Total Syntheses of (–)-Majucin and (–)- Jiadifenoxolane A ...ccc.chem.pitt.edu/wipf/Current Literature/Steph_10.pdf · Total Syntheses of (–)-Majucin and (–)-Jiadifenoxolane

Total Syntheses of (–)-Majucin and (–)-Jiadifenoxolane A, Complex Majucin-Type

Illicium Sesquiterpenes

Matthew L. Condakes, Kevin Hung, Stephen J. Harwood and Thomas J. Maimone J. Am. Chem. Soc., 10.1021/jacs.7b11493

Steph McCabe Wipf Group Current Literature

12/16/2017 1 Steph McCabe @ Wipf Group 12/16/17

12/16/17 Steph McCabe @ Wipf Group 2

The Illicium Family of Sesquiterpenes

Me

H

OO

Me OH

O

O

majucin core

**

* *

*

•  The Seco-‐prezizaane family of sesquiterpenes are produced by Illicium evergreen shrubs/trees

•  20 members possess the majucin core with different oxygenaJon paKerns

•  Several members enhance neurite outgrowth: (–)-‐jiadifenolide (10 nM), (–)-‐jiadifenin, (–)-‐ODNM

•  Axon degeneraJon and neuronal atrophy accompany chronic neurodegeneraJve diseases. Small molecules that promote growth of neurons are of interest

Me

H

OO

MeOH

O

OHO

OHOH(–)-majucin

Me

H

OO

MeOH

O

O

O

OH

H

(–)-jiadifenoxolane A

Me

OO

Me OH

O

OHO

O

(–)-ODNM

Me

OO

Me OH

OOH

O O

MeO

(–)-jiadifenin

OO

Me OH

OOH

Me O

O

(–)-jiadifenolide

Steph McCabe @ Wipf Group 3

(–)-Majucin

12/16/17

Isola-on: 1988 (Guangxi, China) by Sato Illicium majus (Chinese flowering plant) Characteriza-on: 1D/2D NMR, IR, specific rotaJon, melJng point, mass spectrometry, X-‐ray (des-‐C(3)-‐OH) Structural features: fused γ-‐lactone, δ-‐lactone, and four stereodefined hydroxyl groups Synthesis: Maimone (2017) Bioac-vity: None reported

Illicium majus

Yang, C.-‐S.; Kouno, I.; Kawano, N.; Sato, S. Tetrahedron Le=. 1988, 29, 1165

Me

H

OO

MeOH

O

OHO

OHOH(–)-majucin

3

Isola-on: 2009 (Yunnan, China) by Fukuyama Illicium jiadifengpi (Chinese flowering plant) Characteriza-on: 1D/2D NMR, IR, specific rotaJon, mass spectrometry Structural features: fused γ-‐lactone, δ-‐lactone, two stereodefined terJary hydroxyl groups, strained bridging tetrahydrofuran ring Synthesis: Maimone (2017) Bioac-vity: Promotes neurite outgrowth in primary cultured rat corJcal neurons


(–)-Jiadifenoxolane A

Kubo, M.; Okada, C.; Huang J.-‐M.; Harada, K.; Hideaki, H.; Fukuyama, Y. Org. Le=., 2009, 11, 5190

Me

H

OO

MeOH

O

O

O

OH

H


of 1 and 2 were longer than that of the control. It should benoted that 1 exhibits more potent activity at as lowconcentrations as 0.01 µM. A dose of 1 lower than 0.01 µMresulted in a tendency toward reduced promotion of neuriteoutgrowth (data not shown). The present study implied thatmajucin-type sesquiterpenoids are most likely to be a druglikechemical group suitable for showing neurite outgrowth-promoting activity.

In conclusion, three novel seco-prezizaane-type ses-quiterpenoids 1-3 were isolated from the pericarps ofIllicium jiadifengpi. Their structures are unique pentacyclicsesquitepenoids with cagelike structures. To the best ofour knowledge, jiadifenolide (1) is the first example of aseco-prezizaane-type sesquiterpenoid with a γ-lactoneformed between the C-11 carbonyl and the C-4 hydroxygroup. Moreover, compounds 1 and 2 have been found toshow neurite outgrowth-promoting activity in the primarycultured rat cortical neurons. In particular, jiadifenolide(1), which shows potent neurotrophic activity at a low

dose, has a great potential as a lead compound of non-peptide neurotrophic agent useful for the treatment ofneurodegenerative diseases such as Alzheimer’s disease.

Acknowledgment. We thank Dr. Masami Tanaka and Ms.Yasuko Okamoto (TBU) for taking the 600 MHz NMR andmass spectra measurements. This work was supported by aGrant-in-Aid for Scientific Research from the Ministry ofEducation, Culture, Sports, Science, and Technology of Japan(Priority Area, 18032085; 19790027) and the Open ResearchFund from the Promotion and Mutual Corporation for PrivateSchools of Japan.

Supporting Information Available: 1H NMR, 13C NMR,1H-1H COSY, NOESY, HMQC, and HMBC spectra for 1,2, and 3. This material is available free of charge via theInternet at http://pubs.acs.org.

OL9021029

Figure 7. Neurite outgrowth-promoting activity of 1 and 2 in primary cultured rat cortical neurons. (A) Morphology of neurons in thecontrol groups. (B) Morphology of neurons in 0.01 µM 1. (C) Morphology of neurons in 10 µM 2. (D) Quantitative analysis ofneurite outgrowth. In each group, the mean length of the primary dendrite-like processes of 63 neurons was measured. Data areexpressed as means ( SE. The differences between groups were tested with Dunnett’s t test. ##, P < 0.01, **, P < 0.01 vs controlaccording to Dunnett’s t test.

Org. Lett., Vol. 11, No. 22, 2009 5193

Illicium jiadifengpi Morphology of neurons: 10 μM

of (–)-‐jiadifenoxolane A






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Org. Lett., Vol. 11, No. 22, 2009 5193






OL9021029


Org. Lett., Vol. 11, No. 22, 2009 5193

Steph McCabe @ Wipf Group 5 12/16/17

Biosynthetic Pathway

(+)-cedrol

Me

H

H

MeMe

OHMe

Me

H

OO

MeOH

O

OHO

OHOH

(–)-majucin

Me

H

OO

MeOH

O

O

O

OH

H


SN2

12

10

144

H

This Work

(+)-cedrol

Me

H

H

MeMe

OHMe

Me

H

OO

MeOH

O

OHO

OHOH

(–)-majucin

Me

H

OO

MeOH

O

O

O

OH

H


SN2

12

10

144

H

This Work

~ $ 0.05 USD/g

Me

Me

OPPMeMefarnesyl

pyrophosphate

-OPPcyclase

Me

Me

MeMe

Me

Me

MeMe

H Me

Me

MeMe

Me

Me

MeMe

Me

MeMe

Me

allo-cedrane skeleton

seco-prezizaaneskeleton

cedrane skeleton

alkyl shift

acorane skeleton

C-Cscission

•• • •••••

•••••

[O]

illicium sesquiterpenes


(+)-cedrol~ $ 0.05 USD/g

1. PhI(OAc)2, I2, hv

chiral pool

Suarez oxidationMe

H

H

Me

O

Me

Me

H

H

Me

OHMe

H

Courtneidge J. L.; Lusztyk, J.; Page, D.; Tetrahedron Le=., 1994, 35, 1003; Mowbray, C., E.; PaKenden, G. Tetrahedron Le=., 1993, 34, 127; Dorta, R. L.; Francisco, C. G.; Freire, R.; Suaŕez, E. Tetrahedron Le=. 1988, 29, 5429.

R OH +O

OI

Me

H

H

Me

Me

OMe I

Me

H

H

Me

OMe

H

1,5-HAT(6-membered TS ✓)

Me

H

H

Me

OHMe

I

Me

H

H

Me

OHMe

I

Me

H

H

Me

O

Me

PhI(OAc)2, I2hν

alkyl hypoiodite- AcOH for HAT reactions • Ideal arrangement of C-H—X is close to 180°• Distance between X• and C-H is < 3Å

Mechanism?

OMe

H

>20 g scale

Double Suárez Oxidation Me

H

OO

MeOH

O

O

O

OH

H

(+)-cedrol~ $ 0.05 USD/g

1. PhI(OAc)2, I2, hv Me

H

H

Me

Me

OAc

Me

H

H

MeOAc

OMe

2. BH3•THF

then addCrO3•2Pyr

H

Me

H

H

MeOAc

OHMe

3. NaBH4; 72% (2 steps) Me

H MeOAc

OMe

H

4. PhI(OAc)2, I2, hv; 93%

chiral pool

Suarez oxidation

Suarez oxidation

Me

H

H

Me

O

Me

Me

H

H

Me

OHMe

Hthen addAc2O, H3PO4; 67%

H


Courtneidge J. L.; Lusztyk, J.; Page, D.; Tetrahedron Le=., 1994, 35, 1003; Mowbray, C., E.; PaKenden, G. Tetrahedron Le=., 1993, 34, 127; Dorta, R. L.; Francisco, C. G.; Freire, R.; Suaŕez, E. Tetrahedron Le=. 1988, 29, 5429.

>20 g scale

5 g scale

Me

H

OO

MeOH

O

O

O

OH

H

Double Suárez Oxidation

� � �

RuO4 Triple Oxidation


Me

OH MeOAc

O

O

O

7%

CH O

RuO O

O

Bakke, J., M.; Frøhaug, A., E. J. Phys. Org. Chem., 1996, 9, 507

Me

H MeOAc

OMe

H

Me

H MeOAc

O

O

O

Me

H MeOAc

OMe

H OH

RuO4 RuO4

directedoxidation

Me

H MeOAc

OMe

HO OH

RuO4

5. RuCl3•xH2O (3 x 0.3 eq), KBrO3 (2 x 5.0 eq); 72%gram scale

generates RuO4 in situ

3 x [O]

oxidativecleavage

regioselectiveC-H oxidation

•

RuO4 C-H oxidation3°>2°>1°

(4x 3° C-H)Regioselective for (C6) C-H

611 ••

•

Me

H

OO

MeOH

O

O

O

OH

H

We began our synthetic studies in analogy to previous work on6, but found that the strained THF ring formed in the initialSuarez oxidation (I2, PhI(OAc)2, hν) could be convenientlyconverted to acetoxy cedrene (7) simply by adding aceticanhydride and phosphoric acid directly to the reaction mixture(Scheme 1). This procedure delivered 7 in 67% yield and on 120mmol scale.11 Diverging from past work, in which an olefinoxidative cleavage reaction was used to generate a keto acid,10 wefound that 7 could be converted into ketone 8 directly via ahydroboration/double oxidation sequence (BH3·THF/CrO3·2pyr.). The use of Collin’s reagent avoided hydrolysis of theacetate protecting group as compared to many other oxidantsexamined. Ketone 8 was then easily reduced (NaBH4) from theconvex face to give alcohol 9 in 72% yield over 2 steps asessentially a single diastereomer. Taking inspiration from thework of Waegell on simpler cedrene scaffolds,12 we explored theuse of Suarez conditions to oxidize the C-4 methine position atthis stage. Owing to the very close spatial proximity of thesecondary hydroxyl to the ring junction C-4 methine, anexceptionally high yielding (93%) C−H functionalization ensued(I2, PhI(OAc)2, hν). In contrast to our previous work employingiron complexes to oxidize this position, the presence of

preexisting C-14 oxidation had little impact on this trans-formation. Next, prolonged stirring with in situ generated RuO4(RuCl3·xH2O, KBrO3) accomplished a remarkably clean tripleoxidation reaction, cleaving the C-6/C-11 bond and deliveringketone lactone 11.12,13 While not optimized, we were also able toisolate quadruple oxidation product 12wherein an additional C−H bond has been hydroxylated.14

With the construction of the tricyclic propellane-like coreaccomplished in five steps, we were poised to address the crucialmajucin-type γ-lactone which called for the exhaustive oxidationof the cedrol C-12 methyl group (vide supra). In a single,remarkable step, we found that a quadruple oxidation of allC−Hbonds α to the ketone group in 13was achieved under anhydrousRiley oxidation conditions (SeO2, 4 Å MS, Δ).15 In order tofacilitate handling of this compound, it proved essential tomethylate the intermediate acid (K2CO3, Me2SO4) prior toworkup, thus delivering unsaturated keto ester 13. Upontreatment of 13 with L-selectride, a diastereomeric mixture ofallylic alcohols was obtained via 1,2-reduction of the ketonemoiety. When the reaction was quenched with basic methanol,both intermediates converged to enol lactone 14, presumably viaan acetate cleavage/translactonization/alkene isomerization

Scheme 1. Synthesis of Complex Majucinoidsa

aReagents and conditions: (a) PhI(OAc)2 (1.1 equiv), I2 (0.4 equiv), cyclohexane, hν (visible), 1.5 h then Ac2O (10.0 equiv), H3PO4 (2.0 equiv),67%; (b) BH3·THF (1.3 equiv), THF, 1.5 h then CrO3·2pyr (25.0 equiv), DCM, 30 min; (c) NaBH4 (1.5 equiv), MeOH, 30 min, 72% over two steps;(d) PhI(OAc)2 (3.0 equiv), I2 (1.0 equiv), DCM, hν (visible), 0 °C, 1.5 h, 93%; (e) KBrO3 (2 × 5.0 equiv), RuCl3·xH2O (3 × 0.03 equiv), MeCN/CCl4/H2O (2:2:3), 75 °C, 3 d, 72% of 11, 7% of 12; (f) SeO2 (3.5 equiv), 4 Å MS (1.0 mass equiv), diglyme, 130 °C, 4 h then K2CO3 (3.0 equiv),Me2SO4 (1.5 equiv), 1 h; (g) L-selectride (1.2 equiv), THF, −78 °C, 30 min then KOH (10.0 equiv), MeOH, 0 °C, 30 min, 50% over two steps; (h)DMDO (1.5 equiv), 12 h; (i) PhCF3, 170 °C, 2 h; (j) Me4NBH(OAc)3 (7.0 equiv), MeCN/AcOH (3:1), − 40 °C, 16 h, 64% over three steps; (k)TsOH·H2O (2.2 equiv), n-BuOH, 150 °C, 26 h, 71%; (l) LHMDS (3.0 equiv), MoOPH (5.0 equiv), THF, −78 → 0 °C, 2.5 h, 65%; (m)[Ru2(PEt3)6(OTf)3](OTf) (0.1 equiv), NMM (0.2 equiv), TFE/dioxane (1:1), 120 °C, 18 h then i-PrOH (3.0 equiv), 120 °C, 5 h, 75%; (n) OsO4·TMEDA (1.0 equiv), DCM, −78 → 0 °C, 2 h then NaHSO3 (10.0 equiv), H2O, 16 h, 61%; (o) MsCl (5.0 equiv), pyr. (10.0 equiv), DCE, rt →80°C, 15 h, 92%. DMDO = dimethyldioxirane, LHMDS = lithium bis(trimethylsilyl)amide, MoOPH = oxodiperoxymolybdenum(pyridine)-(hexamethylphosphoric triamide).

Journal of the American Chemical Society Communication

DOI: 10.1021/jacs.7b11493J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

B

Rearrangement


Me

H Me

O

O

O

OHO

Me

H MeOAc

O

O

O

Me

H MeOAc

O

O

O

OMeO6. SeO2 (3.5 eq), 4Å MS, diglyme, 130 °C, 4 h then K2CO3 (3.0 eq), Me2SO4 (1.5 eq), 1 h

7. L-selectride (1.2 eq), THF, -78 °C then add KOH (10 eq)/MeOH 0 °C, 30 min; 50% (2 steps)Riley oxidation

X-ray

8. DMDO (1.5 eq),12 h Me

H Me

O

O

OO

OO

H

single diastereomer

Me

H

OO

MeOH

O

O

O

OH

H

Me

H Me

O

O

OO

OO

H 9. PhCF3, 170 °CMe

H

O

O

O OO

Me OH


Formation of the δ-‐Lactone Ring

cascade process. Overall 14, whose rigid tetracyclic skeleton wasconfirmed by X-ray crystallographic analysis, was obtained in50% yield from 11 without intermediate silica-gel purification.In order to rearrange the 5,5-fused ring system found in

tetracycle 14 into the majucinoid 5,6-fused core typified by 1−5,we envisioned employing an α-ketol rearrangement. However,unlike our previous work on 6, this system required atransannular bond migration event (Scheme 2). Experimentally,

we found that enol lactone 14 could be oxidized to a single,somewhat unstable, α-hydroxyketone diastereomer (see 19)using DMDO. A solvent swap from acetone to trifluorotoluenefollowed by heating to 170 °C elicited clean bond reorganizationto the majucin core. Precedented directed reduction (Me4NBH-(OAc)3) of the α-ketol group then furnished known tetracyclicdiol 15 in 76% yield over 3 steps, without the need forintermediate silica-gel purification, and as essentially a singlediastereomer. The structure of 15, which completes a formalsynthesis of 5,3d,4,16 was secured by X-ray crystallographicanalysis.Exploration into the diastereoselective oxidation of the enol

lactone 14 revealed that while DMDO gave α-ketol 19selectively, formation of the epimeric α-ketol 20 could beaccomplished with SeO2 (Scheme 2).17 Reduction of 20 gavediol 21 and X-ray crystallographic analysis unambiguouslyassigned its stereochemistry. Although the rearrangement of α-ketol 19 was facile, 20 did not rearrange under a variety ofconditions.18

To gain access to 1 and 2, we first converted the jiadifenolide-type γ-lactone ring system into the δ-lactone system via simpletreatment with acid (TsOH/n-BuOH, Δ) which unveiledtrisubstituted alkene-containing 16 in 71% yield (Scheme 1).Theodorakis and co-workers have demonstrated the synthesis of(−)-ODNM (3) and (−)-jiadifenin (4) in two and three steps,respectively, from 16.3d,16 Direct α-hydroxylation of δ-lactone 16from the convex face had been reported using the Davisoxaziridine, although reagent byproduct removal provedproblematic.3d Seeking an alternative method, we found thatenolate oxidation with the molybdenum(VI) reagent MoOPHled to the isolation of clean hydroxy lactone 17.19 We viewed 17as an excellent testing grounds for Hartwig’s recently reportedepimerization methodology via Ru-catalyzed transfer hydro-genation.20 Much to out delight, the catalyst [Ru2(PEt3)6-(OTf)3][OTf] in combination with isopropanol delivereddiastereomer 18, a recently isolated natural product itself,21

cleanly in 75% yield. To complete the synthesis of majucin (1) achallenging dihydroxylation was required. While we observed nodesired reactivity of 18 with OsO4, application of precomplexedosmium tetroxide and tetramethylethylenediamine (OsO4·TMEDA) ultimately provided (−)-majucin (1) in 61% yield.22

X-ray crystallographic analysis unambiguously confirmed thestructure of 1. Finally, selective monomesylation (MsCl, pyr.) of(−)-majucin followed by heating elicited a high-yieldingintramolecular etherification to give neurotrophic naturalproduct (−)-jiadifenoxolane A (2) in 92% yield. While theenzymatic pathways to 1−5 are not known, this faciledisplacement could have relevance to the biosyntheticconnection between 1 and 2.In summary, we have demonstrated the first chemical synthesis

of the complex majucin-type natural products (−)-majucin (1)and (−)-jiadifenoxolane A (2) in 14 and 15 steps, respectively,and the formal synthesis of (−)-ODNM (3), (−)-jiadifenin (4),and (−)-jiadifenolide (5) from the chiral-pool feedstock(+)-cedrol, a building block available for ∼$0.05 USD/gram.23

During this process, 13 oxidations were employed; however, 3reduction steps were necessary for oxidation state and stereo-chemical adjustments,24 highlighting existing gaps in theoxidative synthetic repertoire. Nevertheless, combined with ourprevious C−H hydroxylation strategy for the anisatin series, thiswork definitively establishes (+)-cedrol as a versatile platform forthe synthesis of nearly all subtypes of seco-prezizaane naturalproducts. Moreover, the formation of C−H hydroxylatedintermediate 12 hints to the possibility of accessing even furtheroxidized, unnatural analogs of these sesquiterpenoids usingsimilar chemistry.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/jacs.7b11493.

X-ray crystallographic data for 1 (CIF)X-ray crystallographic data for 14 (CIF)X-ray crystallographic data for 15 (CIF)X-ray crystallographic data for 21 (CIF)Experimental procedures and spectroscopic data (PDF)

■ AUTHOR INFORMATIONCorresponding Author*[email protected]

Scheme 2. Stereochemical Considerations for the α-KetolRearrangement of Enol Lactone 14a

aReagents and conditions: (a−c) See Scheme 1; (d) SeO2 (2.0 equiv),pyr, 110 °C, 16 h; (e) Me4NBH(OAc)3 (7.0 equiv), MeCN/AcOH(3:1), −40 °C, 16 h, 51% over two steps.



C

X-ray

O OMo

O OO

HMPAPy

MoOPH =

10. Me4NBH(OAc)3

(7 eq), MeCN/ AcOH -40 °C, 16 h 64% (3 steps)Me

H

O

O

O OO

Me OH

Me

H

O

O

OO

Me OH

OH

directed reductionH

C(10)-epimerization?Me

H

OO

Me OH

O

11. TsOH•H2O (2.2 eq) n-BuOH, 150 °C 25 h, 71%

O 12. LiHMDS (3 eq) MoOPH (5.0 eq) THF, -78 °C to 0 °C 2.5 h; 65%

Me

H

OO

Me OH

O

OHO

10

Me

H

OO

MeOH

O

O

O

OH

H


Ru-cat = [Ru2(PEt3)6(OTf)3][OTf]

Catalyst is more selective for:

•  electron rich 2° OH•  less hindered alcohols

Epimerization of C(10)-OH

Hill, C.K.; Hartwig, J.F. Nature Chem. 2017, 9, 1213

Me

H

OO

MeOH

O

O

O

OH

H

•  [Ru2(PEt3)6(OTf)3][OTf] catalyzes the selecJve oxidaJon of secondary alcohols

Results and discussionDevelopment of catalysts and conditions for the selectiveoxidation of hindered secondary alcohols. Several sequentialphases of catalyst development described in the SupplementaryInformation led to a new ruthenium complex (Fig. 1a andSupplementary Section 2). The precursor Ru(DMSO)4(OTf)2(DMSO, dimethylsulfoxide; OTf, SO2CF3) was generated inacetone solvent and treated with various phosphine ligands to givepotential catalysts. The complexes that result from the addition ofunhindered alkylphosphines PEt3, PMePh2 and PEt2(p-Me2N–Ph)all gave active catalysts for the dehydrogenation of the hinderedmodel alcohol diisopropylcarbinol. Thereafter, a synthesis of aseries of catalyst precursors lacking DMSO ligands was developed(Ru-1, Ru-2 and Ru-3), and the activity of these complexes wasfound to be an order of magnitude greater than that of the systemgenerated in situ. The initial results of the oxidation of a modelhindered alcohol are shown in Fig. 1b. In contrast to priortransition-metal catalysts that do not oxidize such hinderedsecondary alcohols, this ruthenium complex converteddicyclohexylcarbinol into the corresponding ketone at roomtemperature in only three hours. The same oxidation alsooccurred when 1,4-cyclohexanedione or trifluoroacetophenone

was used as a stoichiometric oxidant and the reaction was run intrifluoroethanol solvent.

The reactions of a series of primary and secondary alcohols andmixtures of primary and secondary alcohols with acetone as thehydrogen acceptor and Ru-2 as the catalyst are shown in Fig. 1c.These results show that the oxidation of secondary alcoholsoccurs over the oxidation of primary alcohols. The individual reac-tions of primary alcohols occur to a low conversion over a time thatleads to the full conversion of secondary alcohols, and reactions witha mixture of primary and secondary alcohols preferentially convertthe secondary alcohol into the ketone.

Selective oxidation of polyol natural products to ketonederivatives. Figure 2 summarizes the transfer dehydrogenation of13 polyol natural products and three methyl esters of naturalproducts. This figure shows the products from the oxidationreactions and the configuration of the alcohol unit that underwentoxidation. These reactions occur with several classes of naturalproducts, including steroids, diterpenoids, sesquiterpenoids,iridoids, carbohydrates, alkaloids and macrolides, which shows thebroad applicability of the catalyst system. The ruthenium catalystswe developed display a remarkable selectivity for the oxidation of

OH

OH

Selectivity

OH

OH

11.5 (7.8)

OH

OH OH

OH OH

OH

*10 min reaction*4% loading

*8% loading *8% loading,65 °C

64% (64%)

15% (16%)

*69% (70%)

*6% (9%)

*82% (82%)*88% (91%)

*(2%)

*10 min reaction

*51% (54%)

*24% (58%)

*75% (77%)

*(13%)*13% (27%)

4.3 (4.0)6.3 (3.0)

(45.5) 2.1 (0.9) (5.9)

OH OH

OHOH OH

98% (98%)84% (85%)7% (16%) 5% (12%) (2%)

0.5% Ru-2, 1% NMM

r.t., Me2CO (0.2 M, 65 equiv.), 45 minR R'

OHR" OHand/or

R R'

OR" Oand/or

0.1% Ru-2r.t., 1:1 Me2CO:TFE, 3 h

Cy Cy

O

Cy Cy

OH

99%

cis-Ru(DMSO)4Cl2 + PR3CH3OH

r.t. to 65 °C[Ru2(PR3)6Cl3]Cl

PR3 Catalyst

PMePh2 Ru-1PEt3 Ru-2PEt2(p-Me2N-Ph) Ru-3

[Ru2(PR3)6(OTf)3][OTf] AgOTf, TFE

r.t.

Reaction yields for oxidation of individual alcohols

Reaction yields for competitive oxidation of pairs of alcohols

a

b

c

d

or

0.1% Ru-2, 0.2% NMMr.t., 1.1 equiv. acceptor, TFE, 4 h

Stoichiometric ketone acceptors

CF3

O

OO

tBu Me

O 0.2% Ru-2, 0.4% NMM

1:1 iPrOH:TFE, 45 °C, 3 h tBu Me

OH

99%

Ru-2

NMM

O N

Figure 1 | Model alcohol oxidation and catalyst synthesis. a, Synthesis of the ruthenium catalyst for alcohol-transfer dehydrogenation. b, Mild oxidation of ahindered secondary alcohol is enabled by the catalyst Ru-2. c, Reactions of primary and secondary alcohols show the selectivity for the oxidation ofsecondary alcohols over primary alcohols. Conversions are shown in parentheses. d, The mild reduction of a hindered ketone is enabled by Ru-2 with iPrOHas the reductant. r.t., room temperature. NMM; N-methylmorpholine.

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.2835

NATURE CHEMISTRY | VOL 9 | DECEMBER 2017 | www.nature.com/naturechemistry1214

© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

HO

OH

OH

OO

H

H

H

ORu-cat (0.5%)NMM (1 mol%)

Me2CO65 °C, 31h; 88%

HO

MeHO

Me

H

O

HO

O

O

Ru-cat (1.88%)NMM (3.8 mol%)

Me2CO65 °C, 3 h; 65%

Oppenauer oxidation

M HO

O

M H

MO H

MO

R2

R1

R1

OH

R2

insertion

ligand exchange

β-elimination

O HH

O

R2 R1 sacraficial acceptor

HO

R2

R1

Cy Cy

OH 1:1 Me2CO:TFE, 3 hor

0.1% Ru-cat, 0.2% NMMr.t., acceptor ketoneTFE, 4 h

0.1% Ru-cat

Cy Cy

O

99%


Epimerization of C(10)-OH •  Ru complex catalyzes the reverse transfer

hydrogenaJon from isopropanol to hindered ketones


Me

H

OO

MeOH

O

O

O

OH

H

•  Ru complex catalyzes the site selecJve one-‐step epimerizaJon of secondary alcohols in the absence of an acceptor

Meerwein, Ponndorff, Verley reaction

M HO

R2R1

OR2

R1M H

MO H

R1R2

MO

OH

insertion

ligand exchange

β-H-elimination

O H

R1R2H

O

sacraficial donor

OH

t-Bu

O 0.2% Ru-cat, 0.4% NMM

1:1 i-PrOH:TFE, 3 h t-Bu

OH

99%

HO

O

O

HO

O

OMe

H

H

fusidic acid methyl ester

4% Ru-Cat, 8% NMM, TFE, 70 °C, 11 h, 84%

HO

O

O

HO

O

OMe

H

H

3

3-epi-fusidic acid methyl ester

HH

14. OsO4•TMEDA (1 eq) DCM, -78 °C to 0 °C 2 h; 61% Me

H

OO

MeOH

O

OHO

OHOH

(–)-majucin 7.5 mg

15. MsCl (5.0 eq), pyr (10 eq) DCE, rt to 80 °C, 15 h; 92% Me

H

OO

MeOH

O

O

O

OH

H

(–)-jiadifenoxolane A 2.6 mg


Epimerization of C(10)-OH/ Completion of the Syntheses

* provided by Hartwig group;


Me

H

OO

MeOH

O

O

O

OH

H

Me

H

OO

Me OH

O

OHO

Me

H

OO

Me OH

O

OHO

13. [Ru2(PEt3)6(OTf3)][OTf]* (0.1 eq) NMM (0.2 eq), TFE/ dioxane (1:1) 120 °C, 18 h then add i-PrOH (3 eq) 120 °C, 5 h; 65%

1010

H

We began our synthetic studies in analogy to previous work on6, but found that the strained THF ring formed in the initialSuarez oxidation (I2, PhI(OAc)2, hν) could be convenientlyconverted to acetoxy cedrene (7) simply by adding aceticanhydride and phosphoric acid directly to the reaction mixture(Scheme 1). This procedure delivered 7 in 67% yield and on 120mmol scale.11 Diverging from past work, in which an olefinoxidative cleavage reaction was used to generate a keto acid,10 wefound that 7 could be converted into ketone 8 directly via ahydroboration/double oxidation sequence (BH3·THF/CrO3·2pyr.). The use of Collin’s reagent avoided hydrolysis of theacetate protecting group as compared to many other oxidantsexamined. Ketone 8 was then easily reduced (NaBH4) from theconvex face to give alcohol 9 in 72% yield over 2 steps asessentially a single diastereomer. Taking inspiration from thework of Waegell on simpler cedrene scaffolds,12 we explored theuse of Suarez conditions to oxidize the C-4 methine position atthis stage. Owing to the very close spatial proximity of thesecondary hydroxyl to the ring junction C-4 methine, anexceptionally high yielding (93%) C−H functionalization ensued(I2, PhI(OAc)2, hν). In contrast to our previous work employingiron complexes to oxidize this position, the presence of

preexisting C-14 oxidation had little impact on this trans-formation. Next, prolonged stirring with in situ generated RuO4(RuCl3·xH2O, KBrO3) accomplished a remarkably clean tripleoxidation reaction, cleaving the C-6/C-11 bond and deliveringketone lactone 11.12,13 While not optimized, we were also able toisolate quadruple oxidation product 12wherein an additional C−H bond has been hydroxylated.14

With the construction of the tricyclic propellane-like coreaccomplished in five steps, we were poised to address the crucialmajucin-type γ-lactone which called for the exhaustive oxidationof the cedrol C-12 methyl group (vide supra). In a single,remarkable step, we found that a quadruple oxidation of allC−Hbonds α to the ketone group in 13was achieved under anhydrousRiley oxidation conditions (SeO2, 4 Å MS, Δ).15 In order tofacilitate handling of this compound, it proved essential tomethylate the intermediate acid (K2CO3, Me2SO4) prior toworkup, thus delivering unsaturated keto ester 13. Upontreatment of 13 with L-selectride, a diastereomeric mixture ofallylic alcohols was obtained via 1,2-reduction of the ketonemoiety. When the reaction was quenched with basic methanol,both intermediates converged to enol lactone 14, presumably viaan acetate cleavage/translactonization/alkene isomerization

Scheme 1. Synthesis of Complex Majucinoidsa

aReagents and conditions: (a) PhI(OAc)2 (1.1 equiv), I2 (0.4 equiv), cyclohexane, hν (visible), 1.5 h then Ac2O (10.0 equiv), H3PO4 (2.0 equiv),67%; (b) BH3·THF (1.3 equiv), THF, 1.5 h then CrO3·2pyr (25.0 equiv), DCM, 30 min; (c) NaBH4 (1.5 equiv), MeOH, 30 min, 72% over two steps;(d) PhI(OAc)2 (3.0 equiv), I2 (1.0 equiv), DCM, hν (visible), 0 °C, 1.5 h, 93%; (e) KBrO3 (2 × 5.0 equiv), RuCl3·xH2O (3 × 0.03 equiv), MeCN/CCl4/H2O (2:2:3), 75 °C, 3 d, 72% of 11, 7% of 12; (f) SeO2 (3.5 equiv), 4 Å MS (1.0 mass equiv), diglyme, 130 °C, 4 h then K2CO3 (3.0 equiv),Me2SO4 (1.5 equiv), 1 h; (g) L-selectride (1.2 equiv), THF, −78 °C, 30 min then KOH (10.0 equiv), MeOH, 0 °C, 30 min, 50% over two steps; (h)DMDO (1.5 equiv), 12 h; (i) PhCF3, 170 °C, 2 h; (j) Me4NBH(OAc)3 (7.0 equiv), MeCN/AcOH (3:1), − 40 °C, 16 h, 64% over three steps; (k)TsOH·H2O (2.2 equiv), n-BuOH, 150 °C, 26 h, 71%; (l) LHMDS (3.0 equiv), MoOPH (5.0 equiv), THF, −78 → 0 °C, 2.5 h, 65%; (m)[Ru2(PEt3)6(OTf)3](OTf) (0.1 equiv), NMM (0.2 equiv), TFE/dioxane (1:1), 120 °C, 18 h then i-PrOH (3.0 equiv), 120 °C, 5 h, 75%; (n) OsO4·TMEDA (1.0 equiv), DCM, −78 → 0 °C, 2 h then NaHSO3 (10.0 equiv), H2O, 16 h, 61%; (o) MsCl (5.0 equiv), pyr. (10.0 equiv), DCE, rt →80°C, 15 h, 92%. DMDO = dimethyldioxirane, LHMDS = lithium bis(trimethylsilyl)amide, MoOPH = oxodiperoxymolybdenum(pyridine)-(hexamethylphosphoric triamide).



B

X-ray


Summary of Synthesis

•  13 oxidaJon reacJons [O] •  3 reducJon reacJons [R]

(+)-cedrol

1. PhI(OAc)2, I2, hvMe

H

H

Me

Me

OAc

Me

H

H

MeOAc

OMe

2. BH3•THFthen addCrO3•2Pyr

H

3. NaBH4 72% (2 steps)

Me

H MeOAc

OMe

H 4. PhI(OAc)2, I2 hv; 93%

Suarez oxidation

Suarez oxidation

Me

H

H

Me

O

Me

Me

H

H

Me

OHMe

Hthen addAc2O, H3PO4; 67%

Me

H MeOAc

O

O

O 5. RuCl3•xH2O KBrO3; 72%

Me

H MeOAc

O

O

O

OMeO6. SeO2, 4Å MS K2CO3, Me2SO4

Me

H Me

O

O

O

OHO

7. L-selectride then add KOH/MeOH 50%, (2 steps)

8. DMDO [O] 9. PHCF3, ∆

10. Me4NBH(OAc)3

64% (3 steps)

Me

H

OO

Me OH

O11. TsOH•H2O n-BuOH, ∆

O

12. LiHMDS MoOPh; 65%

Me

H

OO

Me OH

O

OHO

13. [Ru2(PEt3)6(OTf3)][OTf]then add i-PrOH

10

14. OsO4•TMEDA 61%

Me

H

OO

MeOH

O

OHO

OHOH(–)-majucin

15. MsCl, pyr; 92%Me

H

OO

MeOH

O

O

O

OH

H


[O] [O]

[O]

3 x [O]4 x [O] [O]

[O]

[O]

[R]

[R]

[R]

Me

H

H

MeOAc

OHMe

H

Me

H

O

O

OO

Me OH

OH

H

Me

H

OO

Me OH

O

OHO

10

H


•  The first total synthesis of (–)-‐majucin (7.5 mg) was accomplished in 14 steps and 2.2% overall yield

•  The first totals synthesis of (–)-‐jiadifenoxolane A (2.6 mg) was accomplished in 15 steps and 2.0% overall yield

•  ExhausJve oxidaJon of (+)-‐cedrol scaffold (13 [O] reacJons) •  Site-‐selecJve C(sp3)−H bond oxidaJon

•  However, 3 reducJve steps were necessary for oxidaJon state and stereo-‐ chemical adjustments

•  First applicaJon of [Ru2(PEt3)6(OTf)3][OTf] catalyzed 2° alcohol epimerizaJon in total synthesis

Summary

(+)-cedrol

Me

H

H

MeMe

OHMe

Me

H

OO

MeOH

O

OHO

OHOH

(–)-majucin

Me

H

OO

MeOH

O

O

O

OH

H


Documents

Total Syntheses of (–)-Majucin and (–)- Jiadifenoxolane A ...ccc.chem.pitt.edu/wipf/Current Literature/Steph_10.pdf · Total Syntheses of (–)-Majucin and (–)-Jiadifenoxolane