PROGRESS OF STUDIES ON THE NATURAL CEMBRANOIDS FROM THE SOFT CORAL SPECIES OF SARCOPHYTON GENUS - Medicinal Chemistry of Bioactive Natural Products - page 267

cyclization reaction is often the key step in the total synthesis, each of these stra-
tegies will be described in Sections 6.4.1-6.4.4.

6.4.1 Total Synthesis of Sarcophytols

6.4.1.1 Total Synthesis of Sarcophytol A
The first total synthesis of sarcophytol A (3), which was reported by Takayanagi
et al. in 1990, 80,81 was achieved in a highly stereo- and enantioselective manner
starting from E,E-farnesol (91); it included (1) a newly developed Z-selective
(Z : E 35 : 1) Horner-Emmons reaction with a phosphonate nitrile, (2) modified
cyanohydrin macrocyclization, and (3) enantioselective (93% ee) reduction of
macrocyclic ketone 100 as its key steps (Scheme 6-1).
Enantiomerically pure sarcophytol A (3) was obtained by a single recrystalliza-
tion. An improved synthetic process appropriate for a large-scale preparation
with geraniol as the starting material was also developed. It included a new ketal
Claisen rearrangement with 2,2-dimethoxy-2,3-dimethylbatan-2-ol for a-ketol
isoprene elongation, which was applied to the sequence for highly stereoselective
(E : Z 99 : 1) synthesis of trisubstituted g, d-unsaturated aldehydes, and acids
(Scheme 6-2). 82

OH O

CN

Oxid. a

+

CN

92 93

91 94

b c d

CHO

CN

NC OTMS

Cl Cl

X

95 X=OH
96 X=Cl

97 98

e f g

CN

OH

O

OTMS

99

100

(3)

Reagents and Conditions: (a) (EtO) 2 POCH(CN)i-Pr, Tol, 78 C, 96%, (94: 93 35: 1); (b) i. 3 mol%
SeO 2 , 80% t-BuOOH, CH 2 Cl 2 , 52%; ii. CCl 4 ,Ph 3 P, 93%; (c) DIBAL-H, n-hexane, 78 C, then
aq.AcOH, 79%; (d) TMSCN, cat. KCN/18-crown-6 ether complex; (e) LiN(TMS) 2 , THF, 55 C; (f) n-
Bu 4 N þ F in 10% aqueous THF, 89% from 97; (g) chirally modified LiAlH 4 reagents, 88%.

Scheme 6-1