Presenter: Jiaojiao Wang02/01/2020

Presenter

Presentation Notes

They were never able to access haterumaimides J and K the two compounds reported to be the most cytotoxic in the family. Notably, these targets bear oxygenation at C18, but C3 is unfunctionalized. This special arrangement of structural is based on rarely studied terminal-epoxide-initiated polycyclizations.

Presenter

Presentation Notes

Based on their hypothesis, they were trying to synthesis the cyclization precursors related to 7 which is 17 in this page.

Step 1 to 4 / 18

ClO

TMS

Li

162.1 mmol (1.5 equiv)

BF3•OEt2 (1.5 equiv)

THF, -78°C

n-BuLi (1.5 equiv)

THF, -78°C, 10 min

(1 equiv)

THF, -78°C, 30 minwarmed to 0°C over 2h

0°C, 1h

TMSOcrude

NaOH (3 equiv)

CH2Cl2, rt, 14h

72%

TMSO

55.1 mmol

CuI (7 mol%)

THF, -78 °C

MgBr(2.0 equiv)

THF, -78 °C, 30 min-25 °C, 4 h

crudeK2CO3

(3 equiv)

MeOH, 0 °C to rt, 3 hH

HO

66%

(13) Dai, M.; Krauss, I. J.; Danishefsky, S. J. Total Synthesis of Spirotenuipesines A and B. J. Org. Chem. 2008, 73, 9576−9583.

Presenter

Presentation Notes

Then they generated nearly symmetrical diene from methylalumination of alkyne, followed by iododealumination.

Step 5 / 18

Cp2ZrCl2 Al(CH3)3 (2.1 equiv)

(0.25 equiv) DCE, -30 °C

H2O (0.1 equiv)

-30 °C to 0 °C, 1.5 h

H

HO

54.7 mmol, (1 equiv)

DCE, -50 °C to rt, 18 h THF, -50 °C to rt, 5h

I2 (2.1 equiv) HO

I

77%methylalumination Iododealumination

Presenter

Presentation Notes

Deoxychlorination is challenging, because there is a compting elimination processes that generated conjugated dienes.

Step 6 / 18

Cl O

Cl

Cl O

O

Cl

Cl

Cl

14.3 mmol under argonCH2Cl2, 0 °C

HO

I (1 equiv)pyridine (4 equiv)

CH2Cl2, 0 °C to 45 °C, 12hunder argon

Cl

I

70% ee 95%

Villalpando, A.; Saputra, M. A.; Tugwell, T. H.; Kartika, R. Triphosgenepyridine mediated stereoselective chlorination of acyclic aliphatic 1,3- diols. Chem. Commun. 2015, 51, 15075−15078.

Presenter

Presentation Notes

1,1-Disubstituted alkenes, especially those bearing two unbranched alkyl groups, are poor substrates for asymmetric oxidation. Fortunately, dihydroxylation under Sharpless AD conditions proved to be chemoselective.

Step 7 / 18

Step 8 / 18

Cl

I

OHHO

N

NMe2TsCl (1.3 equiv)

(0.75 equiv)

DCM, 0 °C

2.0 mmol (1 equiv)

DCM, 0 °C to rt, 5 h

K2CO3 (3 equiv)

MeOH, rt, 3 h

Cl

IO

90%

Presenter

Presentation Notes

This building block was joined to furan-containing alkyl iodide 16 in an efficient

Step 9 / 18

O

TBS

19.2 mmol (1.4 equiv)

THF, -78 °C to -25 °C(2.5 h)

n-BuLi (1.4 equiv)

THF, -78 °C to rt, 3h

IOTBS

(1 equiv) O

TBS

HO

67%

Step 10 / 18

O

TBS

HO

37.5 mmol (5 equiv)

Ph3P (1.3 equiv)

CH2Cl2, 0 °C CH2Cl2, 0 °C

I2 (1.3 equiv)

N

NH

7.51 mmol (1 equiv)

CH2Cl2, 0 °C to rt, 5 h

O

TBS

I81%

Presenter

Presentation Notes

reductive B-alkyl Suzuki coupling proceeding through the presumed intermediacy of the methoxy-9-BBN ate complex.1

Step 11 / 18

O

TBS

I

BMeO

9-BBN-OMe (4.5 equiv)

1.73 mmol (1.3 equiv)

Et2O, -78 °C

t-BuLi (4.0 equiv)

THF, -78 °C to rt (over 1 h)rt, 3 h

Cl

IO

1.33 mmol (1.0 equiv)

DMF, under argon

K3PO4, (2.5 equiv)Pd(dppf)Cl2•CH2Cl2

(0.15 equiv)H2O, under argon

Cl

Oshield from lightrt, 13 h

O

TBS

85%

Step 12 / 18

Cl

O

O

TBS

0.131 mmol

CH2Cl2/toluene 6:1

2,6-di-t-Bu-pyridine5 mol%

heptane -78°C to -70°C, 30 min

EtAlCl2 (1.7 equiv)

O

TBS

HHO

Cl

45-65%> 20 : 1 d.r.

Presenter

Presentation Notes

Silylation of the neopentylic alcohol and oxidative ring opening of the furan with in situ-carboxylate methylation yielded ketoenoate 20.

Step 13 / 18

O

TBS

HHO

Cl

SiCl

1.09 mmol(3.5 equiv)

N

NH

1.87 mmol(6 equiv)

DMF

0.313 mmol (1 equiv)

DMF, 0 °C to rt, 3 h

O

TBS

HTBSO

Cl

77%

Silylation of the neopentylic alcohol

Step 14 / 18

O

TBS

HTBSO

Cl

0.362 mmol

CH2Cl2, -10°C, 2 h

Rose Bengal (5 mol%)O2, visible light

THF, -20 °C, 10 min

TBAF (1.5 equiv)

N

F

MeI (5 equiv)

THF, -20 °C to rt, 2 h HTBSO

Cl

O

OO O

HTBSO

ClOH

O

K2CO3, MeI, acetone

80%

86%

Presenter

Presentation Notes

Diastereoselective hydrogenation of the alkene, a salt-free Wittig methylenation, and careful partial reduction of the ester provided aldehyde 21

Step 15 / 18

HTBSO

Cl

O

OO

0.268 mmol

Pd/C (15 mol%)

EtOAc, argon to H2

4 hH

TBSO

Cl

O

OO

HTBSO

Cl

O

OO

85%

94%

NaOMe, MeOH

Diastereoselective hydrogenation of the alkene

Step 16 / 18

HTBSO

Cl

O

OO

Ph3P CH2 (3 equiv)

0.251 mmol

Toluene, 0 °C to rt, 1 hH

TBSO

Cl

O

O

75%

HTBSO

Cl

O

O

0.209 mmol

i-Bu2AlH (2.1 equiv)

Toluene, -78 °C, 40 minH

TBSO

Cl

O

H

HTBSO

ClOH

90%

DMP, CH2Cl2

74%

Wittig methylenation

careful partial reduction of the ester provided aldehyde 21

Könst, Z. A.; Szklarski, A. R.; Michalak, S. E.; Pellegrino, S.; Meyer, M.; Zanette, C.; Cencic, R.; Nam, S.; Voora, V.; Horne, D. A.; Pelletier, J.; Mobley, D. L.; Yusupov, M.; Yusupova, G.; Vanderwal, C. D. Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides. Nat. Chem. 2017, 9, 1140−1149.

Step 17 / 18

HTBSO

Cl

O

H

O N

O OO

OBn

57 µmol (1.5 equiv)

CH2Cl2, -78 °C, 30 min

Cy2BOTf (1.7 equiv)

CH2Cl2, -78 °C, 20 min

Et3N (2.5 equiv)

-78 °C to 0 °C, 1.5 h

CH2Cl2, -78 °C

37 µmol (1.0 equiv)

-78 °C to 0 °C, 1.5 h rt, 20 h HTBSO

ClOBCy2

Aux

O

MeO2C

Step 17 / 18

HTBSO

ClOH

NH

O

O

HTBSO

ClOBCy2

Aux

O

MeO2C

NH3/MeOH

then NaH, THF0 °C

47%12 : 1 d.r.

Step 18 / 18

HTBSO

ClOH

NH

O

O

13.4 µmol

THF, 0 °C

HF(x)•pyridine

0 °C to rt, 10 hH

HO

ClOH

NH

O

O

90%

(+)-haterumaimide J

HHO

ClOH

NH

O

O

5.22 µmol

(+)-haterumaimide J

Pyridne (5 equiv)Ac2O (1.2 equiv)

DMAP (0.25 equiv)

CH2Cl2, 0 °C, 30 minH

AcO

ClOH

NH

O

O

77%

(+)-haterumaimide K

Step 18 / 18

Thank you!

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