Asymmetric synthesis of yohimban alkaloids. Total synthesis of

these steps proceed in 85-90% yield, and the last opera- tion, namely removal of the .... of Celite and the filter cake washed with ethyl acetate. The...
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2960

J. Org. Chem. 1991,56,2960-2964

Art i d e s Asymmetric Synthesis of Yohimban Alkaloids. Total Synthesis of (-)-Pseudo- and (-)-Alloyohimban A. I. Meyers,* Thomas K. Highsmith, and Paul T. Buonora Department of Chemietry, Colorado State University, Fort Collins, Colorado 80523 Received October 30,1990 A route to (-)-pseudo and (-)-do isomere of yohimban is described. This asymmetric synthetic approach to indole alkaloids is based on the stereocontrolledalkylation of a-amino carbanions mediated by chiral formamidines. The stereochemically pure enantiomer of the alkylated &carboline 7 is utilized ta bias the subsequent intramole" Diels-Alder cycloaddition of the N-dienamide 8 or the homologous N-acrylamide 12 derived from the alkylated carboline 11. In this fashion, suitable choice of diene and dienophile partners led to the pseudoand alloyohimban isomers l b and IC, respectively.

The yohimban family of alkaloids (1-4) has been the subject of numerous studies involving isolation, biogenesis, pharmacology, and synthesis due in large part to their antihypertensive activity.' While earlier efforts have addressed their syntheses in the racemic mode, only recently have there been any successes in reaching yohimbanoid systems in enantiomerically enriched forms.2 Our studies on the total synthesis of a variety of alkaloids using chiral formamidines as a pivotal template on which to construct a variety of naturally occurring substances has already led to three successful syntheses of indole alkaloids, (-)-deplancheine& (5a), (4-yohimbones (2), and most recently, dihydrocorynantheidol 5b.qd We felt we could reach the yohimbans in an enantiomerically pure state by further implementation of the formamidine methodology coupled with Diels-Alder chemistry. The latter has already been demonstrated by Martin5 and Yamaguchi6as a viable route to complex alkaloids. Thus, our strategy (Scheme I) was to initially alkylate the starting chiral 8-carboline A with allyl chloride to give B. It was expected, on the basis of earlier precedent, that the latter will be formed in relatively high diastereomeric excess. Following formamidine removal, an appropriate diene component would be introduced to give C and the cyclo(1) (a) Szantay, C.; Blasko, G.; Honty, K.; Domye, G. The Alkaloidu; Academic: New York; 1986, Vol. 27, pp 131-268. (b)Chattarjee, A. f i r e Appl. Chem. 1986, 58, 685. (c) See aleo: Martin, S. F.; Rueger, H.; Williameon, S. A,; G r z e j d , 5.J. Am. Chem. Soc. 1987,109,6124. (d) Lounasmaa, M.; Jokela, R. Tetrahedron 1990,46,615. (2) (a) Aube, J.; Wang, Y.; Hammond, M.; Tanol, M.; Takusagawa, F.; Vander Velde, D. J. Am. Chem. SOC.1990,112,4879. (b)Aube, J. Tetrahedron Lett. 1988,29,4509. (c) Hua, D. H. Bharathi, A. N.; Takusagawa, F.; Tsujimoto, A.; Panagadan, A. K.; Hung, M.-H.; Bravo, A. A.; Erpelding, A. M. J. Org. Chem. 1989,54,5659. (d) Riva, R.;Band, L; Danieli, B.; Guanti, G.; Lesma, G.; Palmiaano, G. J. Chem. SOC.,Chem. Commun. 1987, 299. (e) Isobe, M.; Fukami, N.; Goto, T. Chem. Lett. 1985, 71. (3) Meyers, A. I.; Miller, D. B.; White, F. H. J. Am. Chem. SOC.1988, 110,4778. (4) (a) Meyers, A. I.; Sohda, T.;Loewe, M. F. J. Org. Chem. 1986,51, 3108. (b) Loewe, M. F.; Meyers, A. I. Tetrahedron Lett. 1986,26,3291. (4 Meyers, A. I.; Hellring, S. J. Org. Chem. 1982,47,2229. (d) Meyers, A. 1.; Beard, R. J. Org. Chem. 1990,56, in press. (5) (a) Martin, S. F.; Williams, S. A.; Gist, R. P.; Smith, K. M. J. Org. Chem. 1989,48,5170. (b) See also: ref IC. (6) Yamaguchi, R.;Otauji, A.; Utimoto, K. J. Am. Chem. Soc. 1988, 110,2186.

0022-3263/91/1956-2960$02.50/0

.. H'--+

f

OH Sb

W yohlmban isomers wmsl la, C-3,15 (p), G 2 0 (a) psuedo Ib, C-3,20 (PI,G I 5 (4 ello IC, C-3,15,20 (p) Web Id, C-3 (a), G 1 5 , 2 0 (p)

addition performed, leading to the yohimban skeletons D. Alternatively, asymmetric introduction of a dienyl halide in A would produce E, followed by a similar sequence of reactions that should provide the tetracyclic yohimbane skeleton F. The formation of cycloadduct D from C or cycloadduct F from E should also furnish different DEring stereochemistry and thus provide entry into different members of the yohimban family. Furthermore, by introducing the absolute stereochemistry at C-3via alkylation of formamidine A, we could reasonably expect stereochemical control in the DE ring fusion by orbital overlap factors.' It is also noteworthy at this point to emphasize that Diels-Alder precursor C will require inverse demand cycloaddition conditions, whereas Diels-Alder precursor E is typical of the classic process. Our synthetic route, depicted in Scheme 11, began by metalation of the 8-carboline-equipped formamidine 6 readily prepared from 8-carboline and the chiral auxillary (7) For a review of the factors affecting intromolecular Diele-Alder cycloadditione, see: Ciganek, E. Org. React. (N.Y.) 1984, 32, 1.

0 1991 American Chemical Society

Synthesis of Yohimban Alkaloids

J. Org. Chem., Vol. 56,No.9, 1991 2961

Scheme I

In an analogous fashion, (-)-doyohimban was prepared by the route depicted in Scheme 111. Metalation of 6 with tert-butyllithium and alkylation of the resulting lithiated gave the intermespecies with l-bromo-2,4-pentadiene11 diate, which was detached from the chiral auxillary to afford the chiral diene amine 11in 76% yield. HPLC-CSP analysis on the naphthamide l l b gave the ratio of enantiomers as 96:4 (92% ee). Acylation using acryloyl chloride gave an unstable acrylamide which could not be completely characterized and was used immediately in the intramolecular Diels-Alder process. Thus, crude 12 was treated with fused zinc chloride in refluxing THF and gave 13 after 12 h in 96% yield. A study to assess the efficiency of this cycloaddition resulted in the following limits: without ZnClz, refluxing in THF gave the product in 36 h along with considerable decomposition; in the presence of ZnClz, room temperature reaction was complete after 36 h and no loss in yield (9697 %) was noted. Thus, under normal Diels-Alder demand, this ring closure is highly efficient in the presence of a Lewis acid. In order to assess the stereochemistry emanating from the Diels-Alder process in 13, a single-crystal X-ray structure was obtained to verify the stereochemistry. The results confirmed that 13 possessed the C-3a, C-l5a, and C-20a configuration. Thus, all the protons were syn to each other and since the C-3 alkylation is known to be stereospecific to give S configuration at that position, we felt the assignments for alloyohimban were firm. The synthetic route was completed by reduction of the lactam and reduction of the double bond in the E-ring, similar to the pseudoyohimban l b described previously. Both of these steps proceed in 85-90% yield, and the last operation, namely removal of the methoxymethyl group, was all that remained. In the synthesis of pseudoyohimban lb, TMSI was utilized to smoothly remove the methoxymethyl group; however, this was not the case in the all0 series. After various attempts that led to poor yields and side reactions, the MOM group in 14 was removed using aqueous hydrochloric acid3 in 53% yield. Thus, the seemingly slight difference in molecular configuration between l b and IC exhibited a large effect on the removal of a protecting group remote from this site. In addition to the X-ray structure'O obtained for 13, the final product lc was found to be in good agreement with the literature -152" (lit! values for alloyohimban, mp 152-155 "C, [a],, mp 156-157 "C,DI.[ -166"). On the basis of the optical rotation, the alkaloid was reached in 91% ee. In summary, we have demonstrated that the chiral carboline formamidine 6 is once again a viable starting point to a variety of indole alkaloids and yohimban derivatives and, under circumstances where the dienes can be substituted with additional groups (e.g., carbonyl equivalents, etc.), other members of the yohimban family should become accessible.

A

IS

% D

1%

R

0

E

R

R

% F

R

derived from (S)-valin01.~*~ The metalation took place within 15 min to give a red solution of the lithio species that was treated with allyl iodide at -100 "C and then worked up after aqueous quench. Removal of the formamidine auxiliary was accomplished by use of a hydrazine-acetic acid solution, and the allylamine 7 was evaluated for enantiomeric excess. This was accomplished by transforming it to the a-naphthylamide 7a and subjecting it to a chiral stationary-phase HPLC analysis using a Pirkle c01umn.~Integration of the peaks, initially identified by comparing the racemate of 7, showed that the allyl derivative was obtained in >99% enantiomeric excess. The S-configuration depicted for 7 is based upon earlier precedents from our lab~ratory.~** The pentadienoyl group was introduced via its acid chloride affording 8, and the latter, a rather unstable oil, was promptly subjected to heating at 165 OC in xylene to furnish the cycloadduct 9 in 86% yield. The demands of the reverse electronics in the Diels-Alder cycloaddition necessitated these rather harsh conditions. Reduction of the lactam with lithium aluminum hydride followed by catalytic hydrogenation of the E-ring unsaturation gave the pentacyclic indole 10 in 63% over the two steps. The methoxymethyl group was removed with use of trimethylsilyl iodide, furnishing pseudoyohimban l b as the levorotary enantiomer to that previously reported. Comparing physical and spectral data and specific rotations indicated the identity of the material and its optical purity ([a],, -35.0" vs +34.4O,8 pyridine) were on firm ground. Further support for structural agreement was obtained from COSY spectra, which allowed us to assign all the couplings between adjacent proton pair~.~JO (8) Bartlett, L.; Dptoor, N. J.; Hrbek, J.; Klyne, W.; Schmid, H.; Snatzke, G. Helu. Chim. Acta 1971,64, 1238. (9) Uskokovic, M.; Bruderer, H.; Von Planta, C.; Williams,T.;Brossi, A. J . Am. Chem. SOC.1964,86,3364. (10) Copies of COSY rpedra and X-ray data are given in supplementary material.

Experimental Section General Data. Analytical thin-layer chromatography was performed on p m t d aluminum-backed0.2-mm did gel plates (E. M. Science 5554, Kieselgel 60F 254) deactivated with triethylamine. Flash column chromatography was performed on triethylamine deactivated W. R. Grace catalyst-grade951 silica gel. High-pressure liquid chromatography (HPLC)wae performed on a Chiral HPLC, determinationswere made on a Bakerbond DNBPG chiral-phase column (Pirkle covalent N-(3,5-dinitrobenzoyl)phenylglycine, 4.5 mm i.d., 25 cm). Melting pointa were (11) Bender, D. D.; Stakem, F. G.; Heck, R. F. J. Org. Chem. 1982,47, 1278. (12) Wenkert, E.; Chang, C.-J.;Chawla, H. P. S.; Cochran, D. W.; Hagaman, E.W.; King, J. C.; Orito, K. J. Am. Chem. SOC.1976, a,3645.

Meyers et al.

2962 J. Org. Chem., Vol. 56,No.9, 1991 Scheme IIa C

99%

* MeO

-

7, R - H 7a, R -C

8 8

*

33%'8,

'.

0

8

1

86% d

"Reagents and conditions: a, t-BuLi, CHz=CHCHzI,THF, -100 O C ; b, NzH4, HOAc, MeOH, 25 OC; c, NaH, 2,4-pentadienoyl chloride, THF, 0 "C; d, xylene, 168 OC, sealed tube; e, LiAlH,, THF; f, Hz-Pd/C, MeOH; g, trimethylsilyl iodide, CHzClz,0 O C . Scheme IIP

phase extracted twice with additional diethyl ether. The combined organic phases were washed with a brine solution. The volatiles were removed under vacuum and the residue separated into its components via flash chromatography on triethylamine-deactivated silica gel. 12 5 B. Removal of Formamidine Auxiliary. To a room tem8 8 perature 0.05 M solution of the formamidine compound in 8. methanol was added via syringe 10 equiv of glacial acetic acid followed immediately by 10 equiv of hydrazine hydrate. The solution was allowed to stir at room temperature for 2 h and heated to 50 O C for 30 min, and the volatiles were then r e m o d by water aspirator vacuum. The residue was then partitioned between ethyl acetate and 10% sodium bicarbonate solution. The aqueous phase was washed twice with ethyl acetate and the organic phases combined. The combined organic phases were washed with brine. Me0 The ethyl acetate was removed by water aspirator vacuum and the residue passed through a short plug of triethylamine-deactivated silica gel with ethyl acetate. Following removal of the 13 solvent, the valino tert-butyl ether was removed by Kugelrohr oven distillation at 90 OC (0.1"Hg)to yield the desired alkylated amine 7 or 11 as a yellow oil. a Reagents and conditions: a, t-BuLi, 2,6pentadienyl bromide, C. Reduction of Lactams 9 and 13. The lactam was dissdved THF, -100 OC; b, N2H4,HOAc, MeOH; c, CHz=CHCOC1,CHC12, in a 1:l mixture of freshly distilled tetrahydrofuran and diethyl EbN; d, ZnClZ,THF, 65 "C;e, LiAlH,, THF; f, H2,Pd/C, MeOH; ether (0.1 M). To this was added portionwise an excess (2 equiv) 8, HCl(aq). of lithium aluminum hydride. The mixture was brought to reflux and the temperature maintained for 4 h, and then the mixture uncorrected. Elemental analyses were performed by Desert was allowed to cool to room temperature, and 0.1 mL of water Analytics, Tucson, AZ. All reactions were performed under an followed by 0.1 mL of 2 N sodium hydroxide were added. The atmosphere of dry and deoxygenated argon, except when an solvent volume was doubled by addition of diethyl ether, and an aqueous solvent system was used. Solvents tetrahydrofuran and additional 0.3 mL of water was added. The slurry was stirred diethyl ether were stored over and used freshly distilled from for 0.5 h, and 2 g of anhydrous potassium carbonate was added. sodium benzophenone ketyl. Dichloromethane was stored over After being stirred for 1 h, the mixture was fiitered through a bed and freshly distilled from phosphorus pentoxide. Toluene and of Celite and the filter cake washed with ethyl acetate. The solvent xylene were stored over and distilled from sodium metal. All other was removed under reduced pressure to yield the product as a reagenta were purchased from Aldrich Chemical Co., Alfa. Venyellow oil. tron, or Lancaster and used as received unless stated otherwise. D. Hydrogenation of Dehydroyohimbans. The dehydroGeneral Procedures. A. Alkylation of 2-[[9-(Methoxymethyl)-1 ~ , 4 - t e t ~ ~ ~ ~ ~ ~ - a r b o l i n - 2 y l l m e t h y yohimban l a n o l was dissolved in a minimum amount of methylene chloride, added to 10 mL of methanol, and placed into a hytert-Butyl Ether (6). A stirred 0.1 M THF solution of 6* under drogenation bottle. To the mixture was added a catalytic amount argon was m l e d to -100 O C . To this solution is added, dropwise of palladium on carbon. The bottle was sealed and pressured to and slowly, 1.1 equiv of tert-butyllithium as a pentane solution 50 psi with hydrogen gas. The solution was stirred at room over a period of 15 min. The red solution is then allowed to stir temperature for 12 h. The bottle was opened and the mixture for an additional 0.5h. A 1.0 M solution containing 1.5 equiv fdtered through Celite with methylene chloride. The solvent was of the electrophile (which was freshly distilled and/or passed then removed under reduced pressure to yield the reduced product through a plug of alumina) in THF was slowly added over a period 10 or 14. of 0.5 h. The solution was stirred for an additional 6 h at -100 O C and was then quenched by addition of 2-3 equiv of methanol. Allylated Carboline. a. 2 4 [9-( Methoxymethyl)-l(S)-(2The solution was allowed to come to room temperature, and the propenyl). 1,2,3,4-tetrahydro-~-carbolin-2-yl]methylene]solvent was then removed under vacuum. The residue was valinol tert-Butyl Ether. The product was generated through partitioned between diethyl ether and water and the aqueous general procedure A. Allyl iodide was used as the electrophile.

?F$

%

Synthesis of Yohimban Alkaloids The product waa a water white oil. Yield from 1.00 g (2.60 m o l ) is 0.98 g (89%). Flash chromatography with 0.5% triethylamine, 5% dichloromethane, 94.5% hexanea to 0.5% triethylamine, 10% dichloromethane, 89.5% hexanes: TLC (R 0.47; 20% ethyl acetate, 80% hexanes); IR (cm-', neat) 2956, !b22,1461,739; 'H NMR (300 MHz, CDC13, ppm) 2.55-2.98 (m, 6 H), 3.30 (s,3 H), 3.58-3.67 (m, 1 H), 4.13-4.19 (m, 1 H), 5.08 (AB, J = 10.3 Hz, 2 H), 5.26-5.57 (m, 4 H), 5.81-5.93 (m, 1H), 6.09 (dd, J = 10.0 Hz, J = 3.6,l H), 6.39-6.56 (m, 2 H) 7.07-7.26 (m, 2 H), 7.30-7.53 (m, 2 H); '% 18.8,20.8,22.3,27.2,27.3,30.8,38.8,55.8,64.9,72.8, 74.4, 108.8, 109.7, 117.2, 118.6, 120.2, 123.7, 135.2, 135.4, 137.7, 153.8; MS m / e (CI, NHJ calcd 425 amu, found (relative intensity) 426 (loo), 438 (39.1), 188 (51.6), 160 (39.4), 114 (41.9). b. (-)-9-( Met hoxymet hy1)- 1(5)-propenyl- 1,2,3,44etrahydro-@-carboline (7). The product was generated through general procedure B. The product was a pale yellow oil. Yield from 0.447 g (1.05 mmol) is 0.234 g (87%), [a]D-5.96O (c 1.04, THF); IR (cm-', neat) 3244,2900,1495,740; 'H NMR (300 MHz, CDC13, ppm) 1.75 (b s, 1 H),2.45-2.62 (m, 4 H), 2.88-3.10 (m, 2 H), 3.11 (8, 3 H), 4.03 (t,J = 6.43, 1H), 5.00 (8, 1H) 5.07 (dd, J = 3.18 Hz,J = 1.49 Hz, 1 H), 5.18 (AB, J = 11.1Hz, 2 H), 5.67-5.83 (m, 1 HI, 7.00-7.09 (m, 2 H) 7.25 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H); '% 22.4,38.2,38.8,50.4,55.5,74.1,109.1 110.3,117.4,118.0,119.7,121.7,127.5,135.4,136.8,137.4;MS m / e (EI) calcd 256 amu, found (relative intensity) 256 (84.2),252 (34.81, 212 (100). The air and light sensitivity of this material precluded any successful combustion analysis. Diene-Alkylated Carboline. a. 2-[[9-(Methoxymethyl)1(S)-penta-2,4-dienyl- 1,2,3,4-tetrahydro-@-carbolin-2-yl]methylenelvalinol tert -Butyl Ether. The product was generated through general procedure A. l-Bromo-2,4-pentadiene, generated by the method of Heck et al.," was used as the electrophile. The product was a water white oil. Yield from 0.42 g (1.14 mmol) is 0.42 g (82%). Flash chromatography with 0.5% triethylamine, 5% dichloromethane, 94.5% hexanes to 0.5% triethtylamine, 10% dichloromethane,89.5% hexanes: TLC (R, 0.48,20% ethyl acetate, 80% hexanea); IR (cm-', neat) 2971,2927, 2871,1645,1463; 'H NMR (300 MHz, CDCl3, ppm) 0.80.90(m, 6 H), 1.12 (a, 9 H), 1.73-1.86 (m, 1H), 2.64-2.95 (m, 6 H), 3.20 (m, 1 H), 3.25-3.35 (m, 1 H), 3.29 (8, 3 HI,3.40-3.60 (m, 2 H), 5.05 (d, J = 10.1 Hz, 1H), 5.11 (d, J = 16.4 Hz, 1H), 5.42 (AB, J = 11.1Hz, 2 H), 5.76-5.86 (m, 1H),6.14 (dd, J = 15.0 Hz, 10.4 Hz, 1H), 6.24-6.37 (m, 1 H), 7.10-7.23 (m, 2 H),7.41-7.50 (m, 3 H); '% 17.8,20.5,27.6,27.7,30.2,37.2,55.8,64.9,71.1,72.4,14.3, 109.5, 115.6, 118.2, 120.0, 122.0,127.4,131.3,132.9, 135.7, 137.0, 137.5, 153.6; MS m / e (CI, NH3) calculated 452 amu, found (relative intensity) 453 (32.5),452 (83.3), 215 (37.4), 213 (63.71, 160 (30.5),114 (100). The air and light sensitivity of this material precluded any accurate combustion analysis. b. (-)-9-(Methoxymethyl)-1(5)-penta-2,4-dienyl-lt,3,4tetrahydro-@-carboline (11). The product was generated through general procedure B. The product was a pale yellow oil. Yield from 0.246 g (0.55 mmol) is 0.148 g (96%) [a]D-13.2' (c 1.9, THF); IR (cm-',neat) 3312,2969,2927,1649,1602,1463,1107, 1056,742;'H NMR (300 MHz, CDC13, ppm) 2.65-2.80 (m, 3 H), 3.05-3.30 (m, 2 HI,3.28 (s,3 H), 4.20 (m, 1HI, 5.07 (d, J = 22.2 Hz, 1H), 5.13 (dd, J = 28.8,2.0 Hz, 1H), 5.39 (AB,J = 11.1,7.8 Hz, 2 H), 5.79 (dt, J = 1.46, 7.3 Hz, 1HI, 6.27 (m, 2 H), 7.25-7.10 (m, 2 H), 7.47 (d, J = 13.1 Hz, 1 HI, 7.50 (d, J = 7.1 Hz, 1 H); '% 18.4,22.6,37.3,38.9,50.9,55.8,58.2,74.3,109.3, 110.6,116.0, 118.2,119.9,122.0, 127.6, 131.3,133.9,136.8,137.5. Air and light sensitivity precluded any accurate combustion analysis. C h i d Stationary-Phase Analysis of Enantiomeric Purity of 7 and 11. The naphthamides 7a and lla were prepared as follows. To a solution of the secondary amine (10-20 mg) in 3 mL of l,2-dichloroethane under argon was added 2.0 equiv of triethylamine. Then, 1.1equiv of a-naphthoyl chloride was introduced and the mixture allowed to stir for 12 h. The solvent was removed under reduced preasure and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with 5% HC1, once with 10% cold KOH (to remove excess naphthoic acid), and once with brine. The ethyl acetate solution was dried with K2C03and concentrated. After TLC purification (Merck, silica, 0.25-mm plate, twice: once with ethyl acetatepentane-triethylamine (8l:l)and then with 10% 2-propanolhexane),7a gave: 'H NMR (CDC13,ppm) 1.20 (t, 2 H), 2.45-3.20

J. Org. Chem., Vol. 56, No. 9, 1991 2963 (m, 4 H), 3.45-3.82 (m, 2 H), 3.44 (8, 3 H), 5.17-5.77 (m, 4 H), 6.05-6.43 (m, 3 H), 7.00-8.12 (m, 11H). The amide, both racemic and optically active, was made ready for HPLC analysis by preparing solutions in 2-propanol (5 pg per 10 pL). The column flow rate was 3.50 mL/min with 22% 2propanol-hexane as the eluent. Elution times were 4.4 and 5.2 min for racemic 7a. The optically active material showed the absence of the faster moving enantiomer. To verify identification, the optically active amide was mixed with racemic material and coinjected. For 1la, similar characteristics were noted, giving an enantiomeric ratio of 964 f 1. Pentadienylamide 8. To an ice-cooled solution of the allyl@-carboline7 (0.200 g, 0.78 mmol) in freshly distilled methylene of pyridine. This solution chloride was added 126 pL (1.56 "01) was allowed to cool to 0 OC over 15 min, and the flask was alternately flushed with argon and evaculated and subsequently kept under a positive pressure of argon (0.1 atm). Meanwhile, 2,4pentadienoyl chloride was prepared by the addition of excess oxalyl chloride (1mL) to the parent acid (100 mg, 1.02 mmol).13 The mixture was allowed to stir for 1h at room temperature, after which time the exoxalyl chloride was removed in vacuo. The crude acid chloride was then dissolved in 15 mL of freshly distilled methylene chloride and the flask cooled in an iceaalt bath. The &carboline 7a (0.200 g, 0.78 mmol) was cannulated into the acid chloride slowly. After 2 h, the contents of the flask were added to 30 mL of cold water. The aqueous phase was made basic with saturated sodium bicarbonate and then extracted with ether. The ether phase was washed with two 30-mL portions of 5% hydrochloric acid solution, one 30-mL portion of 10% potassium hydroxide, and one portion of water. The organic phase was dried over potassium carbonate and the solvent removed under reduced pressure. The residue was chromatographed on silica gel with ethyl acetate-hexane-triethylamine (8:l:l). The product 8 was obtained as an unstable oil, prone to polymerization (262 mg, 100%): ["ID = +100.4O (c 0.24, THF); IR (cm-', neat) 2919, 1731, 1637,1607,738;'H NMR (300 MHz, CDCl,, ppm) 2.54-2.98 (m, 3 H), 3.27-3.37 (m, 2 H), 3.30 (s,3 H), 3.55-3.67 (m, 1H), 4.2 (dt, 1H),4.94 (m,1H), 5.00-5.57 (m, 5 H), 5.81-5.95 (m, 1H), 6.10 (dd, J = 3.7,9.9 Hz, 1H), 6.39-6.55 (m, 2 H), 7.11-7.38 (m, 3 H), 7.40-7.53 (m, 2 H); 22.2, 38.7, 39.5,47.7,55.8,74.2,76.5, 77.0, 77.4, 108.7, 109.6, 117.2, 118.0, 120.1, 121.3, 122.2, 124.1, 126.8, 134.4, 135.1, 135.2, 137.5, 143.3, 165.9; MS m/e (CI, NHB)calcd 336 amu, found (relative intensity) 337 (69.3),305(loo), 295 (31.4), 215 (48.4). (-)- 1-(Methoxymethy1)-18,19-didehydro-21-oxoyohimban (9). A solution of the triene 8 (0.250 g, 0.744 mmol) in 15 mL of freshly distilled xylenes was placed in a heavy-walled Pyrex tube. The contents were cooled in a liquid nitrogen bath and the tube sealed with a torch. The tube was immersed in a temperature-controlled oil bath (accuracy 1"C) at 168 OC. The reaction was allowed to proceed at thistemperature for 1618h, after which the bath was removed and the contents allowed to cool to room temperature. The contents were again cooled and the tube opened. The solvent was evaporated under reduced pressure and the residue submitted to flash chromatography on silica gel with ethyl acetakhexenetriethylamine(8kl). The product solidifkd upon solvent removal and was recrystallized from THF/ether, giving a white solid (215 mg, 86.0%): mp 199-200 OC; [a]D-73.2O (c 0.65, THF); TLC Rr 0.66, 50% ethyl acetate, 50% hexanes on triethylamine-deactivated silica gel); IR (cm-', neat) 2922, 2844, 1628,1467,744;'H NMR (300 MHz, CDCl,, ppm) 1.35-1.92 (m, 3 H), 2.00-2.30 (m, 4 H),2.73-2.92 (m, 4 H), 3.25 (s,3 H), 4.05-4.86 (m, 2 H), 5.40 (b 8, 2 H), 5.75 (m, 1 H), 6.22 (m, 1 H),7.05-7.26 (m, 2 H),7.41 (d, 1H, J = 7 Hz),7.50 (d, 1H, J = 7 Hz); '% 21.0, 24.3,25.1, 29.6,32.5,36.5,44.0,50.7,55.9, 74.9, 78.4, 109.4, 118.5, 120.4, 122.5, 172.7; MS m / e (CI, NHJ calculated 336, found 337 (loo), 335 (6.7),304.9 (4.7). Anal. Calcd for C2,H,N202: C, 74.97, H,7.19; N, 8.33. Found C, 74.93; H,7.32; N, 8.39. (-)-N-(Methoxymethy1)pseudoyohimban(10). The product was obtained through general procedures C and D without purification between. The product was a pale yellow oil. Yield from 0.200 g of 9 was 0.122 g (63%): [ a ]-24.6' ~ (c 1.29, THF); TLC (Rf 0.08, 50% ethylacetate, 50% hexanes on triethylamine-

'v

(13) Pakraehi, S. C.; Sukhendu, B. M.Heterocycles 1987, 26,1557.

2964 J. Org. Chem., Vol. 56, No.9, 1991 deactivated silica gel); IR (cm-', neat) 3044,2922,2846,1461,1370, 1178, 1105, 1061, 911, 739; 'H NMR (300 MHz CDCl,, ppm) 0.88-2.47 (m, 10 H), 2.7Cb3.00 (m, 6 H), 3.20 (s,3 H), 4.47 (d, J = 4.5 Hz, 1H), 5.39 (d, J = 1.3 Hz, 2 H), 7.08-7.23 (m, 2 H), 7.39 (d, J = 8.2 Hz, 1 H), 7.47 (d, 7.3 Hz, 1 H); 13C 17.4, 26.5, 29.7, 30.5,32.8,35.9,36.5,42.0,51.5,52.5,55.4,55.8,75.0,109.2, 110.9, 118.1,119.9,121.9,127.6,135.2; MS m / e (CI, NHS) calcd 324 m u , found (relative intensity 325 (loo), 323 (41.7), 293 (24.1), 259 (14.7), 122 (11.1). (-)-Pseudoyohimban (lb). To a -78 OC, 0.1 M solution containing the methoxymethyl-protected(-)-pseudoyohimban 10 in methylene chloride was rapidly added 10 equiv of trimethylsilyl iodide. After the solution was stirred for 5 min, 1mL of water was added and the solution temperature allowed to come to mom temperature. The volatiles were removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The aqueous phase was washed with ethyl acetate (3x1 and the combined organic phases washed again with brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The resulting residue was submitted to flash chromatography on triethylamine-deactivated silica gel (0.5% triethylamine, 10% ethyl acetate, 89.5% hexanes). Yield from 0.231 g (0.713 mmol) is 0.160 g (79.5%) mp 123-124 "C (lit! mp from acetone-ether recrystallized 166-167 'C, from methanol-chloroform 100 'C); [a]D -35.0' (c 0.40, pyridine) (lit.@ [ a ] =~ +34.4' (c 0.40, pyridine); TLC (R,0.69; 30% ethyl acetate, 70% hexanes on triethylamine-deactivated silica gel); IR (cm-', neat) 3219, 2946, 2855, 1632, 1450, 1320; 'H NMR (300 MHz, CDCl,, ppm) 0.74-1.39 (m, 6 H), 1.48-1.52 (m, 1 H), 1.63-1.82 (m, 5 H), 1.98-2.05 (m, 1 H), 2.40-2.58 (m, 3 H), 2.97-3.09 (m, 1 H), 3.19-3.35 (m, 2 H), 4.46-4.48 (m, 1H), 7.08-7.19 (m, 2 H), 7.35-7.38 (m, 1 H), 7.48-7.51 (m, 1 H), 7.76 (b s, 1H); 13C 16.9, 25.9,26.3, 30.3,32.9,35.1,36.2,41.7,51.2,51.7,54.1,107.9, 110.8, 118.0, 119.4, 121.4, 128.3, 133.5, 135.5; MS m / e (CI, NH3) calcd 280 amu, found (relativeintensity) 281 (0.7), 279 (7.4), 80.9 (31.8), 79.8 (100). Anal. Calcd for CIJ-I~Nz:C, 81.38; H, 8.63. Found C, 81.35; H, 8.87. (-)"-(Met hoxymethy1)- 16,17-didehydro-21-0~0alloyohimban (13). To a stirred 0 OC solution of 1.3 equiv of acryloyl chloride in dichloromethane was added dropwise via syringe a solution of the amine 11 and 1.5 equiv of dry triethylamine in dichloromethane. After being stirred at 0 "C for 2 h, the reaction was quenched by addition of a cold aqueous solution of saturated sodium bicarbonate. The aqueous phase was washed twice with dichloromethane and the combined organic phases washed with brine. The dichloromethane solution was dried over sodium carbonate and the volatiles removed under reduced pressure. Thin-layer chromatography in 1:l ethylacetatehexanes on triethylamine-deactivated silica gel shows the triene 12 to have an R of 0.62. The residue was dissolved in tetrahydrofuran and added via cannula to 1.2 equiv of thrice-fused zinc chloride. The solution was heated to reflux under argon for 12 h and then cooled to room temperature. The solution was washed with an aqueous saturated ammonium chloride solution and dried over anhydrous sodium carbonate, and the volatiles were removed to yield a yellow crystalline residue. The residue was purified by flash chromatography on triethylamine-deactivated silica gel with 5% dichloromethane in hexanes to give the desired product as colorless crystal. Yield from 1.33g (0.39 "01) iS 0.127 g (96%): mp 160-163 'C; [a]D -37.1' (C 1.40, THF);TLC (R, 0.26; 50% ethyl acetate, 50% hexanes on triethylamineneat) 2928,2842,1732,1630,1465, deactivated silica gel); IR (an-*, 1423,1305,1108,1065,745,734; 'H NMR (300 MHz, CDCl,, ppm) 1.43-1.64 (m, 2 H), 1.85 (m, 1 H), 2.11-2.19 (m, 2 H), 2.63-2.83 (m, 5 H), 3.28 (8, 3 H), 3.74 (m, 1H), 4.88 (dd, J = 11.3,2.2 Hz, 1 H), 5.18 (dd, J = 11.5,2.9 Hz, 1 H), 5.45 (d, J = 2.0 Hz, 2 H), 5.6-5.8 (dd, 2 H), 7.73 (m, 2 H), 7.13-7.27 (m, 2 H), 7.40 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 7.5,l H); 21.5,23.2, 25.3,31.9,33.1, 40.2,40.8,54.6, 55.9, 74.9, 109.3, 112.5, 118.6, 120.4, 122.4, 126.6, 128.3, 128.5, 134.6, 138.5, 172.8; MS m / e (EI)calcd 337, found 338 (25.6, M + 1)337 (loo), 336 (31.1), 305 (11.8). Anal. Calcd

Meyers et al. for C21HUNz02:C, 74.97; H, 7.19; N, 8.33. Found: C, 74.67; H, 7.21; N, 8.35. (-)-N(Met hoxymet hy 1)- 16,lI-didehydroalloyohimban. The product was obtained through general procedure C. The product was a white crystalline solid, mp 80-83 'c, [a]D -56.4' (c 0.53, THF). The yield from 0.22 g (0.677 mmol) is 0.218 g (97%): TLC (RF0.68; 20% ethyl acetate, 80% hexanes on triethylamiine-deactivated silica gel); IR (an-',neat) 2922,1464,1367, 2339,1106,1073,1056,739; 'H NMR (300 MHz, CDC13, ppm) 1.57-1.65 (m, 2 H), 1.86-1.92 (m, 1H), 2.02-2.18 (m, 3 H), 2.27-2.43 (m, 2 H), 2.63-2.75 (m, 2 H) 2.95-3.17 (m, 4 H), 3.27 (s,3 H), 3.48 (d, 1H, J = 9.2 Hz), 5.43 (8, 2 H), 5.71 (8, 2 H), 7.12-7.23 (m, 2 H), 7.41 (d, 1H, 8.0 Hz), 7.49 (d, 2 H, J = 7.4 Hz); '% 22.5,24.3, 33.6,34.3,36.1,52.1,55.7,59.8,61.8,74.8,109.4,111.1,118.2,119.9, 121.7,127.1,127.4,131.0,136.9,138.4;MS m/e (EI)calcd 322 amu,

found (relative intensity) 323 (22.7), 322 (57.6) 307 (11.5). 291 (13.7). This material was carried directly on to 14. (-)-N-(Methoxymethy1)alloyohimban(14). The product was generated by reaction through general procedure D. The yield from 0.211 g (0.65 mmol) is 0.173 g (81.4%). The product was isolated as a yellow semisolid ["ID -106.8O (c 0.41, THF); TLC (R, 0.36) (20% ethyl acetate, 80% hexanes on triethylaminedeactivated silica gel); IR (an-', neat) 2922,2855,2796,1464,1374, 1340,1146,1108,1068,'H NMR (300 MHz, CDCl,, ppm) 1.16-1.46 (m, 4 H), 1.59-1.76 (m, 3 H), 1.91-2.06 (m, 5 HI, 2.52-2.70 (m 2 H), 2.78 (ABX, J = 6.2 Hz,J = 7.6 Hz, J = 11.6 Hz,2 H), 2.88-3.20 (m, 2 H), 3.25 (s,3 H), 3.42-3.46 (m, 1 H), 5.42 (s,2 H), 7.10-7.22 (m, 2 H), 7.39 (d, 8.0 Hz, 1H), 7.47 (d, 7.3 Hz,1H); '% 21.0,22.5, 26.6,26.8,31.2,31.9, 35.6, 52.5,55.6,60.7,62.2, 75.0, 109.4, 111.1, 118.1, 119.8, 121.6, 127.4, 137.1, 138.4; MS m / e (EI)calcd 324, found (relative intensity) 325 (2.5) 324 (9.2), 323 (13.8), 269 (9.0), 268 (18.1), 28.1 (100). (-)-Alloyohimban (IC). The (-)-(metholrymethyl)aUoyohimban (14) was added to 5 mL of a 0 OC solution of 2 N hydrochloric acid, a few drops of dimethylformamide were added, and the solution was stirred for 3 d. The mixture was partitioned between brine and ethyl acetate. The aqueous phase was then neutralized with 2 N potassium hydroxide and extracted with methylene chloride (3x1. The combined organic phases were dried over anhydrous magnesium sulfate and the volatiles removed under reduced pressure. The residue was dissolved into a few drops of dimethylformamideand 5 mL of 2 N potassium hydroxide added. The solution was stirred overnight and neutralized with 2 N hydrochloric acid. The mixture was extracted with methylene chloride (3x1, and the combined organic phases were washed with brine and dried over magnesium sulfate. The volatiles were removed under reduced pressure, and the residue was passed through a plug of triethylamine-deactivated silica gel with methylene chloride to yield a yellow crystalline substance. Trituration with cold diethyl ether gave the product as a colorless crystalline compound. Yield from 0.086 g (0.26 mmol) is 0.039 (c g (53%): mp 152-155 OC (lit.8 mp 156-157 "C); [ a ] -152.3' ~ 0.41, pyridine), lit? [a]D -166.5' (c 0.4, pyridine); TLC (Rt 0.62) (30% ethyl acetate, 70% hexanes on triethylamine-deactivated silica gel); IR (cm-', neat) 3221,3054,2924,2858,1632,1453,1324; 'H NMR (300 MHz, CDCl,, ppm) 1.23-1.44 (m, 4 H), 1.60-1.72 (m, 4 H), 1.88-2.06 (m, 4 H), 2.53 (dd, 11.6 Hz, 3.3 Hz, 2 H), 2.66-2.80 (m, 2 H), 2.91-3.02 (m, 2 H), 3.18-3.21 (m, 1H), 7.05-7.15 (m, 2 H), 7.29 (d, 7.5 Hz, 1 H), 7.47 (d, 7.2 Hz, 1 H), 7.75 (br, 1 H); '% 20.8,21.8,26.5,26.6,30.5,31.6,34.8,36.7,53.4,60.5,62.0, 108.2,110.6, 118.0,119.3, 121.1,127.5, 135.6, 135.9;12MS m / e (CI, NH3 calcd 280 amu, found (relativeintensity) 281 (2.5), 280 (11.6), 279 (13.4), 278 (27.0), 35.1 (100).

Acknowledgment. We are grateful to the National Science Foundation for financial support of this work. Supplementary Material Available: HPLC enantiomer determinations (7a), X-ray data (13), and proton and carbon spectra for lb, IC, and 10 (18 pages). Ordering information is given on any current masthead page.