AN ENANTIOSELECTIVE TOTAL SYNTHESIS OF THE MACRODIOLIDE (-)-(RRR)-COLLETALLOL

Article abstract of DOI:10.1016/0040-4039(91)80367-F

The total synthesis of (-)-colletallol, a naturally occurring macrodiolide, has been completed in 26 steps.An essential step in the sequence is the photo-induced rearrangement of an α,β-epoxy diazomethyl ketone to produce a 4-hydroxy-2-alkenoate.

Full text of DOI:10.1016/0040-4039(91)80367-F

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dircctIy into the diazo ketone 10. Irradiation of this diazo ketone in methanol, ff~Ilowed by silylarion, gave
compound 11. It was then necessary to decide which ester linkage in dilacmne ! should be eonstnlcted first.
Either choice will result in a seco colletallol derivative in which an unsaturated ester needs to be converted
into a free carboxylic acid (in order to accomplish the remaining lactonizntion step), without destroying the
"lncrone" unit already formed. C.onsequently, the nature of the ester group in either seco-colletallol derivative
requires careful consideration. Arbitrarily, we decided to form lactone unit C2-C14 first. For this purpose the
neetyl group at Ci4 needed to bereplaced by the base stable EE group, Then the unsaturated ester was
saponified wqh LiOH and the carboxylic acid 12 was esterified subsequently with 13-phenylsulfonyl ethanol
using dieyclohexylcarbodiimide (DCC) as the coupling reagent7. Subsequent removal of the EE protecting
function with MgBr2~' provided alcohol 13 which was used for the coupling reaction with the CTC6 fragment
B.
The prepan14ion of IYagment B is depicted in scheme 4. Alcohol 6, obtained from poly-(3(R)-hydroxy
C~EE
OEE
OEE
0
OEE
0
J..z-.o,
',
u,
o,
6
14
1S
16
s, (COCl)2, DMSO, NEt3
t. (EtO)2P(O)CH2CO2Et, LiCI, iPr2EtN, CH3CN
u, UOH, THF/H20 1/1
(84%)
(80%)
(97%)
Scheme 4
butyric acid) (see scheme 3), was oxidized m aldehyde 14 and which was then subjected to a Wittig-Homer
chain elongation to give ester lg. Subsequent saponification of this ester gave acid 16.
The coupling of acid 16 with the C8-C14 fragment 13 was successfully accomplished using
DC(]/DMAP as the condensing agents (scheme 5) The "half htctone" derivative 17 obtained in this manner,
was converted into seco-colletallol 18 by successive removal of the EE protecting group with MgBr26 and the
PSE group by treatment with I)BU. The latter deprotection step is a base-induced eIimination reacdon and
does therefore not affect the already formed "lactone" unit between C2 and C14.
Scco-colletallol 18 was subjcctcd to macrolactonization. Several of the various methods described in
the literatures were tried9 but without success. Gratifyingly, the desired ring closure was realized in good
yield by the Yamaguchi procedure employing 2,6 dichlorobenzoyl chloride instead of 2,4,6-rriehlorobenzoyl
chloride used originally10. Final removal of the silyl protecting group at C 11 from 19 gave (-)-(RRR)-('olletal-
lol, m.p. 108 110 "C and [alp2° -58" (c 0.7 in CHCI3). The spectral features (tH-NMR, MS and IR) we/x: in
full accord with those reported for natnrnl colletallol and synthetic racemic R*R*R*-eolletallo111. This
observation leads to the conclusion that natural colletallol has either the RRR or the SSS configuratkm. In
view of the sUuctural relationship with collcttx.liol 4 and colletoketol 2, isolated from the same natural source,
the RRR coafigut-ation is considered to bc the most probabte one.