Synthetic Approaches to Pyrroloindoline Containing Natural Products. MacMillan Group Meeting Joe Carpenter February 18, 2009
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1 Synthetic Approaches to Pyrroloindoline Containing atural Products MacMillan Group eting Joe Carpenter February 18, 2009
2 Synthetic Approaches to Pyrroloindoline atural Products Presentation outline Introduction to pyrroloindolines thods to construct the pyrroloindoline core Biomimetic approach i. aceimc methods ii. Synthesis from chiral pool iii. Enantioselective synthesis "xoindole" approach i. aceimc methods ii. Synthesis from chiral pool iii. Enantioselective synthesis ther methods Conclusions i. aceimc methods ii. Synthesis from chiral pool iii. Enantioselective synthesis
3 Synthetic Approaches to Pyrroloindoline atural Products Introduction Diverse biological activity of pyrroloindolines calabar alkaloids Alzheimer's anticholinergic organophosphate poisoning flustramines and pseudophyrnamines anticancer activity muscle relaxant cholecystokinin antagonist calycanthaceous alkaloids analgesic antibacterial somatostatin agoinst C 2 ardeemins and amauromine reverse multi-drug resistance in cancer cells vasodilator echitamine alkaloids anticancer Pyrroloindolines are isolated from amphibians, marine organisms and plant sources
4 Synthetic Approaches to Pyrroloindoline atural Products Introduction Substitution pattern around central pyrroloindoline varies greatly calabar alkaloids esermethole = physostigmine = C phenserine = CPh flustramines and pseudophyrnamines calycanthaceous alkaloids chimonanthine = ardeemins and amauromine C 2 echitamine alkaloids echitamine vincorine
5 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Perceived to arise via electrophilic attack at indole C-3 position of tryptophan or tryptamine E 2 E 2 E tryptamine Alkylative cyclization allows rapid access to racemic flustramines C 2 Et Zn(Tf) 2, i-pr 2 Et Bu 4 I Toluene, r.t. 70 % C 2 Et ed-al Toluene 96 % (±) debromoflustramine B Tan, G..; Zhu, X.; Ganesan, A. rg. Lett. 2003, 5, 1801.
6 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Perceived to arise via electrophilic attack at indole C-3 position of tryptophan or tryptamine E 2 E 2 E tryptamine Alkylative cyclization allows rapid access to racemic flustramines C 2 Et Zn(Tf) 2, i-pr 2 Et Bu 4 I Toluene, r.t. 70 % C 2 Et ed-al Toluene 96 % (±) debromoflustramine B Tan, G..; Zhu, X.; Ganesan, A. rg. Lett. 2003, 5, 1801.
7 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach néndez used a similar strategy to access the flustramine core C 2 Et i. IC 2 TMS, Et 3 ii. LiMDS iii. prenyl bromide one-pot 86% C 2 Et Et TMS Li Li Et Li Et López-Alvarado, P.; Caballero, E.; Avendaño, C.; néndez, C. J. rg. Lett. 2006, 8, 4303.
8 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Tryptophan derivitaves give rise to possible diastereomers E 1 C 2 2 E C E exo (kinetic) C 2 E C 2 2 endo (thermodynamic) Combined Yield (%) electrophile 1 2 endo:exo PhthSePh PhthSePh PhthSePh PhthSePh PhthSePh PhthSePh Boc C 2 Bn C 2 S 2 Ph S 2 PMP C 2 Boc C 2 C 2 C 2 C 2 C 2 9:1 1:9 1:12 1:11 <2:98 <2:98 -- Crich, D.; uang, X. J. rg. Chem. 1999, 64, 7218.
9 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Application in Danishefsky's synthesis of amauromine and acetylardeemin Boc C 2 Boc Phth SePh ptsa, a 2 S 4 C 2 Cl 2 78 % PhSe Boc 9:1 d.r. Boc C 2 1. Tf, prenyl Bu 3 Sn 2. a 3. TMSI C 2 Boc BP-Cl Boc C 2 Boc Boc C 2 TMSI amauromine 3 Boc Boc C 2 1. D-Ala- Cl 2. TMSI ClC 1. KMDS 2. PBu 3 3. LDA, AcCl Ac 5--acetylardeemin Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116,
10 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Application in Danishefsky's synthesis of amauromine and acetylardeemin Boc C 2 Boc Phth SePh ptsa, a 2 S 4 C 2 Cl 2 78 % PhSe Boc 9:1 d.r. Boc C 2 1. Tf, prenyl Bu 3 Sn 2. a 3. TMSI C 2 Boc BP-Cl Boc C 2 Boc Boc C 2 TMSI amauromine 3 Boc Boc C 2 1. D-Ala- Cl 2. TMSI ClC 1. KMDS 2. PBu 3 3. LDA, AcCl Ac 5--acetylardeemin Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116,
11 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Application in Danishefsky's synthesis of amauromine and acetylardeemin Boc C 2 Boc Phth SePh ptsa, a 2 S 4 C 2 Cl 2 78 % PhSe Boc 9:1 d.r. Boc C 2 1. Tf, prenyl Bu 3 Sn 2. a 3. TMSI C 2 Boc BP-Cl Boc C 2 Boc Boc C 2 TMSI amauromine 3 Boc Boc C 2 1. D-Ala- Cl 2. TMSI ClC 1. KMDS 2. PBu 3 3. LDA, AcCl Ac 5--acetylardeemin Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116,
12 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach The Joullié group synthesis of roquefortine C uses the same strategy as Danishefsky Boc Boc C 2 2 C 2 1. ATU, i-pr 2 Et Boc 2. EDC CuCl 2 (syn elim) 3. TMSI, C roquefortine C isoroquefortine C more stable by 14kJ/mol not found in nature Shangguan,.; ehre, W. J.; hlinger, W. S.; Beavers, M. P. Joullié, M. M. J. Am. Chem. Soc. 2008, 130, ther electrophiles are also competent for pyrroloindoline formation C 2 C 2 S Cl i-pr 2 Et, C 2 Cl 2 92 % S 1:1 d.r. C 2 C 2 1. aney i, C aq 2. ed-al 3. i. Swern ii. 2 S 3 iii. ab 4 ( )-esermethole Kawahara, M.; ishida, A.; akagawa, M. rg. Lett. 2000, 2, 675.
13 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach The Joullié group synthesis of roquefortine C uses the same strategy as Danishefsky Boc Boc C 2 2 C 2 1. ATU, i-pr 2 Et Boc 2. EDC CuCl 2 (syn elim) 3. TMSI, C roquefortine C isoroquefortine C more stable by 14kJ/mol not found in nature Shangguan,.; ehre, W. J.; hlinger, W. S.; Beavers, M. P. Joullié, M. M. J. Am. Chem. Soc. 2008, 130, ther electrophiles are also competent for pyrroloindoline formation C 2 C 2 S Cl i-pr 2 Et, C 2 Cl 2 92 % S 1:1 d.r. C 2 C 2 1. aney i, C aq 2. ed-al 3. i. Swern ii. 2 S 3 iii. ab 4 ( )-esermethole Kawahara, M.; ishida, A.; akagawa, M. rg. Lett. 2000, 2, 675.
14 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Danishefsky used a slight variation to construct the imastatin core C 2 tbu S 2 anth BS, Et 3 80 % C 2 tbu S 2 anth DMD ab 4 75 % C 2 tbu S 2 anth 1. i. Al(g) ii. CbzCl iii. TBSCl 2. ICl 3. Sn 2 6 Pd(PPh 3 ) 4 3 Sn TBS Cbz Cbz C 2 tbu Pd 2 dba 3 AsPh 3 But 2 C Cbz Cbz TBS TBS Cbz Cbz C 2 tbu himastatin Kamanecka, T. M.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 2993 and 2995.
15 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Danishefsky used a slight variation to construct the imastatin core C 2 tbu S 2 anth BS, Et 3 80 % C 2 tbu S 2 anth DMD ab 4 75 % C 2 tbu S 2 anth 1. i. Al(g) ii. CbzCl iii. TBSCl 2. ICl 3. Sn 2 6 Pd(PPh 3 ) 4 3 Sn TBS Cbz Cbz C 2 tbu Pd 2 dba 3 AsPh 3 But 2 C Cbz Cbz TBS TBS Cbz Cbz C 2 tbu himastatin Kamanecka, T. M.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 2993 and 2995.
16 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Electophilic sources of nitrogen have also been shown to work efficiently C 2 IS, Et 3 I I C 2 TMS Pd(Ac) 2 C % C 2 85% C 2 Also works with tryptophan derivatives (45%) C 2 C 2 C 2 CuI, K 2 C 3 ed-al 89% 89% 2 C (±)-psychotrimine ewhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
17 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Electophilic sources of nitrogen have also been shown to work efficiently C 2 IS, Et 3 I I C 2 TMS Pd(Ac) 2 C % C 2 85% C 2 Also works with tryptophan derivatives (45%) C 2 C 2 C 2 CuI, K 2 C 3 ed-al 89% 89% 2 C (±)-psychotrimine ewhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
18 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Dimerization of benzylic radicals allows access to dimeric structures S 2 Ph C 2 C 2 cyclized with 3 P 4 S 2 Ph C 2 C 2 [CoCl(PPh 3 ) 3 ] 2 C 2 C S 2 Ph S 2 Ph C 2 C 2 4 steps to (+)-chimonanthine Ac C aq ab(ac) 3 ( )-calycanthine 85:15 (+)-chimonanthine 100% (+)-folicanthine Movassaghi, M.; Schmidt, M. A. Angew. Chem. Int. Ed. 2007, 46, 3725.
19 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Dimerization of benzylic radicals allows access to dimeric structures S 2 Ph C 2 C 2 cyclized with 3 P 4 S 2 Ph C 2 C 2 [CoCl(PPh 3 ) 3 ] 2 C 2 C S 2 Ph S 2 Ph C 2 C 2 4 steps to (+)-chimonanthine Ac C aq ab(ac) 3 ( )-calycanthine 85:15 (+)-chimonanthine 100% (+)-folicanthine Movassaghi, M.; Schmidt, M. A. Angew. Chem. Int. Ed. 2007, 46, 3725.
20 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Tryptophan derivatives will react with carbenes to give the pyrroloindoline core upon cyclization Et 2 C Et 2 C C 2 Et 2 Cu(Tf) Et 87%, 16:1 dr ( 30 C) 73%, 1.6:1 dr (r.t.) 15 steps ( )-ardeemin, = ( )-acetylardeemin = Ac Qin uses a tethered carbene to access the fully substituted C-3 of Minfiensine Ts 2 CuTf C 2 9 steps (10 steps) C 2 81% Ts (±)-minfiensine e, B.; Song,.; Du, Y.; Qin, Y. J. rg. Chem. 2009, 74, 298. Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.
21 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Tryptophan derivatives will react with carbenes to give the pyrroloindoline core upon cyclization Et 2 C Et 2 C C 2 Et 2 Cu(Tf) Et 87%, 16:1 dr ( 30 C) 73%, 1.6:1 dr (r.t.) 15 steps ( )-ardeemin, = ( )-acetylardeemin = Ac Qin uses a tethered carbene to access the fully substituted C-3 of Minfiensine Ts 2 CuTf C 2 9 steps (10 steps) C 2 81% Ts (±)-minfiensine e, B.; Song,.; Du, Y.; Qin, Y. J. rg. Chem. 2009, 74, 298. Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618.
22 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Catalytic asymmetric approach to the flustramines by the MacMillan group X enantioinriched pyrroloindoline Bn t Bu X Bn t Bu Bn X t Bu Bn t Bu X Austin, J. F.; Kim, S-G.; Sinz, C. J.; Xiao, W-J.; MacMillan, D. W. C. Proc. atl. Acad. Sci. 2004, 101, 5482.
23 Synthetic Approaches to Pyrroloindoline atural Products Biomimetic Approach Catalytic Catalytic asymmetric approach to the to the flustramines by the by the MacMillan group group enantioinriched pyrroloindoline Boc Bn X t Bu Bn 1. X Bn t Bu p-tsa t Bu 20 mol % 2. ab 4 78% yield 90% ee Bn Boc t Bu X 1. MsCl 2. 2 PhSeC % Boc Grubbs metathesis 94% Bn t Bu Boc 1. TMSI 2. (C) n ab 4 89% ( )-flustramine B X Austin, J. F.; Kim, S-G.; Sinz, C. J.; Xiao, W-J.; MacMillan, D. W. C. Proc. atl. Acad. Sci. 2004, 101, 5482.
24 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach The pyrroloindoline core can also readily be attained through a suitable 2-oxoindole alkylation amination reduction generic 2-oxoindole Julian, P. L.; Pikl. J.; Boggess. D. J. Am. Chem. Soc. 1934, 56, Similarities to biomimetic approach but different oxidation state utilized s BS, tbu TF, 2 83% s Cs 2 C 3 SnBu 3 s s 1. a 2. Cs 2 C 3, PhS 73% alane 62% (±)-flustramine A Fuchs, J..; Funk,. L. rg. Lett. 2005, 7, 677.
25 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach The pyrroloindoline core can also readily be attained through a suitable 2-oxoindole alkylation amination reduction generic 2-oxoindole Julian, P. L.; Pikl. J.; Boggess. D. J. Am. Chem. Soc. 1934, 56, Similarities to biomimetic approach but different oxidation state utilized s BS, tbu TF, 2 83% s Cs 2 C 3 SnBu 3 s s 1. a 2. Cs 2 C 3, PhS 73% alane 62% (±)-flustramine A Fuchs, J..; Funk,. L. rg. Lett. 2005, 7, 677.
26 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Evidence for the indole-2-one intermediate Cs 2 C 3 C Fuchs, J..; Funk,. L. rg. Lett. 2005, 7, 677. Dalko invokes the same intermediate in the synthesis of meso-chimonanthine 3 C 2 Cs 2 C 3 C 2 ed-al 75% 95:5 d.r. 57% 3 desmethyl-meso-chemonanthine C 2 nozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun. 2006,
27 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Evidence for the indole-2-one intermediate Cs 2 C 3 C Fuchs, J..; Funk,. L. rg. Lett. 2005, 7, 677. Dalko invokes the same intermediate in the synthesis of meso-chimonanthine 3 C 2 Cs 2 C 3 C 2 ed-al 75% 95:5 d.r. 57% 3 desmethyl-meso-chemonanthine C 2 nozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun. 2006,
28 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach adical cyclization to provide the oxoindole by Ishibashi 3 steps WE BuSn 3 AIB 72% 98% mix E/Z C C C LA C ab 4 (±)-esermethole (formal synthesis) Ishibashi,.; Kobayashi, T.; Machida,.; Tamura,. Tetrahedron 2000, 56, 1469.
29 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Fujisawa pharmaceuticals thio-claisen route to flustramine C core 2 steps C 2 PS 5, pyr K 2 C 3, I C 2 S not isolated 30% S C 2 S 4 steps (±)-debromo-8,8a-dihydroflustramine C Takase, S.; Uchida, I.; Tanaka,.; Aoki,. Tetrahedron 1986, 42, 5879.
30 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Domino olefination/isomerization/claisen rearrangement sequence to flustramines A and B Ac ex Et Et P C 70% yield 98% ee C Ac ex C Ac ex ex C 3, PPh 3 then Ph 3 PC 2 C 5 steps 54% ( )-flustramine B ex Ac ex Et Et P C 70% yield 98% ee C 7 steps ( )-flustramine A Kawasaki, T.; Shinada, M.; Kamimura, D.; hzono, M.; gawa, A. Chem. Commun. 2006, 420.
31 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Domino olefination/isomerization/claisen rearrangement sequence to flustramines A and B Ac ex Et Et P C 70% yield 98% ee C Ac ex C Ac ex ex C 3, PPh 3 then Ph 3 PC 2 C 5 steps 54% ( )-flustramine B ex Ac ex Et Et P C 70% yield 98% ee C 7 steps ( )-flustramine A Kawasaki, T.; Shinada, M.; Kamimura, D.; hzono, M.; gawa, A. Chem. Commun. 2006, 420.
32 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach verman uses two basic strategies to access the pyrroloindoline core Strategy 1: Intramolecular eck reaction Tf 2 Pd(II) Ligand 2 reduction Strategy 2: oxoindole alkylation 1. + Tf Tf 2. ai LA d.r. depends on groups, base, additives solvent and temp
33 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach verman uses two basic strategies to access the pyrroloindoline core Strategy 1: Intramolecular eck reaction Tf 2 Pd(II) Ligand 2 reduction Strategy 2: oxoindole alkylation 1. + Tf Tf 2. ai LA d.r. depends on groups, base, additives solvent and temp
34 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Possible alkylation transition states proposed by verman Tf Si face alkylation favored M Tf M Tf M e face alkylation Tf M Tf Tf M M pen transition states using Li or K enolates with TF/DMPU major C 2 C 1 minor C 2 uang, A.; Kodanko, J. J.; verman, L. E.J. Am. Chem. Soc. 2004, 126,
35 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Bisalkylation strategy in the synthesis of ( )-phenserine Tf 72% 89:11:<1 Tf major C 2 1. p-tsa 2. ai 4 92% C C 2 Cl LiAl 4 MgS 4 90% 1. B 3 2. PC 75% PhC 2 ( )-phenserine uang, A.; Kodanko, J. J.; verman, L. E.J. Am. Chem. Soc. 2004, 126,
36 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach eck cascade to chimonanthine I Bn Bn I 2 C C 2 LDA LDA, I 2 33% Bn 2 C Bn C 2 Al 3 iodoanaline 92% I Bn Bn I 1. a, Bn 2. BCl ,2-DMP, CSA 49% I Bn Bn I (P 3 P) 2 PdCl 2 90% Bn Bn CSA, ab 4 Pb(Ac) 4 ab 4 88% Bn Bn 6 steps 68% ( )-chimonanthine Ac (+)-calycanthine verman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc. 1999, 121, 7702.
37 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Combination of alkylation and eck reaction in verman synthesis of idiospermuline 4 steps Bn Tf LMDS 75% Tf Bn 10 steps Bn 5 steps Pd(Ac) , Pd() 2 Tf Ts (S)-Tol-BIAP 97%, 6:1 d.r. Ts 2. ed-al then a 3 idiospermuline verman, L. E.; Peterson, E. A. Angew. Chem. Int. Ed. 2003, 42, 2525.
38 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Zhu uses a domino eck-cyanation sequence to obtain the oxoindole Pd(Ac) 2 C base Pd 0 L n L I PdL n C PdL n I PdIL n Pinto, A.; Jia, Y.; euville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.
39 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Zhu uses a domino eck-cyanation sequence to obtain the oxoindole I 2 steps [Pd(dba) 2 ] (S)-DIFLUPS 78% yield, 72%ee C 1. LA 2. C, ab 4 60% esermethole F F F F PPh 2 PPh 2 (S)-DIFLUPS Pinto, A.; Jia, Y.; euville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.
40 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Zhu uses a domino eck-cyanation sequence to obtain the oxoindole I 2 steps [Pd(dba) 2 ] (S)-DIFLUPS 78% yield, 72%ee C 1. LA 2. C, ab 4 60% esermethole F F PPh 2 PPh 2 F F esermethole (S)-DIFLUPS C 2 physostigmine Pinto, A.; Jia, Y.; euville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.
41 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Trost asymmetric allylation in the synthesis of ( )-physostigmine 1 1 Mo(0), Base allyl carbonate % yield % ee Proposed model for enantiodescrimination Ar 1 C Mo C 2 favored 1 2 Ar 2 Mo C 1 C disfavored 1 2 Trost. B. M. Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
42 Synthetic Approaches to Pyrroloindoline atural Products The 2-xoindole Approach Trost asymmetric allylation in the synthesis of ( )-esermethole and ( )-physostigmine 2 steps Mo(C 7 8 )(C) 3, L* LitBu TF 98% yield 82% ee tbu s 4, M ai 4 92% recrystallize to 99% ee 2, Et 3 LiAl 4 2 steps PhC 2 ( )-esermethole ( )-physostigmine Trost. B. M. Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
43 Synthetic Approaches to Pyrroloindoline atural Products ther thods Bis-enamine rearrangement to pyrroloindoline core of calabar alkaloids 200 C 2 C 2 C C 2 91% Santos. P. F.; Srinivasan,.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005, 61, Dimethallyl rearrangement to flustramine C BS, r.t. 90% [1,5] (±)-flustramine C Lindel, T.; äuchle, L.; Golz, G.; Böhrer, P. rg. Lett. 2007, 9, 283.
44 Synthetic Approaches to Pyrroloindoline atural Products ther thods Bis-enamine rearrangement to pyrroloindoline core of calabar alkaloids 200 C 2 C 2 C C 2 91% Santos. P. F.; Srinivasan,.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron 2005, 61, Dimethallyl rearrangement to flustramine C BS, r.t. 90% [1,5] (±)-flustramine C Lindel, T.; äuchle, L.; Golz, G.; Böhrer, P. rg. Lett. 2007, 9, 283.
45 Synthetic Approaches to Pyrroloindoline atural Products ther thods [4+1] cyclization of a bis(alkylthio)carbene and indole isocyanate PrS PrS C 3 PhCl, reflux then LA 72% PrS SPr C PrS SPr igby, J..; Sidique, S. rg. Lett. 2007, 9, Aza-Pauson-Khand-type reaction of alkynecarbodiimides TMS Co 2 (C) 8 TMTU 74% TMS acb 3 C 79% TMS 3 steps 3 steps to esermethole Aburano, D.; Yoshida, T.; Miyakoshi,.; Mukai, C. J. rg. Chem. 2007, 72, 6878.
46 Synthetic Approaches to Pyrroloindoline atural Products ther thods [4+1] cyclization of a bis(alkylthio)carbene and indole isocyanate PrS PrS C 3 PhCl, reflux then LA 72% PrS SPr C PrS SPr igby, J..; Sidique, S. rg. Lett. 2007, 9, Aza-Pauson-Khand-type reaction of alkynecarbodiimides TMS Co 2 (C) 8 TMTU 74% TMS acb 3 C 79% TMS 3 steps 3 steps to esermethole Aburano, D.; Yoshida, T.; Miyakoshi,.; Mukai, C. J. rg. Chem. 2007, 72, 6878.
47 Synthetic Approaches to Pyrroloindoline atural Products ther thods Asymmetric synthesis of calabar alkaloids by gasawara 3 steps 71% 2 2 Cl, C aq ab(ac) 3 ai 4 52% (one pot) C 2 Cl LiAl 4 54% ( )-esermethole Tanaka, K.; Taniguchi, T.; gasawara, K. Tetrahedron Letters 2001, 42, 1049.
48 Synthetic Approaches to Pyrroloindoline atural Products ther thods verman synthesis of (+)-minfiensine Boc Pd(Ac) 2, L* Boc TFA Tf C 2 85% yield 99% ee C 2 2 C Boc PPh 2 t-bu Dounay, A. B.; umphreys, P. G.; verman. L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.
49 Synthetic Approaches to Pyrroloindoline atural Products ther thods verman synthesis of (+)-minfiensine Boc Pd(Ac) 2, L* Boc TFA Tf C 2 85% yield 99% ee C 2 2 C Boc 1. 9-BB 2 2, a 2. TPAP, M 63% 25% isomer 2 C PPh 2 Boc 1. TFA t-bu 2. I 2 C 65% I PdCl 2 (dppf) 74% 2 C 1. amds Comins' reagent 2. Pd(Ac) 2, PPh 3 C, 77% 2 C C 2 1. LiAl 4 2. a (+)-minfiensine Dounay, A. B.; umphreys, P. G.; verman. L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368.
50 Conclusions Each method has its strengths and weaknesses Biomimetic approach is rapid and tryptophan is an abundant source of chiral material Few enantioselective methods for pyrroloindoline construction have been developed Efficiently obtaining fully-substituted vicinal stereocenters of the pyrroloindoline core remains a challenge
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