J.A. Gladding et al. / Tetrahedron 67 (2011) 6697e6706
6705
Cl
Cl
Cl
OTBS
OH
OTBS
OTBS
OH
OH
OTBS
OTBS
OTBS
1) DDQ
1 eqv. CSA
1:1 CH2Cl2/EtOH
(64%)
TBSO
TBSO
HO
2) TBSOTf
HO
HO
HO
OTBS
OTBS
(–)-65
Cl
OTBS
(85%, 2 steps)
PMBO
TBSO
TBSO
(+)-48
(–)-66
Cl
OTBS
OH
OTBS
OH
CO2H OPMB
Br
O
Br
OPMB
O
O
O
OTBS
OTBS
DCC, DMAP
MeO
1) TFA/CH2Cl2
2) DDQ/MeOH
(54%, 2 steps)
MeO
+
(–)-66
MeO
O
MeO
HO
TBSO
HO
Br
(86%, 10:1 dr)
OMe
68
OTBS
OMe
OTBS
(–)-8c
TBSO
OMe
67
Scheme 24.
(þ)-48 was subjected to DDQ in the presence of water and the re-
sultantsecondaryhydroxylprotectedastheTBSethertoafford(ꢀ)-65
(Scheme 24). Selective removal of the primary TBS ether was then
accomplished with CSA in CH2Cl2/EtOH to furnish alcohol (ꢀ)-66.
Union of (ꢀ)-8c with benzodiquinane (ꢀ)-66 was performed
with DCC to provide ester 67 as an inseparable mixture (10:1) of
diastereomers (Scheme 24). Presumably, the oxidation of (ꢀ)-22 to
(ꢀ)-8c (Scheme 7) had caused partial racemization of the benzylic
stereocenter. Nonetheless, we chose to test the macrocyclization,
with the understanding that if successful, we could re-visit the ox-
idation and subsequent racemization issues. Removal of the phenolic
PMB group of 67 was accomplished with TFA and the resultant
phenol subjected to oxidative ketalization with DDQ in MeOH to
provide cyclization precursor 68 in 54% over the two steps.
existence with his interest in and contributions to the art world, on
the occasion of receipt of the 2011 Tetrahedron Prize.
Financial support was provided by the National Institutes of
Health (National Institute of General Medical Sciences) through
NIH Grant GM-29028.
Supplementary data
Spectroscopic and analytical data as well as experimental pro-
cedures associated with this article. Supplementary data associated
with this article can be found in online version at doi:10.1016/
Macrocyclization studies began with the use of sodium hydride
as base (Scheme 25). No reaction was observed at 0 ꢁC, but as the
reaction was warmed to room temperature, we observed hydrolysis
of the ester. Changing the base to KHMDS gave the same result,
even when molecular sieves were added to remove adventitious
water. A number of other bases and additives were examined at
room and elevated temperatures, including cesium carbonate, DBU,
BTPP, silver oxide, and triethylphosphine. Only epimerization (with
DBU) and formal ester hydrolysis were observed. In the latter re-
actions, we were able to re-isolate the alcohol fragment, but the fate
of the corresponding acid fragment was unclear. It is possible that
even when moisture was rigorously excluded hydrolysis occurred
through ketene formation, although we did not isolate any species
that would confirm this possibility.
References and notes
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OTBS
O
O
Cl
Cl
OTBS
OH
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Br
O
O
O
MeO
OTBS
OTBS
OTBS
MeO
MeO
Me
O
HO
TBSO
OMe
OTBS
MeO
MeO
HO
O
TBSO
68
69
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Acknowledgements
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This paper is dedicated to Professor Satoshi Omura, outstanding
scientist, scholar and friend, who has enhanced the human
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