Scheme 2. Synthesis of Tetra-Substituted Pyran 3
utilizing 2, prepared from commercially available 4. Key
pyran 3, the C5-C15 fragment, was conceived to be derived
from 5 through a SmI2-mediated reductive cyclization
reaction.5-10
delivered the key intermediate 9 in 93% isolated yield.
Removal of the TBS group proved equally problematic. Upon
exposure to TBAF, a 1:1 mixture of the desired 10 and an
unanticipated 1,3-dioxepane 11 formed. While separable, this
undesired side product was detrimental at this stage of the
synthesis. After surveying a variety of reaction conditions,
we found that addition of a few drops of concentrated HCl
in MeOH at 0 °C smoothly delivered the alcohol 10 in
quantitative yield. Swern oxidation proceeded uneventfully
delivering the key template for the reductive cyclization.5-10
In the event, exposure to SmI2 provided the desired pyran
12 in 69% yield for the three steps. The relative stereochem-
istry of 12 was assigned by NMR and NOE analysis and in
agreement with literature precedent.5-10
The synthesis of pyran 3 is described in Scheme 2.
Monobenzyl protected-1,4-butane diol 6 was oxidized under
Swern conditions to the corresponding aldehyde which was
then subjected to a Brown crotylation reaction to afford 7
as a single diastereomer in 87% ee.11,12 Hydroboration and
chemoselective TBS protection of the primary alcohol
provided 8 in 89% yield for the two steps. 1,4-Addition of
8 to ethyl propiolate proved difficult, resulting in complex
mixtures under a number of reaction conditions.13 Ultimately,
slow addition of ethyl propiolate via syringe pump over 24 h
Once in hand, the secondary alcohol of 12 was protected
and the ester hydrolyzed to produce acid 13 in 85% yield
for the two steps. Curtius rearragement with (PhO)2P(O)N3
(DPPA) provided the aminomethyl congener 14 in 81%
yield.14,15 Finally, an acetylation, benzyl deprotection, and
oxidation sequence afforded target pyran 3, the C5-C15
fragment, in 81% yield for the three steps. Thus, the longest
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