Stereocontrolled synthesis of carbon chains bearing contiguous methyl groups by iterative boronic ester homologations: Application to the total synthesis of (+)-faranal

Full text of DOI:10.1002/anie.200901194

Angewandte
Chemie
DOI: 10.1002/anie.200901194
Assembly-Line Synthesis
Stereocontrolled Synthesis of Carbon Chains Bearing Contiguous
Methyl Groups by Iterative Boronic Ester Homologations: Application
to the Total Synthesis of (+)-Faranal**
Guillaume Dutheuil, Matthew P. Webster, Paul A. Worthington, and Varinder K. Aggarwal*
Carbon chains bearing 1, 3, 5… n polymethyl groups are
ubiquitous in natural products. Recently, effective solutions
for a flexible, stereocontolled synthesis of such arrays have
been achieved by the groups of Feringa-Minnaard,[1] Breidt,[2]
and Negishi.[3] Carbon chains bearing adjacent methyl groups,
although less common, are also frequently encountered[4]
(Figure 1), but a general stereocontrolled solution to this
problem has not been advanced.[5] For example, in the
previous syntheses of the insect pheromone (+ )-faranal
(1),[5b] one or both methyl groups originate from a carboxylic
oxidation state invariably leads to an increase in the total
number of steps required.
We recently reported a method to homologate carbon
chains bearing boronic esters using Hoppeꢀs lithiated carba-
mates.[7,8] Through appropriate choice of the diamine ligand
employed in the lithiation of the carbamate [(À)-sparteine[9]
or OꢀBrienꢀs[10] (+)-sparteine surrogate] we showed that
either enantiomer of either diastereomer of the homologated
product could be easily obtained (Scheme 1). We now
demonstrate the application of this methodology to a
stereocontrolled synthesis of (+ )-faranal and furthermore,
highlight a new one-pot multiple-homologation process.
À
ester to enable control of relative stereochemistry during C
C bond formation (both utilize resolution to achieve absolute
control).[6] Introducing the methyl groups in the wrong
Scheme 1. Access to all four isomers using iterative homologations of
boronic esters. pin=pinacolate.
Our retrosynthetic analysis of (+ )-faranal (1) is shown in
Scheme 2. We envisaged that the target compound could be
obtained through a suitable two-carbon homologation of
boronic ester 2. This intermediate could be obtained, in turn,
Figure 1. Examples of natural products bearing adjacent methyl
groups.
[*] Dr. G. Dutheuil, M. P. Webster, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
Fax: (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
Homepage: http://www.chm.bris.ac.uk/org/aggarwal/
aggarhp.html
Dr. P. A. Worthington
Syngenta, Jealott’s Hill, International Research Centre
Bracknell, Berkshire, RG42 6EY (UK)
[**] We thank Syngenta and EPSRC for support of this work. We also
thank Merck for unrestricted support. V.K.A. thanks the Royal
Society for a Wolfson Research Merit Award and EPSRC for a Senior
Research Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901194.
Scheme 2. Retrosynthetic analysis of (+)-faranal (1).
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Communications
Scheme 3. Model study for the synthesis of (+)-faranal. 9-BBN=9-borabicyclo[3.3.1]nonane.
by two consecutive homologations of boronic ester 5 using the
lithiated carbamate 3 derived from (À)-sparteine. These
homologations were expected to control both the relative and
absolute stereochemistry and thus deliver the required anti
isomer 2. Boronic ester 5 could be obtained from the
corresponding alkyne 6.[11]
Model studies to test the multiple homologation reactions
were initially conducted on geraniol (Scheme 3), which was
converted directly into the allylic boronic ester 8 (93:7, E/Z)
through a novel coupling process employing B2pin2 and the
commercially available palladium catalyst 7.[12] This inter-
mediate 8 was treated with the lithiated carbamate 3,
furnishing the first homologated boronic ester 9 in 78%
yield and 96:4 e.r. (determined by oxidation to the alcohol and
analysis of the Mosherꢀs ester). A further homologation with
the same lithiated carbamate 3 gave boronic ester 10 in 52%
yield, > 98:2 e.r., and 94:6 d.r. (determined as above). A third
homologation with vinyllithium followed by treatment with I2
and NaOMe[13] gave the intermediate alkene 11, which was
directly hydroborated and oxidized to give the alcohol 12 in
76% yield, with the same selectivity. Remarkably, it was
possible to convert boronic ester 8 directly into alcohol 12 by
simply carrying out all three homologations consecutively in
one pot. Not only did this provide substantial savings in time
but it also led to a significant increase in overall yield without
detriment to the selectivity observed (60% yield; 94:6 d.r.;
93:7, E/Z).
Key to the success of this one-pot operation, we believe, is
the fate of the reactive intermediates that are generated. The
lithiated carbamate reacts rapidly with the boronic ester
forming the intermediate ate complex 13 (Scheme 4). An
excess of the lithiated carbamate is employed to ensure
complete reaction with the boronic ester. Fortunately, the
unreacted lithiated carbamate decomposes at a lower temper-
ature than that required to effect the 1,2-metallate rearrange-
ment of the ate complex.[14] Thus, as the reaction mixture is
heated, the excess lithiated carbamate is destroyed and then
the homologated boronic ester is formed ensuring that with
each successive addition of the lithiated carbamate single
homologations occur in high yield.
Scheme 4. Potential reactions of lithiated carbamate. Cb=N,N-diiso-
propylcarbamoyl.
ses.[6] Although vinyl iodide 21 had been reported previ-
ously[11,15] our current route represents a practical improve-
ment as it avoids having to handle HMPA and acetylene. The
route began with a zirconium-catalyzed ethyl alumination[16]
of propyne followed by quenching with I2, to furnish the Z
vinyl iodide 18 (Scheme 5). Subsequent Negishi cross-cou-
pling with the alkyl iodide 19 gave the unsaturated alkyne 20.
Desilylation[17] followed by a second zirconium-catalyzed
carboalumination and trapping with I2 gave the vinyl iodide
21, which was lithiated and coupled with the chloromethyl
boronic ester 22 to furnish 5 with complete E selectivity.
Application of the one-pot, triple-homologation sequence
then furnished alcohol 23 in 69% yield, > 98:2 e.r., 94:6 d.r.,
> 98:2 E/Z. During the course of this work, we discovered
that Lewis acid activation of the carbamate group by MgBr2
was not required to trigger the 1,2-metallate rearrangement;
simply heating to 408C was sufficient. This modification
simplified the one-pot protocol significantly and resulted in a
57% yield of alcohol 23, again without detriment to the
selectivity observed. We have even found that the simple vinyl
iodide 21 can be converted into the complex alcohol 23 in
40% yield in a quadruple-homologation sequence without
purification of any intermediates which avoids having to
handle the sensitive allylic boronic ester 5. Finally, the alcohol
23 was converted into (+)-faranal (1) by PDC oxidation.[6d]
The synthetic material was identical in all respects to the
natural product. The asymmetric, fully stereocontrolled syn-
thesis of (+)-faranal was completed in just six steps from
propyne, a substantial improvement over previously reported
synthesis (19 steps[6c,d], 29 steps[6a,b] and 10 steps[5b]).
Having established a highly effective one-pot protocol for
the direct conversion of the allylic boronic ester 8 into alcohol
12 we began the synthesis of (+)-faranal (1) itself, although
we wished to improve the E/Z selectivity of the alkenes in the
final product as this had been the bane of previous synthe-
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Scheme 5. Total synthesis of (+)-faranal (1). TMS=trimethylsilyl,
Cp=cyclopentadienyl, PDC= pyridinium dichromate, DCM=dichloro-
methane.
In conclusion, we have developed methodology for the
stereocontrolled synthesis of carbon chains bearing adjacent
methyl groups and applied it to a short synthesis of (+)-
faranal. This methodology is akin to a molecular assembly
line in which successive groups are added to a growing chain
with control of a relative and absolute stereochemistry.
Remarkably, these successive additions can be carried out in
one pot with improved efficiency (yield and manpower!) and
without detriment to selectivity. Further work is now ongoing
to identify the practical limits of this multiple-homologation
process.
Received: March 3, 2009
Published online: May 13, 2009
À
Keywords: boronic esters · C C coupling · lithiated carbamates ·
natural products
.
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without purification.
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