Total&Synthesis&of&(–)2Crinipellin&A - Boston...

transcript

Total Synthesis of (–)-‐Crinipellin A Taek Kang, Seog Boem Song, Won-‐Yeob Kim, Byung Gyu Kim, and Hee-‐Yoon Lee* Department of Chemistry, Korea Advanced InsFtute of Science and Technology, Daejeon,

305-‐701, Korea J. Am. Chem. Soc. 2014, 136, 10274–10276.

•  Crinipellins (1 – 5) were first isolated from the basidiomycete Crinipellis s5pitaria in 1979.

•  These compounds display anFbacterial and anFcancer acFvity.

•  Compounds 6 – 9 were isolated late from a different fungal strain, Crinipellis sp. 113 and only show moderate anFcancer acFvity.

•  These are the only known class of tetraquinane natural products.

•  Only previously reported total synthesis of a crinipellin natural product is Piers’ report of the total synthesis of crinipellin B1.

1. Kang, T.; Song, S. B.; Kim, W.-‐Y.; Kim, B. G.; Lee, H.-‐Y. J. Am. Chem. Soc. 2014, 136, 10274–10276.

Ka5e Boknevitz 1 Liu Lab

I. IntroducCon

O O

O O

O O

O O O

O

O

O

O

O

HO

R2

OHOR

HO

HO

HO

OH

R1HO

H H

H

R1 OH

HH

R2

H

1 - crinipellin A, R = H2 - O-acetylcrinipellin A, R = Ac

3 - tetrahydrocrinipellin A

4 - crinipellin B, R1,R2 = O5 - dihydrocrinipellin B,

R1 = H, R2 = OH

6 - dihydrocrinipellin A, R1,R2 = O7 - tetrahydrocrinipellin B,

R1 = H, R2 = OH

8 - crinipellin C 9 - crinipellin D

Total Synthesis of (–)-‐Crinipellin A

•  Eight conFguous stereocenters •  Tetraquinane skeleton •  UFlize their recently reported syntheFc methodology for triquinane synthesis from acyclic

substrates.

2 Liu Lab

II. SyntheCc ConsideraCons N2

C

NN

Extension of TMM strategy to tetraquinane

H

HOOO O

(–)-Crinipellin A

H

TBDPSO10

•OTBDPS

N2

12

HO

13

OOTBS

14

TBDPSO11

III. RetrosyntheCc Analysis

TBDPSO11'


3 Liu Lab

OOTBS a) Ph3PCH3Br, tBuOK

tBuOH, Et2O, RT, 99%

OTBS b) TBAF, THF

RT, 99%

OH c) (COCl)2, DMSO, THF,

Et3N, –78 °C to RT

O

d) Ph3PCCH3COOEtTHF, reflux

91% for 2 steps

e) LiAlH4, Et2O

0 °C to RT, 96%

f) D-DET, TBHP, Ti(OiPR)4

CH2Cl2, –30 °C, 87%

g) (COCl)2, DMSOCH2Cl2

Et3N, –78 °C to RT

HO EtOOCOHO

OO

h) K2CO3Bestmann-Ohira

reagent, MeOH, RT87% for 2 steps

O

i) Fe(acac)3, THF, toluene, –15 °C, 94%

BrMg OMe

OMe

•

MeO OMeOH

j) TBDPSCl, imidazoleDMAP

CH2Cl2, RT, 96%•

MeO OMeOTBDPS

k) p-TsOH•H2O, HCHOTHF, H2O, RT, 93%

•OTBDPS

Ol) NH2HNTs

MeOH, RT, 97%•

OTBDPSNNHTs

14

1616'

14'15'

17'

15''

1917

13

15

19'20

18

IV. Forward Synthesis


4 Liu Lab

•OTBDPS

NNHTs

NaHToluene

reflux87%

H

TBDPSO20 10

•OTBDPS

NNTs

20

HH

•OTBDPS

NN S

OONa

•

NN

TBDPSO

NN

TBDPSO

TBDPSOTBDPSOTBDPSO

H

TBDPSO10


5 Liu Lab

H

TBDPSO10

H

HO10'

H

O22

H

O22'

m) TBAF

THF, 60 °C

n) PCC,

CH2Cl2, RT79% for 2 steps

o) KHMDSDavis' oxaziridine

THF, –78 °C HO

p) DMP, pyr.CH2Cl2, RT

79% for 2 steps

H

O23

O

q) nBuLi(+)-(S)-N,S-dimethyl-S-phenyl-sulfoxime

–78 °C, 80%

H

OHO

SO PhN

s) 2,6-lutidine,TBSOTf

CH2Cl2, RT, 98%

24

r) NaBH(OAc)3

CH2Cl2, RT, 80%

H

HO

SO PhN 25

HO

H

HO

SO PhN 25'

TBSO

t) PDC, TBHPPhH, RT, 40%

H

HO

SO PhN 26

TBSOO

u) toluene

125 °C, 69%

H

27

TBSOOO

v) H2O2, NaHCO3,

THF, H2O, RT, 90%

H

TBSOOO O

27'

w) LiHMDS,Eschenmoser's salt

THF, –78 °C to –70 °C58%

H

TBSOOO O

28

x) TASF, DMF, RT40% with 35%

conversionH

HOOO O

(–)-1


6 Liu Lab

OOTBS

CH2

PPh3

OTBS

Ph3PO

OTBS

14 14'

Mechanism a: Wittig olefination

Cl

O

O

ClSO

Cl OO

OS

ClSCl

+ Cl + CO + CO2

OH

15

-HCl

O S

H

Et3NO SH

O

15'

Mechanism c: Swern oxidation

-SMe2

O

14'

Si

F N(nBu)4

OH

15

+H-TBSF

Mechanism b: TBS deprotection

V. Mechanisms


7 Liu Lab

Mechanism d: Horner-Wadsworth-Emmons olefinationSee mechanism a

15''

O

OEt H

AlH3

OEt

O AlH3 O

HO

13

Mechanism e: LAH reduction

O O

O

O

OH

OHD-DET = L* + Ti(OiPr)4

Ti*LOiPr

OiPr + HO-O-tBu

13

OTiL*

OOtBu HOO

16

Mechanism f: Sharpless Asymmetric Epoxidation

Mechanism g: Swern oxidationSee mechanism c


8 Liu Lab

OO

16'

N2

(MeO)2PO O

Bestmann-OhiraReagent

MeOHN2

(MeO)2PO O

OMe-H N2

(MeO)2PO

OO

P(OMe)2O

N2O • N N

O

NN

OH

O

17

Mechanism h: Seyferth-Gilbert Homologation


9 Liu Lab

BrMg OMe

OMe

Fe(acac)3

-acac

18

LnFe OMe

OMe

O17LnFe

OMeMeOMechanism i:

•

MeO OMeOH

17'

N

HN

Cl SiPhPh

HN N SiPh

Ph

•

MeO OMeOH

17'

•

MeO OMeOTBDPS

19

Mechanism j: TBDPS protection


10 Liu Lab

•

MeO OMeOTBDPS

19

H•

MeOMeO

OTBDPS H

•

MeOOTBDPS

H2O

•

MeO OH2OTBDPS

•

MeO OHOTBDPS

H

PT•

OTBDPSO

19'

Mechanism k: Acetal hydrolysis

•OTBDPS

O

19'

H2NNHTs PT

•OTBDPS

HO HNNH

Ts

-H2O•

OTBDPSNNHTs

20

Mechanism l


11 Liu Lab

Mechanism m:See mechanism b

H

HO10' Cl Cr O

O

O

NH

PCC

PTH

OCrOHO Cl

O

H

OCr OO OH

H

H

O22

Mechanism n: PCC oxidation

H

O22

H

N SiMe3Me3Si

K

N SO O

O

Davis'oxaziridine

H

O

H

O

O

SN

OO

R

+HH

O22'

HO

Mechanism o:


12 Liu Lab

OI

O

OAcOAc

AcOH

O22'

HO

H

O

OIO

O

OAcO

OH H

O23

O

Mechanism p: Dess-Martin Periodinane Oxidation

H

O23

OSO

NPh

H

Li

SO

NPh +H

H

OHO

SO PhN 24

Mechanism q:

H

OHO

SO PhN 24

NaBH(OAc)3H

OO

SO PhN

BAcO

H

OAc

+HH

HO

SO PhN 25

HO

Mechanism r: Hydroxyl-directedRreduction


13 Liu Lab

H

HO

SO PhN 25'

TBSO

O Cr O Cr OO O O O

N H

H

H

HO

SO PhN

TBSO

CrO OH

OO Cr

O

OO

H

HO

SO PhN

TBSOOCr

O OOH

H

HO

SO PhN 26

TBSOO

Mechanism t: Allylic oxidation

H

O

SO PhN 26

TBSOO

H

H

27

TBSOOO

Mechanism u:

Mechanism s: TBS protectionSee mechanism j

H

27

TBSOOO

HO O

H

TBSOOO O

OH

H

TBSOOO O

27'

Mechanism v: Nucleophilic epoxidation


14 Liu Lab

H

TBSOOO O

27'

H

N SiSi

H

TBSO

O O O

NLi

H

TBSOOO O

NMe2H

N SiSi

LiH

TBSOOO O

28

Mechanism w:

Mechanism x: TBAF deprotectionSee mechanism b

H

HOOO O

(–)-Crinipellin A

Total&Synthesis&of&(–)2Crinipellin&A - Boston...

Documents