Scheme 1. Synthesis of 29-Membered Lactone Using Benzoic
Anhydride Method
After assembling these fragments to form the corresponding
seco-acid, we planned to apply our effective monomer-
selective lactone formation to the seco-acid to generate the
desired 29-membered ring backbone.
First, (S)-malic acid (6) was converted into the corre-
sponding triol by the reduction with BH3‚SMe2 in the
presence of B(OMe)3 according to the literature method
(Scheme 2).16 The triol was protected as its PMP acetal, and
the resulting primary alcohol was transformed into the
TBDPS ether 7. Reductive cleavage of the PMP acetal
moiety of 7 with DIBAL regioselectively produced a primary
alcohol 8, and then the hydroxyl group in 8 was replaced
with iodine. Next, cross coupling between the iodide 9 with
Grignard reagent A was examined under various reaction
conditions. After several experimental trials combining metal
salts with ligands, it was found that a complex generated
from CuI with 2,2′-bipyridyl functions as the best promoter
of the coupling reaction to produce the desired 14-carbon
segment 10 in high yield.17 Deprotection of the TBS group
of 10, substitution of the hydroxy group with iodine to
transform iodide 11, and successive cross coupling of 11
with Grignard reagent A were repeated in the presence of
the copper complex to afford the 24-carbon segment 12.
Next, the further conversion of the 24-carbon linear
segment 12 to an elongated 28-carbon seco-acid 17 was tried
as follows: the TBS group of 12 was cleaved with
hydrochloric acid, and the formed primary alcohol was
oxidized with PCC to yield an aldehyde 13. Elongation of
the 4-carbon unit onto 13 was attained by the addition of
Grignard reagent B to 13 as shown in Scheme 2. The
resulting secondary alcohol 14 was protected as its THP
ether. Deprotection of the terminal TBDPS group of 15 by
the treatment with a mixture of TBAF and acetic acid
smoothly occurred to give the corresponding primary alcohol
16, which was directly oxidized to form a carboxylic acid.
Figure 1. Some defensive substances of termite soldiers.
This protocol could be performed using a very simple
procedure, and the desired lactones are obtained within a
very short time under mild conditions since the reaction
quickly proceeds in the presence of a catalytic amount of
basic catalysts, such as DMAP or its N-oxide (DMAPO).
In this paper, we now report an effective synthesis of
2-hydroxy-24-oxooctacosanolide (5), the defensive secretion
of the African termite Pseudacanthotermes spiniger,5 using
MNBA lactonization protocol as part of our continuous
efforts to apply new synthetic methodology to produce
biologically active macrolactones.
Scheme 1 illustrates the retrosynthetic route to the desired
lactone 5, in which three kinds of segments, (S)-malic acid
(6), 10-carbon unit A, and 4-carbon unit B, are involved.
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