Catalytic enantioselective conjugate allylation of unsaturated methylidene ketones

Article abstract of DOI:10.1021/ol102982b

The use of unsaturated methylidene ketones in catalytic conjugate allylations allows a significant expansion in substrate scope and, with appropriate chiral ligands, occurs in a highly enantioselective fashion.(Figure Presented)

Full text of DOI:10.1021/ol102982b

ORGANIC
LETTERS
2011
Vol. 13, No. 5
995–997
Catalytic Enantioselective Conjugate
Allylation of Unsaturated Methylidene
Ketones
Laura A. Brozek, Joshua D. Sieber, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States
morken@bc.edu
Received December 9, 2010
ABSTRACT
The use of unsaturated methylidene ketones in catalytic conjugate allylations allows a significant expansion in substrate scope and, with
appropriate chiral ligands, occurs in a highly enantioselective fashion.
Catalytic enantioselective conjugate addition of organo-
metallic reagents to unsaturated carbonyls is an important
method in asymmetric synthesis. These reactions are usually
accomplished under the aegis of late transition metal cat-
alysts and occur with a broad variety of organometallic
reagents.1 While significant successes have been recorded
with aryl, alkyl, vinyl, and alkynyl nucleophiles, reactions
of allylmetal reagents are much less developed. In recent
studies, we have addressed this limitation and have intro-
duced an enantio- and regioselective catalytic conjugate
addition of allylB(pin) (2, Scheme 1) to arylidene alkyli-
dene ketones (1).2 Mechanistic studies suggest that this
reaction proceeds by way of Lewis acid induced oxidative
addition of the metal to the less hindered alkylidene enone
(to give I), followed by transmetalation and 3,30-reductive
elimination3 via transition state II.4 Thus for substrate 1,
the hexylidene group functions as an activator for allyla-
tion of an aryl-substituted enone. While this strategy is
effective, it leaves a gap in technology for the selective
allylation of alkyl-substituted enones.5 In this manuscript,
we address this issue and describe a general strategy that is
effective for the regio- and enantioselective allylation of
both aromatic and aliphatic substituted enones.
Under the paradigm described above, it appeared plau-
sible that a general catalytic allylation of both aryl- and
alkyl-substituted enones might arise from reactions of
methylidene-substituted enones such as 3 (Table 1). In this
scenario, oxidative addition of the transition metal to the
less hindered methylidene site would be favored, and sub-
sequent 3,30-reductive elimination would deliver the allyl
€
(1) Reviews: (a) Krause, N.; Hoffmann-Roder, A. Synthesis 2001,
€
171. (b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis
(4) For other catalytic reactions that appear to proceed by 3,30-
reductive elimination, see: (a) Keith, J. A.; Behenna, D. C.; Mohr,
J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard,
W. A., III. J. Am. Chem. Soc. 2007, 129, 11876. (b) Bao, M.; Nakamura,
H.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 759. (b) Lu, S.; Xu, Z.;
Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2008, 47, 4366.
(c) Ariafard, A.; Lin, Z. J. Am. Chem. Soc. 2006, 128, 13010.
(5) For another catalytic enantioselective conjugate allylation, see:
(a) Shizuka, M.; Snapper, M. L. Angew. Chem., Int. Ed. 2008, 47, 5049.
For non-enantioselective catalytic version, see:(b) Shaghafi, M. B.;
Kohn, B. L.; Jarvo, E. R. Org. Lett. 2008, 10, 4743.
€
ꢀ
ꢁ
2007, 1279. (c) Alexakis,A.;Backvall, J. E.; Krause, N.; Paimes,O.;Dieguez,
M. Chem. Rev. 2008, 108, 2796. (d) Harutyunyan, S. R.; den Hartog, T.;
Geurts, K.; Minnard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824.
(e) Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46, 7295.
(2) (a) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007,
129, 2214. (b) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130,
4978. For a related process, see: (c) Zhang, P.; Morken, J. P. J. Am.
Chem. Soc. 2009, 131, 12550.
(3) (a) Mendez, M.; Cuerva, J. M.; Gomez-Bengoa, E.; Cardenas,
D. J.; Echavarren, A. M. Chem.;Eur. J. 2002, 8, 3620. (b) Cardenas,
ꢁ
ꢁ
ꢁ
ꢁ
D. J.; Echavarren, A. M. New. J. Chem. 2004, 28, 338.
r
10.1021/ol102982b
2011 American Chemical Society
Published on Web 02/02/2011

Scheme 1
Scheme 2. Enantioselective Conjugate Allylation of 3 with
Diastereoisomeric Ligands
Table 1. Catalytic Conjugate Allylation of Methylidene Ketone
3 with Chiral Taddol-Derived Ligandsa
regioselectivitywasslightlyenhancedwithPdrelativetoNi;
however, the enantioselectivity was diminished. To im-
prove enantioselection a number of other Taddol-derived
phosphorus ligands were examined, and a selection of results
is collected in Table 1 . Some generalizations can be made:
first, Pd-based catalysts provide higher regioselectivity than
their Ni-based counterparts with the Pd catalysts most
often delivering a >20:1 ratio of regioisomeric conjugate
allylation products (cf., entry 1 with 2; entry 3 vs 4). Second,
with phosphonite ligands, the Ni-catalyzed reaction occurs
with higher enantioselection than does the Pd-catalyzed
process (cf., entries 1 and 2). However, with phosphorami-
dite ligands, the opposite is true, and Pd catalysts offer
superior levels of stereocontrol (cf., entries 5 and 6).
entry
L
R
metal
4:5
% yield
er 4
1
2
3
4
5
6
7
8
L1
L1
L2
L2
L3
L3
L4
L5
Ph
Ph
Ni(cod)2
14:1
17:1
21
22
32
15
44
10
50
14
77:23
48:52
51:49
66:34
50:50
75:25
76:24
75:25
Pd2(dba)3
Ni(cod)2
NMe2
2.4:1
20:1
NMe2
Pd2(dba)3
Ni(cod)2
N(CH2)5
N(CH2)5
N(CH2)6
NBn2
1.5:1
35:1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
The observations above stimulated further examination
of Pd catalysts in the presence of phosphoramidite ligands.
While small cyclic and acyclic dialkylamine derived phos-
phoramidite ligands generally furnished the conjugate
allyation product in the 50% ee range, when substitution
was added to the piperidine ring of phosphoramidite ligand
L3, a significant enhancement in selectivity was observed.
Notably, this effect is stereoisomer-specific: (R,R,S)-L6
delivered the conjugate allylation product in 93:7 enantio-
mer ratio whereas (S,S,S)-L6 provided the product in a
28:72 er (Scheme 2). Note that the turnover in enantio-
selection when the enantiomeric Taddol ligand is used in
these experiments suggests that the Taddol backbone is the
dominant enantiocontrolling element of the ligand with the
piperidine substituent serving to embellish selectivity.
As data in Scheme 2 reveals, the enantioselectivity of
conjugate allylation with ligand (R,R,S)-L6 was quite
63:1
>100:1
a Reactions were quenched by addition of H2O. Regioisomer ratio
and enantiomer ratio were determined by GLC analysis.
group to the adjacent internal prochiral alkene. An initial
experiment probing this strategy was conducted with Taddol-
derived phosphonite ligand L16 (Taddol = trans-4,5-bis-
(diphenylhydroxymethyl)-2,2-dimethyldioxolane), the most
effective ligand for conjugate allylation of arylidene alky-
lidene ketones (1). In the event, conjugate allylation of
methylidene substrate 3 (Table 1) in the presence of 5 mol %
Ni(cod)2, 6 mol % ligand L1, and 1.2 equiv of allylB(pin)
provided addition product 4 with high regioselectivity
and moderate enantiocontrol (entry 1). This encouraging
result prompted further study. Examination of ligand
structure L1 with Pd2(dba)3 (entry 2) revealed that the
1
good; however, the reaction yield was suboptimal. H
NMR analysis of the reaction mixture after neutral aque-
ous workup revealed a side product that exhibited reso-
nances corresponding to the boron enolate. The surprising
reluctance of the putative enolate to undergo protonation
was overcome by acidification during the reaction workup:
treatment with saturated ammonium chloride or glacial
acetic acid delivered the reaction product in improved yields.
With an effective ligand for the asymmetric conjugate
allylation of methylidene-activated enones and an effective
(6) For a review of Taddol-derived phosphonites and phosphorami-
dites in catalysis: (a) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed.
2010, 49, 2486. (b) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. Select
examples of hydrogenation:(c) ven den Berg, M.; Minnard, A. J.;
Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa,
B. L. J. Am. Chem. Soc. 2000, 122, 11539. Hydrosilation: (d) Jensen,
J. F.; Svendsen, B. Y.; la Cour, T. V.; Pedersen, H. L.; Johannsen, M.
J. Am. Chem. Soc. 2002, 124, 4558. Hydroboration: (e) Ma, M. F. P.; Li,
K.; Zhou, Z.; Tang, C.; Chan, A. S. C. Tetrahedron Asymmetry 1999, 10,
3259. Cycloaddition: (f) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006,
128, 12370.
996
Org. Lett., Vol. 13, No. 5, 2011

Table 2. Catalytic Asymmetric Conjugate Allylation of
Methylidene Ketones in the Presence of (R,R,S)-L6a
Scheme 3. Synthesis of Cyclohexenone 11
methylidene-based substrate design indeed offers a general
solution to the conjugate allylation problem.
The functional group pattern that results from the
conjugate allylation of methylidene ketones allows trans-
formation of the products in a variety of ways and may
offer shortened enantioselective routes to important com-
pounds. For example, silyl-protected cyclohexenone 11
(Scheme 3) is a critical intermediate in a recent approach
to stenine natural products.7 As depicted in Scheme 3, an
effective enantioselective synthesis of 11 can be achieved in
five steps from 1-butyn-4-ol. Following silyl protection
and reductive iodination with Schwartz’s reagent and I2,8
the alkenyl iodide 8 was isolated in good yield. Subsequent
carbonylative Stille coupling9 provided conjugate allyla-
tion substrate 9.10 Employing the conditions described in
Table 2 the allylation product 10 was obtained and ring-
closing metathesis with the Hoveyda-Grubbs second
generation catalyst11 provided cyclohexenone 11. This five
step route to 11 compares favorably with the non-enantio-
selective eight step route used previously.
In conclusion, we have described a highly regioselective
and enantioselective conjugate allylation of unsaturated
ketones. The orthogonal reactivity of the allyl group and
the methylidene ketone bodes well for the utility of these
reaction products in organic synthesis. Further studies in
this regard are in progress.
a Unless otherwise noted, the reaction was carried out at room
temperature for 14 h and quenched with saturated NH4Cl(aq) or acetic
acid. b Regioselectivity determined by uncalibrated GLC analysis in
comparison to authentic materials. c Isolated yield after purification.
Value is an average of two or more experiments. d Enantiomer ratio
determined by GLC, SFC, or HPLC analysis. e Experiment for 48 h and
quenched with glacial acetic acid at 45 °C for 3 h.
Acknowledgment. We are grateful to the NIH (NIGMS
GM-64451) for support of this work. L.A.B. is grateful
for a LaMattina Fellowship. J.D.S. is grateful for both
LaMattina and Schering-Plough Fellowships
experimental protocol, a study of the substrate scope was
commenced. As depicted in Table 2, the simple pentyl-
substituted substrate is converted to the allylation product
with high levels of stereoinduction and in good yield (entry 1).
This reaction constitutes the first catalytic enantioselective
conjugate allylation of an acyclic aliphatic enone. Other
aliphatic enones also participate in the reaction, and it was
shown that those bearing an aromatic ring (entry 2), those
bearing branched substituents (entries 3 and 6), and sub-
strates with oxygenation in the side chain (entries 4-6) are
also tolerated. Importantly, silyl ethers and more Lewis
basic benzyl ethers are both processed with similar levels of
stereoinduction, thereby indicating the absence of any
complicating interaction between coordinating functional
groups and boron-substituted catalytic intermediates.
Also of note, aromatic enones can also react with good
yield and stereoselection (entries 7-9), suggesting that the
Supporting Information Available. Complete experi-
mental procedures and characterization data (1H and 13
C
NMR, IR, and mass spectrometry). This material is free
of charge via the Internet at http://pubs.acs.org.
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15, 333.
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J. K. J. Am. Chem. Soc. 1984, 106, 6417.
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2004, 126, 9546. (b) Marjanovic, J.; Kozmin, S. A. Angew. Chem., Int.
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J. Am. Chem. Soc. 2000, 122, 8168.
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