Journal of the American Chemical Society
Communication
a
Scheme 4. Union of Fragment A and Fragment B and Total Synthesis of (+)-Zincophorin Methyl Ester
a
Yields are of material isolated by silica gel chromatography. See Supporting Information for further experimental details.
allylic alcohol 8, which is converted to a single diastereomeric
epoxide using the Sharpless protocol.25 Reaction of the epoxide
with Gilman’s reagent delivers compound 9,26 which incorpo-
rates the stereoheptad spanning C6−C12. Hydroformylation of
9 using a XantPhos modified rhodium catalyst27 provides the
linear aldehyde, which upon exposure to methanol in the
presence of substoichiometric p-toluenesulfonic acid delivers the
pyran 10 as a mixture of diastereomers at the anomeric position.
The major diastereomeric pyran 10 could be separated by flash
chromatography and was converted to the tris(triethylsilyl)
ether. Exposure to Swern oxidation conditions results in cleavage
of the primary TES-ether and formation of the aldehyde
Fragment B.28
The union of Fragments A and B is achieved through lithiation
of the primary alkyl iodide Fragment A and subsequent addition
to the aldehyde Fragment B (Scheme 4).29 Synergistic 1,2- and
1,3-stereoinduction effects14 were anticipated to enforce highly
diastereoselective addition. However, under standard reaction
conditions using HMPA as an additive, the adduct 11 formed as a
1:1 ratio of C13 diastereomers. HMPA was necessary to facilitate
Li−halogen exchange of Fragment A, as its omission resulted in
tert-butylation of Fragment B. This was not the case using 4-iodo-
1-butene, which underwent addition to Fragment B in ether in
70% yield to furnish a 2:1 ratio of C13 diastereomers. The
diastereomeric ratio did not change upon introduction of
HMPA, suggesting chelation control was not operative; however,
an improved 99% yield was observed. The Cram−Reetz and
Evans polar models14 assume the C11−OSiEt3 moiety should
predominantly populate a conformation wherein the C11−
OSiEt3 bond dipole cancels the C13 formyl bond dipole. It
appears the negative inductive effect of the highly oxygenated
C10−C3 moiety erodes this conformational bias, leading to
diminished diastereoselectivities (Figure 2). Hence, modification
propionate enolate,11g,16 providing the trans-pyran as a single
diastereomer. Subsequent methanolysis of the thiazole thione
from the crude reaction mixture delivered (+)-zincophorin
methyl ester, which was identical in all respects to the reported
literature material.9 In this way, (+)-zincophorin methyl ester,
which incorporates 13 stereocenters, was prepared in 13 steps
(LLS) with 4 C−C bonds formed using hydrogenative coupling
protocols.
Despite enormous progress in synthetic methods develop-
ment, the vast majority of de novo chemical syntheses remain
distant from the Hendricksonian ideal.31 This is principally due
to (a) the separation of redox and skeletal construction events
and (b) the persistent requirement of protecting groups. Both
deficiencies may be addressed through the design of catalytic
methods that merge redox and C−C bond formation events,5
especially transformations that may be deployed in a site-
selective manner,6 and the new strategies that such methods
evoke. In the present study, transfer hydrogenative couplings that
directly convert lower alcohols to higher alcohols4 are used to
generate triketide stereopolyads that would otherwise require
lengthy multistep syntheses. As demonstrated across diverse
contexts,7 these methods consistenly and significantly enhance
efficiency, bringing us one step closer to the Hendricksonian
ideal.31 More immediately, the concise nature of the present
route to (+)-zincophorin methyl ester will enable access to
material that will allow for a more complete investigation into its
biological properties, studies which are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data. The Supporting
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM093905), and the University of Texas Center for
Green Chemistry and Catalysis are acknowledged for partial
support of this research.
Figure 2. Merged 1,2- and 1,3-stereoinduction model. R1 = C10−C3 of
Fragment B; R2 = C15−C25 of Fragment A.
of the organolithium reagent by chiral 1,2-diamines was
investigated as a means of amplifying stereoselectivity.30 Using
tetramethylcyclohexane diamine, a 3:1 molar ratio of diaster-
eomers was obtained, which could be separated by flash
chromatography. With compound 11 in hand, installation of
the terminal C3 monoketide moiety was achieved using a chiral
REFERENCES
■
(1) Reviews: (a) O’Hagan, D. The Polyketide Metabolites; Ellis
Horwood: Chichester, U.K., 1991. (b) Rohr, J. Angew. Chem., Int. Ed.
C
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX