Catalytic asymmetric synthesis of a functionalized indolizidine derivative. A useful intermediate suitable for the synthesis of various glycosidase inhibitors

0040-4039/93 $6.00+ .00

Tetrahedron Letters, Vol. 34. No . 31 . pp. 4965-4968.1993 Printed in Great Britain

Pcrgamon Press Ltd

Catalytic Asymmetric Synthesis of a Functionalized Indoliz3dine Derivative . A Useful Intermediate Suitable for the Synthesis of Various Glycosidase Inhibitors Se{ji Nukui, Mikiko Sodeoha, and Masakatsu Shibasakla

Faculty of Fbaumaomdcal Sciences, University of Tokyo, Hoogo, Bunkyo-ko, Tokyo 113, Japan

fleet: Indolisidiee deriwuive 7 hat been syntkesind in up to 86% ee by an asymmetric Heck reacawt (Pd(O) BPPFOH, Ag-arcGanaed aeons) swains with procMrmf amyl iodide S. Converdoe of 7 m 8coaiaeine (9) is also described. Indolizidine alkaloids such as castanospetmine (1),l swainsonine (2),2 and pumiliotoxin B (3)3 have received much interest from the synthetic community because of their ability to inhibit glycosidase 4 and cardiotonic activity .5 Moreover, the discovery of the and-HIV activity of castanospermine and its derivatives6 has stimulated both the search for superior therapeutic agents for AIDS treatment and the development of efficient synthetic approaches to such compounds and their analogs . To our knowledge more than 60 syntheses of these compounds have been reported in this decade, and with a few exceptionsg most syntheses of these indolizidine derivatives have utilized natural chiral starting materials such as carbohydrates, amino acid derivatives and tartaric acid derivatives . In this report, we present a catalytic asymmetric synthesis of the functionalized indolizidine derivative 7 (86% ee), a potential synthetic intermediate for these biologically important compounds .

I

2

We recently reported the first example of an asymmetric Heck reaction,9 and since then we1° and othersil have demonstrated that this C-C bond-forming reaction is quite useful for the preparation of various optically active compounds. We planned to use this catalytic asymmetric intramolecular Heck reaction for Scheme 1 1) NaH oUF

l

NH 2)

4

1

J

C (68%)

J 1

H pdL •n Ag salt

5

4965

4966

the synthesis of the indolizidine skeleton . Cyclization of iodide S, easily prepared from amide 4, 12 was expected to give the optically active indolizidine 6 when catalyzed with a chiral palladium(0) complex . First, however, we examined conditions for the cyclization of S using the Pd2(dba)3*CHQ3 complex (5 mol % of Pd), diphenylphoappinobutane (dppb) (12 mol %) and silver phosphate (2 mol equiv) in various solvents .13 It was found the S cyclized smoothly in DMF to give a mixture of the cyclized products 6 and 7 (4.7 : 1) in 67 % yield, and isomerization of 6 to 7 was readily achieved in quantitative yield by the treatment of this mixture with a catalytic amount of Pd/C in McOH at 23 °C . 14 Next, we investigated the extent of asymmetric induction in DMF with a variety of commercially available chiral .ligands (Table 1) .15 Cyclizatiat using (R)-BINAP, the most commonly used ligand in the asymmetric Heck reaction, was quite slow even at 90 °C, and the enantiameric excess of product 7 was only 34%. (R)-(S)-BPPFOH15e was found to be the best ligand for this cyclization, giving 7 as the only cyclized product in 74% enantiomeric excess and in 55% yield . Interestingly, although BPPFA and BPPFOAc are very similar in structure to BPPFOH, these ligands were less effective for this reaction . Table 1 . Ligand Effects on Cyclization of entry 1 2 3 4 5 6 7 8 9

ligand (R)-BINAP (R, R)-NORPHOS (S, S)-DIOP (R, R)-MOD-DIOP (S, S)-BPPM (S, S)-BCPM (R)-(S)-BPPFA (R)-(S)-BPPFOAc (R)-(S)-BPPFOH

5 .11)-

temp. time (°C) 90 90 50 50 50 50 50 50 50

46 h 3d 25 h 21 h 37 h 46 h 8.5 h 14 h 35 h

b) ratio of 6 :7

yield (%)

1 :3.3 1 :2.2 1 : 1 .8 1 :1.1 1.3 :1 1 :5.9 1 :5.5 1 :12 0:1

67 11 63 32 15 6 79 62 45

ee of 7 configuration (%) of 7 34 11 11 42 5 60 45 52 74

R

S R S R R

S S S

a) The iodide S was treated with Pd2(dba)3.CHQ3 (5 mol % of Pd), ligand (12 mol %), A83PO4 (2 mol equiv) . and CaC03 (2 .2 mol equiv) in DMF. The initial cauatration of S was 0 .05 M b) No reaction occurred after 3 days when (S)4R)-PPFA, (R . R)-CHIRAPHOS, or (R)-PROPHOS was used as a ligand. In all cases the enantiomeric excess was unequivocally determined by the HPLC analysis (DAICEL CHIRALPAK AS, hexane-2-propanol, 4 : 1) of 7 before and after isomerization of the mixture of 6 and 7 . Since no significant change in the ce of 7 was observed after isomerization, kinetic resolution in the doublebond migration catalyzed by PdL*n must not be occurring in this case . 16 Table 2 summarizes our studies on the effect of solvent, temperature and silver salt on asymmetric induction. Contrary to previous results9 solvent did not significantly affect the ee of the product . At 50 °C, in DMSO cyclizaton proceeded smoothly to afford the cyclized products with 73% ce and in 89% chemical yield. When the reaction was carried out at 23 °C, the ee of 7 was improved to 81% oe (chemical yield of 82%) . The best result was obtained when silver-exchanged zeolite (Aldrich 36,660-9) was used (Table 2, entry 9) . Indolizidine 7 was obtained in 94% yield and 86% ee . 17 It is noteworthy that silver-exchanged zeolite is very effective for this asymmetric Heck reaction . We have already reported the important role of the silver saltl08 in the asymmetric Heck reaction, and Ag3PO4 generally gives the highest asymmetric induction . However, silver-exchanged zeolite was also found to give high asymmetric induction, and the reaction rate using silver-exchanged zeolite is much faster



4967

Table 2. Effects of Solvent, Silver Salt and Temperatuire on Cyclization of S .a) entry 1 2 3 4 5 6 7 8 9

silver salt

solvent

A83PO4 A83PO4 A83PO4 ADP04 AS3PO4 AS3P04

DMF NMP DMA TMU DMSO DMSO zooliteb) DMSO silver-exchanged etc) DMSO silvaachanged Zooliteb) DMSO-DMF (1 :1)

temp. (°C)

time

50 50 50 50 50 23 23 23 0

21 h 14.5 h 65 h 13 h 2 h 7 h 3.3 h 41 h 5 d

ratio of yield cc of 7 6 :7 (%) 1 :3.3 0 :1 1 :2.9 0 :1 1 :1.7 1 :2.5 1 :4.5 1 :13 1 :1.4

69 21 73 49 89 82 58 42 94

74 71 71 69 73 81 79 76 86

a) The iodide 5 was heated wilt Pd2(dba)3.CHC13 (4 and % of Pd), (R)-(S)-BPPPOH (9.6 and %). A83PO.4 (2 mot equiv) a Wver-xcMnged seo0o (conerpoodiug to ca. 6 equiv of Ag), and Ct O3 (2.2 and equiv). The in" conceaaaBon o( S was OAS M. b) Ald 36,660 .9. Ag oonsem: typically 20 .25%,100 mesh powder . c) AM 38228-0, Ag cootem >35%, granular. than that using AS3PO4. In fact, the reaction proceeded smoothly with silver-exchanged zeolite even at 0 °C, whereas no reaction occurred with AS3PO4 at this temperature To elucidate the absolute configuration of chiral indolizidine derivative 7, (-)-7 obtained from the reaction using (R)-(S)-BPPFOH (86% ee) : [a]D24 -331 ° (c 1 .18, CH2Q2) was converted to known amide 8 and S-conic tine (9) (Scheme 2) . As the optical rotations of saturated amide intermediate 8 and S-coniceine (9) are +3 .0 ° (c 2.1, CH2Q2) and +13.3 ° (c 0.94, EtOH) respectively, the absolute configuration of (-)-7 must be (S).18 It is possible that the cyclization occurs via 10 with the interaction between the hydroxyl group of the ligand and the carbonyl group of the substrate stabilizing the transition state shown and resulting in the predominance of the (S)-enanfomer. Scheme 2 H

H2 Pt0 2

LIAIH4 Et20

AcOEt

23 °C

(97%)

(63%)

9

In conclusion, indolizidine 7 was efficiently synthesized in excellent enantioselectivity (86% ec) with the asymmetric Heck reaction . This functionalized indolizidine is a potentially versatile intermediate for the synthesis of various biologically active indolizidine derivatives including 1, 2, and 3 REFERENCES AND NOTES 1. 2. 3.

a) Hohenschua, L. D.; Bell, E. A.; Jewess, P. J„ Leworihy, D . P.; Pryce, R J.; Arnold, E„ Clardy, J . Phytochemiwy 1991, 20, 811. b) Nash. R J.; Fellows, L . E.; Dring, J. V.; Sdrton, C . H.; Carter, D.; Hegaty, M. P.; Bell, E. A. Phytochemistry 1999, 27,1403 . a) Cdegase, S . M. Dorking, P. R.; HuxtaNte. C. R Amt. J. Chem 1979.32 .2257. b) Schneider. M. J.; Ungemach, F. S.; Broquist, H. P.; Harris, T. M. Tetrahedron 1983 .39.29 . Daly, J. W.; Myers, C . W. Science (Washington D . C.)19f7,156, 970.

4968

4. 5. 6.

7.

8.

9. 10.

11.

12. 13. 14. 15.

16. 17.

18.

For reviews, am a) Fellows, L . E.; Flea, 0. W. J. In Natural Products Isolation; Wafman, 0. H., Cooper, R ., Eds.; Elsevler: Amsterdam, 19M pp 539-559. b) Elbein, A . D„ Molyneux, R . J. In Alkaloids : Chemical and Biological Perspectives; Pelletier, S. W .; Ed . ; Wiley: New York 1987; Vol. 5, Chapter 1, pp 1-54 . Albuquerque, E. X.; Wamiek, J. E.; Maleque, K A .; Kauffman . F. C.; Tambariai, R .; Nimit, Y.; Daly, J . W. Mot. Phanmcol .1981,19.411 . a) Walker, B . D„ Kowalski . K; Gob, W. C.; Kezarsky, K„ Krieger, M .; Rosen, C.; Rohrsclmeider, L; Hasekine, W. A„ Sodroeki, L Proc. Nat Acad. Sci. U. S. A . 1987,84.8120 . b) Gruters, R. A.; Neefjes, J . J.: Taan etse, M.; De Goode, R. E. Y. ; Tulip, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L. Nature 1987.330, 74. c) Fleet, G. W. J.; Katpas, A .; Dwek, R . A; Follows, L. E.; Tyms, A. S .; Peturason, S.; Namgoong, S . K.; Ramadan, N. 0„ Smith, P. W.; Son, J. C.; Wilson, F.; Witty, D. R.; Jacob. 0. S.; Rademacher, T. W. FEES Lea.1988, 237,128. d) Karpas, A. ; Fleet, G. W. I„ Dwek, R. A.; Petursaon, S .; Namgoon& S. K.; Ramsden, N. G„ Jacob, 0. S.; Rademacher, T. W. Proc. Nail Acad. Sd. U. S. A.1988, 85, 9229. e) Sunha, P. S .; Taylor, D. L.; Kong, M. S.; Bowlin, T. L„ Lin, P. S.; Tyms, A. S.; Sjoerdsma, A. Lancet 1969, 1206. f) Montefiori, D. C.; Robinson, W. E.; Mitchell. W. K Proc. Nail Acad. Sex . U. S. A.1988„M8„85 . M) Tyms, A. .9248 S.; Berrie, E. M4 Ryder, T. A. ; Nab . R. 14 Hegarty, M. P.; Taylor, D. L„ Mobberley . M. A.; Davis. J. M.; Bell, E. A.; Jeffries, D. J.; Taylor-Robinson, D.; Fellows, L E. Lancet 1987,1025. For a review on a gnospamine and its derivatives, am a) Burgess, K .; Henderson,1. Tetrahedron 1992, 48,4045 and references cited therein . For recent syntheses of casmnospemnine and its derivatives, see b) Burgess, K„ Chaplin, D . A. Tetrahedron Lat .1992, 33,6077. c) St-Deais, Y.; Chan, TAL J. Org. Ckft 1992, 57,3078. d) Burgess, K.; Chaplin, D. A.; Henderson, L J. Org. Chem .1992, 57.1103 . e) Siriwardene, A . H.; Cldaroni, A.; Riche, C.; Grierson, D. S. J. Org. Chest 1992, 57. 5661 . 1) Mulzer, J . ; Delanlow, H . J. Org. Chem .1"2,57.3194. g) Maggini, M.; Prato, K ; Ranelli, M„ Scorrano, 0. Tetrahedron Lets . IM, 33,6537 . h) Ina, H.; Kiboyashi, C. !. Org. Chest 1993,58 .52. i) Zhou, P.; Salleh, H . M.; Honk, J . F. !. Org. Cheat. 1993, 58. 264. For ensuem syntheses of swainsonine and its derivatives, see,) Ikott N .; Hanald, A. Cheer. Phart Bull. 1990,38, 2712 k) Pearson . W. H.; Lin, K.-C. Tetrahedron Lett.1990, 31, 7571 . 1) He czegh, P.; Kdaos, L; Saillgyi, L ; Zadly, M .; Sztiricskai, F. Tetrohedron .1992, 33.3133. And cited therein. For recent syntheses of pamiliotoxin derivatives, seem) Overman, L E .; Last Robinaon, L . A.; Zablocki, J. J. At Chess Sac. 1992,114, 368. a) Golduein, S . W.; Overman, L E .; Rabinowitz, M. H. !. Org. Chest 1992, 57,1179. o) Aoyagi, S .; Wang, T.-C.; Kibayashi, C. !. Am . Chew Soc. 1992,114, 10653. And cited therein. a) Reymond, J:L.; Vogel, P. J. Chest Soc., Chew . Comm. 1990,1070. b) Reymond, J :L.; Pinkerton, A. A.; Vogel, P. !. Org. Chow 1991, 56, 2128. c) Miller, S . A.; Chamberlin, A. R. !. Asst. Churn, Sac. 1990,112, 8100. d) Adams, C . E.; Walker, F. J.; Sharpless, K . B. !. Org. Chest 1995, 50, 420 . e) Takahata, H.; Banba, Y .; Momose, T. Tetrahedron: Asynwnetry 1990.1 .763. Sato, Y. ; Sodecka, M.; Shibasald, M. J. Org. Chest 1989, 54, 4738 . a) Sato, Y .; Sodooka, M . ; Shibasaki, K Chew. Let:. 1990,1953 . b) Kagecluka, K.; Shi aaati, M . J. Org. Chest 1990, 55. 4093. c) Sato, Y .; Watanabe, S.; Shibasaki, M. Tetrahedron Lea . 1992,33.2589 . d) Saw, Y.; Honda, T.; Shibasaki, K Tetrahedron Lett.1992, 33,2593 . e) Shibasaki, M.; Sato, Y„ Kageehika, K . J. Synth. Org. Chem., Japan 1992, 50, 826. f) Kageehika, K„ Oshima, T . ; Shibasaki, M. Tetrahedron 1"3 .49,1773. S) Kondo. K . ; Sodeeka, K; Maxi, M.; Shibasaki, M. Tetrahedron Lett . in press. a) Carpenter, N. E.; Kucea, D. J.; Overman, L. E. J. Org. Chem 1989,54,-%46. b) Ashimori, A .; Overman, L. E. J. Org. Chesr.1992, 57, 4571 . c) Ozawa, F.; Kubo, A.; Hayashi, T. !. Ana. Chew. Soc. 1991,113, 1417. d) Hayashi, T.; Kubo, A.; Ozawa, F. Pare Appl Chest 1992, 64,421 . e) Oaawa, F.; Kubo, A.; Hayashi, T. Tetrahedron Lea . 1992, 1992,33.1495 . f) Ozawa, F.; Hayashi, T. J. Organomet. Chest 1"2,428,267 . S) Sakamow, T.; Kondo, Y.; Yamanka, H. Tetrahedron Lett.1992, 33,6845. a) Hubert, J . C.; Wijnberg, J . B. P. A. ; Speekamp, W . N. Tetrahedron 1975, 31,1437. b) Shono, T.; Matsmmura, Y.; Uchida, K„ Kobayashi. H. !. Org. Chem .1995. 50, 3243. c) Nishitani, T.; Iwasaki, T. ; Matsutnow, K .; Inorte, I.; Miyoshi, M. J. Org. Chess 1"2.47,1706. No reaction occurred in benzene or NEt3 even after 3 days. In polar solvents such as acetanitrile and THF die desired cydized products 6 and 7 were obtained in 21% (617 .1/1) and 36% (6 only) yam. respectively, after 4 days . The isomerization was also achieved under following conditions : silica gel in acetone ; catalytic amount of t-BuOK a K2C03 in t-BuOH at 23 °C; DBU in wlnene at 100 °C . In all cases no change in eee was observed after die iaanerizatiom . a) Kagan, H. B. Asynsnenzc Synthesis; Morrison, J. D. Ed. ; Academic Press: New Yak, 1985; Vol. 5, p1 . b) Hayashi, T. ; Kumada, K abed. p147 . c) Take* H.; Tachinami, T.; Abunatani. M.; Takahaslu, H.; Morianow . T.; Achiwa, K. Tetrahedron Lett . 1989,30,363. d) Morimoto, T.; Chiba, M.; Achiwa, K. Tetrahedron Lett . 1989, 30,735. e) Haysshi, T.; Mice, T.; Kmnada, K Tetrahedron Lett.1976, 4351 . Enhanced auotiosebaion by kinetic resolution was described by Ozawa and Hayasbi . See reE 11 c). Spectral data of 5: IR (nest) 2926,1664 cm-1; 1H NMR (CDC13) 8 2.26.2.37 (m, 2 10,233 (t,! - 8.0 Hz, 2 H), 4 .21(dd, J=6.8,13 Hz, 2 H), 5.17 (dt, J- 8A.4.0 Hz, I H), 6.03 (d t,!= 8A.1.8 Hz, I H), 6.25 (dt, J - 7.8, 9 .0 Hz, 1H), 6.46 (dt, ! . 7.8,13 Hz, I H); MS m/s 263 (Ml, 167,137 .136 (bp), 96. 7: IR (neat) 2922,1658 exert ; III NMR (C6W 81.531.62 (m, 2 H), 3294.12 (m, 2 H), 4.33-4.45 (m,1 H), 5 .08-5.13 (m, I H), 5.20.5.31 (m, l H), 5.81(ddd, J-10 .0, 5 .5.3.6 Hz, I H), 6.06 (dt, J* 10 .0. 20 Hz, 1 H); MS ads 135 (M+, bp). Hua, D. H.; Bhaeathi, S . N.; Takusagawa, F.; Tsujimoto, A .; Pananngadan, J . A. K .; Hung, M.-H.; Bravo, A . A. ; Brpelding, A. M. !. Ors. Chest 1989, 54, 5659.

(Received in Japan 6 April 1993)