FUMAGILLIN

FUMAGILLIN

CO(CH=CH) 4 C0 2 H

Amongst the metabolic products of Aspergillus fumigatus is a crystalline antibiotic, fumigallin, having antiparasitic and carcinolytic activity. This molecule, characterized by a structural combination of no less than six asymmetric centers and highly reactive functionality, defied attempts at its synthesis for nearly a decade until it was finally secured by Corey and Snider in 1972. A key feature of this synthesis is the application of Diels-Alder reaction for simultaneous introduction of elements of the eight carbon side-chain (borne on the diene, A) in the molecule and a bromoaldehyde functionality suitable for elaboration to the terminal epoxide.

Preparation of the diene

component:

.C0 2 Me \

[

-

^

Se0 2 , DME _Δ , 8 hr

02Me

,C0 2 Me CHO

41%

THF 84%

02Me

© 1. E. J. Corey and B. B. Snider, J. Amer. Chem. Soc, 94, 2549 (1972).

106

CREATIVITY IN ORGANIC SYNTHESIS

Preparation of

fumagillin:

[ C 6 H 6> Δ > K 2 C 03J

K + £

COoMe

80%

®

02Me

:H 2 OH 1 .Br NaBH4,aqTHF[-

C0 2 Me

98%

:H2OTMS Br

}

TMSCI,TEA, THF

90%

fiQl

.C0 2 Me

> CH 2 CI 2 , 0 ° , NaHC0 3

02Me

Cl 80%

^ote 9reater reactivity of trl-substituted vs. di-substituted double bond

_3 1 . B u 4 N + r , THF|

C0 2 Me

2. NaOMe

2. Stereoselectivity of the epoxidation process was anticipated on basis of the six-carbon chain assuming the most stable conformation as depicted in (B). 3. Hydrolysis of the silyl ether linkage under the usual conditions in protic solvents led to a rapid intramolecular attack on the epoxide ring by the liberated primary hydroxyl group.

107

CREATIVITY IN ORGANIC SYNTHESIS

|os0 4 , Pyl-

,C02Me

81%

H

-J

Na^mO—►Mel

47%

H

*Note greater reactivity of equatorial vs. axial secondary hydroxyl group.

Meü,THF

C0 2 Me

OMe )H

Ac20

75%

Py, 50°

95%

OH

1.MsCI,TEA,THF,-l5° 2. Bu 4 N + Br-,THF, rt

Therefore, hydrolysis was carried out under aprotic conditions using tetrabutylammonium fluoride; the use of fluoride ion being suggested by the high value of Si-F bond energy (ca. 135 KCal/Mol).

108

CREATIVITY IN ORGANIC SYNTHESIS

■JK 2 C0 3 ,

MeOHl·

1. Separation by HPLC 2. MeLi-*CICO(CH=CH)4C02H THF,-78° CO(CH=CH)4C02H Fumagillin

109