Case study #1: Strychnine

Transcription

1 Case study #1: Strychnine STRYCIE

2 ature Chemistry 2009, 1,

3 Synthesis of Biotin - ~without- Protecting Groups ClS 2 C Et 2, -60 o C Cl 2 S A Et _ C 2 Cl 2, -20 o C 3 2 S B 3 Curtius rearrangement 3 2 S C 1. a 2 S 3, 2 1. mcpba ab 4 2. Li o, Et 2, Li ai 4 C 2 C D E F MsCl, py. Ms C 2 Ms G 1. a 2 S 2. a S biotin C 2 Funk analysis: 2 rings 3 stereogenic centers 1 S atom 1 urea 7 points = 14 steps Fliri, A.; ehringen,., Chem. Ber. 1980, 113, 607~613

4 ACIE 2009, 48, 2854 The most efficient synthesis, the ideal synthesis, has been defined by endrickson: The ideal synthesis c r e a t e s a c o m p l e x skeleton in a sequence only of successive construction reactions involving no intermediary refunctionalizations, and leading directly to the structure of the target, not only its skeleton but also its correctly placed functionality.

5 Convergent Synthesis: Longest linear sequence = 6 steps Linear Synthesis:

6 Funk Analysis 7 rings 1 basic 1 seven-membered ring [1 alkene] 1 quaternary center 6 stereogenic centers 17 points = 34 steps maximum strychnine

7 Background: Strychnine is a poisonous alkaloid isolated from the seeds of Strychnos nux-vomica, a small climbing shrub found in Africa, Asia and South America. Strychnine is still in use today as a rodent poison and was one of the first alkaloids isolated in a pure state (1818). The complete chemical structure of strychnine was not elucidated until 1947 by Woodward, Prelog and Robinson. In 1951, the X- ray crystal structure determination confirmed the proposed structure and the complete chemical synthesis was achieved by Prof. Robert B. Woodward of arvard University in Below, is an excerpt of the introduction to a paper (Tetrahedron, 1963, 19, 247) by Woodward on the chemical synthesis which gives some interesting insight into the importance of strychnine and the state of alkaloid research after the second World War.

8 Sir Robert Robinson & Robert Burns Woodward Tetrahedron Publications

9

10 "Strychnine! The fearsome poisonous properties of this notorious substance attracted the attention of XVIth century Europe to the Strychnos species which grow in the rain forests of the Southeast Asian Archipelagos and the Coromandel Coast of India, and gained for the seeds and bark of those plants a widespread use for the extermination of rodents, and other undesirables, as well as a certain vogue in medical practice-now known to be largely unjustified by any utility. The isolation of the pure alkaloid from the beans of Strychnos ignatii in 1818 by Pelletier and Caventou was an event of some historical importance, in that it provided a convincing and elegant demonstration of the correctness of the then only recently proposed and revolutionary suggestion that acid-fixing substances are produced in the vegetable kingdom. Thus did circumstance early place ready at the hand of any interested chemist an abundant supply of a pure crystalline compound whose constitution and construction could hardly fail to excite curiosity. But organic chemistry, in its first hundred years, was scarcely equipped for the attack on so formidable an objective, and apart from the determination of the correct empirical formula of the alkaloid, and the discovery of a few simple transformations, no substantial progress was made until the commencement of the massive investigations of the present century. Then, over a period of forty years, one of the great classics of structural organic chemistry was constructed. In that effort, described in more than two hundred fifty separate communications, Robert Robinson played a brilliant and commanding role, and the extensive beautiful experimental contributions of erman Leuchs were of definitive importance. In 1947, the task was finished and strychnine stood revealed as I...It is now possible to contemplate the synthesis of the substance of which it has been said: "For its molecular size, it is the most complex substance known".."

11 A footnote in this paper goes on:.."it will not be lost upon the reader-nor was it on at least some of the observers of the chemical scene in the late nineteen forties- that the almost simultaneous outcomes of decades-long chemical degradative assault, and the incomparably shorter X-ray crystallographic investigations, presaged a future in which so singular an edifice as the chemical structure determination of strychnine was unlikely to find parallels. But it is worthwhile to point out here that the establishment of the structure of strychnine was accompanied by no surcease of interesting chemical developments. The elucidation and further development of the fascinating chemistry of vomicine, the dramatic establishment of the relationships between strychnine and the calabash curare alkaloids, the discovery of intricate new transformations of the strychnine skeleton, the even now rapidly unfolding exciting new chapters in the story of the biogenesis of the Strychnos and related alkaloids, and perhaps also the synthesis here recorded, may be selected as only a few high points in the continuing evolution of the chemistry of strychnine during the last fifteen years. This short history should give pause to those whose talent for despair is lavished upon an organic chemistry ornamented and supplemented- or as they fancy, burdened- by magnificent new tools which permit the establishment in days or weeks of enlightenments which once would have required months or years. While it is undeniable that organic chemistry will be deprived of one special and highly satisfying kind of opportunity for the exercise of intellectual élan and experimental skill when the tradition of purely chemical structure elucidation declines, it is true too that the not infrequent dross of such investigation will also be shed; nor is there any reason to suppose that the challenge for the hand and the intellect must be less, or the fruits less tantalizing, when chemistry begins at the advanced vantage point of an established structure. f course, men make much use of excuses for activities which lead to discovery, and the lure of unknown structures has in the past yielded a huge dividend of unsought fact, which has been of major importance of building organic chemistry as a science. Should a surrogate now be needed, we do not hesitate to advocate the case for synthesis."

12 Thirteen new total syntheses of strychnine have appeared since the classical Woodward synthesis. It is quite instructive to compare and contrast a few of these syntheses. The new syntheses have been reviewed by Beifuss wherein it is stated: Whether the four new total syntheses (to 1994) represent a fundamental improvement over Woodward s strychnine synthesis and the extent of this improvement can certainly be debated. owever, it can not be contested that verman et al. accomplished the first enantioselective synthesis of the natural product, and that Kuehne and Rawal with their respective 17- and 15-step syntheses devised approaches with markedly fewer reaction steps than Woodward s 28-, Magnus 27- and verman s 25-step syntheses.

13 Woodward synthesis: I (C 3 ) 3 C 3 1. C 2, 2 C 3 C 3 2. C 3 I C 3 ac, DMF 2. LiAl C 3 C 2 Et C 3 2. TsCl. pyridine Ac Ts C2 Et Ts C2 Et C 3 C 3 C 2 C 3 C 2 C 3 1. ab 4 2. Ac 2 pyridine 1. I, red P o 2. Ac 2 pyridine 3. C Pd-C 2. a 3. Ac 2 pyridine 1. LiAl 4 2. Br, Ac,! 3. 2 S 4 Ac Ts C2 Et Ac C2 C 3 Ac C 2 C 3 C 3 Ac. C 3 C 3 ac 3 C 3 3, Ac 1. Cl, 2 2. Se 2 K, Et Ac Ts C2 Et Ac STRYCIE Cl, C 3 C 2 C 3 C 2 C 3 C 2 C 3 1. C Ca, TF 1. TsCl, pyridine 2. PhC 2 Sa 3. Ra-i o 2. 2, Lindlar's cat.

14 Woodward Strychnine synthesis 1 3 I 1. 2 C=, 2 Ac, diox., 2 2. I mechanism: step 1 B: mechanism: step 1 3 C I 2 3 I

15 Woodward Strychnine synthesis I mechanism: step 1 1. ac, DMF 2. LA, TF 3. a 2 S 4, CCl I a C C mechanism: step 2 Al Li C Al Li Al Li 2 2

16 Woodward Strychnine synthesis 3 2 C 2 Et 1. benzene, Δ 2. TsCl, py Ts C 2 Et mechanism: step 1 Et 2 C 2 Et 2 C + Et 2 C - 2 mechanism: step 2 Et 2 C Cl S Cl Ts C 2 Et Ts C 2 Et

17 Woodward Strychnine synthesis 4 Ts C 2 Et 1. ab 4, Et, 2 Ts C 2 Et 2. Ac 2, py. Ac mechanism: step 1 B Et a Ts Ar C 2 Et Ts C 2 Et mechanism: step 2 Ts C 2 Et Ts C 2 Et -Ac Ac Ts C 2 Et

18 Woodward Strychnine synthesis 5 Ac Ts C 2 Et 1. 3, Ac 2. a 2 SS 3 Ac Ts C 2 Et C 2 C 2 ozonolysis mechanism R [1,3]-dipolar cycloaddition R primary ozonide R R S S a secondary ozonide R S S a Ac Ts C 2 Et C 2 C 2

19 Woodward Strychnine synthesis 6 Ts C 2 Et Ac C 2 C 2 Cl, Ts C 2 Et C 2 mechanism: Ts C 2 Et + C 2 C 2 Ts C 2 Et C 2 C 2 Ts C 2 Et C 2 C 2 Ts C 2 Et C 2 Ts C 2 Et + C 2 Ts C 2 Et + Ts C 2 Et + Ts C 2 Et C 2

20 Woodward Strychnine synthesis 7 steps 1& 2: mechanisms Ts C 2 Et C 2 1. I, red P o 2. Ac 2, py. 3. C a, Ac C 2 I P S C 2 Et I C 2 C 2 C 2 C 2 C 2 Ac C 2 C 2 step 3: mechanism diazomethane RC 2 R Ac C 2 C 2 step 4: mechanism Ac C 2 C 2 Ac Ac C 2 Ac C 2 Ac C 2

21 Woodward Strychnine synthesis 8 Ac C 2 1. TsCl, py. 2. PhC 2 Sa 3. Ra-i Ac C 2 step 1: mechanism Ac tol S Cl C 2 Ac tol S Cl C 2 Ac tol S C 2 step 2: mechanism S tol S Ac AcS Ts Ac SBn Ra-i Ac C 2

22 Woodward Strychnine synthesis 9 Ac Ac steps 1&2: C Pd-C 2. K, 2, 3. Ac 2, py. Ac Ac Ac Ac C Pd-C C 2 2. K, 2, C 2 step 3: mechanism Ac Ac Ac Ac Ac Ac Ac

23 Woodward Strychnine synthesis 10 Ac 1. Cl, 2 Ac 2. Se 2, Et step 1: mechanism Ac + Ac hydrolysis of acetamide 2 step 2: mechanism Se Se Se Se Se

24 Woodward Strychnine synthesis 11 step 1: mechanism 1. C C a, TF 2. 2, Pd-BaS 4, quinoline (Lindlar's catalyst) 3. LA, ether a C C a aqueous 2. 2, Pd-BaS 4, quinoline work-up (Lindlar's catalyst) step 2: mechanism Al Li + Li Li + Al Li Al Li + Li Li LA Al Al Li

25 Woodward Strychnine synthesis Br, Ac, 120 o C 2. K, Et STRYCIE step 1: mechanism 2 step 2: mechanism K Et K K Et STRYCIE

26 PhSC 2 C 2 2 lit. 2 C C 2 + SPh 1. m-cpba C 2 SPh 1. ClC 2 C 2 CCl 3, C 2 Cl 2 2. a, 3. 50% aq. a, C 2 Cl 2 ClC 2, Bn() 3 Cl 4. Zn, Ac, TF 50% 1. TFAA tbu t-bu 2 C C 2 BPCl, Et 3 69% 2 C C 2 C 2 CL 2 2. a, TF 72% 2 C C 2 2. g, CdC 3, TF 2 81% 2 C C 2 1. BrC 2 C 2 DBU, tol. 2. B 3 -TF 3. a 2 C 3, 83% C 2 C 2 g(ac) 2 Ac 65% C 2 C 2 1. p-c 6 4 S 2 Cl, DMAP Et(i-Pr) 2 1. TIPSTf, DBU C 2 Cl 2 2. LiB 4, TF, (C 2 C 2 ) 2 2. (Et) 2 P()C 2 C 3. Cl 4 p-c S KMDS, TF p-c S 28% 50% 1. Zn, 2 S 4 2. a, 84% C TIPS 1. DIBA, C 2 Cl 2 2. ab 4, 3. 2 Cl, 4. TBDMSTf, DBU 5. S 3, py, DMS Et 3 p-c 6. F-py S 6% C Magnus, et al., J.Am.Chem.Soc., 1992, 114, 4403~4404. a o -anthracenide 85% Weiland-Gumlich aldehyde aac Ac 2 70% strychnine 27 steps 0.03% overall yield

27 Kuehne: short, convergent total synthesis - [3,3]/Mannich Bn C 2 C BF 3 -Et 2, tol.! Bn [3,3] Bn + C C 2 2 Bn 2 C 10% Cl 4 TF 51% overall Bn 2 C 3 SI n-buli, TF Bn 2 C S Bn 2 C DBU, 65 o C Ph C 2 2, Pd-C 67%, C 2 1. acb 3, Ac 2. Ac 2, py. 83% Ac C 2 Li(TMS) 2 TF (Dieckman) 1. ab 4, 2. Ac 2, py. 64% (3 steps) Ac 1. DBU, diox., 2,! 2. Swern ox. 59% 1. KMDS, TF P C 2 Et Et 2. h" DIBA, BF 3 -Et 2 C 2 87% K, Et 85 o C 17 steps ~2% overall yield isostrychnine 28% strychnine Kuehne, M.E.; Xu, F., J.rg.Chem., 1993, 58, 7490~7497

28 Ac esterase Ac meso Ac 1. MsCl, LiCl 2. CF 3 C 2 a 75% acetylcholine t-bu t-bu C 2 Et t-bu 2. a, 1% Pd 2 (dba) 3 Ac t-bu C 2 Et 88% 1. DIBA 2. TIPSCl, MP TMG 3. Jones ox. 63% 1. ClC 2, py. TIPS t-bu triton B 91% t-bu t-bu CCF 3 t-bu Ac TIPS a, 100 o C C 2 Et t-bu TiCl t-bu 4 98% 1. L-selectride PhTf 2, TF 2. 6 Sn 2, LiCl Pd(PPh 3 ) 4, TF 63% acb 3 3 Sn Ac t-bu t-bu C 2 Et TIPS + 1. Ph TIPS 3 P=C 2 (92%) R 2. TBAF (97%) t-bu K Et 75% DCC, CuCl 80 o C, Ph I t-bu Pd 2 (dba) 3, MP Ph 3 As, C, LiCl 80% t-bu (C 2 ) n, a 2 S 4 C, D 98% + aza-cope + Mannich t-bu 1. LDA, CC 2 2. Cl,, Δ CC 2 = methylcyanoformate (Mander's reagent) C 2 C 2 1. Zn, 10% 2 S 4 2. a, 58% C 2 Knight, S.D.; verman, L.E.; Pairaudeau, G., J.Am.Chem.Soc., 1995, 117, 5776~5788 DIBA C 2 Cl 2 aac, Ac 2 C 2 (C 2 ) 2 Ac, 110 o C 51% Wieland-Gumlich aldehyde (-)-strychnine 25 steps ~3% overall yield

29 chanism of the Fisher Indole Synthesis 2 + *1. Ac,! [3,3] LA 2. Ac 2 Ac aspidospermidine

30 Shibasaki, et al., J.Am.Chem.Soc. 2002, 124,

31 Shibasaki: 31 steps

32 Shibasaki: catalytic, asymmetric Michael-type reaction Li 0.1 mol% Al C 2 C mol% Kt-Bu C 2 C 2 91%, > 99% ee; > 1 Kg no chromatography Shibasaki, et al., J.Am.Chem.Soc. 2002, 124,

33 0.1 mol% C 2 C 2 Li Al 0.09 mol% Kt-Bu 91%, > 99% ee; > 1 Kg no chromatography C 2 C 2 Shibasaki: 31 steps 1. Et Ts 2. LiCl, DMS o C 97% 2 steps C 2 LDA 72% PMB C 2 1. ab 3 C, TiCl 4 2. DCC, CuCl, Ph heat 70% 2 steps E:Z 15.7:1 PMB C 2 1. DIBAl- 2. TIPSTf, Et 3 3. CSA, acetone 61% 3 steps PMB TIPS 1. TMSCl Li >6:1 TMS PMB TIPS Pd(dba) 3 -CCl 3 di-allylcarbonate 90% 2 steps PMB TIPS 1. LDA, TMSCl 2. C 20 mol%yb(tf) 3 3. DBU 57% 3 steps PMB TIPS I 2, DMAP I PMB TIPS 2 Sn 3 Pd(dba) 3, Ph 3 As, CuI >99% 2 PMB TIPS 1. SEMCl, DIPEA (99%) 2. F-Et 3 3. Tf 2, DIPEA; EtS EtS 2 SEM 2 PMB SEt SEt Zn o - 4 Cl 77% 2 steps EtS SEt SEM PMB Shibasaki, et al., J.Am.Chem.Soc. 2002, 124,

34 EtS SEt SEM PMB (DMTSF) S EtS S EtS BF 4 acb 3 86% TiCl 4 (68%) PMB SEM SEM PMB 1. 1 Cl, 55 o C 2. Ac 2, py. 3. a, 4. TIPSCl, DMF, im. 51% 4 steps EtS Ac icl 2, ab 4 61% TIPS Ac TIPS 1. S 3 -py Et 3, DMS 2. F-Et 3 83% 2 steps Ac (+)-diaboline 1. a, 2. aac, Ac 2 42% (-)-strychnine 5.2 mg 12/31 steps = protecting group manipulations 7/31 steps = redox changes 19 wasted steps for PG & redox manipulations Shibasaki, et al., J.Am.Chem.Soc. 2002, 124,

35 Woodward strychnine synthesis: 1 PG for +2 steps I (C 3 ) 3 C 3 1. C 2, 2 C 3 C 3 2. C 3 I C 3 ac, DMF 2. LiAl C 3 C 2 Et C 3 2. TsCl. pyridine Ac Ts C2 Et Ts C2 Et C 3 C 3 C 2 C 3 C 2 C 3 1. ab 4 2. Ac 2 pyridine 1. I, red P o 2. Ac 2 pyridine 3. C Pd-C 2. a 3. Ac 2 pyridine 1. LiAl 4 2. Br, Ac,! 3. 2 S 4 Ac Ts C2 Et Ac C2 C 3 Ac C 2 C 3 C 3 Ac. C 3 C 3 ac 3 C 3 3, Ac 1. Cl, 2 2. Se 2 K, Et Ac Ts C2 Et Ac STRYCIE Cl, C 3 C 2 C 3 C 2 C 3 C 2 C 3 1. C Ca, TF 1. TsCl, pyridine 2. PhC 2 Sa 3. Ra-i o 2. 2, Lindlar's cat.

36 Kuehne strychnine synthesis: 2 PG for + 4 steps Bn C 2 C BF 3 -Et 2, tol.! Bn [3,3] Bn + C C 2 2 Bn 2 C 10% Cl 4 TF 51% overall Bn 2 C 3 SI n-buli, TF Bn 2 C S Bn 2 C DBU, 65 o C Ph C 2 2, Pd-C 67%, C 2 1. acb 3, Ac 2. Ac 2, py. 83% Ac C 2 Li(TMS) 2 TF (Dieckman) 1. ab 4, 2. Ac 2, py. 64% (3 steps) Ac 1. DBU, diox., 2,! 2. Swern ox. 59% 1. KMDS, TF P C 2 Et Et 2. h" DIBA, BF 3 -Et 2 C 2 87% K, Et 85 o C 17 steps ~2% overall yield isostrychnine 28% strychnine Kuehne, M.E.; Xu, F., J.rg.Chem., 1993, 58, 7490~7497

37 Kuehne Synthesis: 4 changes in oxidation state C Bn C 2 BF 3 -Et 2, tol.! Bn [3,3] Bn + C C 2 2 Bn 2 C 10% Cl 4 TF 51% overall Bn 2 C 3 SI n-buli, TF Bn 2 C S Bn 2 C DBU, 65 o C Ph C 2 2, Pd-C 67%, Ac isostrychnine C 2 1. acb 3, Ac 2. Ac 2, py. 83% 1. DBU, diox., 2,! 2. Swern ox. 59% K, Et 85 o C 28% strychnine Ac C 2 1. KMDS, TF P C 2 Et Et 2. h" Li(TMS) 2 TF (Dieckman) 17 steps ~2% overall yield C 2 1. ab 4, 2. Ac 2, py. 64% (3 steps) DIBA, BF 3 -Et 2 87% Kuehne, M.E.; Xu, F., J.rg.Chem., 1993, 58, 7490~7497

38 Rawal: Shortest Synthesis on Record - IMDA & eck Reactions 2 C Br Br a, n-bu 4 Br C 2 C DIBA tol. 96% C 1. Bn 2, Et 2 2. TMSCl, ai, DMF 2 2 Bn 1. ClC 2, acetone 2. Pd/C, C 2 4, I Bn 3 SiCl I TMS Bn 2 2 C 2 2 C + 2 C C 2 1. neat benzene 2. ClC 185 o 2 C PhEt 2 99% 2 C C 2 2 C C 2 TMS-I CCl 3 90% C 2 Br I TBS K 2 C 3, DMF, acetone 74% I TBS Rawal, V..; Iwasa, S., J.rg.Chem., 1994, 59, 2685~ Pd(Ac) 2, K 2 C 3 Bu 4 Cl, DMF 2. 2 Cl, TF 71% isostrychnine 15 steps ~10% overall yield Kuehne/Woodward strychnine

39 7 rings 1 basic 1 seven-membered ring 1 alkene 1 quaternary center 6 stereogenic centers 17 points = 34 steps maximum Funk Analysis strychnine Investigator # of steps verall Yield Year Enantioselective? Woodward 28 <0.001% 1954 racemic Magnus % 1992 racemic Kuehne 17 2% 1993 racemic Rawal 15 10% 1994 racemic verman 25 3% 1995 enantioselective

40 review: John Andraos