Enantiospecific synthesis and allylation of all-carbon-substituted a-chiral allylic stannanes

Full text of DOI:10.1002/anie.200901384

Communications
DOI: 10.1002/anie.200901384
Stereoselective Synthesis
Enantiospecific Synthesis and Allylation of All-Carbon-Substituted
a-Chiral Allylic Stannanes**
Eric S. Schmidtmann and Martin Oestreich*
Stereodefined a-chiral allylic stannanes are well-established
nucleophilic allyl-transfer reagents in reagent-controlled
asymmetric synthesis.[1–3] Sufficient chemical stability is
commonly secured by oxygenation at the a[4] or the g[5]
carbon atom of these secondary tin compounds, whereas
allylic systems devoid of heteroatom substitution are fragile
as a result of a pronounced tendency toward 1,3-tin migration
or even decomposition.[1] The absence of mild methods for the
synthesis of these elusive all-carbon-substituted allylic stan-
nanes might have thwarted the development of their chemis-
try until now.[6] Herein, we report an exceptionally facile
synthesis of a-chiral allylic stannanes through both enantio-
specific and regioselective allylic substitution[7] with an
undervalued tin-based zinc compound.[8,9] We also showcase
the value of these new allyl-transfer reagents in enantiospe-
cific and diastereoselective thermal[1,4] and Lewis acid pro-
Scheme 1. Preparation of a-chiral silanes by copper-catalyzed allylic
moted[1,10] carbonyl allylation.
substitution with (Me2PhSi)2Zn.[12] Bz=benzoyl.
Several years ago, we introduced manifold copper-cata-
lyzed reactions of soft bis(triorganosilyl) zinc reagents instead
of hard triorganosilyl lithium reagents for carbon–silicon
bond formation.[11] The success of this chemistry hinges on a
lithium-to-zinc transmetalation step, through which the
nucleophilicity and basicity of the silicon atom is markedly
attenuated. The otherwise essential use of stoichiometric
amounts of copper is therefore unnecessary. For example, the
allylic substitution of allylic benzoates proceeded cleanly in
6). These experimental findings prompted us to also elucidate
the competing reaction pathways in this catalytic process.[12]
On the basis of this enantioselective synthesis of a-chiral
allylic silanes, we set out to elaborate a preparatively useful
route to difficult-to-obtain, stereodefined all-carbon-substi-
tuted allylic stannanes. We synthesized the required bis(trior-
ganostannyl) zinc compounds from the corresponding trior-
ganostannyl chlorides through reductive metalation with
elemental lithium and subsequent lithium-to-zinc transmeta-
lation[13] (Scheme 2).[8]
the presence of copper(I) iodide as
a catalyst with
(Me2PhSi)2Zn as the source of the silicon nucleophile.[11b]
Regioselectivity and the connected preservation of stereo-
chemical integrity were highly dependent on the substitution
pattern (Scheme 1):[12] Cyclic and acyclic “symmetrical”
substrates were almost completely ((S)-1!(R)-2) or partially
racemized ((R)-3!(S)-4), whereas acyclic “nonsymmetrical”
precursors reacted regioselectively with flawless inversion of
the absolute configuration at the a carbon atom ((S)-5!(R)-
Scheme 2. Generation of bis(triorganostannyl) zinc reagents.[8]
[*] Dipl.-Chem. E. S. Schmidtmann, Prof. Dr. M. Oestreich
Organisch-Chemisches Institut
We next tested (Bu3Sn)2Zn with copper(I) cyanide
(5.0 mol%) in the allylic substitution of our three model
substrates, (S)-1, (R)-3, and (S)-5 (see Scheme 1). The desired
allylic stannanes (R)-7, (S)-8, and (R)-9 were formed almost
quantitatively (Scheme 3). As expected, these all-carbon-
substituted stannanes were stable when isolated but remark-
ably labile in solution (in polar solvents)[1b] and on silica gel;
purification by rapid flash chromatography was feasible (see
the Supporting Information for NMR spectra), whereas the
determination of ee values by analytical HPLC or GLC failed.
We therefore decided to immediately subject crude[14] (R)-7,
(S)-8, and (R)-9 to a thermal SE2’ reaction with an aldehyde to
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax: (+49)251-83-36501
E-mail: martin.oestreich@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/research/
oestreich/oe_welcome.html
[**] We thank the Deutsche Forschungsgemeinschaft (Oe 249/3-1) for
financial support as well as BASF AG (Ludwigshafen, Germany) for
the generous donation of enzymes. M.O. is indebted to the Aventis
Foundation for a Karl-Winnacker-Stipendium (2006–2008).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901384.
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Chemie
anti relative configuration from E pre-
cursors; products with a Z alkene geom-
etry are formed preferentially. This out-
come is rationalized by a cyclic transition
state with the substituent at the a carbon
atom in an axial position, an arrangement
which in turn translates into a Z double
bond in the homoallylic alcohol.[15] All
three allylic stannanes of unknown enan-
tiomeric purity reacted with benzalde-
hyde to afford the homoallylic alcohols
syn-10 (4% ee), anti-11 (50% ee), and
anti-12 (99% ee). These ee values corre-
late well with the results obtained for the
series of a-chiral allylic silanes (compare
Schemes 1 and 3). We assume that
copper-catalyzed allylic substitutions
with (R3Si)2Zn and (R3Sn)2Zn occur by
identical mechanisms.[12]
Scheme 3. Preparation of the a-chiral stannanes 7–9 by copper-catalyzed allylic substitution
with (Bu3Sn)2Zn and thermal SE2’ reaction with benzaldehyde.
For the “nonsymmetrical” allylic ben-
zoate (S)-5, both the regioselective allylic
substitution ((S)-5!(R)-9) and the dia-
get an indirect measure of the stereochemical course of the
allylic substitution. These enantiospecific thermal carbonyl
allylation reactions favor the formation of products with a syn
relative configuration from Z precursors and products with an
stereoselective electrophilic substitution ((R)-9!anti-12) are
enantiospecific: The product anti-12 was formed with an
excellent ee value of 99%. The chemical yield was moderate
(Table 1, entry 1), as expected for a thermal SE2’ reaction.[1,4]
Table 1: Enantiospecific and highly anti-diastereoselective thermal SE2’ reactions of a-chiral allylic stannanes with aldehydes.
Entry
Allylic benzoate
R2
Aldehyde
R3
Product
R1
ee [%][a]
99 (S)
Yield [%][b]
d.r.[c]
ee [%][a]
ct [%][h]
1
Ph
Et
Et
Et
Et
Ph
76
44
35
32
90:10
99
100
2[d]
Ph
Ph
Ph
94 (R)
99 (S)
99 (S)
91:9
91
97
94
84
3
c-C6H11
>95:5
93[e]
4
iPr
>95:5
83[f]
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Table 1: (Continued)
Entry
Allylic benzoate
Aldehyde
R3
Product
R1
R2
ee [%][a]
99 (S)
Yield [%][b]
d.r.[c]
ee [%][a]
ct [%][h]
5
Me
48
81:19
92[g]
93
[a] Unless otherwise noted, the ee value was determined by HPLC analysis by using a Daicel chiralcel or chiralpak column (baseline separation of
enantiomers). [b] Yield (with respect to the aldehyde) of the analytically pure material after flash chromatography on silica gel.[15] [c] The diastereomeric
ratio was determined from the 1H NMR spectrum of the crude product mixture by integration of baseline-separated resonance signals of the
diastereomers. The competing thermal allylic 1,3-tin shift produces the regioisomeric allylic stannane and the corresponding homoallylic alcohol
(through an SE2’ reaction with the aldehyde) as by-products. [d] The acetate was used instead of the benzoate. [e] Despite baseline separation of the
signals for the two enantiomers, they could not be integrated accurately owing to the presence of an impurity (probably the diastereomer); the ee value
is certainly greater than 95%. [f] The ee value was determined by GLC analysis by using a hydrodex b-PM column (baseline separation of enantiomers).
[g] The ee value was determined by HPLC analysis after reductive ozonolysis (see the Supporting Information). [h] ct=chirality transfer.
Table 2: Enantiospecific and highly syn-diastereoselective BF3·OEt2-promoted SE2’ reactions of a-chiral allylic stannanes with aldehydes.
Entry
Allylic benzoate
R2
Aldehyde
R3
Product
R1
ee [%][a]
99 (S)
Yield [%][b]
d.r.[c]
ee [%][a]
ct [%]
1
Ph
Et
Et
Et
Et
Et
Ph
56
49
63
62
46
>95:5
99
100
2
3
4
5
Ph
Ph
Ph
Ph
99 (S)
99 (S)
99 (S)
99 (S)
92:8
92:8
92[d]
94[d]
99
93
95
c-C6H11
>95:5
>95:5
100
99
iPr
98
6[e]
Me
99 (S)
50
93:7
99
100
[a] The ee value was determined by HPLC analysis by using a Daicel chiralcel or chiralpak column (baseline separation of enantiomers). [b] Yield
(based on the initial amount of the allylic benzoate) of the analytically pure material after flash chromatography on silica gel. [c] See [c] in Table 1.
[d] See [e] in Table 1. [e] The depicted homoallylic alcohol was not isolated; remaining 3-anisaldehyde reacted with the expected product to give an
isochroman (for full details, see the Supporting Information).
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In a separate experiment, we heated stannane (R)-9 for
several hours at 1508C and thereby proved that allylic
transposition of the tin moiety occurs at a slow rate: An
isomeric ratio of approximately 75:25 in favor of (R)-9 was
detected after 36 h. Encouraged by these promising results,
we tested representative aldehydes in the SE2’ reaction with
(R)-9. Except when iPrCHO was used as the electrophile, the
anti-configured homoallylic alcohols[16] were produced in
essentially enantiomerically pure form (Table 1, entries 1–
4). As meta-methoxy-substituted arenes can be viewed as
masked b-ketoesters,[17] we also prepared the appropriately
substituted allylic stannane and treated it with 3-anisaldehyde
(Table 1, entry 5).
Lewis acid promoted carbonyl allylation reactions, for
example, with BF3·OEt2 as the Lewis acid,[1,2,10] are far more
widespread than thermal SE2’ reactions. They proceed via
acyclic transition states, the precise conformation of which
(that is, antiperiplanar or synclinal) is still under debate.[18]
However, the stereochemical outcome is syn. When an
equimolar mixture of the enantiomerically pure all-carbon-
substituted stannane (R)-9 and an aldehyde was treated with
BF3·OEt2, syn-configured,[17] highly enantiomerically
enriched homoallylic alcohols were formed in good yields;
the diastereoselectivity was reasonably high in all cases
(Table 2, entries 1–5). The methoxy-functionalized system
performed equally well but afforded the desired homoallylic
alcohol only as an intermediate (Table 2, entry 6), which
reacted with remaining aldehyde to form a hemiacetal and
eventually an isochroman (for a mechanistic outline, see the
Supporting Information).
demanding chemistry of tin- and silicon-substituted bifunc-
tional allylic systems.
Received: March 12, 2009
Published online: May 13, 2009
Keywords: allylation · allylic substitution · enantiospecificity ·
.
stannanes · stereoselective synthesis
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enantioselective entry into the attractive chemistry of tin- and
silicon-functionalized allylic building blocks.[19,20] Copper-
catalyzed carbon–tin bond formation did give the enantio-
merically enriched bifunctional building block (R)-14
(Scheme 4); however, this stannane was too unstable for
[7] For selected syntheses of (primary) allylic stannanes by allylic
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conjugate addition); b) M. Oestreich, G. Auer, Adv. Synth. Catal.
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Scheme 4. Synthesis of an a-chiral bifunctional allylic building block.
subsequent steps. Control experiments verified that BF3·OEt2
alone decomposes (R)-14 quantitatively within minutes,
whereas (R)-9 is reasonably stable towards Lewis acids.
Thus, the application of (R)-14 remains a challenge.
Our copper-catalyzed allylic substitution with a bis(trior-
ganostannyl) zinc reagent fills a gap in enantioselective
allylation chemistry. Enantiospecific and diastereoselective
thermal and Lewis acid promoted carbonyl allylation reac-
tions demonstrated the synthetic potential of this formerly
elusive class of a-chiral allylic stannanes. We are currently
testing glyoxalates as electrophiles and will then address the
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Oestreich, Chem. Commun. 2006, 311 – 313 (for reactions with
alkynes, 1,3-dienes, and styrene).
[12] E. S. Schmidtmann, M. Oestreich, Chem. Commun. 2006, 3643 –
3645.
[16] The relative configuration was determined unequivocally for
both diastereomers following a reductive ozonolyis and acetal-
ization (see the Supporting Information).
[17] G. Bringmann, G. Kꢁnkel, T. Geuder, Synlett 1990, 253 – 255.
[18] S. E. Denmark, E. J. Weber, T. M. Wilson, T. M. Willson,
Tetrahedron 1989, 45, 1053 – 1065.
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Maruyama, J. Organomet. Chem. 1985, 292, 311 – 318; b) G. E.
Keck, D. R. Romer, J. Org. Chem. 1993, 58, 6083 – 6089; c) J. M.
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[20] Reaction with glyoxalates would yield versatile Panek-type
systems: R. T. Beresis, J. S. Solomon, M. G. Yang, N. F. Yain, J. S.
Panek, Org. Synth. 1997, 75, 78 – 86.
[13] Although triorganostannyl lithium compounds are already
relatively soft, in contrast to the related hard triorganosilyl
lithium reagents, it is necessary to form the corresponding zinc
compounds to enable the allylic substitution of benzoates and
acetates without deacylation.
[14] Reductive metalation and lithium-to-zinc transmetalation
release substantial amounts of lithium chloride and zinc chloride.
Removal of these Lewis acids by repeated extraction with H2O
might be advantageous (see the Supporting Information).
[15] M. A. Vincent, I. H. Hillier, R. J. Hall, E. J. Thomas, J. Org.
Chem. 1999, 64, 4680 – 4684.
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