Total Syntheses of Manzamine A.
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1 Total yntheses of Manzamine. R E Winkler, 1998 hv D B R akagawa, 2000 [4+2] B R Me P 2 Me B TBDP Pandit, 1991 [4+2] E manzamine Martin, 1999 [4+2] R Me 2 B R R Ramil Baiazitov. ED group meeting. February 21, 2006
2 Manzamine!-carboline D E B aliclona (igmadocia) caerulea Blue aribbean sponge aribbean and awaiian Islands Isolated: iga, T. et al J, 1986, 108, 6404 manzamine Exact Mass: Rings: eight total, five aliphatic (BDE), one 13-membered, one 8-membered, β-carboline Two Z-double - bonds X-ray of l salt tereocenters: five on carbon, four contiguous, one quaternary, one tetrasubstituted
3 Manzamine lkaloids manzamine manzamine B manzamine manzamine F manzamine
4 Manzamine lkaloids 2 2 tryptophan 2 DDQ 1. Pictet-pengler: 37% 2. x: 54% ircinol ircinal manzamine antipodes 2 DDQ ircinol B ircinal B manzamine J Kobayashi, J. et al. J 1992, 57, 2480
5 Biosynthetic ypothesis 2 2 tryptophan 11 3 manzamine dienophile diene dipolarophile Baldwin, J. E.; Whitehead, R.. Tet. Lett., 1992, 33, 2059
6 dienophile Biosynthetic ypothesis! 3 diene 2' 2 2 ircinal B! manzamine B allylic oxidation 2' manzamine keramaphidin B % Baldwin, J. E. et al. hem. Eur. J., 1999, 5, 3154 epoxide rearrangement
7 Pandit s ynthesis of the BDE fragment. Retrosynthesis. D E B D "-carboline 2 Me B D E no 1,5- shift 2 Me [] [4+2]! chirality 2 Me Z-diene manzamine 2 Me 2 Me P I P 2 2 L-serine Pandit, U. K. et al. Tetrahedron, 1991, 47, 2005
8 Pandit s ynthesis of the Diene. 2 Me TBDP Me Me 1. DIBL- PPT 2. ab Me 46% 100% TBDP 1. a(b 4 ) 2 TF/Et, 100% 2. I 2, PPh 3, Im, 79% x DIBL or LiB 4 : stops at aldehyde, low yield I 1. l, 100% 2. TBDPl, 90% I TBDP I TBDP a, DME rt, 7 days 49%, brsm TBDP quinoline, PPT Dina-tark - 2 TBDP 2 TBDP Pandit, U. K. et al. Tetrahedron, 1991, 47, 2005
9 Pandit s ynthesis of the Diene. 2 Me Me Me 100% PPT 2 Me 1. a(b 4 ) 2 TF/Et, 100% 2. I 2, PPh 3, Im, 79% x DIBL or LiB 4 : stops at aldehyde, low yield I 1. l, 100% 2. TBDPl, 90% I TBDP I TBDP a, DME rt, 7 days 49%, brsm TBDP quinoline, PPT Dina-tark - 2 TBDP 2 TBDP Pandit, U. K. et al. Tetrahedron, 1991, 47, 2005
10 Pandit s ynthesis of the Diene. Methylenation.!-alkylation "-alkylation Me 2 1. LiMD 2. Me 2 = 2 TBDP 43% Me 2 TBDP 28% TBDP TMTf TM TBDP Me 2 Me 85% TBDP sterics + electronics!-alkylation Me 2 1. MeI 2. DBU 77% 86% brsm 2 TBDP 2 TBDP Pandit, U. K. et al. Tetrahedron, 1991, 47, 2005
11 Regioselectivity (α vs. γ) TM Li 2 Me Me 2 Me Me
12 Pandit s ynthesis of the D-ubstrate. 2 Me 2 Me! 2 Me Br then l 88% 1. 3, then Zn, c 2. Ph 3 P= 2 Me 76% BF 3, Me TM 77% E/Z=15/1 2 Me Br, c 92% 2 Me " "/!=1/1 2 Me 2 Me 2 Me 2 Me gtf slow 2 Me TBDP DIPE fast TBDP could be isolated 67% TBDP Pandit, U. K. et al. Tetrahedron, 1991, 47, 2005
13 Pandit.. Making the eart of Manzamine. 2 Me TBDP 130 o, 4 h 90%, dr=3.5/1 The "heart" of manzamine 2 Me 1. s 4, Py 2. a 3 3. PPT 78% 2 Me TBDP 2 Me TBDP 69% 21% manzamine TBDP Pandit, U. K. et al. Tetrahedron, 1991, 47, 2005
14 The Transition tate. not conjugated
15 MEM? BrMg TBDP (y 3 P) 2 l 2 Ru==Ph 2 10%, PhMe, rt, 18 h, 55% Pandit.. DE Rings ynthesis. only allyl reacted in the model TBDP MEM MEM TBDP 1. Li, 3 2. I( 2 ) 4 = 2 1. TBF 2. Dess-Martin 3. Ph 3 P= 2 MEM MEM TBDP 1. K/Me 2. 2 =( 2 ) 3 2 ED MEM (y 3 P) 2 l 2 Ru==Ph 2 15%, PhMe, 50 o, 5% D MEM B E D E B First synthesis of the BDE system Pandit, U. K. et al. Pure&ppl. hem. 1996, 68, 659 manzamine
16 Pandit s ynthesis of the BDE fragment. ummary. RM 5% D E B MEM RM 55% D 2 Me B D E 2 Me [] [4+2] chirality! 2 Me Z-diene 90% dr=3.5/1 D B E manzamine
17 akagawa s s BE ynthesis. Retrosynthesis. R 1 B E R 1 R 3 2 R 2 R 1 ir 3 Me R 3 2 R 2 manzamine ow does the substituent R 1 on the nitrogen effect the electrophilicity of the dienophile? akagawa, M. J. eterocyclic hem., 2000, 37, 567
18 akagawa s s Total ynthesis. Models. electronics of the 3-unsubstituted dienophile R 1 3 Me ir 3 R 1 Me M: LUM: xylene, reflux, 5 h R t-bu M: LUM: xylene, reflux, 5 h R 2 M: LUM: xylene, reflux, 5 h 57% Me 2 M: LUM: xylene, reflux, 5 h 50% Me TM M: LUM: ow e-poor the dienophile is? akagawa, M. J. eterocyclic hem., 2000, 37, 567
19 akagawa s s Total ynthesis. Models. 3-alkyl substituted dienophile Me 3 2 Me 2 Me TM xylene x Me decomposition R 1 Me Me 3 2 Me 2 Me Me TM p-cymene, then Ts 27% R akagawa, M. J. eterocyclic hem., 2000, 37, 567
20 1. igh Pressure D akagawa. Further ptimization. Me 2 Me 2. More stable substrate Boc 2 Me Me TM Kb, 90h, PhMe 2. Ts Boc Me 2 Me 1. TF 2. K % Ts dr=1/1 Me 2 Me 2 F 3 MM 2 Me Me TM o, 5h 2. 93% Bs MM F3 TETf 78% Ts F3 easier to prepare 2 Me dr=1/1 2 Me Ts Ph F 3 MM 2 Me 8 steps intra acylation >58% wittig akagawa, M. J. eterocyclic hem., 2000, 37, 567
21 akagawa. Regioselectivity. 2 F 3 MM 2 Me Me TM 85% F 3 Me MM not observed 2 Me 2 TM Bs Bs Me 2 Me 2 Me Me MM F 3 MM F 3
22 akagawa. Regioselectivity. TM Me Me Me 2 Me Me Me observed regioselectivity Me Me Me Me Me 2 opposite regioselectivity Me TM
23 akagawa. Use of ptically Pure Dienophile. Bs Bs= 2 Ph Bs 5 steps Bs Bs Me TB 180 o 20 h then TF Bs Bs Bs Bs 45% dr= % 10 steps Boc 2 1. TF 2. BPl/TE 32% l P BPl B D akagawa, M. J. eterocyclic hem., 2000, 37, 567
24 akagawa s s BE ynthesis. ummary. B E Bs Bs Bs 95% dr=1.13 Bs TB BsMe acylation 32% e-withdrawing protective group (sulfamide) on the lactam is necessary to activate the dienophile very poor diastereoselectivity manzamine akagawa, M. J. eterocyclic hem., 2000, 37, 567
25 Winkler s s Total ynthesis of Manzamine. Retrosynthesys. D E B Pictet- pengler X R X R manzamine ircinal The intramolecular vinylogous amide photoaddition/fragmentation/ Mannich closure sequence hv X R X R X R Prof. Jeffrey D. Winkler University of Pennsylvania, Philadelphia Winkler, J. D.; xten, J. M. J, 1998, 120, 6425
26 Photoaddition/fragmentation/Mannich closure sequence. Model tudy. conformer 1 0 kcal/mol Boc Py, c Me, reflux 58% Boc desired X-ray Boc conformer 2 Boc 3.2 kcal/mol Boc opposite stereoselectivity undesired not observed Winkler, J. D.; ouk, K.. et al. Tetrahedron, 1998, 54, 7045
27 Boc Photoaddition/fragmentation/Mannich DM, rt, 4h, 99% closure sequence Boc hv Boc Boc Boc Py, c reflux, 4h 20% from Boc Boc not determined Winkler, J. D.; xten, J. M. J, 1998, 120, 6425
28 Winkler s s Total ynthesis Boc TB Boc Ph Me 2 e 1. TBl 2. KMD, Me 2 78% dipole repulsion? 2 2 py 48% TB TB Boc Boc Me 2 2 Me eph 1. ab4 2. Msl 3. DBU 80% 1. LiTMP 2. Phel 1. LiTMP 2. Phel 78% 40% 2 Me Boc TB dr=2/1 2 Me Boc TB Boc 2 Me 1. mpb, 2. ame, 69% TB Winkler, J. D.; xten, J. M. J, 1998, 120, 6425
29 Winkler s s Total ynthesis Boc 2 Me 1. TBF, 94% 2. Tsl, 96% 3. TF, 100% 4. DIPE, 12% 2 Me TB Ts 2 Me 1. DIPE, 89% 2. Lindlar, 94% 2 Me 1. DIBL 2. Dess-Martin 75% ircinal 2 DDQ 50% TF 58% manzamine D manzamine Winkler, J. D.; xten, J. M. J, 1998, 120, 6425
30 Winkler s s Total ynthesis of Manzamine. ummary. D E B Pictet- pengler alkyne (89%) vs alkene (12%) cyclization Ts 2 Me [2+3] manzamine ircinal Boc The intramolecular vinylogous amide photoaddition/fragmentation/ Mannich closure sequence hv 20%? one diastereomer? Boc
31 Martin s s Total ynthesis. Retrosynthesis. Prof. tephen F. Martin University of Texas, ustin D E B Pictet- pengler 8, 13- membered rings RM R 2 R 1 R 5 R 4 R 3 manzamine ircinal R 2 R 1 R 5 R 4 IMD R 2 R 5 R 1 R 4 vinylogous amide. e-poor? or e-rich? R 2 l R 1 R 4 R 5 trisubstituted homoallylic amine Is the dienophile e-poor or e-rich?
32 Martin s s Total ynthesis. Model. M. R 1 R 1 l R 2 R 5 R 4 R 2 R 5 R 4 1. n-buli 2. u()li u 2- Li u 2 l 21% 1. Tsl 2. 2 e-rich e-neutral E-dienes R 1 2 Et 1. LiMD 2. l 2 2 Et 1. 2, Pd 2. ab 4 ; l 72% 4 steps 2 2 Et 1. (l) 2 2. mine 77-86% 2 Et Martin,. F. et al J, 2002, 124, 8584 Kocienski, P.; Wadman,. J, 1989, 111, 2363
33 Martin s s Total ynthesis. E-Rich Dienes. E Z R 1 2 Et R 1 2 Et 1. R 1 = (e-neutral diene), a. 180 o, 81%, d/u=2/1; b. Etll 2, 110 o, 17 h: 71%, d/u=6/1 2. R 1 = 2 (e-rich diene), a. Thermal: d/u=2/3; b. Etll 2 : d/u=3/2 desired R 1 2 Et impossible? R 1 undesired 2 Et 1. R 1 = (e-neutral diene), Etll 2 (1.5 eq), 120 o, 100h, 70%, d/u=8/1; thermally- less pure 2. R 1 = 2 (e-rich diene), a. Thermal: stable at <150 o, undesired at 200 o ; slightly better with Etll2 Is the dienophile e-rich? Martin,. F. et al J, 2002, 124, 8584
34 Martin. Electronics of the Diene. LUM: ev M: ev LUM: ev (9.541) M: ev (8.700) LUM: ev (9.445) M: ev (8.835) LUM: ev (8.813) M: ev (9.211) Me Me Me Me Me 2 Me Me 2 2 Me 2 e-rich e-neutral e-poor LUM: ev M: ev Me Me even more e-rich dienophile nother proof that the dienophile I e-rich TBDP R TBDP 2 Me R=Boc, 150 o, 48 h 74% R=, 80 o 2 Me R Martin,. F. et al J, 2002, 124, 8584
35 Martin s s Total ynthesis. E-Poor Diene. 2 Me TBDP( 2 ) 5 Boc 71% TBDP( 2 ) 5 Boc Br 1. PPh 3 2 Me 91% 2. TMTf, then Ts 91% TBDP( 2 ) 5 2 Br p-ts pyroglutaminol acylation 2 a ab 4 Boc TBDP (l) 2 then Et 3 79% R Br 2 Me R TBDP nbu 3 Pd(PPh 3 ) 4 toluene R! 2 Me R 68% TBDP( 2 ) 5 2 Me Boc TBDP TBDP Martin,. F. et al J, 2002, 124, 8584
36 Martin s s Total ynthesis. Bold RM. TBDP( 2 ) 5 2 Me Boc r 3, 20 equiv 30 equiv TBDP( 2 ) 5 2 Me Boc 1. l, Me 2. wern 3. Ph 3 P= 2 47% TBDP DM, -18 o 63% TBDP 2 Me (Me) 2 Boc 1. DIBL 2. Dess-Martin 53% Boc RLi x acylation? 15-membered (Me) 2 (Me) 2 not observed Martin,. F. et al J, 2002, 124, 8584
37 Martin s s Total ynthesis. tepwise RM. (Me) 2 Boc 65% Li (Me) 2 Grubbs I 67% Z-selective free amine present (Me) 2 X-ray 1. K, Me 2. cylation 75% (Me) 2 1. Grubbs I 2. l 26% proximal = bond? Martin,. F. et al J, 2002, 124, 8584
38 Martin s s Total ynthesis. ompletion. 2 DIBL Dess-Martin 63% 89% ircinal 2 DDQ TF Kobayashi manzamine D manzamine Martin,. F. et al J, 2002, 124, 8584
39 ummary. 1. First total synthesis 2. [2+2] then rearangements R E B 2 Me TBDP Winkler, 1998 hv, 20% Pandit, 1991 [4+2], 69% 1. The first synthesys of BDE 2. Use of Z-diene for [4+2] D E manzamine 1. BE fragment 2. Poor diastereoselectivity 3. Influence of the substitution on the nitrogen studied B R akagawa, 2000 Martin, 1999 [4+2], 68% [4+2], 45% R Me 2 B R B R R Me 1. econd and last total synthesis 2. Vinylogous amide is an e-poor dienophile 3. RM, 13: 67%, 8: 26% P by RM 8-membered ring was more difficult to form than the 13-membered
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