Enantioselective synthesis of alkyne-substituted quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution reactions with (i -Bu)2(Alkynyl)aluminum reagents

Article abstract of DOI:10.1021/ja2010829

A catalytic enantioselective method for the formation of alkyne-substituted all-carbon quaternary stereogenic centers is reported. Additions of alkynylaluminums to alkyl-, aryl-, carboxylic ester-, or silyl-substituted allylic phosphates are promoted by 1.0-5.0 mol % loadings of NHC-Cu complexes derived from air-stable and commercially available CuCl₂· 2H₂O. The requisite Al-based reagents are prepared through treatment of the corresponding aryl-, heteroaryl-, alkyl-, or alkenyl-substituted terminal alkynes with diisobutylaluminum hydride in the presence of 5.0 mol % Et ₃N at ambient temperature. The desired 1,4-enynes are obtained in up to 98% yield and >99:1 enantiomeric ratio. Selected Au-catalyzed cyclizations involving the alkyne unit of the enantiomerically enriched products are presented as a demonstration of the methods utility in chemical synthesis.

Full text of DOI:10.1021/ja2010829

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pubs.acs.org/JACS
Enantioselective Synthesis of Alkyne-Substituted Quaternary Carbon
Stereogenic Centers through NHC-Cu-Catalyzed Allylic Substitution
Reactions with (i-Bu)2(Alkynyl)aluminum Reagents
Jennifer A. Dabrowski, Fang Gao, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S Supporting Information
b
to >99:1 enantiomeric ratio (er). One of the most noteworthy
ABSTRACT: A catalytic enantioselective method for the
formation of alkyne-substituted all-carbon quaternary stereo-
genic centers is reported. Additions of alkynylaluminums to
alkyl-, aryl-, carboxylic ester-, or silyl-substituted allylic phos-
phates are promoted by 1.0-5.0 mol % loadings of NHC-Cu
complexes derived from air-stable and commercially available
features of the present studies is that the bidentate NHC complexes
efficiently promote transfer of the alkyne groups. Acetylene-based
moieties usually serve as relatively robust ligands that are not readily
transferred via Cu-based complexes. In contrast, in the reactions
described here, products from i-Bu addition are not observed (<2%
by 1H NMR analysis), and the same class of substrates utilized for
NHC-Cu-catalyzed additions of alkyl-, aryl-, or vinyl groups8 can
be employed (i.e., without the need to use especially activated
alkenes). The utility of the method is illustrated by representative
Au-catalyzed transformations that efficiently convert the enantiose-
lective allylic substitution (EAS) products into heterocyclic struc-
tures bearing a quaternary carbon stereogenic center.
CuCl2 2H2O. The requisite Al-based reagents are prepared
3
through treatment of the corresponding aryl-, heteroaryl-,
alkyl-, or alkenyl-substituted terminal alkynes with diisobuty-
laluminum hydride in the presence of 5.0 mol % Et3N at
ambient temperature. The desired 1,4-enynes are obtained in
up to 98% yield and >99:1 enantiomeric ratio. Selected Au-
catalyzed cyclizations involving the alkyne unit of the enantio-
merically enriched products are presented as a demonstration
of the method’s utility in chemical synthesis.
n spite of significant recent advances in enantioselective
catalysis, the number of protocols that promote the addition
I
of an alkyne group to a C-based electrophile remains relatively
small. Such methods are of value because there are transforma-
tions that are particularly effective with C-C triple bonds.1 Synth-
esis of enantiomerically enriched propargyl alcohols or amines
through reactions with aldehydes,2 ketones,2 or aldimines3 has been
disclosed. However, catalytic processes involving additions of
alkynyl nucleophiles to alkene-based substrates are less common.
Several approaches have been outlined regarding catalytic enantio-
selective conjugate additions of alkynylmetal reagents to unsaturated
carbonyls, leading to the formation of alkyne-substituted tertiary
carbon stereogenic centers.4,5 In instances where a chiral Cu
complex is used,4d,e highly activated substrates, such as Meldrum’s
acid derivatives or R,β-unsaturated thioamides, must be used to
counter the low activity of Cu alkynilides. To the best of our
knowledge, catalytic enantioselective alkynyl additions that generate
an all-carbon quaternary stereogenic center6 remain undisclosed;
nor are we aware of any catalytic allylic substitutions7 that deliver
enantiomerically enriched products through addition of an alkyne.
Herein, we present a catalytic enantioselective protocol for the
reaction of (i-Bu)2(alkynyl)aluminum reagents to trisubstituted
allylic phosphates (eq 1). These additions are promoted by a
1.0-5.0 mol % loading of a copper complex derived from a chiral
bidentate sulfonate-based N-heterocyclic carbene (NHC)8 and air-
One of the most attractive features of Al-based nucleophilic
reagents is the ease with which they can be synthesized from
readily accessible starting materials and used in situ. We have shown
that vinylaluminums, which can be formed efficiently and selectively
by hydrometalation of alkynes with dibal-H, can participate in
highly site- and enantioselective Cu-catalyzed EAS reactions9 or
conjugate additions;10 such vinylmetals might also be accessed
through Ni-catalyzed hydroaluminations of alkynes and utilized in a
similar fashion.11 To access alkynylaluminums, we decided to con-
tinue using the commercially available and inexpensive dibal-H;
such a strategy, however, would require facilitation of the desired
alkyne deprotonation while the competitive hydrometalation route
is inhibited. Toward this end, we took note of the studies by Binger
and the more recently expanded ones by Micouin and co-workers
illustrating that the simple expedience of adding 5.0 mol % Et3N
allows terminal alkynes to be converted to alkynylaluminums in the
presence of dibal-H.12 Accordingly, as illustrated in Scheme 1, we
were able to establish that alkynylaluminum 3a derived from
phenylacetylene undergoes highly efficient (>98% conv in 4.0 h)
EAS with allylic phosphate 2inthepresenceof0.5mol%NHC-Ag
complex 1a and 1.0 mol % CuCl2 2H2O, affording 4a with
3
complete site selectivity (>98% SN20) in 92% yield and 93:7 er.
stable CuCl2 2H2O; the desired products are formed with excep-
Received: February 3, 2011
Published: March 08, 2011
3
tional site selectivity (typically, >98% SN20) in 63-98% yield and up
r
2011 American Chemical Society
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Scheme 1. Preliminary Finding: Synthesis and Efficient Cu-
Table 2. NHC-Cu-Catalyzed Enantioselective Allylic Sub-
stitutions with Aryl-Substituted Allylic Phosphates and
Alkynylaluminumsa
Catalyzed Addition with an Alkynylaluminum Reagenta
a Reactions were performed under a N2 atmosphere (see the Supporting
Information for details). Mes = 2,4,6-Me3C6H2.
a-dSee footnotes a-d of Table 1.
enantioselective (89.5:10.5 er), are significantly less efficient (∼30%
conv) than those bearing a sulfonate (i.e., 1a and 1b). As demon-
strated through the enantioselective syntheses of 4b and 4c, catalytic
EAS can be performed with facility similar to that observed for 4a
with substrates bearing a more sterically demanding branched alkyl
side chain. The less than complete site selectivity observed in the
case of 4b (90% SN20) is unusual; the reason for such a deviation is
unclear at the present time.
Table 1. NHC-Cu-Catalyzed Enantioselective Allylic Sub-
stitutions with Alkynylaluminum Reagent 3aa
Cu-catalyzed EAS reactions with aryl-substituted allylic phos-
phates were examined as well; the results of these studies are
summarized in Table 1. The reactions proceeded with similar or
higher enantioselectivity than for the aforementioned alkyl-
substituted cases (91:9 to >99:1 er vs 92:8 to 94:6 er), but 2.5
mol % 1a or 1b (cf. Scheme 1) was required for >98% conversion
(vs 0.5 mol % for 4a-c). Several additional points regarding the
data in Table 1 merit mention: (1) Although ortho substitution
on the aryl group led to high er values (entries 4 and 5), the
efficiency suffered greatly with an o-Me unit (entry 3). (2) For aryl
rings bearing an electron-deficient group, the catalytic additions
proceeded less efficiently (entries 7 and 8); nonetheless, the
reactions were clean, allowing the desired products to be isolated
in useful yields. (3) In one instance, the Cu complex derived from
1b delivered the desired product in higher enantiomeric purity than
1a (entry 2; >98% conv, 95% SN20, and 63:37 er with 1a).
a Reactions were performed under a N2 atmosphere. nd = not determined.
1
b Determined by analysis of 400 MHz H NMR spectra of unpurified
mixtures. c Yields of isolated products after purification ((5%). d Deter-
mined by HPLC analysis (see the Supporting Information for details).
e Reaction was performed with NHC-Ag complex 1b. f Time = 30 h.
The selection of NHC-Ag complex 1a as the precursor to the
Cu catalyst was based on the preliminary examination of various
chiral carbene ligands.13 Catalyst screening studies indicated that
use of a bidentate NHC complex is critical, as the monodentate
variants proved to be ineffective (<10% conv). Reactions promo-
ted by the ligands containing a phenoxy bridge, although appreciably
As the findings shown in Table 2 indicate, a variety of terminal
alkynes can be easily and efficiently deprotonated and used in the
NHC-Cu-catalyzed EAS process. Reactions with alkyl- (entries
1 and 2) as well as alkenyl-substituted (entry 3) alkynylaluminums
proceeded efficiently to afford the desired 1,4-enynes in 96:4 to
>99:1 er and 82-91% yield after purification. The reaction
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Scheme 2. Cyclic Ether through Au-Catalyzed Cyclization
Scheme 3. Au-Catalyzed Conversion to Cyclic Lactones
ester-containing products in particular. Thus, unsaturated γ-lac-
tones 18a-c were obtained directly in 65%-97% yield, without the
need for initial hydrolysis of the carboxylic ester, through Au-
catalyzed cyclizations of the enantiomerically enriched 1,4-enynes
13a-c.15 It should be noted that treatment of the corresponding
methyl esters (e.g., 12) to the same conditions did not result in any
detectable cyclization.16 The above procedures are unique to alkyne-
containing molecules and cannot be performed on products from
previously reported catalytic EAS reactions (such as those obtained
through vinylmetal additions).8
involving an o-chlorophenylacetylene (entry 4) was exceptionally
efficient and selective (98% yield, >98% SN20, >99:1 er). On the
other hand, as suggested by the example in entry 5, the presence of
a strongly electron-withdrawing substituent within the aryl alkyne
can be detrimental to the catalytic EAS.
In summary, we have presented a method for enantioselective
synthesis of small organic molecules containing readily differenti-
able alkyne and alkene groups; a carboxyl ester unit can be present
in such enantiomerically enriched products as well. In view of the
wealth of transformations that can be performed with the above-
mentioned functional units, catalytic, stereo- and site-selective
variantsof which continueto emerge, the methoddescribed herein
should prove to be of value in the preparation of enantiomerically
enriched organic molecules. Studies regarding site- and enantio-
selective NHC-Cu-catalyzed alkyne additions to other substrate
classes, including those that contain a disubstituted olefin, are in
progress and will be reported in due course.
The enantioselective syntheses of enynes 12, 13b, 14, and 15
underline three additional noteworthy aspects of the method:
(1) Reactions can be performed with R,β-unsaturated esters or
vinylsilane bearing a γ-phosphate to afford products with high
enantiomeric purity wherein the quaternary carbon stereogenic
center is positioned adjacent to a carbonyl group or silyl unit. (2)
There is little or no adventitious reduction of the carboxyl ester
group by residual dibal-H used in the preparation of the
alkynylaluminum. (3) Catalytic EAS can be used with alkynyl-
metal reagents that carry a heterocyclic substituent (cf. 14).
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, spec-
b
tral and analytical data for all products, and crystallographic data
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
’ ACKNOWLEDGMENT
This paper is dedicated to Professor David A. Evans on the
occasion of his 70th birthday. Financial support was provided by the
NIH (GM-47480); F.G. is an AstraZeneca Graduate Fellow. We are
grateful to Dr. Bo Li (Boston College X-ray Facilities) for assistance
in securing X-ray structures. The Center for Mass Spectrometry at
Boston College is supported by the NSF (DBI-0619576).
The potential of the products obtained through NHC-Cu-
catalyzed additions of alkynylaluminums for application in
chemical synthesis is underlined by the transformations shown
in Scheme 2. Primary carbinol 16, obtained through site-selective
hydroboration of enyne 6e, is readily converted to the derived
cyclic enol ether within 4.5 h upon treatment with 2.0 mol %
AuCl3.14 The desired heterocycle (Z-17), the identity of which
was established by X-ray crystallography, was isolated in 95%
yield with 85% Z-selectivity.
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