)-2-phenylcyclohexyl carbonate (36e) 389

Colorless oil, 4.20 g, quantitative. 1H NMR (300 MHz, CDCl3): δ 7.33–7.24 (m, 7H), 7.18–7.13 390

(m, 1H), 6.86–6.83 (m, 2H), 4.92 (td, J = 10.6, 4.4 Hz, 1H), 2.79–2.70 (m, 1H), 2.30–2.25 391

(m,1H), 2.01–1.79 (m, 3H), 1.70–1.36 (m, 4H). HRMS m/z : [M+Na]+ calcd for: C19H20NaO3: 392

319.1310, found: 319.1311. 393

Phenyl (1S,2R)-2-(2-phenylpropan-2-yl)cyclohexylcarbonate (36f) 394


(m, 2H), 7.10 (d, J = 7.8 Hz, 2H), 4.70 (dt, J = 4.8, 4.2 Hz, 1H), 2.04-2.13 (m, 2H), 1.64-1.75 396

(m, 3H), 1.44-1.53 (m, 1H), 1.42 (s, 3H), 1.33 (s, 3H), 1.03-1.29 (m, 3H). 13C NMR (75 MHz, 397

CDCl3): δ 152.8, 151.2, 150.8, 129.4, 128.2, 125.8, 125.6, 125.5, 121.1, 80.0, 51.4, 40.2, 33.3, 398

27.3, 26.8, 26.7, 25.8, 24.7. HRMS m/z: [M+Na]+ Calcd for C22H26O3Na : 361.1774, found: 399

361.1788. 400

(1S,2R,4R)-4-methyl-2-(2-phenylpropan-2-yl)cyclohexyl phenyl carbonate (36g) 401

The carbonate was synthesized following a literature procedure and the spectral details matched 402

the reported data.26

Colorless gum, 1.39 g, quantitative. HRMS m/z : [M+Na]+ calcd for: 403

C23H28NaO3: 375.1936, found: 375.1940. 404

405

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406

(1S,2R,4S)-4-isopropyl-2-(2-phenylpropan-2-yl)cyclohexyl phenyl carbonate (36h) 407


(m, 4H), 4.66 (td, J = 10.7, 4.6 Hz, 1H), 2.17–2.05 (m, 2H), 1.73–1.63 (m, 2H), 1.54–1.37 (m, 409

2H), 1.42 (s, 3H), 1.33 (s, 3H), 1.14–0.90 (m, 3H), 0.81 (d, J = 6.8 Hz, 6H). 13C NMR (75 MHz, 410

CDCl3): δ 152.9, 151.2, 150.7, 129.4, 128.2, 125.5, 121.1, 80.2, 51.0, 43.3, 40.2, 32.9, 32.5, 30.8, 411

27.3, 27.2, 26.2, 20.2, 19.6. HRMS m/z : [M+Na]+ calcd for: C25H32NaO3: 403.2249, found: 412

403.2255. 413

(2S,6S)-2,6-dimethylcyclohexyl phenyl carbonate (36i) 414


(m, 1H), 7.20–7.17 (m, 2H), 4.54 (dd, J = 7.9, 4.0 Hz, 1H), 2.20–2.15 (m, 1H), 2.04–1.95 (m, 416

1H), 1.81–1.72 (m, 1H), 1.54–1.46 (m, 4H), 1.20–1.14 (m, 1H), 1.01 (s, 3H), 0.99 (s, 3H). 13C 417

NMR (75 MHz, CDCl3): δ 153.5, 151.4, 129.4, 125.8, 121.1, 85.1, 31.4, 30.9, 30.4, 19.6, 17.6, 418

14.4. HRMS m/z : [M+Na]+ calcd for: C15H20NaO3: 271.1310, found: 271.1307. 419

General procedure for the syntheses of carbamates 37a-i 420

To a stirred solution of carbonate 36 (1.0 equiv.)equiv.) in absolute ethanol at rt was added 421

hydrazine hydrate (4.3 equiv.)equiv.) and the reaction mixture was refluxed for 1 h. The reaction 422

mixture was concentrated under reduced pressure and the residue obtained was partitioned 423

between cold 10% NaOH and Et2O. The basic aqueous layer was once again extracted with 424

Et2O. The combined organic extracts were washed with water, brine, dried over anhydrous 425

Na2SO4 and concentrated under reduced pressure to afford the desired carbamate as colorless 426

gum (73–98%). The crude carbamate 37 was used in the next step without any purification. 427

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428

3,3-Dimethylbutan-2-yl hydrazinecarboxylate (37a) 429

Colorless oil, 2.7 g, 79% yield. 1H NMR (300 MHz, CDCl3): δ 5.95 (bs, 1H), 4.60 (q, J = 6.3 430

Hz, 1H), 3.56 (bs, 2H), 1.14 (d, J = 6.3 Hz, 3H), 0.88 (s, 9H). IR (neat): ν (cm-1

) 3330, 2920. 431

HRMS m/z : [M+Na]+ calcd for: C7H16NaO2: 183.1104, found: 183.1108. 432

1,1,1-Trifluoro-3-methylbutan-2-yl hydrazinecarboxylate (37b) 433

Colorless oil, 1.0 g, 73% yield. 1H NMR (300 MHz, CDCl3) δ 5.09–4.96 (m, 1H), 3.85 (bs, 2H), 434

2.14 (dq, J = 13.3, 6.8 Hz, 1H), 1.01 (dd, J = 10.4, 6.9 Hz, 6H). 13C NMR (300 MHz, CDCl3) δ 435

157.5, 124.1(q), 74.9 (q), 27.9, 18.9, 17.2. IR (neat): ν (cm-1

) 3340, 2930, 2860. HRMS m/z : 436

[M+Na]+ calcd for: C6H11F3N2NaO2: 223.0670, found: 223.0685. 437

(1S,2S)-2-(Benzyloxy)cyclopentyl hydrazinecarboxylate (37c) 438

Colorless oil, 0.72 g, 90% yield. 1H NMR (300 MHz, CDCl3): δ 7.36–7.32 (m, 5H), 5.92 (bs, 439

1H), 5.11–5.09 (m, 1H), 4.59 (q, J = 11.8 Hz, 2H), 3.91–3.90 (m, 1H), 3.48 (bs, 2H), 2.11–2.06 440

(m, 1H), 1.94–1.89 (m, 1H), 1.81–1.65 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 138.4, 136.1, 441

128.5, 128.2, 127.6, 127.5, 83.8, 80.4, 71.2, 67.2, 30.4, 30.3, 21.5. IR (neat): ν (cm-1

) 3300, 442

2910, 2850, 1700. HRMS m/z : [M+Na]+ calcd for: C13H18N2NaO3: 273.1215, found: 273.1218. 443

(1S,2S)-2-(Benzyloxy)cyclohexyl hydrazinecarboxylate (37d) 444

Colorless oil, 1.49 g, 96% yield. 1H NMR (300 MHz, CDCl3): δ 7.37–7.24 (m, 5H), 5.93 (bs, 445

1H), 4.78–4.71 (m, 1H), 4.64 (d, J = 12.2 Hz, 1H), 4.53 (d, J = 12.2 Hz, 1H), 3.83 (s, 2H), 3.38–446

3.30 (m, 1H), 2.06–2.00 (m, 2H), 1.73–1.62 (m, 2H), 1.47–1.18 (m, 4H). 13C NMR (75 MHz, 447

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CDCl3): δ 158.5, 138.9, 128.2, 127.4, 78.9, 76.3, 71.1, 30.2, 29.8, 23.2. IR (neat): ν (cm-1

) 3300, 448

2926, 2820, 1690. HRMS m/z : [M+Na]+ calcd for: C14H20N2NaO3: 287.1372, found: 287.1375. 449

(1S,2R)-2-Phenylcyclohexyl hydrazinecarboxylate (37e) 450

Colorless oil, 3.10 g, 98% yield. 1H NMR (300 MHz, CDCl3): δ 7.30–7.25 (m, 2H), 7.20–7.18 451

(m, 3H), 5.67 (bs, 1H), 4.88 (td, J = 10.6, 4.4 Hz, 1H), 3.63 (bs, 2H), 2.67–2.59 (m, 1H), 2.19 (d, 452

J = 10.0 Hz, 1H), 1.95–1.75 (m, 3H), 1.61–1.30 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 143.1, 453

128.3, 127.4, 126.3, 49.8, 34.2, 32.7, 25.8, 24.7. IR (neat): ν (cm-1

) 3300, 2910, 2860, 1695. 454

HRMS m/z : [M+Na]+ calcd for: C13H18N2NaO2: 257.1266, found: 257.1265. 455

(1S,2R)-2-(2-Phenylpropan-2-yl)cyclohexyl hydrazinecarboxylate (37f) 456

Colorless gum, 1.20 g, 98% yield. 1H NMR (300 MHz, CDCl3): δ 7.27-7.32 (m, 4H), 7.12-7.18 457

(m, 1H), 4.93 (br s, 1H, -NH), 4.64 (m, 1H), 3.34 (br s, 2H, -NH2), 1.68-1.81 (m, 3H), 1.92-2.10 458

(m, 2H), 1.32 (s, 3H), 1.19-1.29 (m, 4H), 1.20 (s, 3H). 13C NMR (100 MHz, CDCl3): δ127.8, 459

125.4, 124.9, 75.9, 65.9, 51.5, 39.7, 33.8, 28.6, 26.9, 26.0, 24.8, 23.9, 15.3. IR (neat): ν (cm-1

) 460

3340, 2936, 2860, 1705. 461

(1S,2R,4R)-4-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl hydrazinecarboxylate (37g) 462

The hydrazide was synthesized using usual procedure and the characterization is done at the 463

hydrazone stage. Colorless oil, 1.01 g, 93% yield. HRMS m/z : [M+Na]+ calcd for: 464

C17H26N2NaO2: 313.1892, found: 313.1899. 465

(1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyl hydrazinecarboxylate (37h) 466

Colorless oil, 1.04 g, 89% yield. 1H NMR (300 MHz, CDCl3): δ 7.30–7.27 (m,4H), 7.18–7.13 467

(m, 1H), 4.92 (bs, 1H), 4.70–4.55 (m, 1H), 3.70–3.20 (m, 2H), 2.20–1.40 (m, 6H), 1.32 (s, 3H), 468

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1.29–1.24 (m, 1H), 1.21 (s, 3H), 1.09–0.97 (m, 2H), 0.85 (d, J = 4.7 Hz, 6H). 13C NMR (75 469

MHz, CDCl3): δ 127.8, 125.4, 124.9, 76.1, 65.9, 51.1, 43.6, 39.7, 33.4, 32.6, 30.4, 27.3, 20.2, 470

19.6, 15.4. IR (neat): ν (cm-1

) 3320, 2920, 2849, 1700. HRMS m/z : [M+Na]+ calcd for: 471

C19H30N2NaO2: 341.2205, found: 341.2210. 472

(2S,6S)-2,6-Dimethylcyclohexyl hydrazinecarboxylate (37i) 473

Colorless oil, 0.66 g, 89% yield. 1H NMR (300 MHz, CDCl3) δ 5.93 (bs, 1H), 4.49 (dd, J = 8.1, 474

4.2 Hz, 1H), 3.74 (d, J = 4.2 Hz, 2H), 2.11–2.06 (m, 1H), 1.85–1.79 (m, 1H), 1.73–1.64 (m, 1H), 475

1.51–1.40 (m, 4H), 1.17–1.07 (m, 1H), 0.91 (d, J = 5.4 Hz, 3H), 0.89 (d, J = 5.7 Hz, 3H). 13C 476

NMR (75 MHz, CDCl3): δ 158.9, 81.1, 31.4, 31.1, 30.5, 19.6, 17.7, 14.1. IR (neat): ν (cm-1

) 477

3350, 2930, 2844, 1690. HRMS m/z : [M+Na]+ calcd for: C9H18N2NaO2: 209.1266, found: 478

209.1261. 479

General procedure for the syntheses of hydrazones 38a-i 480

To a stirred solution of carbamate 37 (1.0 equiv.)equiv.) in anhydrous acetone at rt was added 481

MgSO4 (0.5 equiv.)equiv.) and the mixture was heated to reflux for 2 h, filtered and washed with 482

dichloromethane. The filtrate was concentrated under reduced pressure and dried to get the 483

desired hydrazone compound 38 as a colorless gum or a white solid in quantitative yield (93-484

100%). The crude compound was used for next step without any purification. 485

3,3-Dimethylbutan-2-yl 2-(propan-2-ylidene) hydrazinecarboxylate (38a) 486

Colorless gum, 3.01 g, 93% yield. 1H NMR (300 MHz, CDCl3) δ 7.44 (bs, 1H), 4.74 (q, J = 6.3 487

Hz, 1H), 2.05 (s, 3H), 1.84 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H), 0.91 (s, 9H). 13C NMR (75 MHz, 488

CDCl3) δ 153.8, 150.5, 78.8, 34.3, 25.6, 25.3, 16.1, 15.1. IR (neat): ν (cm-1) 3230, 2930. HRMS 489

m/z: [M+Na]+ calc. for C10H20N2O2Na: 223.1417, found: 223.1424. 490

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491

492

1,1,1-Trifluoro-3-methylbutan-2-yl 2-(propan-2-ylidene) hydrazinecarboxylate (38b) 493

Colorless gum, 1.28 g, quantitative. 1H NMR (300 MHz, CDCl3) δ 7.71 (bs, 1H), 5.19–5.10 (m, 494

1H), 2.19–2.13 (m, 1H), 2.07 (s, 3H), 1.88 (s, 3H), 1.06–1.00 (m, 6H). 13C NMR (75 MHz, 495

CDCl3) δ 153.1 (152.8), 124.0 (q-129.7, 125.9, 122.2, 118.9), 74.4 (q-75.0, 74.6, 74.2, 73.8), 496

27.9, 25.3, 18.8, 17.2, 16.4. IR (neat): ν (cm-1) 3200, 2920, 1710. HRMS m/z : [M+Na]+ calcd 497

for: C9H15F3N2NaO2: 263.0983, found: 263.1010. 498

(1S,2S)-2-(Benzyloxy)cyclopentyl 2-(propan-2-ylidene) hydrazinecarboxylate (38c) 499

Colorless oil, 0.81 g, 99.6% yield. 1H NMR (300 MHz, CDCl3): δ 7.39–7.36 (m, 2H), 7.34–7.32 500

(m, 3H), 5.24 (bs, 1H), 5.22–5.20 (m, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 501

3.97 (m, 1H), 2.14–1.89 (m, 2H), 1.82 (d, J = 4.8 Hz, 6H), 1.77–1.69 (m, 4H). 13C NMR (75 502

MHz, CDCl3): δ 138.4, 135.9, 128.4, 128.3, 127.5,127.3, 83.7, 71.1, 67.1, 30.4, 30.3, 25.2, 21.6, 503

16.1. IR (neat): ν (cm-1) 3210, 2930, 1700, 1693, 1033. HRMS m/z : [M+Na]+ calcd for: 504

C16H22N2NaO3: 313.1528, found: 313.1536. 505

(1S,2S)-2-(Benzyloxy)cyclohexyl 2-(propan-2-ylidene) hydrazinecarboxylate (38d) 506

Colorless gum, 1.70 g, quantitative. 1H NMR (300 MHz, CDCl3) δ 7.43 (bs, 1H), 7.35–7.21 (m, 507

5H), 4.89–4.82 (m, 1H), 4.66 (d, J = 12.1 Hz, 1H), 4.59 (d, J = 12.1 Hz, 1H), 3.46–3.40 (m, 1H), 508

2.13–2.00 (m, 2H), 2.05 (s, 3H), 1.80 (s, 3H), 1.73–1.63 (m, 2H), 1.46–1.21 (m, 4H). 13C NMR 509

(75 MHz, CDCl3): δ 139.0, 128.1, 127.4, 127.2, 78.6, 71.2, 29.9, 25.3, 23.2, 16.1. HRMS m/z : 510

[M+Na]+ calcd for: C17H24N2NaO3: 327.1685, found: 327.1688. 511

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512

513

(1S,2R)-2-phenylcyclohexyl 2-(propan-2-ylidene)hydrazinecarboxylate (38e) 514

Colorless gum, 3.64 g, 99% yield. 1H NMR (300 MHz, CDCl3): δ 7.32–7.16 (m, 5H), 5.09 (td, J 515

= 10.6, 4.4 Hz, 1H), 2.74–2.67 (m, 1H), 2.30–2.27 (m, 1H), 2.00 (s, 1H), 1.98–1.76 (m, 4H), 516

1.72 (s, 3H), 1.60–1.33 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 153.2, 150.6, 143.1, 128.3, 517

127.3, 126.2, 49.5, 34.7, 32.5, 25.8, 25.2, 24.6, 15.9. IR (neat): ν (cm-1) 3234, 2926, 1710. 518


(1S,2R)-2-(2-Phenylpropan-2-yl)cyclohexyl 2-(propan-2-ylidene)hydrazinecarboxylate (38f) 520

Colorless gum, 1.37 g, 100% yield. 1H NMR (300 MHz, CDCl3): δ 7.22-7.33 (m, 4H), 7.07 (tt, J 521

= 7.0, 1.5 Hz, 1H), 4.73 (dt, J = 10.5, 4.5 Hz, 1H), 2.16 (s, 1H), 2.03-2.13 (m, 2H), 2.01 (s, 3H), 522

1.67-1.90 (m, 3H), 1.62 (s, 3H), 1.32 (s, 3H), 1.22-1.37 (m, 2H), 1.19 (s, 3H), 1.10-1.14 (m, 2H). 523

13C NMR (75 MHz, CDCl3): δ 152.8, 149.9, 127.8, 125.5, 124.5, 75.7, 51.5, 39.6, 33.6, 26.8, 524

26.1, 25.4, 24.7, 15.9. IR (neat): ν (cm-1) 3220, 2936, 1715, 1693, 1529, 1274, 1033. HRMS 525

m/z: [M+Na]+ Calcd for C19H28N2O2Na: 339.2043, found: 339.2047. 526

(1S,2R,4R)-4-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl 2-(propan-2-ylidene) hydrazine 527

carboxylate (38g) 528

Colorless gum, 1.27 g, 98% yield. 1H NMR (400 MHz, CDCl3): δ 7.30-7.17 (m, 4H), 7.03 (t, 529

1H, J = 6.8 Hz), 6.24 (s (br), 1H), 4.72 (td, 1H, J = 10.6, 3.9 Hz), 2.06-1.90 (m, 2H), 1.95 (s, 530

3H), 1.88-1.76 (m, 1H), 1.70-1.61 (m, 1H), 1.57 (s, 3H), 1.53-1.40 (m, 1H), 1.28 (s, 3H), 1.19-531

1.06 (m, 1H), 1.16 (s, 3H), 0.96-0.82 (m, 2H), 0.83 (d, 3H, J = 6.4 Hz). 13C NMR (100.7 MHz, 532

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CDCl3): δ 153.0 (s), 152.9 (s), 150.1 (s), 127.9 (d), 125.6 (d), 124.7 (d), 75.3 (d), 51.2 (d), 42.1 533

(t), 39.6 (s), 34.8 (t), 31.4 (q), 26.4 (t), 25.5 (q), 22.0 (q), 16.1 (q). IR (neat): ν (cm-1

) 3253, 2954, 534

2922, 2870, 1729, 1498, 1229, 1041. HRMS m/z : [M+Na]+ calcd for: C20H30N2NaO2: 535

353.2205, found: 353.2202. 536

(1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyl 2-(propan-2-ylidene) hydrazine 537

carboxylate (38h) 538

Colorless gum, 1.32 g, 96% yield. 1H NMR (300 MHz, CDCl3): δ 7.35–7.28 (m, 4H), 7.09 (t, J 539

= 7.0 Hz, 1H), 6.31 (bs, 1H), 4.72 (td, J = 10.6, 4.5 Hz, 1H), 2.19–2.06 (m, 2H), 2.04 (s, 3H), 540

1.91–1.69 (m, 2H), 1.65 (s, 3H), 1.52–1.45 (m, 1H), 1.35 (s, 3H), 1.31–1.26 (m, 1H), 1.23 (s, 541

3H), 1.15–0.92 (m, 3H), 0.89 (dd, J = 6.7, 3.7 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 152.8, 542

149.9, 127.7, 125.5, 124.5, 75.8, 51.1, 43.6, 39.6, 33.2, 32.6, 30.2, 27.2, 25.3, 20.2, 19.6, 15.9. 543


(2S,6S)-2,6-Dimethylcyclohexyl 2-(propan-2-ylidene)hydrazinecarboxylate (38i) 545

White solid, 0.80 g, quantitative, M.P.: 83-85 ºC. 1H NMR (300 MHz, CDCl3): δ 7.45 (bs, 1H), 546

4.61 (dd, J = 8.5, 4.2 Hz, 1H), 2.17–2.12 (m, 1H), 2.05 (s, 2H), 1.86–1.82 (m, 1H), 1.84 (s, 3H), 547

1.74–1.65 (m, 1H), 1.53–1.41 (m, 4H), 1.20–1.07 (m, 1H), 0.93 (d, J = 2.3 Hz, 3H), 0.91 (d, J = 548

2.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 153.7, 150.3, 80.6, 31.4, 31.2, 30.9, 30.3, 25.1, 19.5, 549

17.6, 16.1, 13.9. HRMS m/z : [M+Na]+ calcd for: C12H22N2NaO2: 249.1579, found: 249.1572. 550

General procedure for the syntheses of oxadiazolines 39a-i 551

To a stirred suspension of Pb(OAc)4 (1.0 equiv.)equiv.) in dry dichloromethane at 0 ºC was 552

added AcOH (0.08 equiv.)equiv.) followed by dropwise addition (over 1 h) of a solution of 553

hydrazone 38 (0.8 equiv.)equiv.) in dichloromethane. The reaction mixture was stirred at rt for 554

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1h, the solid was filtered off, washed with dichloromethane. The filtrate was taken up in a rb 555

flask and satd. NaHCO3 (pH slightly basic) was added dropwise at 0 ºC while stirring. A brown-556

colored solid separated and was filtered off, the organic and aqueous layers were separated and 557

the aqueous layer was once extracted with dichloromethane. The combined organic extracts were 558

washed with water, brine, dried over anhydrous MgSO4 and concentrated under reduced pressure 559

to afford the oxadiazoline 39 (71–98%). The crude product was used in the next step without 560

purification. 561

2-(3,3-Dimethylbutan-2-yloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl acetate (39a) 562

Colorless oil, 0.90 g, 71% yield. 1H NMR (300 MHz, CDCl3) δ 4.83 (q, J = 6.5 Hz, 1H), 2.11 (s, 563

3H), 1.63 (d, J = 3.3 Hz, 6H), 1.31 (d, J = 6.5 Hz, 3H), 0.95 (s, 9H). 13C NMR (75 MHz, CDCl3) 564

δ 169.2, 161.6, 101.7, 83.2, 34.6, 25.6, 24.2, 21.8, 14.9. IR (neat): ν (cm-1) 2944, 1760, 1375. 565

HRMS m/z : [M+Na]+ calcd for: C12H22N2O3Na: 281.1472, found: 281.1483. 566

5,5-Dimethyl-2-(1,1,1-trifluoro-3-methylbutan-2-yloxy)-2,5-dihydro-1,3,4-oxadiazol-2-yl 567

acetate (39b) 568

Colorless oil, 1.46 g, 98% yield. 1H NMR (300 MHz, CDCl3) δ 5.22–5.13 (m, 1H), 2.31-2.24 569

(m, 1H), 2.11 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H), 1.09 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.6 Hz, 570

3H). 13C NMR (75 MHz, CDCl3) δ 169.1, 160.7, 123.5 (q), 101.9, 77.7 (q), 28.1, 24.3, 24.1, 571

21.7, 18.8, 18.7, 17.2. IR (neat): ν (cm-1) 2900, 1760, 1375. HRMS m/z : [M+Na]+ calcd for: 572

C11H17F3N2NaO4: 321.1038, found: 321.1081. 573

2-((1R,2R)-2-(Benzyloxy)cyclopentyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl 574

acetate (39c) 575

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Colorless oil, 0.43 g, 89% yield. 1H NMR (300 MHz, CDCl3) δ 7.44–7.37 (m, 2H), 7.35-7.33 576

(m, 3H), 5.31-5.28 (m, 1H), 4.65 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.09-4.06 (m, 577

1H), 2.23–2.18 (m, 1H), 2.11 (d, J = 2.2 Hz, 3 H), 2.01-1.99 (m, 1H), 1.85–1.73 (m, 4H), 1.64 (s, 578

3H), 1.63 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 169.1, 161.3, 160.9, 138.2, 134.2, 129.1, 128.6, 579

128.4, 127.6, 101.8, 83.9, 83.5, 71.4, 69.9, 30.5, 30.2, 24.2, 21.7. IR (neat): ν (cm-1) 2900, 1760, 580

1366. HRMS m/z : [M+Na]+ calcd for: C18H24N2NaO5: 371.1583, found: 371.1593. 581

2-((1S,2S)-2-(Benzyloxy)cyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl 582

acetate (39d) 583


(m, 1H), 4.60 (s, 2H), 3.53–3.45 (m, 1H), 2.22–2.11 (m, 2H), 2.07 (s, 3H), 1.76–1.70 (m, 2H), 585

1.66 (s, 3H), 1.64 (s, 3H), 1.56–1.22 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 169.1, 161.2, 586

138.7, 128.3, 127.6, 127.5, 101.6, 80.6, 78.4, 71.8, 30.1, 29.7, 24.3, 24.1, 23.4, 23.3, 21.7. IR 587

(neat): ν (cm-1) 2945, 1760, 1360. HRMS m/z : [M+Na]+ calcd for: C19H26N2NaO5: 385.1739, 588

found: 385.1742. 589

5,5-Dimethyl-2-((1S,2R)-2-phenylcyclohexyloxy)-2,5-dihydro-1,3,4-oxadiazol-2-yl acetate 590

(39e) 591

Colorless oil, 0.89 g, 74% yield. 1H NMR (300 MHz, CDCl3): δ 7.30–7.16 (m, 5H), 5.06 (td, J = 592

10.6, 4.4 Hz, 1H), 2.80 (ddd, J = 12.3, 10.9, 3.8 Hz, 1H), 2.32–2.26 (m, 1H), 2.05 (s, 3H), 2.02–593

1.89 (m, 2H), 1.85–1.84 (m, 1H), 1.72–1.56 (m, 3H), 1.54 (s, 3H), 1.53 (s, 3H), 1.51–1.36 (m, 594

1H). 13C NMR (75 MHz, CDCl3): δ 188.9, 160.8, 141.9, 128.3, 127.6, 126.7, 101.5, 81.1, 49.3, 595

33.3, 31.9, 25.6, 24.7, 24.1, 21.7. IR (neat): ν (cm-1) 2930, 1755, 1368. HRMS m/z : [M+Na]+ 596


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5,5-Dimethyl-2-((1R,2S)-2-(2-phenylpropan-2-yl)cyclohexyloxy)-2-acetoxy-2,5-dihydro-598

1,3,4-oxadiazoline (39f) 599


(m, 1H), 4.87 (dt, J = 10.5, 4.5 Hz, 1H), 2.04-2.16 (m, 1H), 2.10 (s, 3H), 1.65-1.76 (m, 2H), 1.59 601

(s, 3H), 1.55 (s, 3H), 1.43-1.52 (m, 2H), 1.35 (s, 3H), 1.31 (s, 3H), 0.98-1.26 (m, 4H). 13C NMR 602

(100 MHz, CDCl3): δ 169.1, 160.6, 150.2, 128.1, 125.7, 125.5, 101.8, 80.3, 51.2, 40.4, 33.0, 603

28.0, 27.5, 25.9, 25.7, 24.7, 24.3, 24.1, 21.8. IR (neat): ν (cm-1) 2940, 1765, 1374, 1216, 1158, 604

1085, 1046, 731. HRMS m/z: [M+Na]+ Calcd for C21H30N2O4Na : 397.2098, found : 397.2108. 605

5,5-Dimethyl-2-((1S,2R,4R)-4-methyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-2,5-dihydro-606

1,3,4-oxadiazol-2-yl acetate (39g) 607

The oxadiazoline 39g was not fully characterized at this stage and used for next step. 0.58 g, 608

73% yield. HRMS m/z : [M+Na]+ calcd for: C22H32N2NaO4: 411.2259, found: 411.2265. 609

2-((1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-5,5-dimethyl-2,5-610

dihydro-1,3,4-oxadiazol-2-yl acetate (39h) 611


(m, 1H), 4.83 (td, J = 10.7, 4.6 Hz, 1H), 2.19–2.08 (m, 2H), 2.10 (s, 3H), 1.72–1.67 (m, 1H), 613

1.59 (s, 3H), 1.54 (s, 3H), 1.52–1.36 (m, 2H), 1.35 (s, 3H), 1.30 (s, 3H), 1.10–0.82 (m, 4H), 0.79 614

(d, J = 2.5 Hz, 3H), 0.77 (d, J = 2.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 169.1, 160.5, 150.1, 615

128.1, 125.6, 125.4, 101.8, 80.5, 50.7, 43.3, 40.3, 32.6, 32.4, 30.9, 27.4, 27.2, 26.3, 24.3, 24.1, 616

21.8, 20.1, 19.5. IR (neat): ν (cm-1) 2944, 1770, 1370, 1158, 1046, 730. HRMS m/z : [M+Na]+ 617


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2-((2S,6S)-2,6-Dimethylcyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-yl 619

acetate (39i) 620

Colorless oil, 0.68 g, 86% yield. 1H NMR (300 MHz, CDCl3): δ 4.74 (dd, J = 8.2, 4.1 Hz, 1H), 621

2.25–2.20 (m, 1H), 2.11 (s, 3H), 2.05–1.96 (m, 1H), 1.80–1.72 (m, 1H), 1.64 (s, 6H), 1.53–1.42 622

(m, 4H), 1.21–1.11 (m, 1H), 0.98 (d, J = 5.1 Hz, 3H), 0.96 (d, J = 5.4 Hz, 3H). 13C NMR (75 623

MHz, CDCl3): δ 168.9, 161.6, 101.5, 84.9, 31.2, 31.2, 30.9, 30.4, 24.1, 24.1, 21.7, 19.5, 17.6, 624

14.1. IR (neat): ν (cm-1) 2960, 1760, 1158. HRMS m/z : [M+Na]+ calcd for: C14H24N2NaO4: 625

307.1633, found: 307.1624. 626

General procedure for the synthesis of the dialkoxycarbene precursors, oxadiazolines 30a-i 627

To a stirred solution of crude oxadiazoline 39 (1.0 equiv.) in dry dichloromethane (0.5 M) at rt 628

under argon was added a solution of alcohol 33 (0.7 equiv.) in dichloromethane (0.5 M) followed 629

by the addition of camphorsulfonic acid (0.03 equiv.). The reaction mixture was stirred at rt for 630

12 h (overnight), diluted with dichloromethane and washed with a satd. NaHCO3 solution, water 631

and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under 632

reduced pressure. The crude compound was purified by flash silica gel column chromatography 633

using 5-10% EtOAc / hexanes to afford the desired dialkoxycarbene precursor 30. 634

(3E,5E)-8-(2-(3,3-Dimethylbutan-2-yloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-oxadiazol-2-635

yloxy)-6-methylocta-3,5-dien-2-one (30a) 636

Colorless oil, 1.23 g, 89% yield. 1H NMR (300 MHz, CDCl3) δ 7.38 (ddd, J = 15.3, 11.4, 1.7 637

Hz, 1H), 6.03 (dd, J = 12.7, 10.9 Hz, 2H), 3.97–3.87 (m, 0.5H), 3.80 (ddd, J = 9.2, 7.9, 4.6 Hz, 638

1H), 3.73–3.56 (m, 1H), 3.29 (q, J = 6.3 Hz, 0.5H), 2.43 (td, J = 6.3, 2.5 Hz, 2H), 2.25 (s, 3H), 639

1.93–1.88 (m, 3H), 1.52 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H), 1.13 (dd, J = 6.4, 4.5 Hz, 3H), 0.86 (d, 640

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J = 13.4 Hz, 9H).13C NMR (75 MHz, CDCl3) δ 198.7, 147.0, 139.1, 137.4, 129.0, 125.6, 118.0, 641

79.4, 77.6, 77.2, 76.8, 62.5, 40.2, 34.8, 27.6, 26.1, 24.1, 17.5, 16.4. IR (neat): ν (cm-1

) 2936, 642

1670. HRMS m/z : [M+Na]+ calcd for: C19H32N2NaO4: 375.2254, found: 375.2270. 643

(3E,5E)-8-(5,5-Dimethyl-2-(1,1,1-trifluoro-3-methylbutan-2-yloxy)-2,5-dihydro-1,3,4-644

oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30b) 645

Colorless oil, 0.67 g, 73% yield. 1H NMR (300 MHz, CDCl3) δ 7.39, 7.36 (dd, J = 15.6 Hz, 1H), 646

6.08-6.00 (m, 2H), 4.24-4.11 (m, 1H), 3.78–3.54 (m, 2H), 2.44 (t, J = 6.3 Hz, 2H), 2.24 (s, 3H), 647

2.17–2.04 (m, 1H), 1.90 (s, 2H), 1.51 (t, J = 6.0 Hz, 6H), 1.01–0.94 (m, 6H). 13C NMR (75 648

MHz, CDCl3) δ 198.8, 146.2, 138.9, 136.0, 129.3, 125.9, 119.9, 62.7, 39.8, 29.0, 27.7, 24.1, 649

23.8, 19.1, 17.7, 16.9. IR (neat): ν (cm-1

) 2928, 1666, 1630. HRMS m/z : [M+Na]+ calcd for: 650

C18H27F3N2NaO4: 415.1821, found: 415.1838. 651

(3E,5E)-8-(2-((1R,2R)-2-(Benzyloxy)cyclopentyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-652

oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30c) 653

Colorless oil, 0.39 g, 77% yield. 1H NMR (300 MHz, CDCl3) δ 7.44–7.37 (m, 1H), 7.33–7.31 654

(m, 5H), 6.06 (dd, J = 5.1 Hz, 1H), 6.05–5.99 (m, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.68 (d, J = 655

11.4 Hz, 1H), 4.56–4.51 (m, 1H), 4.35–3.70 (m, 3H), 2.45 (q, J = 6.9 Hz, 2H), 2.26 (s, 3H), 656

2.05–1.85 (m, 2H), 1.91 (dd, J = 3.9, 1.1 Hz, 3H), 1.75–1.64 (m, 4H), 1.55–1.49 (m, 6H). 13C 657

NMR (75 MHz, CDCl3): δ 198.7, 146.7, 138.9, 136.8, 129.1, 128.3, 128.0, 127.3, 125.5, 119.3, 658

118.9, 84.6, 80.4, 71.1, 66.7, 62.7, 62.3, 39.9, 31.6, 29.9, 27.6, 24.0, 21.4, 17.5. IR (neat): ν (cm-

659

1) 2930, 1660, 1630. HRMS m/z : [M+Na]

+ calcd for: C25H34N2NaO5: 465.2365, found: 660

465.2374. 661

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(3E,5E)-8-(2-((1S,2S)-2-(Benzyloxy)cyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-662

oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30d) 663


(m, 5H), 6.07–5.98 (m, 2H), 4.60 (s, 2H), 3.94–3.69 (m, 3H), 3.43–3.37 (m, 1H), 2.41 (t, J = 6.5 665

Hz, 1H), 2.24 (s, 3H), 2.09–1.91 (m, 2H), 1.88 (s, 3H), 1.63–1.54 (m, 2H), 1.50 (s, 6H), 1.49–666

1.38 (m, 2H), 1.28–1.22 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 198.6, 146.9, 138.9, 137.1, 667

128.9, 128.2, 127.5, 127.3, 125.4, 118.7, 78.4, 75.9, 71.6, 62.3, 40.0, 30.9, 29.1, 27.5, 24.1, 24.0, 668

22.7, 22.5, 17.5. IR (neat): ν (cm-1

) 2930, 1655, 1635. HRMS m/z : [M+Na]+ calcd for: 669

C26H36N2NaO5: 479.2522, found: 479.2520. 670

(3E,5E)-8-(5,5-Dimethyl-2-((1S,2R)-2-phenylcyclohexyloxy)-2,5-dihydro-1,3,4-oxadiazol-2-671

yloxy)-6-methylocta-3,5-dien-2-one (30e) 672


(m, 5H), 6.10–5.88 (m, 2H), 3.79 (td, J = 10.3, 4.3 Hz, 1H), 3.43–3.30 (m, 2H), 2.66–2.30 (m, 674

2H), 2.27 (s, 3H), 2.23 (t, J = 6.7 Hz, 2H), 1.91–1.81 (m, 1H), 1.82 (d, J = 0.9 Hz, 3H), 1.80–675

1.70 (m, 2H), 1.55–1.40 (m, 3H), 1.35 (s, 3H), 1.32–1.26 (m, 1H), 1.16 (s, 3H). 13C NMR (75 676

MHz, CDCl3): δ 198.8, 147.1, 144.0, 139.2, 136.9, 128.9, 128.3, 128.2, 128.1, 128.0, 126.3, 677

125.3, 118.5, 78.3, 62.3, 50.7, 40.1, 34.6, 34.0, 27.6, 25.8, 25.0, 24.0, 23.7, 17.5. IR (neat): ν 678

(cm-1

) 2930, 1660, 1630. HRMS m/z : [M+Na]+ calcd for: C25H34N2NaO4: 449.2416, found: 679

449.2434. 680

(3E,5E)-8-(5,5-Dimethyl-2-((1S,2R)-2-(2-phenylpropan-2-yl)cyclohexyloxy)-2,5-dihydro-681

1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30f) 682

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Colorless oil, 0.56 g, 77% yield. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J = 11.4 Hz, 1H), 683

7.23-7.31 (m, 4H), 7.12 (t, J = 6.7 Hz, 1H), 6.02-6.11 (m, 2H), 3.51-4.13 (m, 3H), 2.42 (t, J = 6.1 684

Hz, 2H), 2.27 (s, 3H), 2.04-2.19 (m, 1H), 1.92 (s, 3H), 1.56-1.87 (m, 2H), 1.49 (s, 3H), 1.45 (s, 685

6H), 1.23-1.34 (m, 3H), 1.28 (s, 3H), 0.83-1.13 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 198.6, 686

151.6, 146.9, 139.0, 137.1, 129.1, 127.9, 125.8, 125.6, 125.0, 117.5, 77.1, 61.9, 51.9, 40.8, 40.0, 687

35.0, 29.5, 27.6, 27.5, 25.8, 24.6, 24.2, 24.1, 23.9, 17.5. IR (neat): ν (cm-1

) 2933, 1660, 1630, 688

1586, 1450, 1362, 1250, 1147, 1090, 987, 736, 691. HRMS m/z: [M+Na]+ Calcd for 689

C28H40N2O4Na : 491.2880, found : 491.2896. 690

(3E,5E)-8-(5,5-Dimethyl-2-((1S,2R,4R)-4-methyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-691

2,5-dihydro-1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30g) 692

Colorless oil, 0.56 g, 91% yield. 1H NMR (400 MHz, CDCl3): δ 7.42 (dd, 1H, J = 15.3, 11.4 693

Hz), 7.34-7.23 (m, 4H), 7.12 (t, 1H, J = 6.8 Hz), 6.09 (d, 1H, J = 15.3 Hz), 6.05 (d, 1H, J = 11.4 694

Hz), 3.87 (td, 1H, J = 10.5, 3.9 Hz), 3.67-3.60 (m, 1H), 3.58-3.51 (m, 1H), 2.43 (t, 2H, J = 6.0 695

Hz), 2.35-2.26 (m, 1H), 2.27 (s, 3H), 1.93 (s, 3H), 1.84-1.77 (m, 1H), 1.55-1.34 (m, 1H), 1.50 (s, 696

3H), 1.46 (s, 6H), 1.34-1.23 (m, 2H), 1.28 (s, 3H), 1.00 (q, 1H, J = 11.6 Hz), 0.91-0.80 (m, 1H), 697

0.85 (d, 3H, J = 6.5 Hz), 0.70 (q, 1H, J = 12.3 Hz). 13C NMR (100.7 MHz, CDCl3): δ 198.9, 698

152.0, 147.1, 139.3, 137.2, 129.2, 128.0, 126.0, 125.8, 125.1, 117.7, 77.1, 62.0, 51.8, 44.1, 40.8, 699

40.1, 34.9, 31.8, 29.8, 27.8, 27.6, 24.3, 24.2, 23.7, 22.3, 17.7. IR (neat): ν (cm-1

) 3054, 2955, 700

2922, 2868, 1633, 1258, 1147. HRMS m/z : [M+Na]+ calcd for: C29H42N2NaO4: 505.3042, 701

found: 505.3051. 702

(3E,5E)-8-(2-((1S,2R,4S)-4-Isopropyl-2-(2-phenylpropan-2-yl)cyclohexyloxy)-5,5-dimethyl-703

2,5-dihydro-1,3,4-oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30h) 704

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Colorless oil, 0.54 g, 57% yield. 1H NMR (300 MHz, CDCl3): δ 7.41 (dd, J = 15.3, 11.4 Hz, 705

1H), 7.31–7.23 (m, 4H), 7.11 (t, J = 6.8 Hz, 1H), 6.06 (t, J = 13.4 Hz, 2H), 4.13–3.47 (m, 3H), 706

2.41 (t, J = 6.3 Hz, 2H), 2.34–2.28 (m, 1H), 2.26 (s, 3H), 2.09–1.98 (m, 1H), 1.92 (s, 3H), 1.90–707

1.85 (m, 1H), 1.62–1.57 (m, 1H), 1.50–1.40 (m, 2H), 1.49 (s, 3H), 1.45 (s, 3H), 1.36–1.19 (m, 708

6H), 1.00–0.76 (m, 3H), 0.71–0.66 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 198.7, 151.6, 146.9, 709

139.1, 137.1, 129.1, 127.9, 125.8, 125.6, 125.0, 117.5, 61.9, 51.7, 43.4, 40.8, 40.1, 34.8, 32.5, 710

31.4, 29.1, 27.7, 27.4, 24.2, 24.1, 20.2, 19.5, 17.5. IR (neat): ν (cm-1

) 2930, 1666, 1645. HRMS 711

m/z : [M+Na]+ calcd for: C31H46N2NaO4: 533.3355, found: 533.3365. 712

(3E,5E)-8-(2-((2S,6S)-2,6-Dimethylcyclohexyloxy)-5,5-dimethyl-2,5-dihydro-1,3,4-713

oxadiazol-2-yloxy)-6-methylocta-3,5-dien-2-one (30i) 714

Colorless oil, 0.33 g, 67% Yield. 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 15.3, 11.4 Hz, 715

1H), 6.06 (dd, J = 15.0, 11.1 Hz, 2H), 3.93–3.73 (m, 2H), 3.39–3.33 (m, 1H), 2.45 (t, J = 6.4 Hz, 716

2H), 2.27 (s, 3H), 2.05–1.98 (m, 1H), 1.93 (s, 3H), 1.88–1.82 (m, 1H), 1.77–1.67 (m, 1H), 1.54 717

(s, 3H), 1.48 (s, 3H), 1.44–1.33 (m, 4H), 1.21–1.02 (m, 1H), 0.99 -0.86 (m, 6H). 13C NMR (75 718

MHz, CDCl3): δ 198.5, 146.9, 138.9, 137.5, 128.9, 125.5, 117.9, 81.4, 62.3, 40.1, 32.1, 31.9, 719

30.5, 27.5, 23.9, 19.6, 18.3, 17.4, 14.4. IR (neat): ν (cm-1

) 2903, 1666, 1640. HRMS m/z : 720

[M+Na]+ calcd for: C21H34N2NaO4: 401.2416, found: 401.2402. 721

rac-Cycloadduct 25 and rac-cycloadduct 40 722

A solution of oxadiazoline 29 (3.00 g, 10.6 mmol) in anhydrous toluene (1.06 L, 0.01M) under 723

argon was heated to reflux for 18 h. The solvent was evaporated under reduced pressure keeping 724

the water bath temperature below 30 ºC (since the product is slightly volatile). Gas 725

chromatography analysis of the crude reaction mixture indicated formation of diastereomers in a 726

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ratio of 93:7. Th crude mixture was purified by flash chromatography using 5% ethyl acetate in 727

hexanes. A colorless liquid (1.86 g, 89%) was obtained as a mixture of two diastereomers (25:40 728

= 93:7). The two diastereomers were separated by silica gel column chromatography using 2.5 to 729

5% ethyl acetate in hexanes. The relative configuration of the isomers was determined by 2D-730

NMR spectroscopy. 25 : 1H NMR (300 MHz, CDCl3): δ 5.72, 5.74 (dd, J = 1.5 Hz, 1H), 5.50, 731

5.52 (dd, J = 2.7, 2.4 Hz, 1H), 4.00 (td, J = 8.1 Hz, 1H), 3.80-3.82 (m, 1H), 3.67–3.75 (m, 1H), 732

3.28 (s, 3H), 2.21 (s, 3H), 1.69–1.98 (m, 2H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 733

207.2, 141.6, 126.2, 116.3, 67.0, 66.8, 57.5, 50.8, 37.5, 30.6, 20.9. IR (neat): ν (cm-1) 3044, 734

2964, 2883, 1713, 1063. LRMS (m/z, relative intensity): 219 ((M+Na)+, 100). HRMS m/z : 735

[M+Na]+ Calcd for: C11H16NaO3: 219.0992, found: 219.0994. 40 :

1H NMR (300 MHz, CDCl3): 736

δ 5.65 (dd, J = 6.3, 1.8 Hz, 1H), 5.54 (dd, J = 6.3, 2.3 Hz, 1H), 4.03 (td, J = 8.1, 2.6 Hz, 1H), 737

3.71 (t, J = 2.0 Hz, 1H), 3.66 (ddd, J = 10.1, 8.4, 6.5 Hz, 1H), 3.35 (s, 3H), 2.19 (s, 3H), 1.92 738

(ddd, J = 12.4, 6.5, 2.6 Hz, 1H), 1.80 (ddd, J = 12.4, 10.1, 8.1 Hz, 1H), 1.19 (s, 3H). 13C NMR 739

(75.5 MHz, CDCl3): δ 207.2, 139.2, 126.8, 116.4, 68.1, 65.4, 58.3, 50.8, 37.2, 29.4, 20.6. 740

General procedure for the synthesis of (4+1) cycloadducts: (26a-i and 41a-i) 741

A solution of oxadiazoline 30a-i (0.15 g, 0.32 mmol) in anhydrous toluene (0.01 M) was heated 742

to reflux for 18-22 h to get the desired (4+1)-cycloadducts 26a-i,41a-i. Ratios were determined 743

by 1HNMR and/or GC analysis of the crude mixture). The stereochemistries of the major 744

diastereomers for 26/41a-c were not assigned. The stereochemistries of the major diastereomers 745

26d-i were assigned based on the data for 26f, since these 5 compounds are similar. The 746

assignment for 26f was based on its conversion to 42 and comparison with the sign of optical 747

rotation from literature data. In addition, a single-crystal X-ray diffraction analysis of a 748

derivative obtained from 41f confirmed the assignement.3 The crude mixtures were purified by 749

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silica gel flash column chromatography using gradients of 1 to 5% EtOAc in hexanes to afford 750

the pure individual diasteromers. 751

Cycloadducts (26a) and (41a) 752

Colorless oils, 60 mg, 79% yield. Ratio 55:45, relative configuration of diastereomers not 753

determined. Major diastereomer : 1H NMR (300 MHz, CDCl3) δ 5.76 (dd, J = 1.5 Hz, 1H), 5.52 754

(dd, J = 3.0 Hz, 1H), 4.00-3.85 (m, 1H), 3.75–3.50 (m, 3H), 2.19 (d, J = 0.6 Hz, 3H), 1.96–1.77 755

(m, 2H), 1.34 (s, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.87 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 756

207.5, 141.7, 126.9, 114.5, 83.2, 76.1, 69.9, 67.2, 59.6, 37.6, 35.3, 30.2, 26.5, 25.6, 21.5, 16.1; 757

IR (neat): ν (cm-1) 2930, 2865, 1710. HRMS m/z : [M+Na]+ calcd for: C16H26NaO3: 289.1774, 758

found: 289.1783; Minor diastereomer: 1H NMR (300 MHz, CDCl3) δ 5.74 (dd, J = 1.5 Hz, 1H), 759

5.52 (dd, J = 3.0 Hz, 1H), 4.00-3.85 (m, 1H), 3.75–3.50 (m, 3H), 2.24 (d, J = 0.6 Hz, 3H), 1.96–760

1.77 (m, 2H), 1.31 (s, 3H), 1.13 (d, J = 6.3 Hz, 3H), 0.84 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 761

207.2, 142.1, 126.7, 116.7, 83.2, 77.1, 68.5, 66.8, 58.2, 36.9, 35.7, 31.1, 26.4, 25.5, 21.6, 17.1. 762

Cycloadducts (26b) and (41b) 763

Colorless oil, 54 mg, 69% yield. Ratio 57:43, relative configuration of diastereomers not 764

determined. Major diastereomer: 1H NMR (300 MHz, CDCl3): δ 5.77 (dd, J = 1.5 Hz, 1H), 5.60–765

5.56 (m, 1H), 4.30-4.23 (m, 1H), 4.10–3.99 (m, 1H), 3.90–3.67 (m, 2H), 2.21 (s, 3H), 2.10–1.80 766

(m, 3H), 1.36 (s, 3H), 1.03-0.94 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 205.8, 140.6, 126.9, 767

115.4, 73.3, 70.4, 68.5, 67.6, 59.2, 36.5, 29.9, 29.8, 20.8, 19.5, 17.4. HRMS m/z : [M+Na]+ 768

calcd for: C15H21F3NaO3: 329.1340, found: 329.1356; Minor diastereomer: 1H NMR (300 MHz, 769

CDCl3): δ 5.72 (dd, J = 1.5 Hz, 1H), 5.60–5.56 (m, 1H), 4.30-4.23 (m, 1H), 4.10–3.99 (m, 1H), 770

3.89–3.67 (m, 2H), 2.19 (s, 3H), 2.10–1.80 (m, 3H), 1.33 (s, 3H), 1.03-0.94 (m, 6H). 13C NMR 771

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(75 MHz, CDCl3): δ 206.7, 141.9, 127.4, 116.3 (q), 73.7(q), 70.4, 68.8, 67.7, 58.9, 36.3, 30.8, 772

29.3, 20.6, 18.0, 17.0. 773

Cycloadducts (26c) and (41c) 774

Colorless oil, 55 mg, 77% yield. Ratio 58:42, relative configuration of diastereomers not 775

determined. Major diastereomer: 1H NMR (300 MHz, CDCl3): δ 7.37–7.27 (m, 5H), 5.79 (dd, J 776

= 6.2, 1.5 Hz, 1H), 5.60–5.49 (m, 1H), 4.62 (s, 2H), 4.14–3.59 (m, 5H), 2.19 (s, 3H), 2.03–1.80 777

(m, 3H), 1.72–1.62 (m, 3H), 1.32–1.21 (m, 2H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): 778

207.3, 141.7, 128.4, 127.7, 127.2, 126.5, 86.2, 79.7, 71.1, 68.3, 67.5, 66.7, 65.2, 58.0, 37.8, 32.5, 779

31.6, 31.1, 30.0, 22.0, 21.5, 21.2; HRMS m/z : [M+Na]+ calcd for: C22H28NaO4: 379.1885, 780

found: 379.1893; Minor diastereomer: 1H NMR (300 MHz, CDCl3): δ 7.37–7.27 (m, 5H), 5.72 781

(dd, J = 6.2, 1.5 Hz, 1H), 5.60–5.49 (m, 1H), 4.52 (s, 2H), 4.14–3.59 (m, 5H), 2.17 (s, 3H), 2.03–782

1.80 (m, 3H), 1.72–1.62 (m, 3H), 1.32–1.21 (m, 2H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): 783

207.1, 138.7, 128.3, 127.3, 126.4, 116.6, 85.2, 79.3, 71.1, 68.2, 67.1, 66.8, 65.2, 57.5, 37.6, 32.0, 784

31.3, 30.9, 29.8, 22.0, 21.6, 21.2. 785

Cycloadducts (26d) and (41d) 786

Colorless oil, 83 mg, 73% yield. Ratio of 26d:41d 67:33. Major diastereomer 26d : 1H NMR 787

(300 MHz, CDCl3): δ 7.37–7.26 (m, 5H), 5.69 (dd, J = 6.4, 1.3 Hz, 1H), 5.51 (dd, J = 6.4, 1.3 788

Hz, 1H), 4.58 (d, J = 12.3 Hz, 1H), 4.47 (d, J = 12.3 Hz, 1H), 3.98–3.42 (m, 5H), 2.22 (s, 3H), 789

1.93–1.33 (m, 10H), 1.26 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 141.5, 139.6, 128.3, 127.6, 790

127.4, 127.3, 126.5, 117.9, 76.4, 72.9, 71.1, 70.6, 68.4, 66.4, 57.7, 37.5, 31.2, 27.9, 25.7, 21.6, 791

20.9, 20.3; HRMS m/z : [M+Na]+ calcd for: C23H30NaO4: 393.2042, found: 393.2043. Minor 792

diastereomer 41d : 1H NMR (300 MHz, CDCl3): δ 7.37–7.26 (m, 5H), 5.71 (dd, J = 6.4, 1.3 Hz, 793

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1H), 5.52 (dd, J = 6.4, 1.3 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 4.50 (d, J = 12.3 Hz, 1H), 3.98–794

3.42 (m, 5H), 2.25 (s, 3H), 1.93–1.33 (m, 10H), 1.24 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 795

141.7, 139.3, 128.3, 127.5, 127.4, 127.3, 126.4, 117.3, 77.4, 72.9, 71.1, 70.6, 68.6, 66.7, 58.1, 796

37.5, 30.0, 27.7, 25.7, 21.8, 21.6, 21.3. 797

Cycloadducts (26e) and (41e) 798

Colorless oil, 62 mg, 88% yield. Ratio of 26e:41e 67:33. Major diastereomer 26e : 1H NMR 799

(300 MHz, CDCl3) δ 7.31–7.13 (m, 5H), 5.67 (dd, J = 6.3, 1.3 Hz, 1H), 5.40 (dd, J = 6.3, 2.7 Hz, 800

1H), 4.08–3.92 (m, 2H), 3.68–3.47 (m, 3H), 2.73–2.65 (m, 1H), 2.17–2.07 (m, 1H), 1.92–1.61 801

(m, 4H), 1.59 (s, 3H), 1.57–1.20 (m, 4H), 1.16 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 145.0, 802

141.8, 128.4, 128.1, 128.0, 126.7, 125.9, 116.6, 74.9, 68.3, 66.9, 58.0, 50.4, 36.9, 33.9, 33.5, 803

30.3, 25.7, 24.7, 21.2. IR (neat): ν (cm-1) 2930, 2866, 1700; HRMS m/z : [M+Na]+ calcd for: 804

C22H28NaO3: 363.1936, found: 363.1935. Minor diastereomer 41e : 1H NMR (300 MHz, CDCl3) 805

δ 7.31–7.13 (m, 5H), 5.60 (dd, J = 6.3, 1.7 Hz, 1H), 5.46 (dd, J = 6.3, 2.7 Hz, 1H), 4.08–3.92 (m, 806

2H), 3.68–3.47 (m, 3H), 2.58–2.48 (m, 1H), 2.18 (s, 3H), 2.17–2.07 (m, 1H), 1.92–1.61 (s, 4H), 807

1.57–1.20 (m, 4H), 0.68 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 145.7, 141.6, 128.4, 128.1, 808

128.0, 126.8, 126.0, 113.8, 75.1, 70.2, 67.5, 59.1, 51.1, 36.5, 34.2, 34.1, 29.9, 25.9, 25.1, 20.3. 809

Cycloadducts (26f) and (41f) 810

Colorless oil, 92 mg, 79% yield. Ratio of 26f:41f 70:30. Isolated yield of individual 811

diastereomers after silica gel column chromatography 26f (55%) and 41f (19%). Major 812

diastereomer 26f : 1H NMR (300 MHz, CDCl3): δ 7.27-7.32 (m, 2H), 7.36-7.38 (m, 2H), 7.16 (t, 813

J = 7.2 Hz, 1H), 5.60 (dd, J = 7.2, 0.9 Hz, 1H), 5.50 (dd, J = 6.1, 2.5 Hz, 1H), 3.73-3.82 (m, 3H), 814

3.46 (dddd, J = 8.7 Hz, 1H), 2.23-2.28 (m, 1H), 2.25 (m, 3H), 1.73 (dd, J = 5.4 Hz, 2H), 1.45-815

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1.62 (m, 5H), 1.41 (s, 3H), 1.39 (t, 3H), 1.29-1.38 (m, 3H), 1.18 (s, 3H). 13C NMR (100 MHz, 816

CDCl3): δ 150.5, 141.4, 127.9, 126.7, 126.6, 125.5, 118.6, 70.8, 69.4, 65.9, 57.4, 49.2, 40.7, 817

37.7, 31.4, 29.3, 29.1, 28.2, 22.8, 22.2, 22.1, 20.3. IR (neat): ν (cm-1) 2934, 2865, 1700. IR 818

(neat): ν (cm-1

) 2939, 2871, 1698. HRMS m/z: [M+Na]+ Calcd for C25H34O3Na : 405.2400, 819

found : 405.2417. [α]23

D: +140.8 (c 4.5, CHCl3). Minor diastereomer 41f : 1H NMR (300 MHz, 820

CDCl3): δ 7.35 (t, J = 1.8 Hz, 1H), 7.27-7.33 (m, 3H), 7.15 (tt, J = 6.9, 1.5 Hz, 1H), 5.68, 5.70 821

(dd, J = 1.5 Hz, 1H), 5.49, 5.51 (dd, J = 2.7 Hz, 1H), 3.91 (dt, J = 8.4, 3.0 Hz, 1H), 3.82 (dt, J = 822

6.3, 2.7 Hz, 1H), 3.75 (m, 1H), 3.67 (q, J = 8.2 Hz, 1H), 2.17 (s, 3H), 1.99 (q, J = 5.4 Hz, 1H), 823

1.87 (dddd, J = 3.1 Hz, 1H), 1.64-1.78 (m, 3H), 1.47 (s, 3H), 1.37-1.44 (m, 3H), 1.35 (s, 3H), 824

1.20-1.29 (m, 3H), 1.16 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 151.1, 141.8, 128.0, 126.6, 825

126.3, 125.4, 116.4, 73.0, 69.7, 67.1, 58.9, 49.9, 40.9, 37.2, 31.2, 30.4, 29.5, 26.5, 25.3, 23.8, 826

22.0, 21.5. HRMS m/z: [M+Na]+ Calcd for C25H34O3Na : 405.2400, found : 405.2413. 827

Cycloadducts (26g) and (41g) 828

Colorless oil, 50 mg, 55% yield. Ratio of 26g:41g 60:40. Major diasteromer 26g : 1H NMR (400 829

MHz, CDCl3): δ 7.34-7.20 (m, 4H), 7.12 (t, 1H, J = 7.1 Hz), 5.67 (d, 1H, J = 6.3 Hz), 5.53 (dd, 830

1H, J = 6.1, 2.3 Hz), 4.05-3.95 (m, 2H), 3.72-3.59 (m, 2H), 2.29 (s, 3H), 2.24-2.16 (m, 1H), 831

1.97-1.77 (m, 3H), 1.47 (s, 3H), 1.43-1.35 (m, 1H), 1.30 (s, 3H), 1.29-1.25 (m, 1H), 1.28 (s, 3H), 832

1.17-1.09 (m, 1H), 0.96-0.66 (m, 3H), 0.88 (d, 3H, J = 6.0 Hz). 13C NMR (100 MHz, CDCl3): δ 833

206.5, 196.7, 153.0, 151.5, 146.9, 146.6, 142.4, 128.2, 128.1, 128.1, 128.1, 126.1, 125.7, 124.9, 834

118.5, 117.7, 77.8, 76.4, 73.2, 68.2, 67.1, 66.7, 58.5, 54.4, 53.7, 53.7, 52.5, 52.0, 45.6, 45.3, 42.9, 835

42.4, 41.9, 41.2, 37.2, 35.2, 35.1, 33.6, 31.7, 31.7, 31.4, 31.3, 29.7, 28.2, 27.7, 27.2, 26.7, 24.6, 836

22.8, 22.7, 22.6, 22.1, 20.8. IR (neat): ν (cm-1

) 3054, 2955, 2924, 2871, 1702, 1060. LRMS 837

(m/z, relative intensity) 419 ((M+Na)+, 100). HRMS m/z : [M+Na]

+ calcd for: C26H36NaO3: 838

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419.2562, found: 419.2568. Minor diastereomer 41g : 1H NMR (400 MHz, CDCl3): δ 7.32-7.23 839

(m, 4H), 7.12 (t, 1H, J = 6.4 Hz), 5.69 (d, 1H, J = 6.2 Hz), 5.55 (dd, 1H, J = 5.9, 2.6 Hz), 3.99 (q, 840

1H, J = 6.6 Hz), 3.92 (td, 1H, J = 10.1, 3.4 Hz), 3.86-3.81 (m, 1H), 3.75 (q, 1H, J = 8.3 Hz), 2.20 841

(s, 3H), 2.15-2.08 (m, 1H), 1.94 (t, 2H, J = 7.0 Hz), 1.82 (td, 1H, J = 9.5, 3.1 Hz), 1.51 (s, 3H), 842

1.45-1.31 (m, 2H), 1.29 (s, 3H), 1.26 (s, 3H), 1.16-1.10 (m, 1H), 0.89-0.63 (m, 3H), 0.85 (d, 3H, 843

J = 6.3 Hz). 13C NMR (100 MHz, CDCl3): δ 207.0, 152.2, 141.6, 128.1, 126.8, 126.0, 125.2, 844

114.7, 74.9, 71.0, 68.1, 60.0, 51.0, 42.8, 40.9, 37.2, 34.8, 31.8, 31.5, 30.2, 28.5, 23.5, 22.5, 21.3. 845

Cycloadducts (26h) and (41h) 846

Colorless oil, 74 mg, 68% yield. Ratio of 26h:41h 85:15. Major diastereomer 26h : 1H NMR 847

(300 MHz, CDCl3): δ 7.34–7.27 (m, 4H), 7.16–7.12 (m, 1H), 5.67 (dd, J = 6.3, 1.3 Hz, 1H), 5.54 848

(dd, J = 6.3, 2.6 Hz, 1H), 3.97–3.86 (m, 3H), 3.62–3.54 (m, 1H), 2.24 (s, 3H), 2.07–1.99 (m, 849

1H), 1.91–1.79 (m, 2H), 1.66–1.46 (m, 4H), 1.40 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.08–0.80 850

(m, 4H), 0.69 (d, J = 6.5 Hz, 3H), 0.67 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 150.2, 851

141.8, 128.7, 127.9, 126.6, 126.2, 125.9, 125.4, 117.9, 73.2, 69.2, 66.3, 57.9, 52.1, 40.8, 38.9, 852

37.5, 33.1, 31.2, 29.8, 29.4, 29.2, 28.4, 23.6, 23.5, 21.9, 20.3, 19.2; HRMS m/z : [M+Na]+ calcd 853

for: C28H40NaO3: 447.2875, found: 447.2883. Minor diastereomer 41h : 1H NMR (300 MHz, 854

CDCl3): δ 7.34–7.23 (m, 4H), 7.16–7.12 (m, 1H), 5.70 (dd, J = 6.3, 1.3 Hz, 1H), 5.53 (dd, J = 855

6.3, 2.6 Hz, 1H), 3.97–3.86 (m, 3H), 3.62–3.54 (m, 1H), 2.19 (s, 3H), 2.10–1.80 (m, 5H), 1.66–856

1.50 (m, 2H), 1.48 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.06–0.82 (m, 4H), 0.69 (d, J = 6.5 Hz, 857

3H), 0.66 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 151.5, 141.7, 128.0, 127.9, 126.8, 858

126.6, 125.2, 115.1, 74.8, 71.0, 67.6, 59.8, 51.2, 42.3, 40.7, 37.3, 32.7, 32.2, 31.4, 30.0, 29.2, 859

26.4, 23.5, 21.4, 20.2, 19.4. 860

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Cycloadducts (26i) and (41i) 861

Colorless oil, 87 mg, 71% yield. Ratio of 26i:41i 51:49. Diastereomer#1: 1H NMR (300 MHz, 862

CDCl3): δ 5.73 (dd, J = 6.3, 1.3 Hz, 1H), 5.54 (dd, J = 6.3, 2.7 Hz, 1H), 4.05–3.95 (m, 1H), 3.89 863

(m, 1H), 3.67–3.56 (m, 1H), 3.50–3.45 (m, 1H), 2.26 (s, 3H), 2.20–2.16 (m, 1H), 1.97–1.76 (m, 864

3H), 1.69–1.63 (m, 1H), 1.52–1.35 (m, 4H), 1.31 (s, 3H), 1.14–0.98 (m, 1H), 0.97 (d, J = 7.0 Hz, 865


67.5, 57.6, 37.5, 32.9, 32.6, 31.8, 31.3, 21.3, 19.9, 19.3. Diastereomer#2 : 1H NMR (300 MHz, 867

CDCl3): δ 5.69 (dd, J = 6.3, 1.3 Hz, 1H), 5.52 (dd, J = 6.3, 2.6 Hz, 1H), 4.04–3.96 (m, 1H), 3.89 868

(m, 1H), 3.67–3.56 (m, 1H), 3.50–3.45 (m, 1H), 2.26 (s, 3H), 2.09–2.05 (m, 1H), 1.97–1.76 (m, 869

3H), 1.69–1.63 (m, 1H), 1.52–1.35 (m, 4H), 1.28 (s, 3H), 1.14–0.98 (m, 1H), 0.93 (d, J = 6.8 Hz, 870


66.8, 57.7, 36.8, 32.9, 32.7, 31.6, 31.2, 21.6, 20.0, 18.9. HRMS m/z : [M+Na]+ calcd for: 872

C18H28NaO3: 315.1936, found: 315.1922. 873

Benzyloxyalkynol 45. 874

To a stirred solution of alkyne 4427

(209 mg, 1.30 mmol) in THF (1 mL) at -78 ºC was added n-875

BuLi (0.60 mL, 1.30 mmol, 2.17M in hexanes) and the reaction mixture was stirred at 0 ºC for 876

1.5 h. This alkynyllithium solution was cannulated to a pre-stirred suspension of cerium chloride 877

(320 mg, 1.30 mmol) in THF (3.3 mL) over a period of 18 h at 0 ºC (cerium chloride was 878

handled in a glove box). The reaction mixture was stirred at 0 ºC for 2 h when a solution of 879

ketone 42 (40.0 mg, 0.22 mmol) in THF (1 mL) at 0 ºC was added. The reaction mixture was 880

stirred at 0 ºC for 4 h and then at rt for 18 h. The reaction mixture was quenched by addition of 881

10% aqueous AcOH and extracted with ethyl acetate (3 x 20 mL). The combined organic 882

extracts were washed with a saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, 883

Page 47 of 68



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filtered and concentrated under reduced pressure. The crude product was purified by silica gel 884

flash column chromatography using 10% ethyl acetate in hexanes to get desired propargylic 885

alcohol 45 as colorless oil (50 mg, 67%) along with 7 mg of recovered ketone 42 (corrected yield 886

= 82% based on recovered starting material). 1H NMR (300 MHz, CDCl3): δ 7.38-7.26 (m, 5H), 887

4.77 (dd, 1H, J = 11.6, 1.1 Hz), 4.50 (d, 1H, J = 11.6 Hz), 4.27 (q, 1H, J = 6.6 Hz), 3.83-3.66 (m, 888

2H), 1.99-1.39 (m, 8H), 1.46 (d, 3H, J = 6.6 Hz), 1.19 (d, 3H, J = 6.6 Hz), 1.03 (s, 3H), 0.91 (d, 889

3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3): δ 138.1, 128.6, 128.1, 127.9, 87.7, 86.6, 80.4, 890

70.7, 64.8, 60.4, 54.7, 50.8, 39.8, 32.4, 30.3, 27.3, 22.7, 22.5, 22.3, 18.2. HRMS m/z: [M+Na]+ 891

calcd for C22H32NaO3: 367.2249, found: 367.2253. 892

Fully saturated diol 46. 893

To a stirred solution of propargylic alcohol 45 (35.0 mg, 0.10 mmol) in THF (1 mL) under an 894

atmosphere of hydrogen was added Pd/C 10% w/w (3.5 mg) and the mixture was stirred for 24 h. 895

The reaction mixture was filtered through celite, washed with THF (2 mL) and the filtrate was 896

concentrated under reduced pressure. The crude compound was purified by silica gel flash 897

column chromatography using 5% EtOAc / hexanes to afford the title compound 46 as colorless 898

oil (18 mg, 73%). 1H NMR (300 MHz, CDCl3): δ 3.78 (dt, 1H, J = 10.6, 7.8 Hz), 3.70 (ddd, 1H, 899

J = 10.6, 8.6, 4.8 Hz), 1.86-1.21 (m, 16H), 0.98 (s, 3H), 0.97 (d, 3H, J = 6.5 Hz), 0.93 (d, 3H, J = 900

6.5 Hz), 0.91 (t, 3H, J = 6.9 Hz). 13C NMR (75.5 MHz, CDCl3): δ 84.4, 60.4, 51.9, 48.4, 38.8, 901

37.9, 35.4, 28.9, 26.2, 24.4, 24.0, 23.9, 20.4, 19.7, 14.3. IR (neat) ν (cm-1) 3589-3134 (br), 2955, 902

2873, 1469, 1049. HRMS m/z: [M+Na]+ calcd for C15H30NaO2: 265.2144, found: 265.2137. 903

Alkenols 47a and 47b 904

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49

To a stirred solution of propargylic alcohol 45 (100 mg, 0.29 mmol) in THF (10 mL) was 905

added 5% Pd/C (10 mg) and the mixture was vigorously stirred under H2 atmosphere for 3 h. The 906

reaction mixture was filtered through celite, washed with THF (5 mL) and the filtrate was 907

concentrated under reduced pressure. The crude product was purified by silica gel flash column 908

using 20% ethyl acetate / hexanes to afford allylic alcohols 47a (23 mg, 31%) and 47b (18 mg, 909

24%, structure confirmed by X-ray). 1H NMR (300 MHz, CDCl3) 47a: δ 5.41-5.42 (m, 2H), 910

4.91-4.98 (m, 1H), 3.67-3.72 (m, 2H), 1.79-1.93 (m, 2H), 1.40-1.71 (m, 7H), 1.28 (d, J = 6.3 Hz, 911

3H), 1.16-1.25 (m, 2H), 0.98 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H). 1H NMR 912

(300 MHz, CDCl3) 47b: δ 5.43-5.49 (m, 2H), 4.85-4.93 (m, 1H), 3.64-3.75 (m, 2H), 2.75 (bs, 913

1H), 1.79-1.95 (m, 2H), 1.42-1.68 (m, 7H), 1.27 (d, J = 6.3 Hz, 3H), 1.24-1.25 (m, 1H), 0.98 (s, 914

3H), 0.96 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H). IR (neat): ν (cm-1) 3300, 2955, 1460. 915

HRMS m/z: [M+Na]+ calcd for C15H28NaO3: 279.1936 , found: 279.1944. 916

Triol 48. 917

To a stirred solution of a mixture of allylic alcohols 47a and 47b (22.5 mg, 0.88 mmol) in THF 918

(2 mL) was added PtO2 (3.0 mg, 0.01 mmol) and the mixture was stirred vigorously under 919

hydrogen atmosphere for 20 h. The reaction mixture was filtered through celite, washed with 920

THF (3 mL) and the filtrate was evaporated under reduced pressure. The crude product was 921

purified by silica gel flash chromatography using 10% ethyl acetate / hexanes to get title 922

compound 48 as colorless oil (7.9 mg, 35%). 1H NMR (300 MHz, CDCl3): δ 3.85-3.65 (m, 3H), 923

2.56 (s (br), 2H), 1.89-1.68 (m, 5H), 1.67-1.53 (m, 4H), 1.53-1.31 (m, 3H), 1.30-1.22 (m, 1H), 924

1.21 (d, 3H, J = 6.2 Hz), 0.99 (s, 3H), 0.98 (d, 3H, J = 6.5 Hz), 0.93 (d, 3H, J = 6.5 Hz). 13C 925

NMR (75.5 MHz, CDCl3): δ 83.7, 69.2, 60.2, 51.9, 48.4, 38.5, 36.0, 34.9, 33.3, 29.1, 24.3, 24.1, 926

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24.1, 20.3, 19.7. IR (neat) ν (cm-1) 3644-3047 (br), 2953, 2872, 1376, 1050. HRMS m/z: 927

[M+Na]+ calcd for C15H30NaO3: 281.2087, found: 281.2092. 928

(±)-(But-3-yn-2-yloxy)(t-butyl)dimethylsilane (49) 929

To a stirred solution of 3-butyn-2-ol (5.00 g, 71.3 mmol) in anhydrous DMF (25 mL) at 0 ºC 930

under argon was added a solution of imidazole (12.14 g, 178.3 mmol) in DMF (10 mL) followed 931

by dropwise addition of a solution of t-butyldimethylsilyl chloride (13.97 g, 92.74 mmol) in 932

DMF (25 mL). The reaction mixture was stirred at rt for 12 h, diluted with water (1000 mL) and 933

extracted with diethyl ether (2 x 400 mL). The combined organic extracts were washed with 1N 934

HCl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced 935

pressure. The crude product was purified by silica gel column chromatography using hexanes to 936

1% Et2O in hexanes to afford the desired product 49 as a colorless liquid (9.0 g, 68%). 1H NMR 937

(300 MHz, CDCl3): δ 4.51 (q, J = 6.6 Hz, 1H), 2.36 (d, J = 2.1 Hz, 1H), 1.42 (d, J = 6.6 Hz, 3H), 938

0.90 (s, 9H), 0.12 (d, J = 4.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 86.5, 71.3, 58.9, 25.9, 939

25.8, 25.5, 18.3, -4.5, -4.9. 940

t-Butyldimethylsilyloxy alkynol (50) 941

To a stirred solution of TBS protected propargylic alcohol 49 (5.93 g, 32.0 mmol) in THF (25 942

mL) at -78 ºC was added dropwise a solution of n-BuLi (2.05 g, ~12.8 mL of 2.5 M / hexanes) 943

and the mixture was stirred at 0 ºC for 1h. This alkynyllithium solution was then cannulated to a 944

pre-stirred (18 h at rt under argon atmosphere) suspension of CeCl3 (7.89 g, 32.0 mmol, handled 945

in glove box) in THF (82 mL) at 0 ºC and the mixture was stirred at that same temperature for 1 946

h. A solution of ketone 42 (1.0 g, 5.4 mmol) in THF (10 mL) was then added dropwise and 947

stirring was continued at 0 ºC for 4 h and then at rt for 18 h. The reaction mixture was quenched 948

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by dropwise addition of cold 10% AcOH (30 mL) and aqueous layer was extracted with diethyl 949

ether (3 x 40 mL). Ether extracts were washed successively with water (50 mL), brine (50 mL), 950

dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude 951

product was purified by silica gel flash column chromatography using 10% EtOAc / hexanes to 952

afford the title compound 50 as colorless oil (1.62 g, 81%). 1H NMR (300 MHz, CDCl3) δ 953

(ppm) 4.55 (q, J = 6.6 Hz, 1H), 3.69-3.77 (m, 1H), 1.73-1.90 (m, 5H), 1.44-1.61 (m, 5H), 1.39 954

(d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 1.01 (s, 3H), 0.88-0.91 (m, 12H), 0.11 (s, 3H), 0.10 955

(s, 3H). 13C NMR (75.5 MHz, CDCl3): δ 89.2, 85.5, 80.3, 60.4, 59.2, 54.6, 54.5, 50.7, 39.9, 956

32.6, 30.2, 27.2, 25.9, 25.5, 22.7, 22.4, 18.4, 18.1, -4.5, -4.9. IR (neat) ν (cm-1) 3391, 2953, 957

2934, 2866, 1460, 1362, 1250, 992. HRMS m/z: [M+Na]+ calcd for C21H40NaO3Si: 391.2639, 958

found: 391.2623. 959

Alkyne triol 51. 960

To a stirred solution of compound 50 (519 mg, 1.41 mmol) in THF (4.7 mL) at 0 ºC was added 961

TBAF (1.83 mL, 1.83 mmol, 1M in THF) and the reaction mixture was stirred at rt for 2 h. A 962

satd aqueous solution of ammonium chloride (10 mL) was added and the mixture was extracted 963

with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium 964

sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash 965

chromatography using 25% ethyl acetate in hexanes to afford the desired product 51 as colorless 966

oil (344 mg, 96%). 1H NMR (300 MHz, CDCl3): δ 4.53 (q, 1H, J = 6.6 Hz ), 3.81-3.60 (m, 2H), 967

3.22-2.92 (m, 3H), 1.93-1.68 (m, 4H), 1.61-1.46 (m, 3H), 1.42 (d, 3H, J = 6.6 Hz), 1.12 (d, 3H, J 968

= 6.3 Hz), 1.00 (s, 3H), 0.88 (d, 3H, J = 6.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 88.6, 86.4, 969

80.2, 60.1, 58.2, 54.9, 50.5, 39.9, 32.9, 30.1, 27.2, 24.3, 22.6, 22.4, 18.3. IR (neat) ν (cm-1) 970

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3685-3039 (br), 2955, 2871, 1369, 1076. HRMS m/z: [M+Na]+ calcd for C15H26NaO3: 971

277.1774, found: 277.1785. 972

Acetate-diol 54. 973

To a stirred solution of alcohol 50 (200 mg, 0.54 mmol) in DCM (6 mL) at 0 ºC was added 974

triethylamine (0.46 mL, 3.31 mmol) followed by the dropwise addition of acetyl chloride (0.12 975

mL, 1.66 mmol). The reaction mixture was then stirred at rt for 3 h and the crude mixture was 976

taken up in 1N HCl. The layers were separated, the aqueous phase extracted twice with DCM, 977

the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and 978

evaporated under reduced pressure. The crude product was purified by silica gel flash column 979

chromatography using 10% EtOAc / hexanes to afford the desired acetyl compound as colorless 980

oil. (185 mg, 83%). 1H NMR (300 MHz, CDCl3): δ 4.55 (q, J = 6.6 Hz, 1H), 4.13 (t, J = 7.5 Hz, 981

2H), 2.03 (s, 3H), 1.54–1.91 (m, 9H), 1.39 (d, J = 6.6 Hz, 3H), 1.14 (dd, J = 1.8 Hz, 3H), 1.02 (s, 982

3H), 0.89 (s, 12H), 0.11 (s, 6H). 13C NMR (75.5 MHz, CDCl3): δ 171.2, 89.3, 84.9, 80.3, 62.4, 983

59.2, 54.4, 50.7, 35.3, 32.1, 30.2, 27.2, 25.9, 25.5, 22.6, 22.5, 21.2, 18.3, 17.9, -4.6. HRMS m/z: 984

[M+Na]+ calcd for C23H42O4SiNa: 433.2744, found: 433.2746. 985

To a stirred solution of the above acetate (95.0 mg, 0.22 mmol) in THF (3 mL) at rt was added a 986

solution of TBAF (172 mg, 0.66 mmol, 0.66 mL of 1M / THF solution) and the mixture was 987

stirred at rt for 1 h. The reaction mixture was diluted with diethyl ether (4 mL) and washed with 988

water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under 989

reduced pressure. The crude compound was purified by silica gel column chromatography using 990

30% EtOAc / hexanes to afford the title compound 54 as colorless oil (61 mg, 89%). 1H NMR 991

(300 MHz, CDCl3): δ 4.54 (q, J = 6.6 Hz, 1H), 4.09-4.24 (m, 2H), 2.25-2.35 (m, 1H), 2.03 (s, 992

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3H), 1.72-1.89 (m, 4H), 1.53-1.62 (m, 4H), 1.42 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H), 993

1.02 (s, 3H), 0.88 (d, J = 6.3 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ 171.5, 88.8, 86.03, 80.1, 994

62.5, 58.4, 54.5, 53.5, 50.6, 35.6, 32.7, 30.2, 27.2, 24.4, 22.5, 21.2, 18.1. HRMS m/z: [M+Na]+ 995

calcd for C17H28O4Na: 319.1879, found: 319.1878. 996

Ynone 55 997

To a stirred solution of propargylic diol 54 (50.0 mg, 0.17 mmol) in EtOAc (4 mL) was added 998

IBX (142 mg, 0.51 mmol) and the solution was heated to reflux for 3 h, filtered through celite 999

and the filtrate was concentrated under reduced pressure. The crude compound was purified by 1000

silica gel column chromatography using 10% EtOAc / hexanes to afford the title compound 55 as 1001

colorless oil (46 mg, 94%). 1H NMR (300 MHz, CDCl3): δ 4.14 (t, J = 7.35 Hz, 2H), 2.35 (s, 1002

3H), 2.04 (s, 3H), 1.43-1.99 (m, 9H), 1.14 (d, J = 6.6 Hz, 3H), 1.06 (s, 3H), 0.92 (d, J = 6.3 Hz, 1003

3H). 13C NMR (75.5 MHz, CDCl3): δ 184.3, 171.2, 94.0, 86.4, 79.9, 62.0, 54.9, 51.6, 34.9, 32.7, 1004

32.2, 30.0, 27.4, 22.4, 22.2, 21.1, 17.9. HRMS m/z: [M+Na]+ calcd for C17H26O4Na: 317.1723, 1005

found: 317.1726. 1006

Ketone 56 1007

To a stirred solution of propargylic ketone 55 (84.0 mg, 0.29 mmol) in THF (4 mL) was added 1008

5% Pd/C (8.4 mg) and the mixture was stirred under an atmosphere of H2 for 10 h. The reaction 1009

mixture was filtered through celite and concentrated under reduced pressure. The crude 1010

compound was purified by silica gel column chromatography using 30% EtOAc / hexanes to 1011

afford the title compound 56 as colorless oil. (58 mg, 73%) (Note: Hydrogenation using PtO2 as 1012

a catalyst also gave the same dehydration product). 1H NMR (300 MHz, CDCl3): δ 4.36 (bs, 1013

1H), 4.12 (t, J = 7.65 Hz, 2H), 2.13-2.59 (m, 3H), 2.03 (s, 3H), 1.45-1.83 (m, 10H), 0.97 (d, J = 1014

Page 53 of 68



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54

6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H), 0.86 (s, 3H). 13C NMR (75.5 MHz, CDCl3): δ 208.5, 1015

171.2, 143.5, 137.3, 62.4, 49.5, 44.8, 38.4, 35.7, 29.9, 27.8, 27.4, 26.6, 21.5, 21.4, 21.2, 18.9. IR 1016

(neat) ν (cm-1): 1717.9, 1737.4, 1363.9, 1233, 1028. HRMS m/z: [M+Na]+ calcd for 1017

C17H28O3Na: 303.1931, found: 303.1932. 1018

Ynone 57 1019

To a stirred solution of alcohol 51 (135 mg, 0.53 mmol) in DMSO (4 mL) was added IBX (892 1020

mg, 3.18 mmol) and the reaction mixture was stirred at rt for 2.5 h. Then, EtOAc (60 mL) was 1021

added and the mixture was filtered. Water (60 mL) was added to the filtrate and the phases were 1022

separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers 1023

were washed with brine (3 x 60 mL), dried over sodium sulfate, filtered and evaporated under 1024

reduced pressure. The crude product was purified by silica gel flash chromatography using 10% 1025

ethyl acetate in hexanes to get title compound 57 as colorless oil (106 mg, 80%). 1H NMR (300 1026

MHz, CDCl3): δ 9.83 (t, 1H, J = 2.5 Hz), 2.60 (dd, 1H, J = 15.7, 2.5 Hz), 2.45-2.35 (m, 1H), 1027

2.35-2.30 (m, 3H), 2.06-1.87 (m, 3H), 1.86-1.69 (m, 3H), 1.63-1.48 (m, 1H), 1.30-1.21 (m, 3H), 1028

1.14 (d, 3H, J = 6.4 Hz), 0.92 (d, 3H, J = 6.4 Hz). 13C NMR (75.5 MHz, CDCl3): δ 202.2, 184.1, 1029

93.2, 86.5, 79.3, 55.6, 51.4, 51.2, 33.9, 32.7, 30.0, 27.4, 22.5, 22.1, 19.0. IR (neat) ν (cm-1) 1030

3659-3150 (br), 2958, 2872, 2206, 1717, 1677, 1223. HRMS m/z: [M+Na]+ calcd for 1031

C15H22NaO3: 273.1461, found: 273.1471. 1032

Aldol adduct 59 1033

To a stirred solution of ketoaldehyde 57 (41.0 mg, 0.16 mmol) in EtOAc (5 mL) was added 10% 1034

Pd/C (5 mg) and the mixture was stirred vigorously under a hydrogen atmosphere for 18 h. The 1035

reaction mixture was filtered through celite and the filtrate was evaporated under reduced 1036

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55

pressure. The crude product was purified by silica gel flash chromatography using 30% ethyl 1037

acetate in hexanes to afford the β-hydroxy ketone compound 59 as a single diastereoisomer. 1038

(colorless oil, 20 mg, 48%). 1H NMR (300 MHz, CDCl3): δ 4.03 (ddd, 1H, J = 15.2, 9.9, 5.0 1039

Hz), 2.58 (ddd, 1H, J = 13.6, 9.9, 3.7 Hz), 2.26 (dd, 1H, J = 13.6, 3.7 Hz), 2.18 (s, 3H), 2.09-1.85 1040

(m, 3H), 1.83-1.68 (m, 2H), 1.67-1.34 (m, 6H), 1.09 (d, 3H, J = 6.6 Hz), 1.01 (s, 3H), 0.95 (d, 1041

3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3): δ 211.8, 82.3, 67.3, 55.7, 49.0, 47.6, 43.3, 36.9, 1042

33.4, 29.8, 29.1, 25.7, 23.2, 22.7, 20.0. IR (neat): ν (cm-1) 3609-3104 (br), 2953, 2926, 2869, 1043

1705, 1052. LRMS (m/z, relative intensity) 254 (M+, 10), 170 (20), 109 (65), 43 (100). HRMS 1044

m/z: [M+Na]+ calcd for C15H26O3Na: 277.1780, found: 277.1783. 1045

Diols 60 and 61 1046

To a stirred solution of alkyne 50 (217 mg, 0.59 mmol) in THF (6 mL) was added 5% 1047

Pd/alumina (10 mg) and the mixture was stirred under a H2 atmosphere for 12 h. The crude 1048

product was purified by flash silica gel column chromatography using 10% EtOAc / hexanes to 1049

afford three products as colorless oils, the desired hydrogenated product 60 (175 mg, 80%), the 1050

partial hydrogenation i.e. alkene 61 (19.64 mg, 9%), and the hydrogenolysis product 46 (8.6 mg, 1051

6%). Compound 60 : 1H NMR (300 MHz, CDCl3): δ 3.69-3.80 (m, 3 H), 1.40-1.83 (m, 14H), 1052

1.15 (dd, J = 3.0 Hz, 3H), 0.98 (s, 3H), 0.93 (d, J = 6.2 Hz, 6H), 0.88 (s, 9H), 0.05 (s, 6H). 13C 1053

NMR (75.5 MHz, CDCl3): [signals in parentheses correspond to the diastereomer but we do not 1054

know which signal belongs to which isomer] δ 84.1 (83.9), 69.5 (69.4), 60.4 (60.3), 52.2 (51.8), 1055

48.4 (48.3), 38.9 (38.8), 35.4 (35.8), 33.8 (34.1), 33.6, 28.9, 26.1, 24.4 (24.3), 24.1 (24.0), 23.9, 1056

20.5 (20.3), 19.9 (19.7), 18.3, -4.5. IR (neat) ν (cm-1) 3454, 2954-2930, 2465, 1066, 997. 1057

HRMS m/z: [M+Na]+ Calc. for C21H44O3SiNa: 395.2952, found: 395.2944. Partial 1058

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56

hydrogenation product 61 : 1H NMR (300 MHz, CDCl3): δ 5.46 (dd, J = 7.8 Hz, 1H), 5.28 (dd, 1059

J = 13.5, 9.6 Hz, 1H), 4.95-5.10 (m, 1H), 3.69 (q, J = 6.2 Hz, 2H), 1.44-1.84 (m, 10H), 1.27 (d, J 1060

= 6.3 Hz, 3H), 0.98 (d, J = 10.5 Hz, 3H), 0.94 (d, J = 5.4 Hz, 3H), 0.88-0.91 (bs, 12H), 0.08 (d, J 1061

= 33.3 Hz, 3H), 0.07 (d, J = 3.6 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): [signals in parentheses 1062

correspond to the diastereomer but we do not know which signal belongs to which isomer] δ 1063

134.3 (134.9), 134.0 (132.3), 86.8 (86.9), 65.8 (66.9), 60.6 (60.6), 55.3 (55.1), 51.5 (51.3), 39.9 1064

(39.7), 33.1, 29.6 (29.9), 26.9, 26.2 (26.1), 25.4 (25.1), 23.1 (22-8), 22.5 (22.6), 18.9 (19.0), 18.3 1065

(18.2). IR (neat): ν (cm-1) 3330, 2950, 1466, 990. HRMS m/z: [M+Na]+ calcd for 1066

C21H42NaO3Si: 393.2795, found: 393.2791. 1067

Terminal alkene 62 1068

To a stirred solution of alcohol 60 (130 mg, 0.35 mmol) in ethyl acetate (6.0 mL) was added IBX 1069

(0.29 g, 1.05 mmol) and the reaction mixture was heated to reflux for 3 h. The reaction mixture 1070

was filtered through celite, washed with ethyl acetate (10 mL), the filtrate was dried over 1071

anhydrous Na2SO4 and concentrated under reduced pressure to afford the desired aldehyde as 1072

colorless oil (128 mg, 99%) which was used in the next reaction without purification. 1H NMR 1073

(300 MHz, CDCl3): δ 9.81 (s, 1H), 3.72-3.79 (m, 1H), 2.43 (t, J = 2.7 Hz, 2H), 1.42-1.92 (m, 1074

11H), 1.11-1.14 (m, 6H), 0.97 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 1075

6H). 13C NMR (75.5 MHz, CDCl3): [signals in parentheses correspond to the diastereomer but 1076

we do not know which signal belongs to which isomer] δ 203.9, 83.1 (83.4), 69.2, 52.2, 51.9 1077

(51.8), 51.5 (51.4), 48.4 (48.3), 38.7, 36.1 (36.2), 34.4, 33.3, 28.8 (28.7), 26.0, 24.2 (24.1), 24.1 1078

(24.0), 23.8 (23.7), 20.9 (20.8), 20.3 (20.2), 18.1, 14.2, -4.8 (-4.3). IR (neat): ν (cm-1) 3412, 1079

2959, 2886, 1470. HRMS m/z: [M+Na]+ calcd for C21H42O3SiNa: 393.2795, found: 393.2795. 1080

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To a stirred suspension of methyl triphenylphosphonium bromide (231 mg, 0.65 mmol) in THF 1081

(6 mL) at -78 ºC was added a solution of n-BuLi (41.5 mg, 0.26 mL-2.5M / toluene) and the 1082

mixture was stirred at the same temperature for 30 minutes when a solution of aldehyde (120 mg, 1083

0.32 mmol) in THF (3 mL) was added and after 30 minutes of stirring the cooling bath was 1084

removed. After 45 minutes of stirring at rt, reaction mixture was quenched by addition of ice 1085

cold 1N HCl (20 mL) and extracted with diethyl ether (2 x 40 mL). Ether extract was washed 1086

with water (40 mL), brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated 1087

under reduced pressure. The crude compound was purified by silica gel flash column 1088

chromatography using 2% EtOAc / hexanes to afford the desired product 62 as colorless oil (101 1089

mg, 84%). 1H NMR (300 MHz, CDCl3): δ 5.76-5.89 (m, 1H), 4.98-5.05 (m, 2H), 3.71-3.78 (m, 1090

1H), 1.99 (d, J = 7.5 Hz, 2H), 1.25-1.74 (m, 11H), 1.14 (d, J = 6.0 Hz, 3H), 0.93-0.98 (m, 9H), 1091

0.89 (s, 9H), 0.05 (s, 6H). 13C NMR (75.5 MHz, CDCl3): [signals in parentheses correspond to 1092

the diastereomer but we do not know which signal belongs to which isomer] δ 136.2, 116.9, 84.5 1093

(84.8), 69.5 (69.4), 52.8 (52.5), 49.5 (49.4), 41.3 (41.2), 37.1, 34.3, 33.8, 33.0, 28.5 (28.4), 26.4, 1094

26.1, 24.5(24.4), 23.9(24.1), 23.4 (23.3), 20.5 (20.3), 20.2 (19.9), 18.3, 14.3, -4.5. HRMS m/z: 1095

[M+Na]+ calcd for C22H44O2SiNa: 391.3008, found: 391.3017. 1096

Ketone 63 and dihydrofuran 64 1097

To a stirred solution of TBS protected alcohol 62 (198 mg, 0.54 mmol) in THF (6 mL) at 0 ºC 1098

was added a TBAF solution (351 mg, 1.34 mL 1M / THF) and the mixture was stirred at rt for 1 1099

h. The reaction mixture was diluted with diethyl ether (20 mL) and washed with water (20 mL), 1100

brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. 1101

The crude compound was purified by silica gel flash column chromatography using 30% EtOAc 1102

/ hexanes to afford the desired alcohol as a white solid (124 mg, 91%, MP: 73-74 ºC). 1H NMR 1103

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(300 MHz, CDCl3): δ 5.76-5.90 (m, 1H), 5.00-5.06 (m, 2H), 3.74-3.80 (m, 1H), 2.00-2.02 (m, 1104

2H), 1.36-1.91 (m, 12H), 1.21 (d, J = 6.0 Hz, 3H), 0.97 (d, J = 3.3 Hz, 3H), 0.99 (s, 3H), 0.94 (d, 1105

J = 6.6 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ 136.0, 117.0, 84.5, 68.8, 52.6, 49.4, 41.3, 1106

34.2, 33.3, 32.9, 28.3, 24.5, 23.7, 23.1, 20.2, 20.0. IR (neat) ν (cm-1) 3328, 2953, 2880, 1464, 1107

1411,1134, 992. HRMS m/z: [M+Na]+ calcd for C16H30O2Na: 277.2138, found: 277.2139. 1108

To a stirred solution of alcohol (120 mg, 0.47 mmol) in DCM (4 mL) at rt was added a solution 1109

of N-methylmorpholine N-oxide (NMO, 110 mg, 0.94 mmol) in DCM (2 mL) followed by 1110

addition of 4Aº molecular sieves powder (50 mg) and tetra-n-propylammonium perruthenate 1111

(TPAP, 16.0 mg, 0.05 mmol). The reaction mixture was stirred for 30 minutes, diluted with 1112

DCM (10 mL) and water (5 mL). Biphasic mixture was filtered through celite, layers were 1113

separated, organic layer was dried over anhydrous MgSO4, filtered and concentrated under 1114

reduced pressure. The crude compound was identified as compound 64. It was purified by silica 1115

gel flash column chromatography using 2.5% EtOAc / hexanes to afford the desired product 63 1116

as colorless oil. (89 mg, 75%). Compound 63 : 1H NMR (300 MHz, CDCl3): δ 5.78–5.64 (m, 1117

1H), 5.02–4.94 (m, 2H), 2.64–2.54 (m, 1H), 2.49–2.43 (m, 2H), 2.30–2.18 (m, 1H), 2.14 (s, 3H), 1118

2.12–2.10 (m, 2H), 2.04–2.02 (m, 2H), 1.79–1.71 (m, 1H), 1.49–1.25 (m, 4H), 0.98 (s, 3H), 0.97 1119

(d, J = 3.6 Hz, 3H), 0.95 (d, J = 3.6 Hz, 3H); HRMS m/z: [M+Na]+ calcd for C16H28O2Na: 1120

275.1987, found: 275.1994. Compound 64 : 1H NMR (300 MHz, CDCl3): δ 5.74-5.88 (m, 1H), 1121

4.98-5.06 (m, 2H), 4.38 (br, 1H), 2.61 (d, J = 15.6 Hz, 1H), 2.40 (d, J = 15.3 Hz, 1H), 1.77-1.97 1122

(m, 5H), 1.74 (s, 3H), 1.45-1.68 (m, 5H), 0.98 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.84 1123

(s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.2, 135.9, 117.1, 99.4, 94.4, 54.2, 49.9, 40.2, 34.0, 1124

32.3, 29.9, 25.5, 22.9, 22.2, 17.5, 13.7. 1125

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Bis-alkene 24 and ketone 65 1126

To a stirred suspension of methyltriphenylphosphonium bromide (212 mg, 0.59 mmol) in THF 1127

(4 mL) at -78 ºC was added a solution of n-BuLi (38 mg, 0.23 mL 2.5M / toluene) and the 1128

mixture was stirred at the same temperature for 30 minutes when a solution of ketone 63 (50.0 1129

mg, 0.32 mmol) in THF (1 mL) was added and after 45 minutes of stirring, the cooling bath was 1130

removed and stirring was continued at rt for 30 min. The reaction mixture was quenched by 1131

addition of ice cold 1N HCl (10 mL) and extracted with diethyl ether (2 x 25 mL). Ether extracts 1132

were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered and 1133

concentrated under reduced pressure. The crude compound was purified by silica gel flash 1134

column chromatography using 2% EtOAc / hexanes to afford the desired diene 24 as colorless 1135

oil (28 mg, 56%) and the elimination product 65 as colorless oil (17 mg, 37%). Compound 24: 1136

1H NMR (300 MHz, CDCl3) δ 5.77-5.91 (m, 1H), 5.01-5.06 (m, 2H), 4.71 (s,2H), 2.15-2.21 (m, 1137

2H), 2.02 (d, J = 7.2 Hz, 2H), 1.82-1.91 (m, 1H), 1.75 (s, 3H), 1.38-1.71(m, 6H), 1.22-1.30 (m, 1138

2H), 0.99 (d, J = 6.9 Hz, 3H), 0.97 (s, 3H), 0.95 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, 1139

CDCl3): δ 146.9, 136.1, 117.2, 109.7, 84.8, 52.6, 49.5, 41.4, 35.4, 34.5, 32.3, 28.5, 24.5, 23.3, 1140

22.9, 20.3, 20.1. IR(neat): ν (cm-1) 2953, 2880, 1464, 1411, 1134, 992. HRMS m/z: [M+Na]+ 1141

calcd for: C17H30ONa : 273.2189, found: 273.2199. Compound 65: 1H NMR (300 MHz, 1142

CDCl3): δ 5.64-5.78 (m, 1H), 4.94-5.02 (m, 2H), 2.55-2.64 (m, 1H), 2.43-2.49 (m, 2H), 2.19-1143

2.25 (m, 1H), 2.14 (s, 3H), 2.10 (d, J = 6.6 Hz, 2H), 2.03 (d, J = 6.9 Hz, 2H), 1.71-1.79 (m, 1H), 1144

1.25-1.48 (m, 3H), 0.98 (s, 3H), 0.96 (d, J = 3.6 Hz, 3H), 0.94 (d, J = 3.6 Hz, 3H). 13C NMR 1145

(100 MHz, CDCl3): δ 143.4, 137.8, 136.2, 116.5, 50.8, 44.9, 44.7, 35.5, 30.0, 27.7, 27.4, 26.1, 1146

21.6, 21.4, 19.0. HRMS m/z: [M+Na]+ calcd for C16H26ONa: 257.1881, found: 257.1893. 1147

rac-Carotol (1) 1148

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To a stirred solution of bis-alkene 24 (40.0 mg, 0.16 mmol) in dry dichloromethane (7 mL) at rt 1149

under argon was added Grubb’s-I catalyst (13 mg, 0.02 mmol) and the mixture was heated to 1150

reflux for 9 h. The reaction mixture was concentrated and the crude residue was purified by silica 1151

gel column chromatography using 1% Et2O in hexanes to afford the desired product 1 as 1152

colorless oil. (24.51 mg, 69%) The spectral data obtained were identical with the literature 1153

reported data (ref. 24). 1H NMR (300 MHz, CDCl3) δ 5.31 (br t, J = 5.7 Hz, 1H, H-9), 2.26 (br 1154

d, J = 13.8 Hz, 1H, H-10a), 2.07 (br t, J = 5.7 Hz, 2H, H-7a,b), 1.90-1.98 (m, 1H, H-6a), 1.76-1155

1.83 (m, 2H, H-4,11), 1.70-1.75 (m, 1H, H-10b), 1.67 (br s, 3H, H-14), 1.44-1.64 (m, 4H), 1.29 1156

(ddd, J = 9.6, 5.7 Hz, 1H, H-2a), 1.14 (br s, 1H, -OH), 0.99 (d, J = 6.6 Hz, 3H, H-13), 0.94 (s, 1157

3H, H-15), 0.93 (d, J = 6.6 Hz, 3H, H-12). 13C NMR (100 MHz, CDCl3) δ 138.7 (C-8), 122.3 1158

(C-9), 84.7 (C-5), 52.7 (C-4), 49.2 (C-1), 39.6 (C-2), 38.8 (C-10), 34.6 (C-6), 29.6 (C-7), 27.7 1159

(C-11), 25.4 (C-14), 24.5 (C-3), 24.2 (C-12), 21.6 (C-13), 21.5 (C-15). IR(neat): ν (cm-1) 3522, 1160

2954, 2926, 1448, 1460, 1374. 1161

t-Butyldimethyl(2-methylbut-3-yn-2-yloxy)silane (66) 1162

To a stirred solution of 2-methyl-3-butyn-2-ol (15.0 g, 178 mmol) in anhydrous DMF (30 mL) at 1163

0 ºC under argon was added a solution of imidazole (30.35 g, 445.8 mmol) in DMF (20 mL) 1164

followed by dropwise addition of solution of t-butyldimethylsilyl chloride (34.94 g, 231.8 mmol) 1165

in DMF (70 mL). The reaction mixture was stirred at rt for 12 h. The mixture was then diluted 1166

with water (1 L) and extracted twice with diethyl ether (400 mL). The combined organic extracts 1167

were washed with 1N HCl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated) 1168

the crude product was purified by silica gel column chromatography using 1% Et2O in hexanes 1169

to afford the desired product 66 as a colorless liquid. 33.25 g (94%). 1H NMR (300 MHz, 1170

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CDCl3): δ 2.38 (s, 1H), 1.47 (s, 6H), 0.86 (s, 9H), 0.17 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 1171

89.5, 70.8, 66.3, 33.1, 25.9, 25.8, 18.2, -2.7, -2.8. 1172

Alkyne-Diol 67 1173

To a 100 mL rb flask containing anhydrous CeCl3 (3.16 g, 12.8 mmol, weighed in a glove box) 1174

at 0 ºC under argon was added THF (30 mL) and the mixture was stirred at rt for 18 h. In another 1175

flask containing a stirred solution of alkyne 66 (2.38 g, 12.8 mmol) in THF (20 mL) at -78 ºC 1176

under argon, was added dropwise n-BuLi (5.12 mL, 12.8 mmol, 2.5M in hexanes). This reaction 1177

mixture was stirred at 0 ºC for 1.5 h and then transferred slowly using a cannula to the cerium 1178

chloride-THF suspension at 0 ºC. The resulting orange suspension was stirred at 0 ºC for 2 h 1179

when a solution of ketone 42 (0.40 g, 2.17 mmol) in THF (10 mL) was added dropwise at 0 ºC. 1180

The reaction mixture was stirred at 0 ºC for 4 h and then at rt for another 18 h. The reaction 1181

mixture was cooled to 0 ºC, 10% aqueous AcOH (60 mL) was added and aqueous layer was 1182

extracted with diethyl ether (2 x 75 mL). The combined organic extracts were washed with a satd 1183

solution of NaHCO3, water, brine, dried over anhydrous Na2SO4, filtered and evaporated under 1184

reduced pressure. The crude product (2.5 g, dark red oil) was purified by flash chromatography 1185

using ethyl acetate in hexanes (10:90) to afford the desired product 67 as light orange oil. (0.655 1186

g, 79%, corrected yield 87% -based on recovered starting material-hydroxy ketone). 1H NMR 1187

(300 MHz, CDCl3): δ 3.66-3.81 (m, 2H), 1.73-1.93 (m, 4H), 1.49-1.67 (m, 6H), 1.46 (s, 6H), 1188

1.15 (d, J = 6.3Hz, 3H), 1.02 (s, 3H), 0.91 (d, J = 6.3 Hz, 3H), 0.86 (s, 9H), 0.17 (s, 6H). 13C 1189

NMR (100 MHz, CDCl3): δ 92.0, 84.4, 80.4, 66.6, 60.4, 54.5, 50.7, 39.8, 33.1, 33.0, 32.5, 30.2, 1190

27.2, 25.8, 22.7, 22.4, 18.2, 18.0, -2.60, -2.62. IR (neat): ν (cm-1) 3610-3160 (br), 2960, 2940, 1191

2854, 1466, 1250, 1090. HRMS m/z: [M+Na]+ calcd for: C22H42O3SiNa : 405.2795, found: 1192

405.2807. 1193

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Saturated diol 68 1194

To a stirred solution of alkyne 67 (0.65 g, 1.69 mmol) in ethyl acetate (25 mL) at rt was added 1195

5% Pd/Al2O3 and the mixture was stirred vigorously under an H2 atmosphere for 5 h. The 1196

reaction mixture was filtered through celite, washed with ethyl acetate (20 mL) and concentrated 1197

under reduced pressure. The crude compound (0.6 g) was purified by silica gel flash column 1198

chromatography using 10% ethyl acetate in hexanes to afford the title compound 68 as colorless 1199

oil. (0.532 g, 81%). 1H NMR (300 MHz, CDCl3): δ 3.66-3.83 (m, 2H), 1.38-1.85 (m, 14H), 1.21 1200

(d, J = 6.9 Hz, 6H), 0.98 (s, 3H), 0.93, 0.97 (dd, J = 6.3 Hz, 6H), 0.86 (s, 9H), 0.08 (s, 6H). 13C 1201

NMR (75 MHz, CDCl3): δ 84.2, 73.6, 60.3, 52.0, 48.4, 38.9, 38.7, 35.5, 32.1, 30.4, 29.6, 28.9, 1202

26.0, 24.4, 23.9, 20.3, 19.9, 18.2, -1.9. IR (neat): ν (cm-1) 3640-3100 (br), 296, 2890, 1390, 1203

1050. HRMS m/z: [M+Na]+ calcd for: C22H46O3SiNa : 409.3108, found: 409.3118. 1204

Alkene 69 1205

To a stirred solution of alcohol compound 68 (0.41 g, 1.06 mmol) in ethyl acetate (15 mL) at rt 1206

was added IBX (0.89 g 3.18 mmol) and the mixture was heated to reflux for 3 h. The reaction 1207

mixture was filtered through celite, washed with ethyl acetate (20 mL), filtrate was concentrated 1208

under reduced pressure to afford the crude aldehyde compound as colorless oil. (0.39 g, 97%). 1209

This crude aldehyde compound was pure enough and was used for next step without purification. 1210

1H NMR (300 MHz, CDCl3): δ 9.82 (t, J = 2.1 Hz, 1H, -CHO), 2.45 (d, J = 2.1 Hz, 2H), 1.98 1211

(bs, 1H, -OH), 1.83, 1.87 (dd, J = 6.6 Hz, 1H), 1.52-1.72 (m, 8H), 1.38-1.49 (m, 1H), 1.19 (d, J = 1212

7.8 Hz, 6H), 1.11 (s, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.84 (s, 9H), 0.07 (s, 1213

6H). 13C NMR (75 MHz, CDCl3): δ 204.0, 83.3, 73.5, 52.2, 51.7, 48.6, 38.6, 36.3, 33.0, 30.4, 1214

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29.7, 28.8, 26.1, 25.9, 24.3, 23.9, 21.0, 20.1, 18.2, -1.89. IR (neat): ν (cm-1) 3409, 2960, 2885, 1215

1477, 1369, 896. HRMS m/z: [M+Na]+ calcd for: C22H44O3SiNa : 407.2952, found: 407.2961. 1216

To a stirred suspension of methyl triphenylphosphonium bromide (0.25 g, 0.70 mmol) in dry 1217

THF (4 mL) at -78 ºC under argon was added dropwise a solution of n-BuLi (0.28 mL, 0.70 1218

mmol, 2.5 M in hexanes) and the light yellow colored suspension was stirred at the same 1219

temperature for 30 min. Then a solution of aldehyde (0.09 g, 0.23 mmol) in THF (3 mL) was 1220

added dropwise. The reaction mixture was stirred at -78 ºC for 30 min and then at rt for 45 min. 1221

0.5N HCl (10 mL) was added slowly to the reaction mixture at 0 ºC and extracted with diethyl 1222

ether (2 x 20 mL). The combined organic extracts were washed with water, brine, dried over 1223

anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified 1224

by silica gel flash column chromatography using 5% ethyl acetate/hexanes to afford the title 1225

compound 69 as colorless oil. (65 mg, 72%). 1H NMR (300 MHz, CDCl3): δ 5.77–5.91 (m, 1H), 1226

4.99–5.05 (m, 2H), 2.01 (d, J = 6.3 Hz, 2H), 1.81-1.91 (m, 1H), 1.36-1.78 (m, 9H), 1.20 (d, 1227

J=4.8 Hz, 6H), 0.93-0.98 (m, 9H), 0.86 (s, 9H), 0.08 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 1228

136.2, 116.9, 84.6, 73.6, 52.7, 49.5, 41.4, 38.9, 34.4, 31.3, 30.3, 29.7, 28.5, 26.0, 24.6, 23.3, 20.3, 1229

20.2, 18.3, -1.8. HRMS m/z: [M+Na]+ calcd for: C23H46O2SiNa : 432.3267, found: 432.3271. 1230

Diene 24 and tetrahydrofuran 70 1231

To a stirred solution of compound 69 (0.34 g, 0.89 mmol) in dry THF (7 mL) at 0 ºC under argon 1232

was added a solution of tetra-n-butylammonium fluoride (0.70 g, 2.67 mmol, 2.67 mL of 1M in 1233

THF) and the mixture was stirred at rt for 2 h. The reaction mixture was diluted with diethyl 1234

ether (20 mL) and washed with water, brine, dried over anhydrous Na2SO4 and concentrated 1235

under reduced pressure. The crude compound was purified by silica gel flash column 1236

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chromatography using 10% ethyl acetate/hexanes to afford the desired alcohol as colorless gum. 1237

(0.231g, 97%). 1H NMR (300 MHz, CDCl3): δ 5.77-5.90 (m, 1H), 5.01-5.06 (m, 2H), 2.02 (d, J 1238

= 7.2 Hz, 2H), 1.82-1.93 (m, 1H), 1.56-1.79 (m, 6H), 1.52 (s, 3H), 1.37-1.48 (m, 2H), 1.23 (d, J 1239

= 1.2 Hz, 6H), 0.98 (d, J = 6.9 Hz, 3H), 0.97 (s, 3H), 0.95 (d, J = 6.9 Hz, 3H). 13C NMR (75 1240

MHz, CDCl3): δ 136.1, 117.1, 84.5, 71.1, 52.9, 49.5, 41.4, 37.4, 34.4, 31.1, 29.8, 29.3, 28.5, 1241

24.5, 23.3, 20.4, 20.3. IR (neat): ν (cm-1) 3690-3110 (br), 2960, 2866, 1370, 1079. HRMS m/z: 1242

[M+Na]+ calcd for: C17H32O2Na : 291.2295, found: 291.2294. 1243

To a stirred solution of the above alcohol compound (40.0 mg, 0.15 mmol) in dichloromethane 1244

(2 mL) at 0 ºC under argon was added a solution of Martin’s sulfurane (200 mg, 0.30 mmol) in 1245

dichloromethane (4 mL) and the mixture was stirred at rt for 45 min. The reaction mixture was 1246

concentrated and the residue was dissolved in diethyl ether (20 mL), washed with brine (10 mL), 1247

dried and concentrated under reduced pressure. The crude compound was purified by silica gel 1248

column chromatography using 1% ethyl acetate/hexanes to afford the diene 24 as colorless oil 1249

(24 mg, 64%) as well as compound 70 (5%). Diene 24 : 1H NMR (300 MHz, CDCl3) δ 5.77-1250

5.91 (m, 1H), 5.01-5.06 (m, 2H), 4.71 (s,2H), 2.15-2.21 (m, 2H), 2.02 (d, J = 7.2 Hz, 2H), 1.82-1251

1.91 (m, 1H), 1.75 (s, 3H), 1.38-1.71(m, 6H), 1.22-1.30 (m, 2H), 0.99 (d, J = 6.9 Hz, 3H), 0.97 1252

(s, 3H), 0.95 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 146.9, 136.1, 117.2, 109.7, 1253

84.8, 52.6, 49.5, 41.4, 35.4, 34.5, 32.3, 28.5, 24.5, 23.3, 22.9, 20.3, 20.1. IR(neat): ν (cm-1) 1254

2953, 2880, 1464, 1411, 1134, 992. HRMS m/z: [M+Na]+ calcd for: C17H30ONa : 273.2189, 1255

found: 273.2199. Compound 70 : 1H NMR (300 MHz, CDCl3) δ 5.89–5.75 (m, 1H), 5.03–4.96 1256

(m, 2H), 2.07–2.01 (m, 1H), 1.96–1.88 (m, 3H), 1.84–1.64 (m, 4H), 1.57–1.47 (m, 3H), 1.44–1257

1.33 (m, 1H), 1.30 (s, 3H), 1.22 (s, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H), 0.91 1258

(s, 3H). 13C NMR (75 MHz, CDCl3): δ 136.4, 116.7, 97.9, 81.2, 53.6, 48.6, 42.7, 38.9, 34.0, 1259

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31.3, 29.4, 29.3, 27.2, 25.2, 22.0, 20.9, 20.2. HRMS m/z: [M+Na]+ calcd for: C17H30ONa : 1260

273.2189, found: 273.2194. 1261

Acknowledgements: 1262

We thank the Université de Sherbrooke and the Natural Sciences and Engineering Research 1263

Council (NSERC) of Canada for financial support. 1264

1265

1 (a) Williams, C. A.; Harborne, J. B. Phytochem. 1972, 11, 1981−1987. (b) Alarcon, L. D.; Pena, A. E.; Gonzales

de C., N.; Quintero, A. Rev. Soc. Chim. Peru 2009, 75, 221−227. 2 (a) Levisalles, J.; Rudler, H. Bull. Soc. Chim. Fr. 1964, 2020−2021. (b) Levisalles, J.; Rudler, H. Bull. Soc. Chim.

Fr. 1967, 2059−2066. 3 Gund, M.; Déry, M.; Spino, C. Org. Lett. 2016, 18, 4280–4283.

4 (a) De Broissia, H.; Levisalles, J.; Rudler, H. Bull. Soc. Chim. Fr. 1972, 11, 4314−4218. (b) De Broissia, H.;

Levisalles, J.; Rudler, H. J. Chem. Soc., Chem. Commun. 1972, 855. (c) Levisalles, J.; Rudler, H. Bull. Soc. Chim.

Fr. 1968, 7, 299−300. 5 Bennett, N. B.; Stoltz, B. M. Chem. Eur. J. 2013, 19, 17745−17750.

6 For a review on approaches to this and other related carbon skeleton, see Foley, D. A; Maguire, A. R. Tetrahedron

2010, 66, 1131−1175 and references cited therein. 7 Yamasaki, M. J. Chem. Soc., Chem. Commun. 1972, 606–607.

8 Audenaert, F.; Dekeukeleire, D.; Vandewalle, M. Tetrahedron 1987, 43, 5593–5604.

9 Foley, D. A.; O’Leary, P.; Buckley, N. R.; Lawrence, S. E.; Maguire, A. R. Tetrahedron 2013, 69, 1778−1794.

10 For a review on dialkoxycarbenes, see: Warkentin, J. Acc. Chem. Res. 2009, 42, 205−212.

11 Rigby, J. H.; Brouet, J.-C.; Burke, P. J.; Rohach, S.; Sidique, S.; Heeg, M. J. Org. Lett. 2006, 8, 3121–3123.

12 Rigby, J. H.; Cavezza, A.; Ahmed, G. J. Am. Chem. Soc. 1996, 118, 12848−12849.

13 (a) Beaumier, F.; Dupuis, M.; Spino, C.; Legault, C. Y. J. Am. Chem. Soc. 2012, 134, 5938−5953. (b) Boisvert, L.;

Beaumier, F.; Spino, C. Org. Lett. 2007, 9, 5361−5363. (c) Spino, C.; Rezaei, H.; Dupont-Gaudet, K.; Bélanger, F.

J. Am.Chem. Soc. 2004, 126, 9926−9927. 14

(a) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc. 1998, 120, 3664−3670. For the use of a

dialkylthiocarbene in synthesis, see: (b) Rigby, J. H.; Dong, W. Org. Lett. 2000, 2, 1673−1675. For a synthetic

approach to indole alkaloids using dimethoxycarbene, see: (c) Rigby, J. H.; Burke, P. J. Heterocycles 2006, 67,

643−653. 15

El-Saidi, M.; Kassam, K.; Pole, D. L.; Tadey, T.; Warkentin, J. J. Am. Chem. Soc. 1992, 114, 8751−8752. 16

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Kassam, K.; Pole, D. L.; El-Saidi, M.; Warkentin, J. J. Am. Chem. Soc. 1994, 116, 1161−1162. 18

Rigby, J. H.; Cavezza, A.; Heeg, M. J. Tetrahedron Lett. 1999, 40, 2473–2476. 19

Chronologically, we completed the optimal synthesis of carotol before testing the better chiral auxiliary 28h. We

did not find it necessary to repeat the sequence starting from 35h. 20

Srikrishna, A.; Nagaraju, G.; Ravi, G. Synlett, 2010, 3015−3018. 21

Wender, P. A.; Bi, F. C.; Brodney, M. A.; Gosselin, F. Org. Lett. 2001, 3, 2105−2108. See also ref. 17. 22

Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem Soc. Chem. Commn. 1987, 1625–1627. 23

(a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vols. 1−3. (b) Fu, G.

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Bülow, N.; König, W. A. Phytochemistry 2000, 55, 141–168. 25

Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392−4398. 26

Budovská, M.; Kutschy, P.; Kožár, T.; Gondová, T.; Petrovaj, J. Tetrahedron 2013, 69, 1092–1104. 27

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Figure captions:

Figure 1. Biologically important natural products exhibiting a bicyclo[5.3.0]decane core.

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Figure 2: Conformations of the dialkoxycarbenes and transition states (TS) leading to the

intermediate cyclopropanes.

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