The enantioselective allylation and crotylation of sterically hindered and functionalized aryl ketones: Convenient access to unusual tertiary carbinol structures

Article abstract of DOI:10.1002/anie.200600910

(Chemical Equation Presented) A strained allylsilane reagent is highly effective in the enantioselective allylation of hydroxyphenylketones. The method is uniquely tolerant both of sterically hindered aliphatic ketones and highly functionalized diaryl ket

Full text of DOI:10.1002/anie.200600910

Angewandte
Chemie
and enantioselectivity has been reported. Our own recent
investigations into the use of strained allylsilanes[6] for
enantioselective aldehyde allylations and crotylations[7]
prompted us to wonder whether these reagents might be
rendered reactive enough for ketone allylation (Scheme 1).
Preliminary experiments showed that with either reagent 1 or
2, no reaction could be induced with acetophenone under a
variety of conditions.
Synthetic Methods
DOI: 10.1002/anie.200600910
The Enantioselective Allylation and Crotylation
of Sterically Hindered and Functionalized Aryl
Ketones: Convenient Access to Unusual Tertiary
Carbinol Structures**
Scheme 1. Asymmetric aldehyde allylation.
Noah Z. Burns, Blaine M. Hackman, Pui Yee Ng,
Ian A. Powelson, and James L. Leighton*
Reagent 1 may also be employed for the enantioselective
allylation of both aldehyde- and ketone-derived acylhydra-
zones (Scheme 2).[8] Mechanistic investigations showed that
The development of reagents and catalysts for the enantio-
selective allylation of ketones has been an important goal in
asymmetric synthesis for many years. Over the past decade,
some important and seminal advances have been recorded,
but most of these require the use of potentially toxic tin-based
allyl reagents.[1] More recently, Chong,[2] Shibasaki,[3] Soder-
quist,[4] and Yamamoto[5] have recorded truly remarkable
advances. With only a few notable exceptions, however, the
scope of reactions that gives useful levels of efficiency and
enantioselectivity remains limited to aryl methyl, cyclohex-
enyl methyl, and tert-butyl methyl ketones and structurally
related derivatives thereof. There is no current solution at all
for the enantioselective allylation of several important classes
of ketones, including highly sterically hindered aryl alkyl
ketones and diaryl ketones. In addition, only limited success
has thus far been recorded in enantioselective ketone
crotylation reactions, and no method that can produce both
the syn and anti diastereomers with high levels of diastereo-
Scheme 2. Proposed hydroxyketone allylation.
the reaction of phenylsilane 3 with the benzoylhydrazone of
benzaldehyde gave 4, as revealed by X-ray crystallography.[8b]
Thus, it was discovered that these reactions proceed by
covalent attachment of the acyl oxygen atom of the hydrazone
to the allylsilane reagent by displacement of the chloride and
that the liberated HCl protonates the amino group of the
pseudo-ephedrine. The success of the hydrazone allylations
may thus be attributed both to their intramolecular reaction
pathway and to the presumably significant increase in Lewis
acidity of the silane because of the protonation of the amino
group. We reasoned that a suitable nucleophile (e.g., phenol)
attached to the ketone substrates might mechanistically
mimic the acylhydrazones, and therefore we set out to
screen such hydroxyketones for reactivity with 1 and 2.
2’-Hydroxyacetophenone was treated with both 1 and 2.
Although 1 failed to provide a clean reaction, 2 successfully
[*] N. Z. Burns, B. M. Hackman, Dr. P. Y. Ng, I. A. Powelson,
Prof. Dr. J. L. Leighton
Department of Chemistry
Columbia University
New York, NY 10027 (USA)
Fax: (+1)212-932-1289
E-mail: leighton@chem.columbia.edu
[**] Financial support was provided by the National Institutes of Health
(GM 58133). N.Z.B. was the recipient of a Pfizer Summer Under-
graduate Research Fellowship and an NSF-REU Fellowship. I.A.P.
was supported by the Irving Langmuir Scholars Program. We are
grateful to Amgen, Merck Research Laboratories, and the Arthur C.
Cope Fund for unrestricted research support as well.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Enantioselective allylation of 2’-hydroxyphenylketones.
allylated the ketone to give tertiary carbinol 5 with encour-
aging levels of efficiency and enantioselectivity (Scheme 3).
After optimization, the product could be obtained in 75%
Entry
1
Conditions
A
Product
Yield [%]
75
ee [%]
83
Scheme 3. Asymmetric ketone allylation.
2
3
A
A
65
64
81
82
yield and 83% ee. Consistent with our mechanistic hypoth-
esis, no allylation products were observed in the reactions of
3’- and 4’-hydroxyacetophenone with 2. Although the poor
performance of 1 is not well understood, we were nevertheless
encouraged by the reaction of 2 with 2’-hydroxyacetophenone
and undertook a survey of the reaction scope.
4
5
6
A[a]
A[a]
B
67
63
62
88
93
93
In the hydroxyacetophenone series, substitution of the
phenol ring was tolerated with minimal impact on reaction
performance (Table 1, entries 1–3). Remarkably, highly steri-
cally hindered ketones could be tolerated as the isopropyl,
and even the tert-butyl ketone, substrates were not only
smoothly allylated but were allylated with improved enantio-
selectivity (entries 4 and 5). Aryl and heteroaryl ketones were
also well tolerated (entries 6–10), thus providing access to
enantiomerically enriched diaryl allyl tertiary carbinols.
These products are particularly noteworthy in that they
would likely be quite difficult to access by allylation of diaryl
ketones without recourse to the directing-group strategy
employed herein. Indeed, in all previous reports concerning
enantioselective ketone allylation, no diaryl ketones have
been reported as successful substrates. Thus, the method
allows access to truly novel optically
7
8
B
B
75
76
94
88
9
B[a]
69
90
95
90
active tertiary carbinols, for which
there is no obvious alternate
approach. Escitalopram, the single
enantiomer of the selective seroto-
10
B[b]
nin-reuptake
inhibitor
Celexa,
makes the importance of diaryl car-
binol derivatives of this type clear. A
reasonable entry into systems such
[a] Reaction time=48 h. [b] Reaction temperature=08C.
as these is demonstrated (entry 10) and further the tolerance
of the reaction to extensive functionalization of the aryl rings
is shown.
In constructing a mechanistic and stereochemical model
for these reactions, the following assumptions, based on the
X-ray crystal structure of 4, were made: 1) The phenol
displaces the chloride from the silane, and HCl thus generated
protonates one of the amino groups, and 2) the ketone oxygen
atom and the protonated amino group occupy apical positions
on the trigonal bipyramidal intermediate. Only two such
intermediates are possible (A and B; Scheme 5). In A, the
indicated steric and electrostatic interactions may plausibly
be posited, whereas in B, which correctly predicts the
observed major enantiomer, no such interactions are present.
Further, it is noteworthy that the chairlike transition state
depicted in C is consistent with the diastereoselectivity
observed in the crotylation reactions described in Scheme 4.
With only two limited exceptions,[3,5] the development of
general enantioselective methods for ketone crotylation has
proved elusive, and it was thus of interest to examine the
corresponding cis- and trans-crotylsilanes in the present
context. Previously reported cis-crotylsilane 6[7c] was found
to crotylate 2’-hydroxybenzophenone to give 7 in 63% yield
and with excellent diastereo- and enantioselectivity
(Scheme 4). The corresponding trans crotylsilane 8[7c] pro-
vided 9 in 58% yield and with excellent diastereo- and
enantioselectivity. These reactions represent the first method
for the highly diastereo- and enantioselective synthesis of
both the syn- and anti-crotyl diastereomers derived from
ketones.
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ketone (1.0 mmol) was then added (neat or as a solution in toluene or
CH2Cl2 (1 mL)), and the resulting mixture was either cooled to 08C,
left at ambient temperature, or heated to 408C (see Table 1 and
Scheme 4). After 24 or 48 h (see Table 1 and Scheme 4), the reac-
tion was quenched by the addition of methanol (3 mL). The mixture
was concentrated, and the residue was dissolved in CH2Cl2 (10 mL).
Water (5 mL) was added, and the layers were separated. The aqueous
layer is extracted with CH2Cl2 (3 ” 10 mL), and the combined organic
layers were dried (MgSO4), filtered, and concentrated. Purification of
the residue by flash chromatography on silica gel yielded the pure
tertiary homoallylic alcohol in the yields and stereoselectivities
reported in Table 1 and Scheme 4. See the Supporting Information
for full details.
Scheme 4. Enantioselective ketone crotylation.
Received: March 8, 2006
Published online: May 3, 2006
Keywords: allylation · allylsilanes · crotylation ·
.
enantioselectivity · ketones
[1] a) M. Nakamura, A. Hirai, M. Sogi, E. Nakamura, J. Am. Chem.
Soc. 1998, 120, 5846; b) L. F. Tietze, L. Völkel, C. Wulff, B.
Weigand, C. Bittner, P. McGrath, K. Johnson, M. Schäfer, Chem.
Eur. J. 2001, 7, 1304; c) S. Casolari, D. DꢀAddario, E. Tagliavini,
Org. Lett. 1999, 1, 1061; d) H. Hanawa, S. Kii, K. Maruoka, Adv.
Synth. Catal. 2001, 343, 57; e) K. M. Waltz, J. Gavenonis, P. J.
Walsh, Angew. Chem. 2002, 114, 3849; Angew. Chem. Int. Ed.
2002, 41, 3697; f) A. Cunningham, S. Woodward, Synlett 2002, 43;
g) J. Lu, M.-L. Hong, S.-J. Ji, Y.-C. Teo, T.-P. Loh, Chem.
Commun. 2005, 4217.
[2] T. R. Wu, L. Shen, J. M. Chong, Org. Lett. 2004, 6, 2701.
[3] R. Wada, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2004, 126, 8910.
[4] E. Canales, K. G. Prasad, J. A. Soderquist, J. Am. Chem. Soc.
2005, 127, 11572.
[5] M. Wadamoto, H. Yamamoto, J. Am. Chem. Soc. 2005, 127,
14556.
[6] For reviews on the chemistry of allylsilanes, see: a) C. E. Masse,
J. S. Panek, Chem. Rev. 1995, 95, 1293; b) L. Chabaud, P. James, Y.
Landais, Eur. J. Org. Chem. 2004, 3173.
Scheme 5. Mechanistic and stereochemical model.
[7] a) J. W. A. Kinnaird, P. Y. Ng, K. Kubota, K.; X. Wang, J. L.
Leighton, J. Am. Chem. Soc. 2002, 124, 7920; b) K. Kubota, J. L.
Leighton, Angew. Chem. 2003, 115, 976; Angew. Chem. Int. Ed.
2003, 42, 946; c) B. M. Hackman, P. J. Lombardi, J. L. Leighton,
Org. Lett. 2004, 6, 4375; d) X. Zhang, K. N. Houk, J. L. Leighton,
Angew. Chem. 2005, 117, 960; Angew. Chem. Int. Ed. 2005, 44,
938.
[8] a) R. Berger, P. M. A. Rabbat, J. L. Leighton, J. Am. Chem. Soc.
2003, 125, 9596; b) R. Berger, K. Duff, J. L. Leighton, J. Am.
Chem. Soc. 2004, 126, 5686.
A simple and convenient method for the enantioselective
allylation and crotylation of hydroxyphenylketones has been
described. An extraordinary and unprecedented degree of
steric hindrance in the ketones is tolerated, and a wide variety
of diaryl and heteroaryl ketones are excellent substrates as
well, thus leading to structurally novel optically active tertiary
carbinols that appear to be otherwise quite difficult to access.
In addition, it is further remarkable that the same reagents
that are effective for aldehydes are also effective for these
ketone allylation and crotylation reactions, despite the fact
that the aldehyde and ketone reactions are clearly mechanis-
tically distinct processes. Current goals for this project include
the extension of the method to additional classes of ketones
and a more detailed understanding of the mechanism.
Experimental Section
General procedure for the enantioselective allylation and crotyla-
tion of 2’-hydroxyphenyl ketones: A round-bottomed flask was
charged with reagent 2, 6, or 8 (1.5 mmol) and toluene or CH2Cl2
(5 mL; see Table 1 and Scheme 4). The desired 2’-hydroxyphenyl
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