Total Syntheses of (+)-Echinopine A and B: Determination of Absolute Stereochemistry Thomas Magauer,* Johann Mulzer, and Konrad Tiefenbacher

Org. Lett. 2009,11, 5306-5309.

Total Synthesis of Echinopines A and B K. C. Nicolaou,* Hanfeng Ding, Jean-Alexandre Richard, and David Y.-K. Chen*

JACS 2010 ASAP

Roxanne Atienza16 March 2010

Short Literature

Echinopines A and B

Isolated from Echinops Spinosus by Shi, Kiyota, and co-workers in 2007.

‣ [3.5.5.7] carbon framework‣ Five contiguous stereocenters‣ 2 are quaternary

Magauer/Tiefenbacher Retrosynthesis

HCO2R

DA

C

B

FG

R2

R1 H

HH

X N2

CO2R

A C B

A

III

HHH

OR

O1

10 3 11

157

6

BA

CD

3D land

2D land

• potential for cis-trans isomerization if X = O

• if X = CH2, risk of regioselectivity issues with cyclopropanation

cis-fused AB guaianolideAC diquinane precursor

Retrosynthesis Path II

HHH

OR

O1

10 3 11

157

6

BA

CD

HHHH

R11

10 3

7

6

BA

C

O

H

A C

R1

H O

1 7H

A C

R1

H O

1 7

H

H OO

O

+

1 (R=H)2 (R=Me)

3a (R1=Me)3b (R1=H)

4a (R1=Me)4b (R1=H)

5a (R1=Me)5b (R1=H)

6 1,5-cyclooctadiene

Forward SynthesisH

H OO

O

H

HOO

Me

OOEt

H

H OO

O

H

HOO

H

OOMe

H

HOO

ROH

(EtO)2P(O)CHMeCO2EtNaH, THF, reflux

80%, E:Z = 1.5:1

(Me)3SiCH2CO2Me,LDA, THF, -78°C

95%, E:Z = 1.5:1

DIBAL, CH2Cl2,-50 to -30°C

93% from 7a98% from 7ba: R = Meb: R = H

rac-6

(+)-6

rac-7a

(+)-7b

rac-8a(+)-8b

H

H

R

O

H

H

R

O

1) NBSH, PPh3, DEAD, THF, -40°C to rt2) PPTS, acetone/H2O, reflux

1) KHMDS, HMPA, allyliodide, THF, -78°C

2) DBU, toluene, 110°C

68% from 8a; dr = 1.2:166% from 8b: dr = 3.5:1

90% from 9a; dr = 3:189% from 9b; dr = 2.3:1 rac-9a

(+)-9brac-4a(+)-4b

Models for stereoselective [3,3]

O

O R

NNH

HSO2Ar

O

O R

NHN

HSO2Ph

O

O

NNH

HSO2Ar

RO

O

R

NHN

HSO2Ph

desired configuration in Myers [3,3]

undesired configuration in Myers [3,3]

Forward Synthesis

H

H

H

O(+)-4b

HHH

H

O

Grubbs II (5 mol%)CH2Cl2, reflux

84%

3b

HHHH

O

HHH

HHH

MeOO

OMe

O

1) PhNTf2, KHMDS, THF, -78°C, 80%

2) Pd(OAc)2, PPh3, CO, NEt3, DMF/MeOH, 50 °C, 96%3) Me3SOI, NaH, DMSO, rt, 99%

1) PhNTf2, KHMDS, THF, -78°C, 80%

2) (1-methoxyvinyloxy)trimethylsilane Pd(PPh3)4, LiOAc, THF, reflux, 54%

Path A

Path B

10

11

Forward Synthesis

HHH

HHH

OMe

O

1) DIBAL, CH2Cl2, -30°C, 86%

2) IBX, DMSO, rt, 96%3) MeOCH2PPh3Cl, t-BuOK, THF, 0°C; then 6N HCl; then pH=7, NaBH4, rt, 80%

Path A

Path B

OH

12

13

CH2I2, Et2Xn, DCM, 0°C89%

10

11

HHH

OHHO

1) DMDO, acetone, rt2) LiAlH4, THF, 50°C

69% from 12; dr = 16.6:190% from 13; dr = 5:1 14

The End

HHH

OHHO

14

HHH

OH15O

O

IBX, DMSO, rt;then NaClO2,NaH2PO4,2-methyl-2-butene

t-BuOH, H2O72$

MePPh3Brt-BuOK, THF,reflux, 62%

HHH

OH(+)-1

O

HHH

OMe(+)-2

OCH2N2,

Et2O, rt, 99%

Nicolaou/Chen Retrosynthesis

HHH

OR

OB

AC D

1 (R=H)2 (R=Me)

3

SmI2 - mediatedring closure HH

OAC

DO

OTBS

IntramolecularRh-catalyzedcyclopropanation

TBSOH O

N2CO2Me

4

OA

Forward Synthesis

Oa) Br2, 98%b) BH3 · PhNEt3, 90%, ≥95% ee

c) n-BuLi, 80%

TBSOTBSO

d) TBSCl, e) O3, then PPh3f) piperidine

g) NaBH4, 84% over 4 steps

OH

h) CH3C(OEt)3, 86%i) LiOH, 100%

TBSOH

CO2H

TBSOH

CO2H j) methyl potassium malonate, CDI, MgCl2, 78%TBSO

HO

N2CO2Me

k) p-ABSA, 97%

PMBOH

O

CO2Me

l) Rh(OAc)4, 70%m) HF·pyrn) PMB-TCA,over 2 steps, 73%

PMBOH

OTf

OTBS

o) PhNTf2, LDA, 77%p) Dibal-Hq) TBSOTf,

over 2 steps, 89%

PMBOH

CH2OH

OTBS

r) Pd(PPh3)4CO, MeOH, 85%s) Dibal-Hor

t) Stille coupling82%

Alternative to acid 13

The End

PMBOH

CH2OH

OTBS

a) H2, PtO2, 69%b) DMP, 93%

HH

TBSO

PMBOO

HH

TBSO

c) HWE, 96%d) NaBH4, NiCl298%

e) Dibal-Hf) DDQ, over 2 steps, 96%

HO

HO

ISmIII

a) DMP81%

HH

TBSOO

O

HH

TBSOH

OOHH

AcOb) SmI2, HMPA, 50%

c) DMPd) Ac2O, 81% over 2 steps

OTBSO

e) SmI2, 92%f) TsOH, 100%g) Tebbe, 87%

HHH

HO

HHH

O

h) oxidationi) Ph3PCH2OMe,LHMDS

j) TsOH,58% over 3 steps

HHH

HO2C

k) NaClO2, 94%

Side by Side Comparison

• Magauer/Tiefenbacher

• 15 steps

• stereoselective installation of vinyl group with Myers’ [3,3] sigmatropic rearrangement

• closure of highly strained seven-membered ring B through RCM

• Started with rings A and C

• Chen/Nicolau

• 38 steps

• formation of both C and D rings through Rh-catalyzed cyclopropanation

• closure of highly strained seven-membered ring B through SmI2 ring closure

• Started with only ring A