Enantioselective Total Synthesis of (+)-Homochelidonine by a Pd II - - - PowerPoint PPT Presentation

▶

Nov 14, 2023 39 likes •204 views

Enantioselective Total Synthesis of (+)-Homochelidonine by a Pd II - Catalyzed Asymmetric Ring-Opening Reaction of a meso -Azabicyclic Alkene with an Aryl Boronic Acid Helen A. McManus, Matthew J. Fleming and Mark Lautens* Angew. Chem. Int. Ed.

SLIDE 1

Enantioselective Total Synthesis of (+)-Homochelidonine by a PdII- Catalyzed Asymmetric Ring-Opening Reaction of a meso-Azabicyclic Alkene with an Aryl Boronic Acid

Helen A. McManus, Matthew J. Fleming and Mark Lautens*

Angew. Chem. Int. Ed. 2007, 46, 433

Amol Kulkarni @ Wipf Group 1 1/14/2007

SLIDE 2

Introduction

Hexahydrobenzo[c]phenanthridine class of alkaloids
1 and 2 isolated from the roots of Chelidonium majus
Cytotoxic, inhibits tubulin polymerization
Major component of the drug Ukrain, a semisynthetic

preparation from C. majus alkaloids

Fully aromatic A and D rings, partially hydrogenated B and

C rings, C11-hydroxy group and 3-contiguous syn- stereocenters

NMe O O MeO OMe HO A B C D

(+)-homochelidonine (1)

NMe O O HO O O

(+)-chelidonine (2)

NH O O HO O O

(-)-norchelidonine (3)

NMe O O HO MeO

(+)-chelamidine (4)

OMe OH NMe O O HO O O

(+)-chelamine (5)

Amol Kulkarni @ Wipf Group 2 1/14/2007

SLIDE 3

Total Synthesis of Chelidonine

First total synthesis of dl-chelidonine using intramolecular

[4+2] cycloaddition strategy

Oppolzer, W. and Keller, K. J. Am. Chem. Soc. 1971, 93, 3836

N H O OBn

1. NaH, DMF, 0˚C

2. Br O O O O N O OBn O O NaI (cat.)

1. Br2, CH2Cl2, -12 ˚C
2. KOt-Bu
3. DBU, HMPA

N O OBn O O

-xylene, 120 ˚C

N O OBn O O [4+2] N O O O O O O O O O O OBn O N O O O O H3C H H OH H

chelidonine 1 2 3 4 5

Amol Kulkarni @ Wipf Group 3 1/14/2007

SLIDE 4

Total Synthesis of Homochelidonine

15 linear steps, 11 % overall yield

Yoshida, M.; Watanabe, T; Ishikawa, T. Tetrahedron Lett. 2002, 43, 6751

O O O O O MeO MeO

Arnottin

1. OsO4; NaHSO3
2. (CH3)2C(OCH3)2

p-TsOH. H2O, DMF O O O O O MeO MeO O O 1

1. NH2OH.HCl, pyridine,

0˚C, 2h

2. TiCl3, NaBH3CN,

NH4OAc, dioxane O NH2 O O O MeO MeO O O 2

1. LiAlH4, THF, rt
2. (CF3CO)2O, pyridine
3. NaHCO3 (aq.), MeOH

O O O O OH MeO OMe NHCOCF3 HO DEAD, PPh3, THF rt, 3 h O O O O MeO OMe NCOCF3 HO NMe O O MeO OMe HO

Homochelidonine

3 4

Amol Kulkarni @ Wipf Group 4 1/14/2007

SLIDE 5

Homochelidonine: Retrosynthetic Analysis

Ring-opening of azabicyclo-alkene with aryl

boronic acid as the key step in synthesis

NMe O O HO OMe MeO NBoc O O OMe MeO O NBoc O O OMe MeO HN O O OMe MeO Boc OPG PdII-catalyzed asymmetric ring-opening reaction OMe MeO OPG B(OH)2 N O O Boc + 1 2 3 4 5

McManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433

Amol Kulkarni @ Wipf Group 5 1/14/2007

SLIDE 6

Pd-Catalyzed Alkylative Ring Opening

The product was obtained in good yield and

as a single diastereomer

Lautens, M.; Renaud, J.-L.; Hibbert, S. J. Am. Chem. Soc. 2000, 122, 1804

O R2Zn (1.5 equiv), CH2Cl2 Pd(dppf)Cl2 (5 mol %), rt OH R R Me Et t-Bu vinyl TMSCH2 yield (%) 80 92 72 55 67 de (%) > 98 > 98 > 98 > 98 > 98 O OPMB OPMB + Me2Zn Pd(dppf)Cl2 (5 mol %) 1,2-DCE, reflux, 60 % OPMB OPMB OH Me O Pd(CH3CN)2Cl2 (5 mol %), L* Et2Zn (1.5 equiv), CH2Cl2, rt OH Et L = (R)-tol-BINAP

4, 98 % yield 96 % ee 1 2 3

Amol Kulkarni @ Wipf Group 6 1/14/2007

SLIDE 7

Proposed Mechanism

Carbopalladation: rate-limiting step

Lautens, M.; Hibbert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001, 123, 6834

Pd Cl Cl P P R2Zn transmetalation Pd R X P P (X = R or Cl) Substrate R2Zn O Pd P P R syn-carbopalladation O P P R Pd

oxygen

elimination R OPdL2X + R2ZnX- R OZnX

1 2 3 4 5

Amol Kulkarni @ Wipf Group 7 1/14/2007

SLIDE 8

Addition of Aryl Boronic Acids to Bicyclic Alkenes

Addition of heteroaryl boronic acids to oxa- and aza-

bicyclic alkenes

Lautens, M.; Dockendorff, C. Org. Lett. 2003, 5, 3695

O ArB(OH)2 (1.2 equiv) Pd(DPPP)Cl2 (1 mol %) Cs2CO3 (5.0 M in H2O) (1.0 equiv) MeOH, rt OH Ar OH OH OH OH Br OMe MeO O 83 % 74 % 86 % 83 % Boc N ArB(OH)2 (1.5 equiv) Pd(DPPP)Cl2 (1 mol %) Cs2CO3 (5.0 M in H2O) (1.0 equiv) MeOH, 60 ˚C, 15 h NHBoc Ar NHBoc NHBoc NHBoc NHBoc Me2N OMe 71 % 93 % 86 % 99 % O S 1 2 3 4

Amol Kulkarni @ Wipf Group 8 1/14/2007

SLIDE 9

Homochelidonine: Retrosynthetic Analysis

NMe O O HO OMe MeO NBoc O O OMe MeO O NBoc O O OMe MeO HN O O OMe MeO Boc OPG PdII-catalyzed asymmetric ring-opening reaction OMe MeO OPG B(OH)2 N O O Boc + 1 2 3 4 5

McManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433

Amol Kulkarni @ Wipf Group 9 1/14/2007

SLIDE 10

Synthesis of the Intermediates

McManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433

MeO MeO Br Br BBr3, CH2Cl2 rt, 2 h, quant. HO HO Br Br CH2BrCl, Cs2CO3 DMF, 110 ˚C, 3 h 75 % Br Br O O N-Boc-pyrrole n-BuLi, PhMe,

78 ˚C to rt, 17 h

71 % Boc N O O MeO OMe OH NBS, THF, rt 30 min, 89 % MeO OMe OH Br CH2(OMe)2, LiBr, TsOH rt, 15 h, 72 % MeO OMe Br OMOM 1.n-BuLi, THF, -78 ˚C, 45 min then B(OiPr)3, -78 ˚C to rt

2. aq. NH4Cl

(63 %) MeO OMe B(OH)2 OMOM

1 2 3 4

Amol Kulkarni @ Wipf Group 10 1/14/2007

SLIDE 11

Asymmetric Ring-Opening Reaction

McManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433

Amol Kulkarni @ Wipf Group 11 1/14/2007

SLIDE 12

Acid-stable protecting group on the Nitrogen

McManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433

Protecting Group Manipulations

Amol Kulkarni @ Wipf Group 12 1/14/2007

SLIDE 13

Completion of the Synthesis

McManus, H.; Flemming, M.J.; Lautens, M. Angew. Chem. Int. Ed. 2007, 46, 433

Amol Kulkarni @ Wipf Group 13 1/14/2007

SLIDE 14

Conclusion

Enantioselective total synthesis of (+)-

Homochelidonine was achieved in 14 steps with 15 % overall yield from 4,5-dibromovertrole.

A new and general strategy for the synthesis of

hexahydrobenzo[c]phenanthridine alkaloids using highly enantioselective Pd(II)-catalyzed ring-

pening reaction of a meso-azabicycle with aryl

boronic acid has been established.

Application of this methodology to the synthesis
f other alkaloids is under investigation.

Amol Kulkarni @ Wipf Group 14 1/14/2007

SLIDE 15

Phosphine Ligands

PPh2 PPh2 (S)-BINAP P(tol)2 P(tol)2 (S)-tol-BINAP PPh2 H3C Ph2P CH3 H H (S,S)-chiraphos O O (S)-monophos P NMe2 O O O O PAr2 PAr2 (S)-segphos OMe t-Bu t-Bu Ar = P P Me-duphos Fe PPh2 PPh2 dppf

Amol Kulkarni @ Wipf Group 15 1/14/2007

SLIDE 16

ROH + LiBr + CH2(OCH3)2 p-TsOH (cat.) H O OCH3 Li Br R O CH3 H + p-TsO- ROCH2OCH3 + LiBr + CH3OH

Gras, J.-L. et al., Synthesis 1985, 74-75.

Amol Kulkarni @ Wipf Group 16 1/14/2007