Asymmetric Synthetic Access to the HetisineAlkaloids:Total Synthesis of (+)-Nominine

Kevin M. Peese and David Y. GinChem. Eur. J. 2008, 14, 1654 - 1665J. Am. Chem. Soc. 2006, 128, 8734

N

MeH

OH

H

H

H

N

Me

OR

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C20 - Diterpenoid Alkaloids

Me

RN

Me

RN

Me

NR

Me

N

Me

RN

Me

RN

C20 - diterpenoids

atisane class kaurane class

veatchinetype

napellinetypeatisine

typedanudatine

type

hetidine type

hetisinetype

Me

N

R4

R3

R2

R5

H

R6

R1

Nominine

R1, R2, R3, R4, R6 = H, R5 =OH

Kobusine

R1, R2, R4, R6 = H, R3, R5 = OH

Pseudokobusine

R1, R2, R4 = H, R3, R5, R6 = OH

Hetisine

R3, R5, R6 = H, R1, R2, R4 = OH

Wang, Liang The Alkaloids 2002, 59, 1

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• A subclass of C20-diterpenoid alkaloids consisting of >100members.

• Isolated predominantly from Aconitum and Delphinium genera,but also Rumex, Consolidia, and Spirea.

• Pharmacological Activity:– vasodialating– antiarrhythmic– immunomodulatory– analgesic

Hetisine Alkaloids

Wang, Liang The Alkaloids 2002, 59, 1

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Proposed Biosynthesis of Hetisine Alkaloids

Wang, Liang The Alkaloids 2002, 59, 1

MeMe

Me

Me

Me

OPP

MeMe

Me

Me

OPP

H

MeMe

Me

H

copalyldiphosphate

synthase

copalyl diphosphateCPP

atis-16-ene

geranylgeranyldiphosphate

(GGPP)

Me

NR

Me

NR

Me

N

atisine type

hetidine type

hetisinetype

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N

CO2Et

O

Br

Oi-Pr

OMe

MeMgBr, 94%3:2

N

CO2Et

Br

Oi-Pr

OMe

OHN

CO2Et

Oi-Pr

MeOO

+

steps

N

Br OAc

OMe

OH

AcO

AgO2C(NO2)3C6H2, MeNO2,53 %

N

OAc

OMe

OH

AcO

Studies towards the Total Synthesis of Hetisine Alkaloids

Williams, Mander Org. Lett. 2003, 5, 3499Williams, Mander, Bernhardt, Willis

Tetrahedron 2005, 61, 3759

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Studies towards the Total Synthesis of Hetisine Alkaloids

HO

O

O

OMe

1. TBSCl, ImH

2. p-TsOH, Me2CO, 49%

3. Li, NH3, t-BuOH,

NCCO2Me, -78 oC, 69%TBSO

OMe

OH

CO2Me

TBSOOMe

H

1. NaH, MOMCl, 95%2. Li, NH3, t-BuOH, 69%

TBSOOMe

H

NH

MeO2C

1. Li, NH3, t-BuOH, 95%2. CDCl3, HCl, 60%

1. DDQ, HCl, 70%2. FeCl3, TMSCl, 21%

CO2H

OMe6 steps

TBSOO

H

NH

MeO2C

TBSOO

HN

CO2Me

H

H

HO

6 steps

Hutt, Mander J. Org. Chem. 2007, 72, 1030

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Total Synthesis of (±)-Nominine

Summary:40 steps, 0.15% overall yieldMuratake, Natsume Tetrahedron Lett. 2002, 43, 2913Muratake, Natsume Angew. Chem. Int Ed. 2004, 43, 4646

NC O

OMOMO

H

OAc

1. LDA, TMSCl2. LAH, THF3. CbzCl, Et3N , 63%4. NaBH3CN, HCl, 90%

N

OMOMO

H

OH

Cbz

steps

N

OMOMO

H

Cbz

AIBN, Bu3SnH, PhMe,SiO2, 57%

N

OMOMO

H

CbzN

HO

H

Cbz

OAc

N

MeH

OH

HH

1. Pd(OAc)2, Et3N, Et3SiH2. SOCl2, Py, 80%3. K2CO3, MeOH, 95%

steps

Br

MeO

I

13 steps

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Model Studies

TMS

OH1. Swern ox.2. BnNH2

TMS

NBn

MeO OTMS

ZnCl2, CH2Cl2, 61%(overall)

BnN

O

TMS

BnN

ORROTf Z

NBn

ROR

R

R = H, CO2Me, SO2PhYields: 20-43 %

OTf

Me

NH2

OTf

Me

N

TMS

O

Me

N

TMS

O

CO2Me

Me

N+

TMS

OMe

CO2Me

TfO-

TMSCHO, ZnCl2Danishefsky's diene

55%, 1.2:1 dr (Ph3P)4Pd, LiCl, 87%

Bu3SnCO2Me

MeOTf- stable and unreactive towards intramolecular cycloaddition

- underwent intermolecular addition with DMAD

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Model Studies - 3-Oxidopyridinium Betains

3-Oxidopyridinium betains, introduced by Katritzky, are stable and isolable 1,3-dipolesundergoing cycloaddition reactions at positions 2 and 6.

N+

OR

N+

O

OTf

Me

O

OClH3N

CN

Me

HN

OBr2, AcOH:H2O 1:1

65%

CN

Me

NO

PhMe, 170 oC,

5 d, 73%

NaBH4, MeOH, 99%

2. KCN, 18-crown-6 (Ph3P)4Pd, PhH, 75%

1.

CN

Me

N

OH

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Model Studies - 3-Oxidopyridinium Betains

Me

NO

PhMe, reflux, 70%SO2Ph

N

O

Me

SO2Ph

H

Me

NO

PhMe, 120 oC, 67%SO2Ph

BnO

Me

NO

SO2Ph

BnOSO2Ph

N

Me OOBn

Me

NO N

O

MeH

NO2

NO2

H

H

PhMe, 170 oC (µW)

14% 81%

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Intramolecular Cycloaddition

Due to lower Resonance Stabilization Energies (RSEs), 3-oxoisoquinolines are ideal partnersfor the cycloadditions reactions. Ground-state destabilization of the substrate may facilitateformation of the desired pentacycle.

N N

PhPh

AgMe

Me

Me

S

N N

PhPh

AgMe

Me

Me

S

O

OO

O

O

O

O

CO2Me

(CuOTf)2 PhH, Me2Zncat. then Tf2O, 88%, 84% ee

O

CO2MeMe

cat. =

CN

CN

OMe

O

MeO

OMeN3

OMe

O

MeO

MeOMe

HN

CN

Me

NOMe

O

CN

N

MeH

HO

OMe

CHOMe

PBu3, NaBH(OAc)3, 79%, 3:3:2:2 dr

TFA:CH2Cl293%

CN

N

MeH

H

OMeO180 oC, THF

A:B 1:3.6

AB

+

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Completion of Synthesis

Completion of the synthesis involved adjustment of the oxidation state followed by Diels-Aldercyclization. Notably, the non-conjugate enone proved to be more stable thermodynamicisomer.

N

MeH

O

HH

CN

N

MeH

H

OMeO CN

N

MeH

H

OMe

1. NaBH4, EtOH, 23 oC

2. SOCl2, CH2Cl2, reflux

3. Bu3SnH, AIBN, PhH, reflux

68% (3 steps)

1. DIBAL-H, 85%2. Ph3P=CH2, 96%

N

MeH

H

OMe

Na, i-PrOH, THF, NH3 -78 oC

then HCl (aq), 97%

X-ray

1. Ph3P=CH2, 77%2. SeO2, t-BuO2H, CH2Cl2, 66%, 7:1 dr

N

MeH

H

O

9:1 MeOH/pyrrolidine,

60 oC, 78%

N

MeH

OH

H

H

H

X-ray

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• Gin and Peese completed a total synthesis of (±)-nominine in 15 steps(longest linear sequence) and 6.1 % overall yield.

• Introduction of a chiral center via asymmetric conjugate addition allowed forcompletion of a synthesis of (+)-nominime in 16 steps and 1.3% overall yield.

• Convergent construction of the polycyclic core relied on a series ofcycloadditon (3+2 and 4+2) reactions demonstrating power of a well-plannedsynthesis.

Summary

N

MeH

OH

H

H

H

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