A multicomponent Ni-, Zr-, and Cu-catalyzed strategy for enantioselective synthesis of alkenyl-substituted quaternary carbons

Article abstract of DOI:10.1002/anie.201309456

The availability of enantiomerically enriched carbonyl-containing compounds is essential to the synthesis of biologically active molecules. Since catalytic enantioselective conjugate addition (ECA) reactions directly generate the latter valuable class of molecules, the design and development of such protocols represents a compelling objective in modern chemistry. Herein, we disclose the first solution to the problem of ECA of alkenyl groups to acyclic trisubstituted enones, an advance achieved by adopting an easily modifiable and fully catalytic approach. The requisite alkenylaluminum reagents are synthesized with exceptional site- and/or stereoselectivity by a Ni-catalyzed hydroalumination process, and the necessary enones are prepared through a site- and stereoselective zirconocene-catalyzed carboalumination/acylation reaction. The all-catalytic procedure is complete within four hours, furnishing the desired products in up to 77 % overall yield and 99:1 enantiomeric ratio. One-two-three punch: Ni-catalyzed alkyne hydroalumination, Zr-catalyzed alkyne carbometalation/acylation, and Cu-catalyzed enantioselective conjugate addition are combined for accessing acyclic organic molecules that contain an alkene-substituted quaternary carbon stereogenic center. The entire process takes less than four hours and affords products in up to 77 % overall yield and 99:1 enantiomeric ratio. Copyright

Full text of DOI:10.1002/anie.201309456

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DOI: 10.1002/anie.201309456
Multicomponent Catalysis
A Multicomponent Ni-, Zr-, and Cu-Catalyzed Strategy for
Enantioselective Synthesis of Alkenyl-Substituted Quaternary
Carbons**
Kevin P. McGrath and Amir H. Hoveyda*
Abstract: The availability of enantiomerically enriched car-
bonyl-containing compounds is essential to the synthesis of
biologically active molecules. Since catalytic enantioselective
conjugate addition (ECA) reactions directly generate the latter
valuable class of molecules, the design and development of
such protocols represents a compelling objective in modern
chemistry. Herein, we disclose the first solution to the problem
of ECA of alkenyl groups to acyclic trisubstituted enones, an
advance achieved by adopting an easily modifiable and fully
catalytic approach. The requisite alkenylaluminum reagents
are synthesized with exceptional site- and/or stereoselectivity
by a Ni-catalyzed hydroalumination process, and the necessary
enones are prepared through a site- and stereoselective
zirconocene-catalyzed carboalumination/acylation reaction.
The all-catalytic procedure is complete within four hours,
furnishing the desired products in up to 77% overall yield and
99:1 enantiomeric ratio.
has been achieved by means of a strategy that, in the majority
of cases, involves catalytic site- and/or stereoselective prep-
aration of the starting materials.
The central role of an effective chiral promoter notwith-
standing, the efficiency and selectivity with which the
substrates and reagents are accessed is critical in a catalytic
enantioselective process. We envisioned a multicomponent
ECA protocol entailing catalytic synthesis of the unsaturated
carbonyl compounds as well as the nucleophilic alkenyl
partners prior to their union, which is in turn promoted by
a third catalyst (Scheme 1). The all-catalytic method would
ideally exhibit maximum versatility by providing access to an
array of enones and nucleophilic entities, generated readily
and selectively with inexpensive, easily available, and robust
reagents and catalysts. It would be preferable if efforts
regarding the isolation and purification of the catalytically
generated starting materials were kept to a minimum.
T
he significance of enantiomerically enriched carbonyl-
containing compounds to the availability of biologically
active molecules places considerable value on transforma-
tions such as catalytic enantioselective conjugate addition
(ECA).[1,2] While progress has been made in the development
of efficient ECA protocols, notable shortcomings remain
unaddressed. Among the underdeveloped approaches are
those that involve the less reactive acyclic a,b-unsaturated
carbonyl compounds and furnish products with all-carbon-
substituted quaternary stereogenic centers.[3,4] Of the limited
number of reported instances,[5] only a few pertain to linear
substrates, and most involve highly activated electrophiles
(e.g., nitroalkenes or Meldrumꢀs acid derivatives).[6,7] As far
as we are aware, none of the existing approaches deal with the
addition of alkenyl units, readily functionalizable moieties
that allow access to a variety of useful enantiomerically
enriched derivatives.[8] Here, we disclose the first examples of
catalytic ECA of alkenyl metal reagents to acyclic trisubsti-
tuted enones, generating products that contain all-carbon-
substituted quaternary stereogenic centers. The desired goal
Scheme 1. The general and fully catalytic strategy for the generation
and enantioselective coupling of two fragments by an enantioselective
conjugate addition (ECA) reaction.
The multicomponent transformation in Scheme 2 is
illustrative of the power of the approach. The alkenylalumi-
num reagent was obtained in two hours by site- and
stereoselective Ni-catalyzed addition of aluminum hydride
to phenylacetylene (93% b, > 98% E).[9] The same aryl
alkyne served as the starting point for the site- and
stereoselective Zr-catalyzed aluminum methyl addition/acyl-
ation sequence,[10] furnishing the enone substrate after 45 min
(2; > 98% a, > 98% E, 80% yield).[11] The union of the two
catalytically generated components was accomplished by
subjection of the alkenylaluminum species and enone 2 to
2.5 mol% of the AgI-based N-heterocyclic carbene (NHC)
complex 1a[12] and 5.0 mol% of CuCl2·2H2O in tetrahydro-
[*] K. P. McGrath, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
[**] Financial support was provided by the NIH (GM-47480). We thank
Dr. F. Haeffner for helpful discussions, Matthew T. Villaume for
experimental assistance and Boston College Research Services for
providing access to computational facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309456.
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95:5. Enones prepared by the carboalumination/acylation of
alkynes bearing an electron-donating (e.g., entry 1, Table 1;
40% yield) or an electron-withdrawing aryl unit (e.g., entry 2,
63% yield) are effective substrates. Zirconocene-catalyzed
reactions uniformly deliver > 98% E selectivity. Heterocyclic
alkenylaluminum reagents, represented by 3g, formed in
96.5:3.5 e.r., and alkyl-substituted enones (Table 1, entries 7
and 8) were converted to products in 90.5:9.5–97:3 e.r. and 31–
44% overall yield. In some instances, maximum selectivity
calls for 1b as the catalyst precursor.
Unlike the transformations with b-substituted cyclic
enones,[8c] the use of a silyl-substituted alkenylaluminum
species is not necessary for obtaining high e.r. values with
linear enones. The need for the initial preparation of a silyl-
substituted alkyne and subsequent proto-desilylation is obvi-
ated. Attempts to effect NHC–Cu-catalyzed ECAwith acyclic
trisubstituted enones and silyl-containing Al-based reagents
led to < 2% conversion.[8c] The latter finding underscores the
challenge of effecting the formation of products containing
all-carbon-substituted quaternary centers from acyclic sub-
strates.
Issues vis-ꢁ-vis the diminished reactivity of sizeable
nucleophilic entities raise the question of whether acyclic
trisubstituted enones would participate in efficient ECA
processes involving a-substituted alkenylaluminum reagents
(derived from hydroaluminations catalyzed by [Ni-
(dppp)Cl2]).[9] Addition of aryl- or heteroaryl-substituted a-
alkenylaluminum compounds and aryl- or alkyl-substituted
substrates furnish b-alkenyl ketones in better yields and
enantioselectivities than the analogous reactions of the less
encumbered b-alkenylmetal variants (Table 2; 29–77% over-
all yield and 92:8–99:1 e.r.).
Scheme 2. Proof-of-principle: Effective combination of three catalytic
processes, culminating in the formation of a product containing an all-
carbon-substituted quaternary stereogenic center in high enantiomeric
purity in less than a total of four hours.
furan (thf) at 228C; there was complete conversion to the
desired product after 45 min (< 2% addition of a-alkenyla-
luminum species). b-Alkenylketone
Enantioselective synthesis of 5 in Scheme 3 illustrates that
the catalytic process can be performed with n-alkyl (vs.
3a was accordingly obtained in
Table 1: Multicomponent catalytic reactions with b-alkenylaluminum reagents.[a]
64% overall yield and 98:2 e.r. by
a process that requires a total of less
than four hours. The solution of the
alkenylaluminum species was used
directly, whereas the enone was
purified by silica gel chromatogra-
phy; when the procedure was car-
ried out without purification of 2,
ketone 3a was isolated in 41%
overall yield (vs. 64%) and with
identical enantioselectivity (98:2
e.r.).
Aryl-, heteroaryl- and alkyl-
substituted alkynes can be utilized.
The facile modularity[13] of the mul-
ticomponent approach permits easy
access to a variety of products in
high e.r. Examples involving b-
alkenylaluminum reagents are pre-
sented in Table 1; the desired com-
pounds are isolated in 24–60%
overall yield. Products are obtained
Entry
R1; R2
ECA
Prod.
Carbomet./acyl. yield [%];[c]
ECA yield [%][d]
e.r.[e]
conv. [%][b]
1
2
3
4
5
6
7
8
9
pMeOC6H4; C6H5
pBrC6H4; C6H5
>98
>98
>98
>98
>98
>98
>98
>98
>98
3b
3c
3d
3e
3 f
3g
3h
3i
40; 75
63; 60
80; 60
80; 72
80; 60
80; 54
61; 51
80; 55
80; 60
98:2
96:4
96.5:3.5
98:2
98:2
96.5:3.5
97:3
90.5:9.5
94.5:5.5
C6H5; pMeOC6H5
C6H5; pF3CC6H5
oMeOC6H4; C6H5
C6H5; 3-thienyl
[e]
Cy; C6H5
[e]
CH2C6H5; C6H5
C6H5; Cy
3j
[a] Reactions were performed under N2 atmosphere; enones generated with >98% E selectivity in all
cases. [b] Determined by analysis of 400 MHz 1H NMR spectra of unpurified mixtures (Æ2%). [c] Yield
of isolated and purified products (Æ5%). [d] Determined by HPLC analysis; see the Supporting
with e.r. values that typically exceed Information for details. [e] NHC-Ag complex 1b was used as catalyst precursor.
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Table 2: Multicomponent catalytic reactions with a-alkenylaluminum reagents.[a]
There are instances where the
zirconocene-catalyzed carbometa-
lation is inefficient or the terminal
alkyne is prohibitively expensive;[14]
examples are shown in Scheme 4.
Such substrates were prepared by
Wittig-type olefinations. Ketones
10–15 were obtained readily in 57–
90% yield and 97:3–99:1 e.r. (Sche-
me 4a). The catalytic ECA with
unsaturated keto ester 16 shows
that the reaction not only proceeds
efficiently (68% yield) and with
high enantioselectivity (97:3 e.r.),
Entry
R1; R2
ECA
Prod.
Carbomet./acyl. yield [%];[c]
ECA yield [%][d]
e.r.[e]
conv. [%][b]
1
2
3
4
5
6
7
8
C6H5; C6H5
>98
>98
>98
88
>98
>98
>98
>98
>98
>98
>98
>98
>98
4a
4b
4c
4d
4e
4 f
4g
4h
4i
80; 82
40; 95
88; 88
60; 48
80; 95
80; 80
80; 97
80; 71
40; 81
63; 95
62; 87
80; 85
61; 83
99:1
97.5:2.5
99:1
99:1
98:2
97:3
98:2
99:1
98:2
99:1
95:5
97.5:2.5
92:8
pMeOC6H4; C6H5
mFC6H4; C6H5
oFC6H4; C6H5
C6H5; pMeOC6H5
C6H5; pF3CC6H5
C6H5; mF3CC6H5
C6H5; oFC6H5
pMeOC6H4; 3-thienyl
pBrC6H4; C6H5
(CH2)3OTBS; C6H5
À
C C bond formation is fully site-
selective (Scheme 4b); only the
product containing the more steri-
cally demanding quaternary carbon
stereogenic center b to the ketone
unit is formed exclusively (17/18 >
98:2), underscoring the lower reac-
tivity of enoates.
9
10
11
12
13
4j
4k
4l
[e]
[e]
CH2C6H5; C6H5
Cy; C6H5
The sequence in Scheme 5,
regarding the enantioselective syn-
thesis of antimicrobial enokipo-
din B,[15] demonstrates the utility of
our method. Conversion of aryl-
substituted terminal alkyne 20 and
phenylacetylene to 21 proceeds in
57% overall yield and 95:5 e.r.; this
4m
[a] Reactions were performed under N2 atmosphere; enones generated with >98% E selectivity in all
cases. [b] Determined by analysis of 400 MHz 1H NMR spectra of unpurified mixtures (Æ2%). [c] Yield
of isolated and purified products (Æ5%). [d] Determined by HPLC analysis; see the Supporting
Information for details. [e] NHC-Ag complex 1a was used as catalyst precursor. TBS=tert-butyl-
(dimethyl)silyl.
methyl) ketones; attempts to effect reaction with the bulkier
isopropyl ketone resulted in extensive decomposition after
4.0 h. Enynes easily undergo carbometalation/acylation en
route to 1,4-dienes such as 6 (78% yield and 96:4 e.r.;
Scheme 3). Alkenyl-substituted a-alkenylaluminum species
serve equally well, as manifested by the enantioselective
formation of 7 (92% yield, 98:2 e.r.). Synthesis of ketones 8
and 9 in high e.r. shows that enones accessed by reaction with
commercially available and inexpensive Et3Al are suitable
substrates.
Scheme 3. Products obtained from catalytic multicomponent enantio-
selective reactions with an enyne, an n-alkyl ketone, and Et3Al. Enones
generated with >98% E selectivity in all cases; yields are overall for
the entire three-component process. See the Supporting Information
for details.
Scheme 4. a) Products of NHC–Cu-catalyzed ECA reactions with a,b-
unsaturated ketones not efficiently or cost-effectively accessible
through Zr-catalyzed carbometalation/acylation. b) ECA reaction pro-
ceeds with site-selectivity. Yields refer to catalytic ECA; see the
Supporting Information for details.
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Scheme 5. Application of the multicomponent catalytic enantioselec-
tive process to the synthesis of enokipodin B. Conditions: a) 1.5 equiv
ICl, Et2O/CHCl3 (2:1), 228C, 3.0 h; 75% yield; b) 1.2 mol% [Pd-
Scheme 6. DFT calculations indicate that the major enantiomer likely
arises from the mode of addition A (vs. B).
ꢀ
(PPh3)2Cl2], 2.0 mol% CuI, 1.2 equiv HC CSi(Me)3, 22–858C 4.0 h;
c) KOH, MeOH, thf, 228C, 3.0 h; 94% overall yield (2 steps). See the
Supporting Information for details.
alkenyl-based nucleophiles and acyclic enones. In most
cases, reagents and substrates are obtained by catalytic
processes as well. The above attributes, the variety of
functionalizations feasible with alkenes and carbonyls, and
the importance of enantiomerically enriched entities with
a quaternary carbon stereogenic center underscore the value
of the approach presented in this report.
is in spite of the carbometalation/acylation of highly electron-
rich 20 proceeding in an atypical 67:33 E/Z selectivity.[11]
Control experiments indicate that the Z isomer affords the
same enantiomer but the ECA is comparatively less effi-
cient.[16] The alkenyl group of unsaturated ketone 21 has been
utilized as a convenient precursor to an aldehyde, which was
subsequently reacted with the neighboring ketone to generate
the desired cyclopentenone.[15] The route in Scheme 5 com-
pares favorably with a recent alternative that generates 21 in
11 steps from commercially available materials[15] (vs. five
steps from 19, which can be purchased).
Received: October 30, 2013
Keywords: carboalumination · conjugate additions · copper ·
.
N-heterocyclic carbenes · quaternary carbon center
[1] For scholarly reviews on catalytic ECA reactions, see: a) S. R.
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[2] For applications of catalytic ECA reactions that afford all-
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molecule natural product synthesis (all involve cyclic enones),
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carbonyl compounds that afford all-carbon-substituted quater-
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Clavier, M. Mauduit, A. Alexakis, J. Am. Chem. Soc. 2006, 128,
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We carried out DFT calculations to gain insight regarding
the origins of the high enantioselectivity. The catalytic cycle
appears to involve initial conjugate addition of (alkenyl)CuI
complex followed by reductive elimination of the (alkenyl)
CuIII alkyl intermediate.[17] Transformation through a mecha-
nism whereby the cuprateꢀs alkenyl unit is directly transferred
to the enone substrate in a redox-neutral process was found to
be less favored by roughly 7–9 kcalmolÀ1. Complex A
(Scheme 6) represents the lowest energy pathway, consistent
with the identity of the major isomers; complex B, leading to
the minor enantiomers, is about 1.6 kcalmolÀ1 higher in
energy. In the latter case, simultaneous coordination of the
substrate with the Lewis acidic aluminum bridge and Cu
center dictates that the enone binds in its energetically more
demanding s-trans conformation (vs. s-cis in A), engendering
severe A(1,3) strain between the ketone and alkene substitu-
ents. In the absence of an aluminum connector, the transition
state for addition to the same face as the complex is
appreciably higher in energy. The above mechanistic issues
underscore the challenges associated with ECA of acyclic
compounds where, unlike the more rigid cyclic systems,
reaction can proceed via several possible conformers.
In closing, we have introduced the first protocol for
catalytic ECA reactions that form products with quaternary
all-carbon-substituted stereogenic centers and involve
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Tomioka, J. Org. Chem. 2008, 73, 4578 – 4581; h) C. Ladjel, N.
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[10] a) E. Negishi, D. Y. Kondakov, D. Chouiery, K. Kasai, T.
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loadings, but at lower yields (e.g., with 10 mol% [Cp2ZrCl2], 2
was obtained in 70% yield after purification). Since the Zr-based
salt is inexpensive, we opted to follow the higher yielding
procedure with the higher loading.
[11] Synthesis of trisubstituted enones by established procedures is
not straightforward. Horner– Emmons-type transformations are
severely inefficient (vs. the derived carboxylic esters); for
example, reaction with acetophenone under standard conditions
(1.2 equiv NaH, 228C, 18 h) leads to < 2% conversion to the
desired enone. Another approach includes addition of
a Grignard reagent to acetoacetone in the course of a day,
followed by treatment with oxalic acid at reflux for 30 min; the
stereoisomeric purity of the resulting enones has not been
reported (N. J. A. Martin, B. List, J. Am. Chem. Soc. 2006, 128,
13368 – 13369). Yet a different procedure calls for an acid
chloride as the starting material, entails a three-step process that
requires a total of 36 h, and generates the stereoisomerically
pure a,b-unsaturated ketone in ca. 26% overall yield after
purification (Ref. [2d]).
[12] See the Supporting Information for data on catalyst screening.
[13] In principle, any entity or procedure can be modified; however,
it is the ease with which alterations can be implemented that is
critical. We underscore such distinction by the use of the term
“facile modularity”.
[14] The alkynes required for synthesis of 10–13 are too costly. In the
case of p-trifluorophenyl-substituted 13–15, the carbometalation
procedure proved to be inefficient (ca. 15% conv. under the
conditions shown in Scheme 2).
[15] a) M. Yoshida, Y. Shoji, K. Shishido, Org. Lett. 2009, 11, 1441 –
1443; for an earlier enantioselective route to enokipodins, see:
b) S. Kuwahara, M. Saito, Tetrahedron Lett. 2004, 45, 5047 – 5049.
[16] The reason for the low stereoselectivity in this particular Zr-
catalyzed carbomethylation/acylation sequence is unclear. Con-
trol experiments indicate that the Z enone is first converted to
the E isomer, which undergoes ECA more readily. However, the
latter sequence leads to the generation of some unidentified
impurities and thus a lower overall yield.
´
´
reagents, see: k) P. Kwiatkowski, K. Dudzinski, D. Łyzwa, Org.
Lett. 2011, 13, 3624 – 3627.
[4] For catalytic ECA of aryl-based nucleophiles to cyclic a,b-
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arylboronic acids, a) R. Shintani, W.-L. Duan, T. Hayashi, J.
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Angew. Chem. Int. Ed. 2008, 47, 8211 – 8214; with Rh complexes
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Nagaosa, T. Nishimura, T. Hayashi, J. Am. Chem. Soc. 2009, 131,
13588 – 13589; with Rh complexes and triarylboroxines, e) R.
Shintani, M. Takeda, T. Nishimura, T. Hayashi, Angew. Chem.
2010, 122, 4061 – 4063; Angew. Chem. Int. Ed. 2010, 49, 3969 –
3971; with Rh complexes and arylaluminum reagents, f) C.
Hawner, D. Mꢂller, L. Gremaud, A. Felouat, S. Woodward, A.
Alexakis, Angew. Chem. 2010, 122, 7935 – 7938; Angew. Chem.
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[6] For catalytic ECA of C-based nucleophiles to especially
activated acyclic substrates affording all-carbon-substituted
quaternary stereogenic centers, see: with alkylmetal reagents:
a) J. Wu, D. M. Mampreian, A. H. Hoveyda, J. Am. Chem. Soc.
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nucleophiles, see: f) H. Kawai, Z. Yuan, T. Kitayama, E.
Tokunaga, N. Shibata, Angew. Chem. 2013, 125, 5685 – 5689;
Angew. Chem. Int. Ed. 2013, 52, 5575 – 5579; for catalytic ECA
with a CN-based nucleophile, see: g) one example reported in:
C. Mazet, E. N. Jacobsen, Angew. Chem. 2008, 120, 1786 – 1789;
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[7] For ECA of Me3Al and Et3Al to b,b-substituted acyclic enones,
see: a) K. Endo, D. Hamada, Y. T. Shibata, Angew. Chem. 2013,
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[17] N. Yoshikai, E. Nakamura, Chem. Rev. 2012, 112, 2339 – 2372.
[8] For Cu-catalyzed ECA with alkenyl-based nucleophiles and b-
substituted cyclohexenones, see: a) D. Mꢂller, C. Hawner, M.
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