Our approach to 1 deviates from the pioneering work of
Giese,8a in that it focuses on the union of 2 and 3 through
an aldol condensation-olefin metathesis sequence as an
avenue to the macrocycle (Figure 1). The configuration of
the C-2 methyl group in soraphen corresponds to the
thermodynamically favored one. Ring-chain tautomerism of
the pyran unit in 1 forms a transient â-ketoester that
undergoes facile epimerization at C-2. Thus, the correct C-2
epimer will ultimately result regardless of the initial con-
figuration at this center.8 The assembly of segments 2 and 3
relies on modern asymmetric methodology, rather than on
educts from the “chiral pool”. This shortens the synthesis to
a significant extent.
Scheme 1. Synthesis of Fragment 2
As outlined in Scheme 1, a Corey-Shibata asymmetric
carbonyl reduction10 and a Brown allylboration11 are the key
steps in the synthesis of 2. Ozonolysis of commercially
available 4 and reductive workup in the presence of TsOH12
gave 5, reduction of which to 6 proceeded with 92% ee.13a,b
Release of the dimethylacetal (TFA in moist CHCl3)14 set
the stage for allylboration of aldehyde 8 with reagent 11,15
followed by Tamao16 oxidation of the intermediate allylsilane
(not isolated). Compound 9 was obtained in 51% yield and
70% de.13c O-Methylation furnished the desired 2.
(4) Bedorf, N.; Schmburg, D.; Gerth, B.; Reichenbach, H.; Ho¨fle, G.
Liebigs Ann. Chem. 1993, 1017.
(5) (a) Reichenbach, H.; Ho¨fle, G.; Augustiniak, H.; Bedorf, N.; Forche,
E.; Gerth, K.; Irshik, H.; Jansen, R.; Kunze, B.; Sasse, F.; Steinmetz, H.;
Trowitzch-Kienast, W. EP282455 A2, 1988 (Ciba-Geigy AG). (b) Re-
view: Vincent, G. Dissertation, Universite´ Claude Bernard Lyon 1, 2005.
(6) Wan, H.; Sjolinder, M.; Schairer, H. U.; Leclerque, A. J. Microbiol.
Methods 2004, 57, 33. (b) Shen, Y.; Volrath, S. L.; Weatherly, S. C.; Elich,
T. C.; Tong, L. Mol. Cell 2004, 16, 881.
The methylation step often produced a mixture of 2 and
the two monomethylated derivatives of 9. Rather than forcing
the reaction to completion by adding more Meerwein salt
and Proton Sponge,17 we found it expedient to work up the
reaction and resubmit the mixture of monomethylated
products to methylation under identical conditions. Whatever
the reasons for such a behavior, conversion of 9 to 2 was
thus effected in a satisfactory 70% overall yield. The
diastereoisomers produced during the allylboration reaction
were separated at this stage.
(7) Gubler, M.; Mizrahi, J. WO03011867 A1, 2003 (Hoffman-La Roche
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(8) Total synthesis: (a) Abel, S.; Faber, D.; Hu¨ter, O.; Giese, B. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2466. (b) Abel, S.; Faber, D.; Hu¨ter, O.;
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R. Chem. Commun. 2003, 1358. (b) Bo¨hlendorf, B.; Bedorf, N.; Ho¨fle, G.;
Schummer, D.; Sutter, M. US 4,997,820, 1991 (Ciba-Geigy AG). (c) Sutter,
M.; O’Sullivan, A.; Ho¨fle, G.; Bo¨hlendorf, B.; Kiffe, M. EP0540469A1,
1992 (Ciba-Geigy AG). (d) Bo¨hlendorf, B.; Bedorf, N.; Ho¨fle, G.;
Schummer, D.; Sutter, M. US 4,940,804, 1990 (Ciba-Geigy AG). (e)
Bo¨hlendorf, B.; Bedorf, N.; Ho¨fle, G.; Schummer, D.; Sutter, M. US 4,-
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Schummer, D.; Jahn, T.; Ho¨fle, G. Liebigs Ann. Chem. 1995, 803. (h) Sutter,
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The synthesis of a convenient form of 3 started with a
stereochemically matched18 Evans aldol condensation19 of
aldehyde 1920 with 12, followed by O-protection to give 14
(Scheme 2). Difficulties were encountered during attempts
to produce aldehyde 15 through release of the terminal TBS
group and oxidation of the emerging primary alcohol. This
was due to the proclivity of the latter to lactonize with
concomitant expulsion of the Evans oxazolidinone. Among
various remedies that were examined for such ills,21 direct
oxidation of 1422 (5 equiv of PCC, 3 days) emerged as the
best solution, providing 15 in 82% yield.
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(13) Configurations and ee’s were determined by the Mosher method:
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