synthesis of alkaloid ( )-205b via stereoselective

Synthesis of Alkaloid (−)-205B via Stereoselective Reductive Cross-Coupling and Intramolecular [3+2]

Cycloaddition

Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 15237-15240.

Kara George Rosenker Current Literature 6 October 2012

N

H

H

Me

HMe

Me

NH

MeMe

H H

H

Me

H

(!)-205B

Kara Rosenker @ Wipf Group of 16 10/6/2012

(−)-205B Isolation, Structure, and Biological Activity

§  Isolated in 1987 by Daly and co-workers from the skin extracts of the Panamanian frog Dendrobates pumilio

§  The structure was first reported as 1 and revised in 1998 by Daly and co-workers based on extensive FTIR, NMR, and HRMS

§  The absolute sterochemistry was reported in 2003 by Toyooka and co-workers based on their total synthesis of (+)-205B

§  (−)-205B possesses an unusual and unique 8b-azaacenaphthylene ring system containing 5 asymmetric centers

§  Target of interest due to intriguing structure and the discovery that the unnatural enantiomer, (+)-205B, blocks the 7α nicotinic acetylcholine receptor in a selective fashion

Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M. W.; Daly, J. W. Tetrahedron 1987, 43, 643. Tokuyama, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. An. Asoc. Quim. Argent. 1998, 86, 291. Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Angew. Chem. Int. Ed. 2003, 42, 3808. Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.; Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004, 66, 1061.

N

H

H

Me

HMe

Me

NH

MeMe

H H

H

Me

H

(!)-205B

N

H

H

Me

HMe

Me1

5a

8

2a

5a

8

2a


Toyooka and Co-Workers: (+)-205B

Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Angew. Chem. Int. Ed. 2003, 42, 3808. Tsuneki, H.; You, Y.; Toyooka, N.; Kagawa, S.; Kobayashi, S.; Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004, 66, 1061.

N

H

H

Me

HMe

Me(!)-205B

Intramolecular MannichN

H

H

Me

HMe

Me(+)-205B

5a

8

2aBocN

HMe

HMe

OO

EtO2C

NO

O

CO2MeH

Me H

NO

O

CO2MeH

Me H MeH

Asymmetric Conjugate Addition

NMeO2CH

Me H

CO2Me

H OTBDPSNMeO2CCO2Me

H OTBDPS

Asymmetric Conjugate Addition

Absolute Stereochemistry

§  30 steps (longest linear) §  Determined the absolute stereochemistry of the natural product to

be (−)-205B §  Key features:

§  Stereocontrolled Michael-type additions to enaminoesters


Smith and Co-Workers: (-)-205B

Smith, A. B; Kim, D.-S. Org. Lett. 2005, 7, 3247.

§  19 steps (longest linear) §  5.6% overall yield §  Key features:

§  Dithiane three-component linchpin coupling §  One-pot sequential construction of the indolizidine ring

N

H

H

Me

HMe

Me(!)-205B

N

H

H HO

HMe

SS

Me

OTBDPS

OTBSTsHN

OO

SS

OO

TsNS S

TBS Me

OTBDPS

O

RCMOne-pot Sequential

Cyclization

Three-Component Linchpin Coupling


Comins and Co-Workers: (-)-205B

Tsukanov, S. V.; Comins, D. L. Angew. Chem. Int. Ed. 2011, 50, 8626.

§  11 steps (longest linear) §  8% overall yield §  Key features:

§  Asymmetric N-acylpyridinium reaction §  Tsuji-Trost allylic amination of a vinylogous amide

N

H

H

Me

HMe

Me(!)-205B

NH

MeO

Me NH

MeO

HN

OOAc

N

O

CO2R*N

OMeTIPS

RCMConjugateAddition Tsuji-Trost

Cross-Metathesis


Title Paper: Retrosynthesis of (−)-205B


R1

O

HN TMS

Li

TMS

R2

R3

OHR1

NHHO

R2

R3

1. three-component coupling2. N-oxidation

direct [3+2]

sequential [3,3]/[3+2]

H

O

R4

(-H2O)

N

R2

R1O

R3

N

R2

R1O

R3

R4

R4

Control of reaction pathway dictates stereochemistry of the heterocyclic product

NH

MeMe

H H

H

Me

HNH

HMe

Me

H HH

TMS

MeOOMe

HO NO

CO2BuH

HMeH

MeO

MeO

MeH

HO

OBuO

MeMeO

OMe

NHHO

MeHMeO

OMe

O Me

Me OH

aza-Sakurai,alkene isomerization,

deoxygenation

N!O bond cleavage,conversion of ester

to allylsilane

condensation,intramolecular [3+2]

cycloaddtionreductive cross-coupling,

N-oxidation

(!)-205B


(E)-anti-Homoallylic Primary Amines

Schaus, J.V.; Jain, B.; Panek, J. S. Tetrahedron 2000, 56, 10263.

§  Chela&on-‐controlled addi&on reac&ons of chiral crotylsilanes for the synthesis of (E)-‐an&-‐homoallylic carbamates

§  Asymmetric crotyla&on and allyla&on reac&ons of imines and oximes

§  Iminine propargyla&on

Ramachandran, P. V.; Burghardt, T. E. Chem. – Eur. J. 2005, 11, 4387.

Song, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2002, 43, 8653.

White, J. D.; Hansen, J. D. J. Org. Chem. 2005, 70, 1963.

Ph H

N SiMe3

Ph

NH2

Me92% ee, 96% de

BIcpMeO

Icp

MeH

K

78%

H

O

Me CO2MeSiMe2Ph H2NCO2Me

TiCl4CO2Me

HN

Me

MeBnO

MeBnO

50%, 30:1 dr

CO2Me

R

N

H

Bn

R

NHBn

Me87% (9:1 dr)

TMSTi(Oi-Pr)4i-PrMgCl TiL3

•TMS

HMe

TMSO

Me H

P(O)(OEt)2

NH

Me

BocHNBocHNN

H

OH BIcpIcp

HO


Methodology: Stereodefined Homoallylic Hydroxylamines

§  Reaction proceeds with aromatic and aliphatic aldehydes

§  Delivers stereodefined (E)-anti-homoallylic amines as single diastereomers

Angew. Chem. Int. Ed. 2009, 48, 3648; Org. Lett. 2009, 11, 5402; J. Am. Chem. Soc. 2009, 131, 17548.; J. Org. Chem. 2010, 75, 8048; . J. Am. Chem. Soc. 2011, 133, 9216.

R1 H

O R2

R3

OHR1

NH2

R2

R3

dr ≥ 20:1; E:Z ≥ 20:1rs ≥ 20:1

LiHMDS; Ti(Oi-Pr)4,RLi or RMgCl

Et2O

R1 H

N R2R3

R4

OHTi(Oi-Pr)4c-C5H9MgCl

Et2O R1

NHR2

R3

R4

(E)

anti≥ 95% ee

≥95% eeR1 H

N OH R3

R4

OH

R1

NHHO

R3

R4

not observed

reductive cross-coupling

R1 H

OR2

R3

O

R1 H

NTMS

R1H

NTMS

TiOi-Pr

Oi-Pr

TiOi-Pr

Oi-Pr R1H

NTMSTi

Oi-Pr

Oi-Pr

LiHMDS

Et2O

Ti(Oi-Pr)4s-BuLi

TiOi-Pr

Oi-Pr

OTiOi-Pr

H

R3

R2

NTMS

R1

H

N TiO

R2H

R3i-PrO

TMS

R1R1

NH2

R2

R3


Methodology: 1-Aza-7-oxabicyclo[2.2.1]heptanes

Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2011, 133, 9216.

Me

PhNO

Ph

A

N

Me

PhO

PhDds ≥ 20:1

toluene, 120 °C

74%

NO

PhH

MeRH N

O

HH

MeRPh

DB (C, minor)

vs[3+2]

[3,3]

NO

PhH

MeRH

NRH

MePh

H

ONR MePhO N

O

HH

MeRPh

[3+2]

A

R = (CH2)2Ph

Ph

NH

Me

PhH H

O

Me

PhNO

Ph

N

Me

PhO

Ph

N

Me

PhO

Ph

toluene, 50 °C

84% A67%

B C

B + C = 17% (B:C = 2.5:1)

HO


Methodology: 1-Aza-7-oxabicyclo[2.2.1]heptanes

Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2011, 133, 9216.

R1

NH2

R2

R3H

O N

R2

R1

OR3

O

OEt

toluene 4Å mol. sieves

rt to 120 °C2-12 h

CO2Me

2,3-anti; 3,4-syn; 4,5-anti; 5,6-anti

5 34

26

NO

R2H

R1HH N

O

HH

R2R3R1

major product

vs[3+2]

[3,3]

NR2

H

R1H

NR3H

R2R1

H

O

NR3 R2R1O N

O

HH

R2R3R1

[3+2]

EtO2C

R3O

R3

EtO2C

EtO2C

not observed

EtO2C EtO2C

EtO2C


Ti-Mediated Reductive Cross-Coupling

H

O

Me OH

O

OTMS

NH2O

O MeTMS

A

A, LiHMDS, Et2O; then Ti(Oi-Pr)4, s-BuLi;

then B

57%B

(91% ee) (91% ee)


NH2O

O MeTMSOTi

Oi-Pr

HTMS

Me

NTMSO

OH

N TiO

MeH

TMSi-PrO

TMS

O

O(91% ee)

HMeO

OMe

O Me

Me OH

low conversion poor steroselection

MeMeO

OMe

NHHO

Me

reductive coupling


Stereochemical Analysis of Reductive Cross-Coupling

NH2O

O Me TMS

NH2O

OMeTMSO Tii-PrO

H

TMS Me

N

H

TMS

O

O

NH2O

O Me TMS

NH2O

OMeTMS

O Tii-PrO

H

TMS Me

NTMSH

O

O


NH2O

O MeTMSOTi

Oi-Pr

HTMS

Me

NTMSO

OH

N TiO

MeH

TMSi-PrO

TMS

O

O(91% ee)

NH2O

O MeTMS

OTiOi-Pr

HTMS

Me

NTMS

HO

O


Asymmetric Synthesis of (−)-205B

N

CO2BuH

MeH

OTMS N

O

CO2BuHH

MeH

O

O TMS

O

O

dr ! 20:1

1. LAH, THF2. DMP, CH2Cl23. NaH, C, DME

51%

MeO

OP

TMS

OMeO

OMe

C

NO

HH

MeH

O

O TMS

OMe

O

TMS(E:Z = 2:1)

NO

HH

MeH

O

O TMS

TMS

NH

MeR

H H

TMS

HOH

R = CH2TMS

NH

MeR

H H

HH

R = CH2TMS

HO

1. DIBAL, CH2Cl22. NBSH, PPh3, DIAD NMM, -15 °C to rt

55%

Zn, HOAc; THF, 3 N HCl

82%


NH

MeTMS

HO

toluene, 4Å mol. sieves120 °C

67%

NH2O

O MeTMS

(BzO)2, K2HPO4, DMF;then N2H4, MeOH

50%

(91% ee)

O

O

H CO2Bu

O


Cationic Annulation: Aza-Sakakurai vs Aza-Cope

NH

MeR

H H

HH

R = CH2TMS

HO

NH

MeR

H H

TMS

HOH

aza-Sakurai

NH

MeR H

H

Me

HHO

N

R

H

HHO

MeH

TMS

N

R

H

HHO

MeH

TMS

H

-H+

N H

HHO

MeH

TMS

R

[3,3] N H

HOMe

H

TMS

retro aldol

aldolR

N H

HHOMe

H

TMSR

retro aldol aldol

NO

HH

MeH

O

O TMS

TMSZn, HOAc;

THF, 3 N HCl



Completion of (−)-205B

NH

MeMe

H H

H

Me

H

(!)-205B

NH

MeH H

HHO

NS

N

1. KOt-Bu, 18-crown-62. TCDI ,4-DMAP

59%

1. AIBN, Bu3SnH2. p-TsOH, benzene

61%

NH

MeH H

HHHO

TMS



Conclusion §  Completed the asymmetric total synthesis of (−)-205B in 17 steps §  Successfully employed two stereoselective synthetic methods developed in

their laboratories §  Ti-mediated reductive cross-coupling of allylic alcohols with aldehydes

§  Path-selective intramolecular [3+2] cycloaddition of glyoxylate-based

homoallylic nitrones

R1

O

HN TMS

Li

TMS

R2

R3

OHR1

NHHO

R2

R3

1. three-component coupling2. N-oxidation

R1

NHHO

R2

R3

direct [3+2]

sequential [3,3]/[3+2]

H

O

R4

(-H2O)

N

R2

R1O

R3

N

R2

R1O

R3

R4

R4


synthesis of alkaloid ( )-205b via stereoselective

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