JOC, 2011, 76, 1605

8102019 JOC 2011 76 1605

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Published February 22 2011

r 2011 American Chemical Society 1605 dxdoiorg101021jo102112k | J Org Chem 2011 76 1605ndash

1613

ARTICLE

pubsacsorgjoc

Concise Enantiospecific Stereoselective Syntheses of (thorn)-Crispine Aand Its (-)-Antipode

Mahender Gurramdagger Balazs GyimothyDagger Ruifang Wangdagger Sang Q Lamdagger Feryan Ahmeddagger and R Jason Herr dagger

daggerMedicinal Chemistry Department Albany Molecular Research Inc (AMRI) PO Box 15098 26 Corporate Circle Albany New York 12212-5098 United StatesDaggerChemistry amp Innovation Department AMRI Zahony utca 7 H-1031 Budapest Hungary

bS Supporting Information

ABSTRACT

An enantiospeci1047297c and stereoselective total synthesis of the natural product (thorn)-crispine A has been demonstrated employing aPictet-Spengler bis-cyclization reaction between commercially available (R )-(-)-methyl 2-amino-3-(34-dimethoxyphenyl)-propanoate and 4-chloro-11-dimethoxybutane to preferentially provide the cis tricyclic adduct Decarboxylation by a convenienttwo-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32 from the aminoacid The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available ( S)-(thorn)-amino acid

The pyrroloisoquinoline alkaloid (thorn)-crispine A [(R )-(thorn)-1 Figure 1] was 1047297rst isolated in 2002 from the Mongolian thistleCarduus crispus1 and has since emerged as a natural producttarget of interest due largely to reports of its cytotoxic activity and similarity to known congeners shown to exhibit antidepres-sant-like activity2 Within the decade several concise syntheses of racemic crispine A have been described diff ering mainly in thestrategies utilized to construct the pyrrolidine ring3 Interestinglysynthetic reports of this heterocycle can also be found in theliterature prior to its identi1047297cation as a natural product extract orits naming as crispine A4 A number of directed enantioselectivesyntheses of this alkaloid have also recently appeared in theliterature5 along with asymmetric preparations of the (S)antipode6 as well as crispine A analogues7 We nevertheless

sought to contribute our own novel asymmetric approach basedon a Pictet-Spengler bis-cyclization reaction between enantio-pure methoxytyrosine derivatives and an acetal bearing a teth-ered terminal leaving group This was envisioned to provideintermediate adducts that would undergo a concomitant secondcyclization to provide the tricyclic pyrrolo[21-a]isoquinolinecore of crispine A in one step This communication summarizesour results toward this goal

The 1047297rst intermolecular condensation reaction between β-phenethylamine and an aldehyde surrogate in the presence of HCl to aff ord a tetrahydroisoquinoline was described in 1911 by Pictet and Spengler8 and later applied to the preparation of tetrahydro- β-carbolines from tryptamines by Tatsui9 Since that

time the Pictet-Spengler condensation reaction10 has becomeone of the most widely used methods for the preparation of 1-substituted tetrahydroisoquinoline and tetrahydro- β-carbolinenatural products and related alkaloids with diverse biological

activities11

When electron-rich R-substituted- β-phenethyl-amines are condensed with aldehydes or aldehyde surrogatesthe chirality of the R-substituted center can in1047298uence thetransition state conformation such that the thermodynamically more stable 13-cis stereochemistry is generally observed in thetetrahydroisoquinoline products1213 Thus we envisioned thekey step of our stereocontrolled construction of the crispine A core to provide a new chiral center through 13-transfer of chirality from an enantiopure methoxytyrosine precursor topreferentially provide a 13-cis adduct

Figure 1 Natural product (thorn)-crispine A and its unnatural (-)-antipode

Received October 25 2010

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1607 dxdoiorg101021jo102112k | J Org Chem 2011 76 1605ndash1613

The Journal of Organic Chemistry ARTICLE

R-amino acid proton H-5 and the methine proton H-10b It is well-known that 13-disubstituted dihydroisoquinolines prefer toadopt a framework resembling a half-chair conformation wheresubstituents can attain pseudoequatorial dispositions15 As aresult irradiation of the axial H-5 proton at 36 ppm resultedin an increased signal for the axial H-10b proton at 37 ppm as

well as for one of the two diastereotopic protons H-6 on the

adjacent methylene at 25 ppmIn contrast 13-disubstitution on the 13-trans isomer(5S 10bR )-8a forces the H-10b proton to assume a pseudoequa-torial con1047297guration to accommodate the half-chair conformation(Figure 2) As a result irradiation of the R-amino acid protonH-5 at 42 ppm does not result in a measurable NOE enhance-ment of the C-10b proton at 37 ppm and vice versa leading tothe designation of (5S 10bR )-8a as the minor 13-trans stereo-isomer As expected irradiation of proton H-5 resulted in signalenhancements for one of the two diastereotopic protons H-6 onthe adjacent methylene at 28 ppm as well as for the pseudoaxialproton H-1 on the fused pyrrolidine ring at 24 ppm

We propose a plausible mechanism for the transformation asdepicted in Scheme 1 Several equivalents of tri1047298uoroacetic acid

play a role in inducing elimination of methanol 1047297rst in elimina-tion from dimethyl acetal 3 to provide a reactive oxonium ionspecies that undergoes attack by the amino acid (S)-(thorn)-2a Theresulting hemiaminal 9 may then undergo acid-catalyzed

expulsion of methanol to provide the thermodynamically favored( E)-iminium intermediate 10 Electrophilic aromatic substitu-tion then takes place to ultimately form the 1-(3-chloropro-pyl)tetrahydroisoquinoline adducts (1S 3S)-6a and (1R 3S)-6bThis is followed by the facile intramolecular displacement of thependant alkyl chloride by the nitrogen to provide the tricyclicproducts (5S 10bS)-7a and(5S 10bR )-8a From our examination

of the reaction conditions we surmise that the role of 4 Aring molecular sieves is to largely sequester the two eliminatedequivalents of methanol driving the reaction to 10

A rationale to describe the observed 13-cis stereoselectivity of the ring closure step in the Pictet-Spengler cyclization isproposed in Scheme 2 Intramolecular approach of the pendantaromatic from the diastereotopic re face of the iminium species( E)-10 forces the molecule to attain of a half-chairconformation15 to facilitate molecular orbital overlap and allows

both the R-ester and 3-chloropropyl substituents to adoptpseudoequatorial dispositions in the developing transition statecon1047297guration Upon ring closure and rearomatization this con-1047297guration leads to a 13-cis relationship between the substituentsfor the tetrahydroisoquinoline product (1S 3S)-6a

In order for the pendant aromatic to approach from the si faceofimine( E)-10 however thealignment to a half-chair conformationforces the R-ester substituent into a pseudoaxial disposition aless favorable energy state (Scheme 2) In addition a developing

Scheme 1 Proposed Reaction Mechanism of the Pictet-Spengler bis-cyclization reaction

Scheme 2 Proposed Rationale for the Selective Generation of the cis Adduct (5S10bS)-6a

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A 13 strain interaction between proton H1 and the ester moiety inthe developing transition state contributes to disfavor thisarrangement However ring closure and rearomatizationthrough this disfavored by accessible conformation leads to a13-trans relationship between the substituents for the tetrahy-droisoquinoline product (1R 3S)-6b As one might predict onthe basis of energy considerations the bias to pass through thetransition state conformation by attack onto the re face of

iminium intermediate 10 is re1047298ected in the observed ratio of products 6a6b favoring the 13-cis diastereomer 6a

In order to probe the eff ects of the phenethylamine R-substituent on the facial selectivity of the two-step cyclization

we made a small eff ort to evaluate the consequences forselectivity utilizing the slightly larger benzyl ester (S)-(thorn)-2b(eq 1) Although it has been demonstrated that the size of thealdehyde (or surrogate) can aff ect the stereochemistry at thenewly formed tetrahydroisoquinoline C-1 position10 we werenot aware of many recent examples comparing the size of thephenethylamine R-substituent to the resulting stereoselectivity from 13-chiral transfer16 Although examples within one reportsuggested that the diff erence in size of phenethylamine R-esters

would not signi1047297cantly change the 13-cistrans product ratio17

we were initially surprised to 1047297nd that increasing the size of the R-methyl ester (S)-(thorn)-2a to the benzyl ester (S)-(thorn)-2b18

diminished the preference for the 13-cis isomer (5S 10bS)-7from 451 to 21 Although we cannot at present proposeconsiderations to account for this observation these eff ectsmay be analogous to the loss of stereoselectivity noted in similarsystems when the relative size of the aldehyde component isincreased19

The enantiopure tricyclic tetrahydroisoquinoline isomers werethen individually elaborated to the natural product and antipodeisomers of crispine A as shown in Scheme 3 First 13-trans isomer(5S 10bR )-8a the minor adduct from the Pictet-Spengler cycliza-tion was converted to the methylselenyl ester (5S 10bR )-11 by the

use of dimethylaluminum methaneselenolate20 Subjection of (5S 10bR )-11 to radical decarboxylation conditions2122 led tothe natural product isomer of crispine A [(R )-(thorn)-1]15 in 42isolated yield for the two-step process The measured opticalrotation [R]20Dthorn90 (c 10CHCl3)for(R )-(thorn)-1 was consistent

with the two literature values reported in chloroform of [R]25Dthorn97 (c 11)5b and [R]23D thorn100 (c 10)5a and was a singleenantiomer by chiral HPLC analysis (seeSupporting Information)

Similarly the cis isomer (5S 10bS)-7a the major adduct fromthe Pictet-Spengler cyclization was converted to the methyl-selenyl ester (5S 10bS)-12 as shown in Scheme 3 As with theregioisomer (5S 10bR )-11 the radical decarboxylation protocoltransformed (5S 10bS)-12 to the unnatural antipode of crispine

A [(S)-(-)-1]16 in 39 isolated yield for the two-step processThe alkaloid enantiomer (S)-1 was found to rotate polarized lightin an equal but opposite manner to (R )-1 and was also shown to

be a single isomer by chiral HPLC analysis (see SupportingInformation) This con1047297rms the identity of both intermediates7a and 8a as a diastereomeric pair and also demonstrates that noappreciable epimerization had occurred during the syntheticmanipulations to (S)-(-)- and (R )-(thorn)-1

The Pictet-Spengler bis-cyclization reaction was then applied to

commercially available (but quite a bit more expensive) (R )-(-)-methyl 2-amino-3-(34-dimethoxyphenyl)propanoate [(R )-(-)-2a] as shown in Scheme 4 Thus a slight excess of 4-chloro-11-dimethoxybutane (3) was added to a stirring suspension of (R )-(-)-methyl 2-amino-3-(34-dimethoxyphenyl)propanoate[(R )-(-)-2a] and 4 Aring molecular sieves in a 41 mixture of methylene chloride and tri1047298uoroacetic acid at room temperature

After 4 h the components had converted to a mixture of tetra-hydroisoquinoline isomers from which the 13-cis isomer(5R 10bR )-7a was isolated by chromatography in 82 yield Thispreferentially formed tricyclic adduct was then subjected to theselenyl esteri1047297cation and radical decarboxylation two-step protocolto provide the enantiopure natural product (thorn)-1 with an overall

Scheme 3 Elaboration of L-DOPA-Derived Tricycles to (thorn)- and (-)-Crispine A

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32 isolated yield from the amino acid The optical rotation chiralHPLC analysis and other spectral data were found to match the(R )-(thorn)-1 isomer prepared through the route using (S)-(thorn)-2a

con1047297

rming the chiral integrity of this asymmetric approachDuring the time we were determining suitable conditions forthe bis-condensation reaction with the bis-methoxy precursor(S)-(thorn)-2a we also explored the feasibility for synthesis with themuch less expensive (S)-(thorn)-methyl 2-amino-3-(34-dihydroxy-phenyl)propanoate [(S)-(thorn)-13]23 which is derived fromL-DOPA (Scheme 5) Thus (S)-(thorn)-13 was subjected to thePictet-Spengler condensation conditions with 2-(3-chloro-propyl)-13-dioxolane (4) at room temperature cleanly provid-ing a 41 mixture of tetrahydroisoquinoline isomers (1RS 3S)-14ab in a 451 ratio (as determined by 1H NMR and LC-MSanalyses) However even upon prolonged stirring at roomtemperature the mixture of diastereomers did not cyclize tothe tricyclic adducts as was seen with the bis-methoxy precursors

(S)-(thorn)-2a although upon workup and puri1047297cation of the crudereaction mixture we found that the individual adducts sponta-neously cyclized on exposure to silica gel providing both the13-cis isomer (5S 10bS)-15 and 13-trans isomer (5S 10bR )-16

as they were eluted from the chromatography column Alterna-tively when the conversion from (S)-(thorn)-13 to the (1RS 3S)-14ab mixture under the Pictet-Spengler condensation

conditions was judged to be complete the solids were removedfrom the reaction mixture by 1047297ltration the 1047297ltrate was concen-trated and the residue was dissolved in acetonitrile Treatment of the resulting mixture with triethylamine allowed the secondcyclization to take place at room temperature in 1 h providing(5S 10bS)-15 and (5S 10bR )-16 in a 451 ratio of stereoisomersfavoring the 13-cis epimer and were separated by columnchromatography to provide the individual isomers

In a separate experiment we subjected the 451 mixture of (5S 10bS)-15 and (5S 10bR )-16 diol isomers to alkylation con-ditions with excess iodomethane and potassium carbonate inacetonitrile at room temperature (eq 2) After separation of the components by chromatography the dimethoxy products(-)-(5S 10bS)-7a and (thorn)-(5S 10bR )-8a were individually iso-

lated in a ratio of yields re1047298ecting the starting composition and were each found to match the spectral data for (5S 10bS)-7a and(thorn)-(5S 10bR )-8a prepared by the route from amino acid ester(S)-(thorn)-2a and dimethyl acetal precursor 3

Scheme 4 Preparation of (thorn)-Crispine A from D-DOPA-Derived Precursor ( R )-(-)-2a

Scheme 5 Pictet-Spengler Cyclization of (S)-(thorn)-13 with 2-(3-Chloropropyl)-13-dioxolane (4)

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In summary we have demonstrated an asymmetric total synth-esis of both the natural product (thorn)-crispine A and its unnatural(-) antipode employing a Pictet-Spengler bis-cyclization reac-tion between commercially available L- and D-DOPA-derivedprecursors and an aldehyde surrogate bearing a terminal leavinggroup This procedure preferentially provides 13-cis tetrahydro-isoquinoline adducts that undergo a concomitant second cycliza-

tion to generate the tricyclic pyrrolo[21-a]isoquinoline core of crispine A in one step Decarboxylation by a convenient two-stepprotocol provides the enantiopure natural product in three stepsfrom the amino acid The opposite antipode may also be similarly prepared from the minor 13-trans adduct formed during the bis-cyclization We have since this time applied our strategy to theasymmetric preparation of other natural product alkaloids which

will be reportedin due courseWe have also initiated investigationsinto computational analyses of transition state models which wealso hope to advance as warranted

rsquoEXPERIMENTAL SECTION

GeneralExperimental All nonaqueous reactions were performedunder an atmosphere of dry nitrogen unless otherwise specified Com-mercial grade reagents and anhydrous solvents were used as receivedfrom vendors and no attempts were made to purify or dry thesecomponents further Removal of solvents under reduced pressure wasaccomplished with a rotary evaporator using a Teflon-linedKNF vacuumpump Flashcolumn chromatography was performedusing an automatedmedium-pressure chromatography system using normal-phase disposa-

ble prepacked silica gel columns Melting points are uncorrected Data forproton NMR spectrawere obtained 300 or 500 MHz and are reported inppm δ values using tetramethylsilane as an internal reference Low-resolution mass spectroscopic analyses were performed on a singlequadrupole mass spectrometer utilizing electrospray ionization (ESI)High-resolution mass spectroscopic analyses were performed on a time-of-flight mass spectrometer utilizing electrospray ionization (ESI)

(5S10bS)-Methyl 89-Dimethoxy-1235610b-hexahydr-

opyrrolo[21-a]isoquinoline-5-carboxylate [(5S10bS)-7a] and(5S10bR)-Methyl 89-Dimethoxy-1235610b-hexahydropyr-rolo[21-a]isoquinoline-5-carboxylate [(5S10bR)-8a] from(S)-(thorn)-Methyl 2-Amino-3-(34-dimethoxyphenyl)propanoate[(S)-(thorn)-2a] 4-Chloro-11-dimethoxybutane (3 090 mL 60 mmol)

was added to a stirringsuspensionof commerciallyavailable (S)-(thorn)-methyl2-amino-3-(34-dimethoxyphenyl)propanoate [(S)-(thorn)-2a 13 g 5 mmol]and4 Aring molecular sieves(1 g) in a mixture ofanhydrous methylene chloride(20 mL) and trifluoroacetic acid (5 mL) at room temperature undernitrogen The mixture was stirred for 4 h at which time the conversion tothe intermediate (1RS 3S)-methyl 1-(3-chloropropyl)-67-dimethoxy-1234-tetrahydroisoquinoline-3-carboxylate [(1RS 3S)-6ab] was judged to

be complete (gt99 conversion of the intermediate by LC-MS analysis)The solids were removed by filtration and the solvents were removed from

theorganic filtrate under reduced pressureThe residue was purified by flashcolumn chromatography on silica geleluting withTHFmethylene chloride(14) to first afford theless polar isomer (5S 10bS)-7a (11 g80) asa lightorange solid[R]20D -012 (c 10CHCl3)mp91-94 C 1HNMR(500MHzCDCl3) δ 658 (s 1H) 657 (s1H) 385 (s6H) 380 (s3H) 370(t J = 73 Hz 1H) 359 (dd J = 52 68 Hz 1H) 317 (dd J = 115 35 Hz1H)308 (dd J = 85 60 Hz 1H) 290 (dd J = 45 115Hz 1H) 249(dd

J = 80 40 Hz 1H) 241-232 (m 1H) 192-180 (m 3H) 13C NMR (125 MHz CDCl3) δ 1729 1476 1476 1302 1247 1110 1085 631616 560 559 521 488 300 293 220 ESI MS m z 2921 [M thorn H]thornHRMS (ESI) m z 2921555 [M thorn H]thorn (2921549 calculated for C16H21

NO4thornH) The relative 13-stereochemistry was determined as cis based onan 1H NOE NMR experiment (500 MHz CDCl3) irradiation of the H5proton(359ppm) resulted in a 4 enhancementof theH10b protonsignal

(370ppm) aswell as3 for H3R (290ppm) and 2 for H6R (249ppm)Further elution afforded the more polar isomer (5S 10bR )-8a (025 g 18)as an amorphous colorless solid [R]20D thorn009 (c 10 CHCl3) mp 91-95 C 1H NMR (500 MHzCDCl3)δ 659 (s 1H) 657 (s1H) 425 (t J =75Hz1H)384(s6H)376(t J =55Hz1H)370(s3H)319-314(m1H) 307 (dd J = 55158 Hz 1H) 297(dd J = 55158 Hz 1H) 282(q J =74Hz1H)243-236(m1H)196-184(m2H)173-166 (m1H) 13C NMR (125 MHz CDCl3) δ 1733 1477 1473 1307 12421100 1090 589 579 559 559 521 519 328 295 233 ESI MS m z2921 [M thorn H]thorn HRMS (ESI) m z 2921555 [M thorn H]thorn (2921549calculated for C16H21NO4 thorn H) The relative 13-stereochemistry wasdetermined as trans based on a 1H NOE NMR experiments (500 MHzCDCl3) irradiation of the H5 proton (425 ppm) resulted in no enhance-ment of the H10b proton signal (376 ppm) but did result in 3enhancement for H6R (297 ppm) and 2 for H7 (657 ppm) irradiationof the H10b proton (376 ppm) resulted in no enhancement of the H5proton signal(425ppm) butdidresult in3enhancementforH1 β (173-166 ppm) and 1 for H2 β (196-184 ppm)

Preparation of (5S10bS)-Methyl 89-Dimethoxy-1235610b-hexahydropyrrolo[21-a]isoquinoline-5-carboxylate [(5S

10bS)-7a] and (5S10bR)-Methyl 89-Dimethoxy-1235610b-

hexahydropyrrolo[21-a]isoquinoline-5-carboxylate [(5S10bR)

-8a] by Pictet-Spengler Bis-cyclization Reaction with 2-(3-Chloropropyl)-13-dioxolane (4) Using the procedure described forthe preparation of (5S 10bS)-7a and (5S 10bR )-8a from (S)-(thorn)-2a butinstead utilizing 2-(3-chloropropyl)-13-dioxolane (4 18 mL 120 mmol)flash column chromatography on silica gel afforded the mixture of isomers(5S 10bS)-7a and (5S 10bR )-8a (210 g 75) as an off-white solid Themixture was determined to be a 451 mixture of isomers by 1H NMR andHPLC analyses but was not further purified to isolate the diastereomers

(5S10bS)-Benzyl 89-Dimethoxy-1235610b-hexahydro-pyrrolo[21-a]isoquinoline-5-carboxylate [(5S10bS)-7b] and(5S10bR)-Benzyl 89-Dimethoxy-1235610b-hexahydro-pyrrolo[21-a]isoquinoline-5-carboxylate [(5S10bR)-8b] from(S)-Benzyl 2-Amino-3-(34-dimethoxyphenyl)propanoate [(S)-2b] Using theprocedure described forthe preparation of (5S 10bS)-7a

and (5S 10bR )-8a from (S)-(thorn)-2a but instead utilizing the free basederived from (S)-benzyl 2-amino-3-(34-dimethoxyphenyl)propanoate

p-toluenesulfonate [(S)-2b 3 pTsOH18 040 g 12 mmol) flash columnchromatography on silica gel first afforded the less polar isomer(5S 10bS)-7b (027 g 60) as a brown gum 1H NMR (CDCl3 500MHz) δ 740-732 (m 5H) 657 (s 1H) 656 (s 1H) 523 (s 2H)384 (s 3H) 382 (s 3H) 369-359 (m 2H) 321-307 (m 2H) 291(dd J = 46 163 Hz 1H) 250-244 (m 1H) 237-235 (m 1H)189-181 (m 3H) ESI MS m z 3681 [M thorn H]thorn Further elutionafforded themore polar isomer (5S 10bR )-8b (013 g31) as anorangegum 1H NMR (CDCl3 300 MHz) δ 731-727 (m 3H) 722-718(m2H)656(s1H)654(s1H)513(s2H)428(t J =79Hz1H)384 (s 3H) 383 (s 4H) 320-316 (m 1H) 316-293 (m 2H) 283(q J = 71 Hz 1H) 240-235 (m 1H) 191-186 (m 2H) 197-160

(m 1H) ESI MS m z 3681 [M thorn H]thorn

(5S10bR)-Se-Methyl 89-Dimethoxy-1235610b-hexa-hydropyrrolo[21-a]isoquinoline-5-carboselenoate [(5S10bR)-11] A solution of dimethylaluminum methaneselenolate (060 mL12 mmol ca 2 M in toluene) was added dropwise to a degassed stirringsolution of (5S 10bR )-methyl 89-dimethoxy-1235610b-hexahydro-pyrrolo[21-a]isoquinoline-5-carboxylate [(5S 10bR )-8a 290 mg 10mmol] in anhydrous methylene chloride (5 mL) at 0 C under nitrogenThe mixture was stirred at 0 C for 30 min and then warmed to roomtemperature stirring for a total of 1 h The mixture was treated with wetsodium sulfate and extracted with diethyl ether (2 25 mL) Thecombined organic extracts were dried with anhydrous magnesiumsulfate and filtered and the solvents were removed under reducedpressure The residue was purified by flash column chromatography on

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silica gel elutingwith hexanesethyl acetate(91)to provide (5S 10bR )-Se-methyl 89-dimethoxy-1235610b-hexahydropyrrolo[21-a]iso-quinoline-5-carboselenoate [(5S 10bR )-11 270 mg 76] as a lightorange solid (this material was stored in the dark and used immediately in the next step) [R]20D thorn006 (c 10 CHCl3) mp 95-97 C 1HNMR (500 MHz CDCl3) δ 663 (s 1H) 658 (s 1H) 440 (t J = 75Hz 1H) 384 (s 6H) 334 (t J = 65 Hz 1H) 332 (t J = 25 Hz 1H)292 (d J = 55 Hz 2H) 278-275 (m 1H) 240-238 (m 1H) 206(s 3H) 198-184 (m 2H) 179-176 (m 1H) 13C NMR (125 MHzCDCl3) δ 2099 1478 1477 1312 1246 1111 1090 696 575560 559 542 339 297 253 38 ESI MS m z 3560 [M thorn H]thornHRMS (ESI) m z 3560765 [M thorn H]thorn (3560765 calculated forC16H21NO3Se thorn H)

(R)-89-Dimethoxy-1235610b-hexahydropyrrolo[21-a]isoquinoline [(thorn)-Crispine A (R)-1]15 from Selenyl Ester

(5S10bR)-11 Tri-n-butyltin hydride (300 mg 10 mmol) was addedto a stirring mixture of (5S 10bR )-Se-methyl 89-dimethoxy-1235610b-hexahydropyrrolo[21-a]isoquinoline-5-carboselenoate [(5S 10bR )-11 180 mg 050 mmol) and AIBN (14 mg 0080 mmol) in anhydrous

benzene (85 mL) at room temperature under nitrogen after which themixture was heated to reflux and stirred for 3 h The cooled mixture wastreated with saturated aqueous sodium fluoride (15 mL) and the biphasic

mixture was stirred at room temperature for 15 min The mixture wasextracted withmethylenechloride(3 20 mL)and thecombined organicextracts were dried with magnesium sulfate and filtered and the solvents

were removed under reduced pressure The residue was purified by flashcolumn chromatography on silica gel eluting with methylene chloridemethanol (491) to provide (thorn)-crispine A [(R )-1 64 mg 55] as acolorless solid [R]20D thorn90 (c 10 CHCl3) lit [R]23D thorn1004 (c 10CHCl3)5a [R]25Dthorn969 (c 11CHCl3)

5bmp86-88 C(litmp187-89 C) 1H NMR (500 MHz CDCl3) δ 661 (s 1H) 657 (s 1H) 384(s 6H) 341 (t J = 97 Hz 1H) 318 (dd J = 28 46 Hz 1H) 309-286(m 2H) 273 (dt J = 168 38 Hz 1H) 266-260 (m 1H) 255 (dd

J = 110 95 Hz 1H)236-228 (m1H) 198-188 (m1H) 188-182(m 1H) 177-167 (m 1H) 13C NMR (125 MHz CDCl3) δ 14741473 1308 1262 1114 1089 629 560 559 531 483 305 280

233 ESI MS m z 2341 [M thorn H]thorn

HRMS (ESI) m z 2341495 [M thornH]thorn (2341494 calculated forC14H19NO2thornH) The enantiomeric purity

was determined by HPLC(Chiralcel OJ heptaneethanol = 95510 mLmin 240 nm t R (minor) = 96 min t R (major) = 106 min) 978 ee

(5S10bS)-Se-Methyl 89-Dimethoxy-1235610b-hexa-hydropyrrolo[21-a]isoquinoline-5-carboselenoate

[(5S10bS)-12] Using the procedure described for compound(5S 10bR )-8a but instead utilizing (5S 10bS)-7a (5S 10bS)-12 (250mg 71) was isolated as a light orange solid (this material was stored inthe dark and used immediately in the next step) [R]20D -036 (c 10CHCl3) mp 95-98 C 1H NMR (500 MHz CDCl3) δ 663 (s 1H)661 (s 1H) 386 (s 3H) 384(s 3H) 379-378 (m 1H) 366 (t J = 7Hz 1H) 313-311 (m 1H) 304-292 (m 2H) 268-263 (m 1H)236-232 (m 1H) 207 (s 3H) 199-186 (m 3H) 13C NMR (125

MHzCDCl3) δ 21061478 14741313 125011111090 696 595574 565 553 339 282 224 38 ESI MS m z 3560 [M thorn H]thornHRMS (ESI) m z 3560765 [M thorn H]thorn (3560765 calculated forC16H21NO3Se thorn H)

(S)-89-Dimethoxy-1235610b-hexahydropyrrolo[21-a]isoquinoline [(-)-Crispine A (S)-1]156 from Selenyl Ester(5S10bS)-12 Using the procedure described for compound (R )-1

but instead util izing (5S 10bS)-12 (-)-crispine A [(S)-1 65 mg 56) was isolated as a colorless solid [R]20D -95 (c 13 CHCl3) lit forantipode [R]23D thorn1004 (c 10 CHCl3)5a [R]25D thorn969 (c 11CHCl3)

5b mp 86-88 C (lit mp for antipode1 87-89 C) Thespectral data were matched with the data from the correspondingantipode (R )-1 The compound was shown to be a single enantiomer

by chiral HPLC analysis (see Supporting Information) The

enantiomeric purity was determined by HPLC (Chiralcel OJ hep-taneethanol = 955 10 mLmin 240 nm t R (major) = 96 min t R (minor) = 108 min) 966 ee

(5R10bR)-Methyl 89-Dimethoxy-1235610b-hexahydro-pyrrolo[21-a]isoquinoline-5-carboxylate [(5R10bR)-7a] from

(R)-(-)-Methyl 2-Amino-3-(34-dimethoxyphenyl)propanoate

[(R)-(-)-2a] Using the procedure described for the preparation of

(5S 10bS)-7a from (S)-(thorn)-2a but instead utilizing commercially available(R )-(-)-methyl 2-amino-3-(34-dimethoxyphenyl)propanoate [(R )-(-)-2a 024 g 10 mmol] flash column chromatography on silica gel affordedthe less polar isomer (5R 10bR )-7a (023 g 82) as a viscous orange oilThe spectral data were matched with the data from the correspondingantipode (5S 10bS)-7a

(5R10bR)-Se-Methyl 89-Dimethoxy-1235610b-hexa-hydropyrrolo[21-a]isoquinoline-5-carboselenoate

[(5R10bR)-12] Using the procedure described for compound(5S 10bR )-12 but instead utilizing (5R 10bR )-7a (020 g 060 mmol)(5R 10bR )-12 (017 g 71) was isolated as a light orange solid which

was stored in the dark and used immediately in the next step [R]20Dthorn036 (c 10 CHCl3) mp 95-97 C The spectral data were matched

with the data from the corresponding antipode (5S 10bS)-12(R)-89-Dimethoxy-1235610b-hexahydropyrrolo[21- a]

isoquinoline [(thorn)-Crispine A (R)-1]15 from Selenyl Ester(5R10bR)-12 Using the procedure described for compound (R )-1from selenyl ester (5S 10bR )-11 but instead utilizing (5R 10bR )-12(010g 030mmol)(thorn)-crispineA [(R )-1 0030 g 55] was isolated asa colorlesssolid [R]20Dthorn95 (c 10 CHCl3) lit[R]23Dthorn1004 (c 10CHCl3)5a [R]25D thorn969 (c 11 CHCl3)

5b mp 86-88 C (lit mp87-89 C) The spectral data were matched with the data from thecorresponding compound (R )-1 prepared from the selenyl ester(5S 10bR )-11 The enantiomeric purity was determined by HPLC(Chiralcel OJ heptaneethanol = 955 10 mLmin 240 nm t R (minor) = 96 min t R (major) = 106 min) 978 ee

(5S10bS)-Methyl 89-Dihydroxy-1235610b-hexahydro-pyrrolo[21-a]isoquinoline-5-carboxylate [(5S10bS)-15] and(5S10bR)-Methyl 89-Dihydroxy-1235610b-hexahydropyr-

rolo[21-a]isoquinoline-5-carboxylate [(5S10bR)-16] from(S)-(thorn)-Methyl 2-Amino-3-(34-dihydroxyphenyl)propanoate[(S)-(thorn)-13] 2-(3-Chloropropyl)-13-dioxolane (4 090 mL 60 mmol)

was added to a stirring suspensionof commerciallyavailable (S)-(thorn)-methyl2-amino-3-(34-dihydroxyphenyl)propanoate [(S)-(thorn)-13 12 g 50mmol] and 4 Aring molecular sieves (1 g) in a mixture of anhydrous methylenechloride(20 mL) andtrifluoroacetic acid(5 mL) at roomtemperatureundernitrogen Themixture wasstirred at room temperaturefor 4 h at which timethe conversion to theintermediate(1RS 3S)-methyl1-(3-chloropropyl)-67-dihydroxy-1234-tetrahydroisoquinoline-3-carboxylate [(1RS 3S)-14ab]

was judged to be complete (gt99 by LC-MS analysis) The solids wereremoved by filtration and the solvents were removed from the organicfiltrate under reduced pressure The residue was dissolved in anhydrousacetonitrile (50 mL) triethylamine (045 mL16 mmol) was added and the

mixture was stirred at room temperatureunder nitrogen for 1 h Thesolvent was removed under reduced pressure to provide a crude residue that was judged to be a mixture of tricycliccompounds (5S 10bS)-15 and (5S 10bR )-16 in a 451 ratio (HPLC and 1H NMRanalyses) Theresidue was purified

by flash column chromatography on silica gel eluting with THFmethylenechloride (14) to first afford the less polar isomer (5 S 10bS)-methyl 89-dihydroxy-1235610b-hexahydropyrrolo[21- a]isoquinoline-5-carboxylate[(5S 10bS)-15 091 g 76] as a light yellow solid [R]20D -036 (c 13CH3OH) mp 95-99 C 1H NMR (CD3OD 500 MHz) δ 651 (s 1H)650 (s 1H) 375 (s 3H) 343-337 (m 2H) 319-315 (m 1H) 300(dd J = 49 131 Hz 1H) 288 (dd J = 50 130 Hz1H) 237-227 (m2H) 189-182 (m 2H) 176-174 (m 1H) 13C NMR (125 MHzCD3OD) δ 1741 1453 1450 1298 1247 1156 1131 650 638525 508 316 301 225 ESI MS m z 2641 [M thorn H]thorn HRMS (ESI)

8102019 JOC 2011 76 1605




m z 2641233 [M thorn H]thorn (2641236 calculated for C14H17NO4 thorn H)Further elution afforded the more polar isomer (5S 10bR )-methyl 89-dihydroxy-1235610b-hexahydropyrrolo[21-a]isoquinoline-5-carbox-

ylate [(5S 10bR )-16 022 g 12] as an amorphous colorless solid[R]20D thorn014 (c 10 CH3OH) 1H NMR (CD3OD 500 MHz) δ 652(s 1H) 651 (s 1H) 410 (t J = 85 Hz 1H) 367 (s 3H) 336 (dd J =70 20 Hz 1H) 310-306 (m 1H) 294-289 (m 1H) 285-276(m 2H) 234-227 (m 1H) 188-182 (m 2H) 167-159 (m 1H)13C NMR (125 MHz CD3OD) δ 1746 1453 1450 1302 12411155 1139 602 601 535 524 359 308 240 ESI MS m z 2641[M thorn H]thorn

(5S10bS)-Methyl 89-Dimethoxy-1235610b-hexa-hydropyrrolo[21-a]isoquinoline-5-carboxylate [(5S10bS)-7a] and (5S10bR)-Methyl 89-Dimethoxy-1235610b-hexahydropyrrolo[21-a]isoquinoline-5-carboxylate[(5S10bR)-8a] Iodomethane (012 mL 11 mmol) and potassiumcarbonate (041 g 30 mmol) were added to a solution of crude isomers(5S 10bS)-15 and(5S 10bR )-16(026 g10mmol 451 ratio) in anhydrousacetonitrile (10 mL) at room temperature under nitrogen The mixture wasstirred for 14 h after which the solvents were removed under reducedpressure and the residue was purified by flash column chromatography onsilica gel eluting with THFmethylene chloride (14) to first afford the less

polar isomer (5S 10bS)-methyl 89-dimethoxy-1235610b-hexahydro-pyrrolo[21-a]isoquinoline-5-carboxylate [(5S 10bS)-7a 022 g 75] asa light orange solid Further elution afforded the more polar isomer(5S 10bR )-methyl89-dimethoxy-1235610b-hexahydropyrrolo[21-a]iso-quinoline-5-carboxylate [(5S 10bR )-8a 0050 g 16] as a colorless solidThe spectral data for both compounds matched with the data from thecorresponding compounds as prepared from the dimethoxyphenyl pre-cursor (S)-(thorn)-2a

rsquoASSOCIATED CONTENT

bS Supporting Information Proton and carbon NMR spec-tra for all compounds prepared This material is available free of charge via the Internet at httppubsacsorg

rsquoAUTHOR INFORMATION

Corresponding AuthorE-mail rjasonherramriglobalcom

rsquoACKNOWLEDGMENT

The authors wish to thank AMRI colleagues Larry Yet formany helpful chemistry discussions Helene Y Decornez andDouglas B Kitchen for computational consultation and KentKaltenborn for high resolution mass spectrometry data

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Chem Soc 2001 123 3462 (b) Kapat A Kumar P S Baskaran S Beilstein J Org Chem 2007 3 49 (c) Kumar P S Kapat A BaskaranS Tetrahedron Lett 2008 49 1241 (d) Saber M Comesse S Dalla

V Daich A Sanselme M Netchitailo P Synlett 2010 14 2197(8) Pictet A Spengler T Ber Dtsch Chem Ges 1911 44 2030(9) Tatsui G J Pharm Soc Jpn 1928 48 92(10) For the most recent reviews see (a) Cox E D Cook J M

Chem Rev 1995 95 1797 (b) Larghi E L Amongero M Bracca A B J Kaufman T S Arkivoc 2005 xii 98 (c) Czarnocki Z Siwicka A Szawkato J Curr Org Chem 2005 2 301 (d) Youn S W Org Prep Proced Intl 2006 38 505

(11) For the most recent reviews see (a) Scott J D Williams

R M Chem Rev 2002 102 1669 (b) Chrzanowska M RozwadowskaMD Chem Rev 2004 104 3341 (c) Edwankar C R Edwankar R VNamjoshi O A Rallapalli S K Yang J Cook J M Curr Opin Drug

Disc Devel 2009 12 752 (d) Nielsen T E Meldal M Curr Opin Drug Discovert Dev 2009 12 798

(12) This is the general case in which the intermediate iminium saltis linear (ie not cyclic) allowing the adoption of the ( E)-con1047297gurationin the chairlike transition state For examples see (a) Yamada SKonda M Shioiri T Tetrahedron Lett 1972 22 2215 (b) Massiot GMulamba T J Chem Soc Chem Commun 1983 1147 (c) DomiacutenguezE Lete E Badiacutea D Villa M J Castedo L Domiacutenguez DTetrahedron 1987 43 1943 (d) Van der Eycken J Bosmans J-P

Van Haver D Vandewalle M Hulkenberg A Veerman W Nieu- wenhuizen R Tetrahedron Lett 1989 30 3873 (e) Bailey P DHollinshead S P McLay N R Morgan K Palmer S J PrinceS N Reynolds C D Wood S D J Chem Soc Perkin Trans 1

1993 431 (f) Bringmann G Weirich R Reuscher H Jansen J RKinzinger L Ortmann T Liebigs Ann Chem 1993 877 (g) CarrilloL Badiacutea D Domiacutenguez E Anakabe E Osante I Tellitu I Vicario

J L J Org Chem 1999 64 1115 (h) Katritzky A R Mehta S He H- Y J Org Chem 2001 66 148 (i) Tang Y F Liu Z Z Chen S ZTetrahedron Lett 2003 44 7091 (j) Wang Y Liu Z Z Chen S ZLiang X T Chin Chem Lett 2004 15 505 (k) Shiraiwa T Kiyoe RChem Pharm Bull 2005 53 1197 (l) Liu Z Z Wang Y Tang Y FChen S Z Chen X G Li H Y Bioorg Med Chem Lett 2006 16 1282 (m) Chen J Chen X Zhu J J Am Chem Soc 2006 128 87(n) Aubry S Pellet-Rostaing S Faure R Lemaire M J HeterocyclChem 2006 43 139 (o) de la Figuera N Fiol S Fernandez J-CForns P Fernandez-Forner D Albericio F Synlett 2006 12 1903 (p)

Aubry S Pellet-Rostaing S Fenet B Lemaire M Tetrahedron Lett

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2006 47 1319 (q) Chakka S K Andersson P G Maguire G E MKrugerH G Govender T Eur J Org Chem 2010 972 (r) Liao X WDong W F Liu W Guan B H Liu Z Z J Heterocycl Chem 2010 47 50

(13) On the other hand substrates that generate a cyclic intermedi-ate iminium salt (eg arising from precursors where the amine moiety istethered to the aldehyde) force the adoption of the (Z )-con1047297guration inthe transition state leading to a preference for the formation of 13- trans

products For examples see (a) Tomioka K Kubota Y Koga K JChem Soc Chem Commun 1989 1622 (b) Tomioka K Kubota YKoga K Tetrahedron 1993 49 1891 (c) Garciacutea E Arrasate S Ardeo

A Lete E Sotomayor N Tetrahedron Lett 2001 42 1511 (d) AllinS M James SL Martin W P Smith T A D Tetrahedron Lett 2001 42 3943 (e) Bahajaj A A Vernon J M Wilson G D J Chem Soc

Perkin Trans 1 2001 1446 (f) Allin S M James S L Martin W PSmith T A D Elsegood M R J J Chem Soc Perkin Trans 12001 3029 (g) Gonzalez J F de la Cuesta E Avende~no CTetrahedron 2004 60 6139 (h) Garciacutea E Arrasate S Lete ESotomayor N J Org Chem 2005 70 10368 (i) Nielsen T E MeldalM J Comb Chem 2005 7 599 (j) Aubry S Pellet-Rostaing SLemaire M Eur J Org Chem 2007 5212 (k) Allin S M Towler JGaskell S N Saha B Martin W P Page P C B Edgar MTetrahedron 2010 66 9538

(14) Although precursor (S)-(thorn)-2a was predicted to ultimately provide the opposite absolute con1047297guration of naturally occurringcrispine A it was much less expensive and more readily available thanthe enantiomeric D-DOPA-derived building block (R )-(-)-2a forcarrying out our eff orts(a) Tsuda Y Hosoi S Ishida K Sangai MChem Pharm Bull 1994 42 204 (b) Airiau E Spangenberg TGirard N Schoenfelder A Mann A Salvadori J Taddei M Chemmdash Eur J 2008 14 10938

(15) See ref 12c and Iba~nez A F Yaculiano G B MoltrasioIglesias G Y J Heterocycl Chem 1989 26 907

(16) Variation in size for the reported cases in which the phenethyl-amine R-substituents aff ect the stereochemical outcome for 13-disub-stituted tetrahydroisoquinolines have been limited to cases wherethe intermediate iminium species is cyclic (see ref 13) This eff ect for13-disubstituted tetrahydro- β-carbolines has been well-studied see ref

10 and Van Linn M L Cook J M J Org Chem 2010 75 3587(17) Nakamura S Tanaka M Taniguchi T Uchiyama MOhwada T Org Lett 2003 5 2087

(18) Ishihara K Fushimi M Org Lett 2006 8 1921(19) For example see ref 12j and Landoni N Lesma G Sacchetti

A Silvani A J Org Chem 2007 72 9765(20) (a) Kozikowski A P Ames A J Org Chem 1978 43 2735

(b) Kozikowski A P Ames A Tetrahedron 1985 41 4821 (c)Kozikowski A P Teurouckmantel W Reynolds I J Wroblewski J T

J Med Chem 1990 33 1561 (d) Schwartz C E Curran D P J AmChem Soc 1990 112 9272

(21) (a) Stojanovic A Renaud P Synlett 1997 181 (b) Quirante J Escolano C Bonjoch J Synlett 1997 179 (c) Quirante J Vila XEscolano C Bonjoch J J Org Chem 2002 67 2323 (d) Heureux N

Wouters J Norberg B Mark o I E Org Biomol Chem 2006 4 3898(22) The tactic of using a natural chiral amino acid or derivative as a

template for induced asymmetry in a carbon-carbon bond formingreaction to prepare amine heterocycles followed by excision of theR-functionality by decarboxylation through a selenyl ester intermediateis a strategy that has found similar utility For examples see ref 20c and21d and (a) Martin S F Chen K X Eary C T Org Lett 1999 1 79(b) Deiters A Chen K Eary C T Martin S F J Am Chem Soc2003 125 4541 (c) Allin S M Thomas C I Allard J E Doyle KElsegood M R J Tetrahedron Lett 2004 45 7103 (d) Allin S MThomas C I Doyle K Elsegood M R J J Org Chem 2005 70 357(e) Allin S M Duff y L J Bulman Page P C McKee V Edgar MMcKenzie M J Amat M Bassas O Santos M M M Bosch JTetrahedron Lett 2006 47 5713 (f) Allin S M Khera J S With-erington J Elsegood M R J Tetrahedron Lett 2006 47 5737 (g)

Allin S M Gaskell S N Elsegood M R J Martin W P Tetrahedron

Lett 2007 48 5669 (h) Amat M Santos M M M Gomez A M Jokic D Mollins E Bosch J Org Lett 2007 9 2907 (i) Amat MSantos M M M Bassas O Llor N Escolano C Gmez-Esqu AMolins E Allin S M McKee V Bosch J J Org Chem 2007 72 5193 For other decarboxylation methods that achieve this strategysee refs 5d 12a and 13f and(j) Yamada S Akimoto H Tetrahedron

Lett 1969 36 3105 (k) Akimoto H Okamura K Yui M Shioiri TKuramoto M Kikugawa Y Yamada S Chem Pharm Bull 1974

22 1614 (l) Konda M Shioiri T Yamada S Chem PharmBull 1975 23 1025 (m) Yamada S Y Tomioka K Koga K Tetrahedron Lett1976 17 61 (n) Tsuda Y Hosoi S Ishida K Sangai M Chem

Pharm Bull 1994 42 204(23) Scheuroollkopf S Tetrahedron 1983 39 2085 Although precursor

(S)-(thorn)-13 was predicted to ultimately provide the opposite absolutecon1047297guration of naturally-occurring crispine A it was much lessexpensive and more readily available than the enantiomeric D-DOPA-derived building block (R )-(-)-14 for carrying out our eff orts

8102019 JOC 2011 76 1605


8102019 JOC 2011 76 1605
















8102019 JOC 2011 76 1605





















8102019 JOC 2011 76 1605





con1047297









8102019 JOC 2011 76 1605



























8102019 JOC 2011 76 1605







































8102019 JOC 2011 76 1605












rsquoACKNOWLEDGMENT


rsquoREFERENCES
























8102019 JOC 2011 76 1605


























8102019 JOC 2011 76 1605
















8102019 JOC 2011 76 1605





















8102019 JOC 2011 76 1605





con1047297









8102019 JOC 2011 76 1605



























8102019 JOC 2011 76 1605







































8102019 JOC 2011 76 1605












rsquoACKNOWLEDGMENT


rsquoREFERENCES
























8102019 JOC 2011 76 1605


























8102019 JOC 2011 76 1605





















8102019 JOC 2011 76 1605





con1047297









8102019 JOC 2011 76 1605



























8102019 JOC 2011 76 1605







































8102019 JOC 2011 76 1605












rsquoACKNOWLEDGMENT


rsquoREFERENCES
























8102019 JOC 2011 76 1605


























8102019 JOC 2011 76 1605





con1047297









8102019 JOC 2011 76 1605



























8102019 JOC 2011 76 1605







































8102019 JOC 2011 76 1605












rsquoACKNOWLEDGMENT


rsquoREFERENCES
























8102019 JOC 2011 76 1605


























8102019 JOC 2011 76 1605



























8102019 JOC 2011 76 1605







































8102019 JOC 2011 76 1605












rsquoACKNOWLEDGMENT


rsquoREFERENCES
























8102019 JOC 2011 76 1605


























8102019 JOC 2011 76 1605







































8102019 JOC 2011 76 1605












rsquoACKNOWLEDGMENT


rsquoREFERENCES
























8102019 JOC 2011 76 1605


























8102019 JOC 2011 76 1605












rsquoACKNOWLEDGMENT


rsquoREFERENCES
























8102019 JOC 2011 76 1605


























8102019 JOC 2011 76 1605


























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JOC, 2011, 76, 1605