A more comprehensive and highly practical solution to enantioselective aldehyde crotylation

Article abstract of DOI:10.1021/ja200712f

The enantioselective crotylation of aldehydes with 1,2- diaminochlorocrotylsilane reagents is effectively catalyzed by Sc(OTf) ₃. The one significant limitation on the utility of these reagents-substrate scope-has thus been addressed. The net r

Full text of DOI:10.1021/ja200712f

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A More Comprehensive and Highly Practical Solution to
Enantioselective Aldehyde Crotylation
Hyunwoo Kim, Stephen Ho, and James L. Leighton*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S Supporting Information
b
Scheme 1
ABSTRACT: The enantioselective crotylation of aldehydes
with 1,2-diaminochlorocrotylsilane reagents is effectively
catalyzed by Sc(OTf)3. The one significant limitation on
the utility of these reagents ꢀ substrate scope ꢀ has thus
been addressed. The net result is the most comprehensive
and highly practical method for enantioselective aldehyde
crotylation yet advanced.
ue to the direct relevance of the products to important
classes of natural products, the development of diastereo-
D
and enantioselective aldehyde crotylation reactions has been the
subject of an enormous amount of effort over the past three
decades. The first generally highly diastereo- and enantioselec-
tive and practicable solution was advanced by Brown in 1986,1
and remarkably, this chiral crotylborane methodology remains
the most widely employed to the present day.2 Despite what
might be assumed based on its near-total dominance of the
market, the Brown method does suffer both from an inability to
fully or even partly overcome the inherent diastereofacial bias of
certain chiral aldehydes3 and from significant practical liabilities.4
Because of this, efforts to supplant it as the method of choice have
continued,5 with only limited success.
binding or protonating one of the boronate oxygen atoms. Initial
experiments quickly revealed that whereas both Brønsted and
Lewis acids could effectively catalyze the reactions of 1 and 2 with
aldehydes, the Brønsted acid catalyzed reactions were generally
less highly enantioselective. A broad screen of Lewis acids
revealed that Sc(OTf)3 provided the best combination of high
enantioselectivity and effective catalysis.10 Thus, treatment of
R-methylcinnamaldehyde with reagents (S,S)-1 and (S,S)-2 and
5 mol % Sc(OTf)3 in CH2Cl2 at 0 °C for 1 h led to the isolation of
products 5 and 6 as single diastereomers (g40:1 dr) in 87% yield
and 94% and 91% ee, respectively (Scheme 2).
Our previously reported crotylsilanes 1 and 2 are crystalline
solids that may be prepared in bulk and stored, and that react with
aldehydes at 0 °C over the course of ∼20 h to consistently
provide enantioselectivities (93ꢀ99% ee) among the highest
ever recorded for aldehyde crotylation reactions (Scheme 1).6
While these characteristics go a long way toward realization of a
more practical and user-friendly system, the reagents suffer from
one highly significant limitation: the substrate scope is exceed-
ingly narrow with aromatic, unsaturated, and sterically hindered
aliphatic aldehydes all giving moderate to low yields, or even, in
many cases, no product at all. For example, reagents 1 and 2
completely fail to react productively or at all with 3, R-methyl-
cinnamaldehyde, and 4.
Scheme 2
Because the successful crotylation of aldehydes such as 4 is
relevant to several current synthetic projects in our group, we
recently decided to revisit this methodology and attempt to solve
the reactivity problem. We had two relevant pieces of informa-
tion at the outset: (1) protonation of our aminochlorosilane
Lewis acids (by way of reaction with protic nucleophiles, which
displace the chloride and generate an equivalent of HCl) leads to
a significant boost in their reactivity,7 and (2) Lewis acids8
(Sc(OTf)3 is particularly effective) and Brønsted acids9 may be
used to catalyze the reactions of allylboronates with aldehydes by
The results of a survey of the crotylation reactions of three
standard aldehydes using silanes (S,S)-1 and (S,S)-2 are com-
piled in Table 1. As shown, the yields and enantioselectivities are
Received: January 24, 2011
Published: April 12, 2011
r
2011 American Chemical Society
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Table 1. Sc(OTf)3-Catalyzed Aldehdye Crotylation
Reactions
Scheme 3
entry
R
silane
yield (%)
ee (%)
1
2
3
4
5
6
PhCH2CH2
PhCH2CH2
Ph
(S,S)-1
(S,S)-2
(S,S)-1
(S,S)-2
(S,S)-1
(S,S)-2
96
96
94
96
96
93
96
97
93
91
95
91
Ph
(E)-PhCHdCH
(E)-PhCHdCH
excellent across the board (in all cases the diastereoselectivity
was g40:1), whereas the corresponding reactions without Sc(OTf)3
required significantly longer reaction times (∼20 h) and pro-
vided yields that were in the range 52ꢀ83%.6
Complex chiral aldehydes such as 3 represent one of the more
important classes of aldehydes for crotylation reactions, and any
method that would lay claim to being a comprehensive solution
should be able to provide for high levels of reagent control for all
possible stereochemical permutations. Commonly employed
Roche ester-derived aldehydes 7 and 811 were treated with
(S,S)-1 and (S,S)-2 using the standard conditions outlined above,
and in every case the reactions proceeded with excellent diaster-
eoselectivity (g97:3 dr, major diastereomer:sum of all minor
diastereomers) corresponding to reagent control (Scheme 3).
While these results were encouraging, it is also the case that
aldehydes with a chiral center at the β-position (e.g., 3) can be
more challenging, and indeed most of the cases where the Brown
reagents cannot override the diastereofacial bias of a chiral
aldehyde fall into this category.3bꢀe We therefore prepared
aldehyde 9 and subjected it to reaction with (S,S)-1 and
(R,R)-1 using the same reaction conditions as above. Although
the reactions were slower, requiring ∼4 h at ambient temperature
to proceed to completion, they delivered the products of reagent
control (10a and 10b, respectively) in good yields and with
excellent levels of diastereoselectivity. Product 10b is of parti-
cular interest because the Brown method cannot deliver this
stereochemical permutation at all with a β-TBS protecting group
on the aldehyde3d and with better than 2:1 diastereoselectivity
with a β-PMB protecting group.3c Aldehyde 11 was also sub-
jected to crotylation with (S,S)-1 leading to the isolation of 12 in
86% yield and with 94:6 diastereoselectivity. The stereochemical
array in 12 is another that may not be accessed highly selectively
with the Brown method,12 further supporting the claim that the
present method is possessed of greater scope and an ability to
override the diastereofacial biases of some of the most difficult
chiral aldehydes.
Alternatively, the unpurified reaction mixture may be submitted
to a Tamao oxidation/diastereoselective tautomerization reaction13
to provide 14 in 82% yield (with 8:1 diastereoselectivity for the
stereocenter R to the ketone) and 97% ee. This one pot
conversion of 4 to 14 explicates our interest in aldehydes like 4
and highlights the power of the methodology rapidly to deliver
stereochemically complex polyketide fragments.
Scheme 4
Although the main focus of this study is crotylation reactions,
we have confirmed that, as expected, Sc(OTf)3 is an effective
catalyst for the corresponding reactions of the parent allylsilane
reagent 15.14 Thus, reaction of aldehydes 7 and 8 with (S,S)-15
and 5 mol % Sc(OTf)3 (CH2Cl2, 0 °C, 1 h) gave the illustrated
products in 77 and 83% yields respectively and with >99:1
diastereoselectivity in both cases (Scheme 5).
Finally, we examined the crotylation of aldehyde 4, one of the
more sterically and electronically deactivated aldehydes relevant
to polyketide natural product synthesis imaginable. Reaction
with (R,R)-2 and 5 mol % Sc(OTf)3 (CH2Cl2, 23 °C, 3 h) led to
the isolation of 13 in 81% yield and 97% ee (Scheme 4).
In order fully to leverage the fact that the silane reagents are
crystalline solids and render the experimental procedures as
straightforward as possible, we have prepared mixtures of the
crotylsilanes 1 and 2 and the allylsilanes 15 with Sc(OTf)3 in a
25:1 molar ratio for which we propose the general names
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Scheme 5
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterization data, and stereochemical proofs. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
leighton@chem.columbia.edu
’ ACKNOWLEDGMENT
This work was supported by a grant from the National
Institutes of Health (NIGMS R01 GM58133). We gratefully
acknowledge the National Science Foundation for acquisition of
a 400 MHz nuclear magnetic resonance spectrometer (CRIF
0840451).
EZ-CrotylMix and EZ-AllylMix (Scheme 6). The use of 650 mg
of an EZ-CrotylMix (or 635 mg of an EZ-AllylMix) per 1.0 mmol
of aldehyde corresponds to 1.1 equiv of the silane and 4.4 mol %
of Sc(OTf)3. Thus, treatment of 1.0 mmol of R-methylcinna-
maldehyde with 650 mg of (S,S)-cis EZ-CrotylMix (in CH2Cl2 at
ambient temperature for 30 min) resulted in the isolation of 5 in
89% yield and 92% ee.15 The EZ-CrotylMix stoichiometry
(in the form of (R,R)-trans EZ-CrotylMix) also sufficed for
less reactive aldehdye 4, giving 13 in 85% yield and 97% ee.
Of course, additional Sc(OTf)3 or EZ-CrotylMix may be added
to the reactions of particularly unreactive aldehydes, but this
EZ-CrotylMix/EZ-AllylMix formulation appears to be effective
for most aldehydes.
’ REFERENCES
(1) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(2) By performing a citation analysis on the two papers in ref 1, we
have identified 32 distinct uses of the Brown crotylation method
published in original research papers just in the period of 2009ꢀ2010.
(3) For example, see: (a) Brown, H. C.; Bhat, K. S.; Randad, R. S.
J. Org. Chem. 1989, 54, 1570. (b) Ogawa, A. K.; Armstrong, R. W. J. Am.
Chem. Soc. 1998, 120, 12435. (c) Kobayashi, Y.; Lee, J.; Tezuka, K.;
Kishi, Y. Org. Lett. 1999, 1, 2177. (d) Nicolaou, K. C.; Fylaktakidou,
K. C.; Monenschein, H.; Li, Y.; Weyershausen, B.; Mitchell, H. J.; Wei,
H.-X.; Guntupalli, P.; Hepworth, D.; Sugita, K. J. Am. Chem. Soc. 2003,
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C.; Valeria D’Auria, M. Tetrahedron: Asymmetry 2003, 14, 1787.
(4) The preparation of the requisite cis- or trans-crotylborane
reagent entails the carefully (low and variable) temperature-controlled
metalation of either cis- or trans-2-butene with n-BuLi and KOt-Bu,
addition of the resulting crotylpotassium species to either (þ)- or
(ꢀ)-(ipc)2BOMe, and then addition of BF3•OEt2 and the aldehyde.
In addition, the workup procedure entails the oxidative cleavage of the
borane from the product alcohol, which has the side effect of generating
2 equiv of isopinocampheol that can, and often does, render product
isolation significantly more laborious.
Scheme 6
(5) (a) Roush, W. R.; Ando, K; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339. (b) Roush, W. R.;
Grover, P. T. J. Org. Chem. 1995, 60, 3806. (c) Garcia, J.; Kim, B. M.;
Masamune, S. J. Org. Chem. 1987, 52, 4831. (d) Hafner, A.; Duthlaer,
R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F. J. Am.
Chem. Soc. 1992, 114, 2321. (e) Jain, N. F.; Takenaka, N.; Panek, J. S.
J. Am. Chem. Soc. 1996, 118, 12475. (f) Denmark, S. E.; Fu, J. J. Am.
Chem. Soc. 2001, 123, 9488. (g) Lachance, H.; Lu, X.; Gravel, M.; Hall,
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Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 8044. (i) Kim,
I. S.; Han, S. B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514.
(6) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004,
6, 4375.
(7) (a) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004,
126, 5686. (b) Burns, N. Z.; Hackman, B. M.; Ng, P. Y.; Powelson, I. A.;
Leighton, J. L. Angew. Chem., Int. Ed. 2006, 45, 3811.
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124, 11586. (b) Ishiyama, T.; Ahiko, T.; Miyaura, N. J. Am. Chem. Soc.
2002, 124, 12414.
Sc(OTf)3 is an effective catalyst for the enantioselective
crotylation of aldehydes using crotylsilanes 1 and 2, and this
has resulted in a dramatic increase in the scope of aldehydes that
may be effectively crotylated using this methodology. Indeed,
based primarily on the reactions of aldehydes 4, 7, 8, 9, and 11, we
may conclude that our method has a broader scope than any other
asymmetric crotylation methodology. That the silanes
and Sc(OTf)3 are crystalline solids has further facilitated the
EZ-CrotylMix formulation,16 rendering this methodology the
most comprehensive and highly practical solution to the enduring
problem of enantioselective aldehyde crotylation yet advanced.
(9) (a) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am.
Chem. Soc. 2005, 127, 12808. (b) Rauniyar, V.; Hall, D. G. Angew. Chem.,
Int. Ed. 2006, 45, 2426. (c) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am.
Chem. Soc. 2008, 130, 8481. (d) Barnett, D. S.; Moquist, P. N.; Schaus,
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S. E. Angew. Chem., Int. Ed. 2009, 48, 8679. (e) Jain, P.; Antilla, J. C. J. Am.
Chem. Soc. 2010, 132, 11884.
(10) Details of the results of our screen of Lewis acids are provided in
the Supporting Information.
(11) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348.
(12) The analogous Brown crotylation of the β-OPMB aldehyde
corresponding to 11 proceeded with 2:1 diastereoselectivity favoring the
product analogous to 12 (see ref 3c). Although there is no evidence in
the literature that β-OPMB and β-acyloxy groups have dramatically
different impacts on the diastereoselectivities of these reactions, we
nevertheless note the caveat that we cannot in this case make a direct
comparison.
(13) Spletstoser, J. T.; Zacuto, M. J.; Leighton, J. L. Org. Lett. 2008,
10, 5593.
(14) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946.
(15) The experimental procedure is as follows: To a solution of 650
mg of (S,S)-cis EZ-CrotylMix in 10 mL of CH2Cl2 was added 1.0 mmol
of R-methylcinnamaldehyde. The mixture was stirred vigorously for 30
min (Sc(OTf)3 is only sparingly soluble in CH2Cl2, the stirring
promotes its faster and more complete dissolution) and then concen-
trated. The residue was treated with Et2O and 1 M HCl, and the
resulting mixture was stirred vigorously for 1 h. The mixture was filtered
(with Et2O washes) to recover the diamine as its bis HCl salt (in 95%
yield), and the layers of the biphasic filtrate were separated. The aqueous
phase was extracted with Et2O, and the combined organic phases were
dried (MgSO4), filtered, and concentrated. The homoallylic alcohol 5
thus obtained was >95% pure (see the Supporting Information for a 1H
NMR spectrum of this material) but, for the purposes of obtaining an
accurate isolated yield, was purified by flash chromatography. In most
cases the entire procedure can be executed in ∼2ꢀ6 h.
(16) The allyl- and crotylsilanes and the EZ-CrotylMixes are com-
mercially available from Sigma-Aldrich and Strem. The EZ-Allylmixes
are in the late stages of development and will be available soon.
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