Inter- and Intramolecular [4+3] Cycloaddtions Using Epoxy Enol silanes As Functionalized Oxyallyl Cation Precursors

Total Synthesis of the Lycopodium Alkaloid (+)-Serratezomine A

N OH

HCH3

O

O

(+)-Serratezomine A

Chandra, A.; Pigza, J. A.; Han, J. S.; Mutnick, D.; Johnston, J. N. J. Am. Chem. Soc. 2009, 131, 3470

OO

OTES

10% TESOTf

94°C, CH2Cl2

15 min

O

OH

82% yield95% ee

Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W.; Chiu, P. J. Am. Chem. Soc. 2009, ASAP

Daniel Tzvi Cohen Short Literature March 31, 2009

OH

(+)-Serratezomine Background

1. Hiroshi, M.; Mika, A.; Naotoshi, Y.; Junichi, K. J. Org. Chem., 2000, 65, 62412. Morita, H.; Kobayashi, J. J. Org. Chem., 2002, 67, 5378

Isolated from Lycopodium Serratum club moss by Kobayashi1 as a trifuloroacetic acid salt

Polycyclic structure that joins a 5,6 system with a 6,6-spirocyclic ring with a bridging lactone

Isomerization to form the more stable γ-lactone is possible2

Six stereogenic carbons

C-8 being the biggest obstacle in the total synthesis

No previous total synthesis

N OH

H

CH3

O

O

1

4

12

1315

8N

H

CH3

OH

1

4

12

1315

O

O

8

Retro-synthesis of Serratezomine A

N OH

HCH3

O

O

(+)-Serratezomine A

N OP

HCH3

OH CO2Et

N OP

CH3

OH CO2Et

N OP

CH3

CO2EtO

N OP

CH3

CO2EtO

R

R

N

A

B

CO2Et

OTBS

CH3

Cl

O

Synthesis of Fragment A

Prabhakaran, E. N.; Nugent, B.M.; Williams, A. L.; Nailor, K. E.; Johnston, J.N., Org. Lett., 2002, 4, 4197

Me

O

MeO

Conden.NH2

+ N

PMP

Me

nBu3SnH, AlBN

Benzene, 80 °C

N

SnnBu3

PMPMe

A

free radical-mediated alkyne aminostannation

Mechanism for AminostannationN N

CNNC

-N2

NC

SnnBu32 H SnnBu3

N

PMP

N

SnnBu3

PMPMe

vinyl radical

SnnBu3

N

SnnBu3

PMPMe

A

N

SnnBu3

PMPMe

SnnBu3H

Synthesis of Fragment B & Joining with Fragment A

Sia2BH; NaOOH

82 %

CO2Et

OTBS

CH3

HO

1) DMP, CH2Cl2, 97 %

2) NaClO2, NaH2PO4

t -BuOH, H2O

2-methyl-2-butene 95 %

CO2Et

OTBS

CH3

HO

O

OTBS

CH3

EtO2C

O

N

MePMP

(COCl)2, DMF, CHCl2

then

N

SnnBu3

PMPMe65%

A

CO2Et

OTBS

CH3O

N

PMPMe

O

CO2Et(-)-Ipc2B CH3

THF, -60 °C

then NaOOH

CO2Et

OH

CH3

Browns crotylation reagent11:1 dr, 92 % ee

TBSCl, imid.

DMF

CO2Et

OTBS

CH3

78 %, 2 steps

Brown Crotylation Reagent

TS- accounts for selectivity

O

BH3C

H

HH

H3C

H

H

CH3

CH3

R

H3C

H3C

CH3

H

H

‡

CH3

B CH3H CO2Et

O

then NaOOH CO2Et

11:1 dr, 92 % ee

OH

CH3

+

Continued Synthesis of (+)-Serratezomine A

OTBS

CH3

EtO2C

O

N

MePMP

Ce(NH4)2(NO3)6

CH3CN:H2O

58 %

OTBS

CH3

O

HN

CO2Et

O

O

CH3TBS

N

EtO2C

CAN, CH3CN

0 °C

56 % > 23:1 dr

TMS

NaBH4, iPrOH

3 °C to 0 °C, 3 h

84 % > 3:1 dr

OTBS

CH3

CO2Et

HO

NMsCl, Et3N CH2Cl2

0 25 °C

98 %

OTBS

CH3

CO2Et

O

NMs

OTBS

CH3

CO2Et

O

NMs

HO

1) BH3•DMS, THF, 0 °C

then NaOOH

2) DMAP, CH2Cl2

51 % "86 % conversion of SM"

Final Steps in the Synthesis of (+)-Serratezomine A

OTBS

CH3

CO2Et

O

NMs

HO

1) MsCl, Et3N CH2Cl2, 0 °C

2) satd. aq. NH4Cl

rt, 20 h

OTBS

CH3

CO2Et

O

Ms

N

MeSO3-

NaBH3CN

MeOH, 0 °C

quant, 2 steps

OTBS

CH3

CO2Et

O

Ms

N

H

1) 0.1 M NaOH

MeOH, 34 °C

2) TBAF

THF, 40 °C

33 %, 2 steps

N OH

HCH3

O

O

(+)-Serratezomine A

Summary and Conclusions for the Synthesis of (+)-Serratezomine A

First reported total synthesis of (+)-serratezomine A

Use of β-stannyl enamine methodology developed in their group

Sterically controlled oxidative allylation using CAN and TMS-allyl

Minimal use of protecting groups

17 steps (2.4 mg isolated, 1.7 overall percent yield)

1H, 13C NMR, and optical rotation matched with the literature value of the natural product

Inter- and Intramolecular [4+3] Cycloaddtions UsingEpoxy Enol silanes As Functionalized Oxyallyl

Cation Precursors

Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W.; Chiu, P. J. Am. Chem. Soc. 2009, ASAP

Dienes and allyl cations are a useful way to make 7 membered rings

Cyclic dienes (furan, cyclopentadiene) provide sterochemically definded bicyclic structures

New methods to generate allyl cations are an ongoing area of research

Mild and chemoselective methods are needed to generate the oxyallyl cations to allow for functional group compatibility

Intramolecular [4+3] cycloadditions can be used for late stages in natural product synthesis

+ 4 + 3

Intermolecular [4+3] Cycloadditions

1. Ohno, M.; Mori, K.; Hattori, T.; Eguchi, S. J. Org. Chem. 1990, 55, 6086

NOT VERY USEFUL

Previous work1

OHH

5 equiv.

+ H

Me3SiOO 10% TMSOTf

50 °C, CH2Cl2

O

R2

O

OH

R1R1

yield = 12 %

O

O

R2

OH

R1

R1

OR1R

1

5 equiv.

R1= H or Me

+ R2TESO

O 10% TESOTf

T °C, CH2Cl2

O

R2

O

OH

R1R1

R2 = H or Ph

T= 50 to 94 °C

yield = 31 - 75 %

O

O

R2

OH

R1

R1

Intramolecular [4+3] Cycloadditions

O (i) n-BuLi, (-50 °C - 0°C)

(ii) 5-bromopentene

Grubbs 2nd gen.

MVK

O O

O

Preparation of Substrate

68 % over 2 steps

Ru

Cl

Cl

PhP(Cy)3

NNMesMes

NaBH4 Luche reduction

CeCl3, MeOH/CHCl3

O

OH (+/ )

96 % Ti(O-i-Pr)4

(+)-diisopropyl-L-tartrate

t-BuOOH, PhMe, CH2Cl2

O

OH ( )

O

OH (+)

O

52 %

Ti(O-i-Pr)4

( )-diisopropyl-D-tartrate

t-BuOOH, PhMe, CH2Cl2

O

OH (+)

O

69 %

PDC

CH2Cl2 RT

O

O ( )

O

67 %

Intramolecular [4+3] CycloadditionO

O

OTES

O

O ( )

O

1) LHMDS, -78 °C, THF

2) TESCl

76 - 79 %(+)

96 % ee

10% TESOTf

-94°C, CH2Cl2

15 min

O

OH

82% yield95% ee

OH

O

O

OHH

( )

Proposed Mechanism

OTES

OO

TESOTf

Et3Si

OOTES

H

H

OTES

OTES

H

OTES

H

O

OO

OTES (+)

OTES

H

H

O

TESO - 2 TES

O

OHO

H

H

Sickle Configuration

W-type Configuration

PREFERRED

O

OTES

- 2 TESOTES

O

OHO

H

OTES

H

H

O

RO

OTES

H

H

O

TESO

Substrate ScopeO

OTES

R2O

R3

R1 10 % TESOTf

78 to 94 °C, CH2Cl2

OOH

R3R2

R1O

OOH

H

R1O

76 %

OOH

H

R1O

81-83 %

R1 = methyl R1 = sillyl ether

OOH

H

O

70 %

R2 = methyl

R2

OOH

R3

O

52 % R3 = methyl

OOH

R3

O

7 %

OOH

H

O

40 %

R2/R3 = methyl

OOH

H

O

57 %

R2

R1 R1

R2

Can this be used for 5-7 systems?

O

OTESO

R1 10 % TESOTf

78 °C, CH2Cl2

OH

R2

R1O

HO

58 %

Competes with the formation of a substituted furan

O

COMe

OH

23 %

Summary & Conclusions

Development of lewis acid catalyzed [4 + 3] cycloadditions using epoxy enol triethylsilanes as

oxyallyl cations

Synthetically useful to make hydroxylated cycloheptanoids (high selectivity/decent yields)

Build molecular complexity in a single step

Mild conditions may allow for this methodology to be used for late stages in natural product

synthesis