Chen Zhihua (M2)

Literature Semminar

Total synthesis of Spongistatin
1. Introduction:
Isolation: Pettit et al. J. Org. Chem. 1993, 58, 1302.
Kitagawa et al. Tetrahedron Lett. 1993, 34, 1993.
Fusetani et al. JACS. 1993, 115, 3977.
The antitumor activity of Spongistatin family has been
described as "probably the best to date in the NCI ' sevaluation programs."
Small natural supply:(400 kg of sponge provided 13.8mg of spongistatin 1)

Total synthesis of spongistatins/Altohytins
Review: Chem. Rev. 2005, 105, 4237
1. Evans synthesis of spongistatin 2/Altohytin C
Angew. Chem., Int. Ed. 1997, 36, 2738.
Angew. Chem., Int. Ed. 1997, 36, 2741.
Angew. Chem., Int. Ed. 1997, 36, 2744.
Tetrahedron 1999, 55, 8671.
2. Kishi synthesis of spongistatin 1/Altohytin A
3. Smith synthesis of spongistatin 2/Altohytin A
4. Paterson synthesis of spongistatin 1/Altohytin A
5. Crimmins synthesis of spongistatin 1, 2/Altohytin A, C
6. Heathcock synthesis of spongistatin 2/Altohytin C
JACS. 2003, 115, 12844.
JACS. 2003, 115, 12836.
J. Org. Chem. 2000, 65, 4145.
7. Smith synthesis of spongistatin 1/Altohytin A
Structural features:
1. 24 stereocenters together with a 42-memberedmacrolactone ring
2. Two spiroacetal units (AB and CD)

3. Densely substituted tetrahydropyran rings (E and F)

Contents:
1. Heathcock synthesis of AB-ring segment(Palladium-catalyzed hydrogenolysis andPd-catalyzed asymmetric allylic alkylation)
2. Heathcock synthesis of CD-ring segment(stereocontrolled kinetic spirocyclization reaction)
3. Heathcock and Evans synthesis of E,F-ring segment(Catalytic asymmetric anti-aldol reaction:)
4. Heathcock connection of AB, CD, E, F-ring segment

1Retrosynthetic analysis:
Scheme 1. Heathcock synthesis of spongistatin 2/Altohytin C

1. Heathcock synthesis ofspongistatin 2/Altohytin C:(A highly convergent synthetic route)

Point of Heathcock synthesis of AB-ring,CD-ring segment:
1. Similar approaches to the AB and CD
spiroketal subunits.
2. Stereocontrolled kinetic spirocyclization
3. Prepared 9.6g AB-ring, CD-ring segment(a total of 62 step, with a longest linear
sequence of 35 steps.)

Scheme 2. Retro-synthesis of the AB-ring segmentScheme 3.Retro-synthesis of CD-ring segment:

2

Heathcock synthesis of the C1-C28 Portion:

Target compound

1. Synthesis of the AB-ring segment
Scheme 4. Synthesis of the AB-ring segment(d) tBuOAc, LDA, THF

910(ref: Tetrahedron 1992, 48, 4067.)
H
O
EtO2C

B H
O

NaBH4

10OEt
OH
EtO2C

BH3SMe2

CO2Et

OBH3
EtO2C

9-1
Diethyl (S)-malate

T1

CO2Et

H

H

9-2

B
O

O

EtO

CO2Et
T2

Relative reation: Diol protection

EtOH

3-pentananone,TsOH

OHOH

OH

EtO

Et

Et

OOOOHTHF
90%

0%

Carbohydr. Res., 1978, 65, 2293

10(ref: Tetrahedron Lett 1987, 28, 155.)

11O

EtOH

tBuO C2OTIPS
10-d

EtO

Et B

B

Et2BOMe

Ot

MeOH

Et

BuO2C

TIPSO
HO

OTIPStO
BuO2C

11H-Scheme 5. Synthesis of the AB-ring segment
Scheme 6. Synthesis of the AB-ring segment

Scheme 7. Synthesis of the AB-ring segment

Scheme 8. Synthesis of the AB-ring segment

430

31 (ref: Chem. Lett 1984, 1017.)

Scheme 9. Mechanism

Scheme 10. Ligand effectRTable 1. Ligand effect
SMLigand

Pd

Ratio of product
LHRR

PdPdL

HfavoredLH

disfavored

L = electron rich ligand

Recent report of Pd-catalyzed asymmetric allylic alkylation:
Table 2. Reaction of various allyl enol carbonates of acylic ketones

Trost et al. JACS. 2005, 127, 17180.

Scheme 11. Double bond geometry controls theconfiguration and enantiomeric excess of product

Scheme 13. Proposed mechanism
Scheme 12. Model for the enantioselectivity

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2. Synthesis of the CD-ring segment:

Scheme 14. Synthesis of 35

Target compounds

35Scheme 15. Synthesis of the CD-ring segment34

41 (stereocontrolled kinetic spirocyclization reaction)
Scheme 16. Conformations of CD-ring(Single anomeric effect)

Scheme 17. Evans synthesis of CD-ring segment

6Scheme 18. Mechanism of spirocyclization

Scheme 19. A kinetic result

Recent report of stereocontrolled kinetic spirocyclization reaction:
Tan D. S. et al. JACS. 2005, 127, 13796.
Scheme 20. Epoxide-based approach to the synthesisof spiroketals

Table 4. Spirocyclization product ratios

Table 3. Alcohol-induced spirocyclizations

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Scheme 21. Synthesis of the CD-ring segment

Scheme 22. Connection of AB-ring segment with
CD-ring segment.

3.0. Synthesis of E,F-ring segment:
Scheme 23. Heathcock retro-synthesis of E,F-ring segment(C29-C51)

C29-C51 iodide required 44 steps witha longest linear sequence of 33 steps.
The overall yield was 6.8%, and 2 gof the iodide 23 was prepared.

23

But, not excellent stereocontrol!

8Scheme 24. Heathcock of synthesis of E,F-ring segment:

3. Evans synthesis of E,F-ring segment
Scheme 25. Evans retro-synthesis of E,F-ring segment

Points of Evans synthesis ofE,F-ring segment:
1. Similar approaches to theE,F-ring subunits.
2. Stereocontrolled

9Scheme 26. Synthesis of E-ring segment

46

Scheme 27. Evans synthesis of F-ring segment:

48

Felkin selective additionof silyl ketene acetal:
Nu
Nu

MeM
SH

O

RL
L: large
M: middle
S: smallH
H

O

ONu=EtSOTES

R=Catalytic asymmetric anti-aldol reaction:a. Catalytic enantioselective anti-aldol reaction using Tin(II) complex.

Evans et al. JACS. 1997, 119, 10859.
JACS. 1997, 119, 7893.

Table 4. enantioselective anti-aldol reaction between
methyl pyruvate and silyl ketene acetals

10Scheme 28. Anti-selectivity
OTMS

E

Scheme 29. Anti and syn control.

t

S BuL.A.

L.A.

O
MeH
O

H

O

Me
StBu

TMSO

O

Me

Met

disfavored TS

BuS

OTMS

favored TS
Anti-aldol product

OTMS
Z

StBu
O

O

H

MeMe

MeO2C

Me

MeO2C

t

BuS

OTMS

TMSO

H

Scheme 30. Enantioselective formation of (5)MeStBuAnti-aldol productb. Anti-selective asymmetric aldol reaction using zirconium complex
Scheme 31. Effect of geometry of the silyl enolates

Kobayashi et al. JACS. 2002, 124, 3292.

Scheme 33. Assumed transition states

Scheme 32. Assumed catalyst structurec. Catalytic asymmetric synthesis of anti-1,2-diols using organocatalysis
List et al. JACS. 2000, 122, 7386.
Scheme 34. Anti-aldol
Scheme 35. Potential transition states11d. Anti-selective catalytic aldol reactions of amides with aldehydes
Kobayashi et al. JACS. 2006, 128, 8704.
Table 5. Various aldehydes

Scheme 36. Assumed catalytic cycle

Synthesis of E,F-ring segment (continued):
MeScheme 39.

Scheme 37. Evans synthesis of F-ring segment

6566R2R11)

OO

H
MeR

R1H
R R1

disfavored

MeR2OO

favored

Down:
MeOO

R2RO65a2)

R1=OTBS
R2=(CH2)4OBn
R=Ring F

MeR2O
H

R1O

ROC

R R1OMeOMe-R2H

favoredUp:
OMe- Me3)O

OMe Me
R2

O

R2ROC

H
R R1

O H
R1
disfavored

Scheme 38. Evans connection of E-ring and F-ring segment

Scheme 41. Evans synthesis of E,F-ring segment

12Scheme 40. 6566

Felkin selective additond withelectron withdrawing group (w)

LHRO

H-Scheme 42. Evans synthesis of E,F-ring segment

NuMeOW

E RingH
Ring FO

MeOfavoredO

Ring FRingEH
disfavoredH-4. Heathcock connection of AB, CD, E, F-ring segment
Scheme 41.

Scheme 42.

Acknowledgment:
Thanks a lot to Dr. Aoyama, Mr. Maki,Mr. Morimoto for their useful advice.

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