Copper-catalyzed enantioselective allylic substitution with readily accessible carbonyl- and acetal-containing vinylboron reagents

Article abstract of DOI:10.1002/anie.201202856

More with boron: The title reaction was developed to generate quaternary carbon stereogenic centers through the use of commercially available vinylboron reagents (see scheme, MOM=methoxymethyl, NHC=N-heterocyclic carbene, pin=pinacolato). Application of t

Full text of DOI:10.1002/anie.201202856

Angewandte
Chemie
DOI: 10.1002/anie.201202856
Enantioselective Catalysis
Copper-Catalyzed Enantioselective Allylic Substitution with Readily
Accessible Carbonyl- and Acetal-Containing Vinylboron Reagents**
Fang Gao, James L. Carr, and Amir H. Hoveyda*
Catalytic enantioselective allylic substitution (EAS) reactions
are of prominent utility in chemical synthesis.[1] Such trans-
formations generate a stereogenic center adjacent to an
alkene, which can be further functionalized to afford a range
of other enantiomerically enriched molecules. Despite note-
worthy advances, several issues remain unresolved in this
area. Nearly all the existing protocols require nucleophilic
metal-based reagents, which, while often the source of high
reactivity, are not well suited when certain commonly
occurring functional groups are present. Moreover, whereas
significant focus has been placed on additions of alkyl
groups,[1] reported examples of catalytic processes that lead
to incorporation of aryl or heteroaryl,[2] allyl,[3] alkynyl,[4] or
Scheme 1. A route for enantioselective synthesis of Pummerer ketone
might involve catalytic allylic substitution with a carbonyl-containing
allenyl[5] moieties are markedly small in number.
The corresponding reactions resulting in additions of vinyl
units have received attention only recently. Efforts in these
laboratories have led to the development of catalytic EAS
with vinylmetal species, generated through hydroalumina-
tions of alkynes[6] (with di-iso-butylaluminum hydride) and
vinyl group, followed by a catalytic diastereoselective intramolecular
conjugate addition and catalytic ring-closing metathesis. pg=protect-
ing group, pin=pinacolato.
À
used in situ for site- and enantioselective C C bond forma-
Herein, we outline a method for catalytic EAS reactions
that proceed with vinylboron reagents,[11] including those that
contain a carboxylic ester or an acetal unit, which are either
purchased or can be prepared by Cu-catalyzed processes.[12]
The coupling reactions are promoted by sulfonate-bridged
bidentate N-heterocyclic carbene (NHC) complexes of
copper and generate all-carbon quaternary stereogenic cen-
ters.[13] The desired products, including those with an ester, an
aldehyde, or an acetal group, are formed in up to 98% yield,
more than 98% SN2’ selectivity and more than 98:2 enantio-
meric ratio (e.r.). Utility is demonstrated by concise enantio-
selective syntheses of Pummerer ketone as well as its hitherto
undisclosed anti isomer, where diastereoselective intramolec-
ular conjugate additions, controlled by cinchona alkaloid
catalysts, and Ru-catalyzed ring-closing metathesis comple-
ment the NHC–Cu-catalyzed EAS process.
tion.[7] Nonetheless, vinylaluminum reagents with a hetero-
atom substituent at their allylic position cannot be efficiently
prepared by hydrometalation.[8] The above shortcoming is
underlined by the sequence shown in Scheme 1, regarding
a projected enantioselective synthesis of Pummerer ketone,[9]
an intermediate in morphine biosynthesis.[10] The key step
would ideally involve EAS with a carbonyl-substituted
reagent, leading to the formation of an a,b-unsaturated
ester that could then be subjected to a diastereoselective
intramolecular conjugate addition. The analogous vinylalu-
minum species are inaccessible. In contrast, the correspond-
ing vinylboron reagents are prepared readily; however, an
efficient method for catalytic EAS involving such entities
does not exist. Such protocols would notably enhance the
general utility of this important class of transformations.
We initiated our investigations by probing the ability of
different NHC–Cu complexes to promote reaction between
commercially available n-hexyl(pinacolato)vinylboron 9 and
o-methoxyphenyl-containing allylic phosphate 7a; the
expected product (8a) contains an ortho-alkoxy-substituted
aryl unit, as required in the proposed approach to enantio-
selective synthesis of Pummerer ketones (see Scheme 1). The
presence of NaOMe is to assist the formation of the NHC–
Cu-vinyl intermediate (via the methoxy-bearing boronate).[14]
Preliminary studies indicated that the transformation is
sluggish at ambient temperature (ꢀ 30% conversion with
various catalysts). Therefore, in contrast to Cu-catalyzed
reactions with the related allenylboron reagent,[5] which
proceed to completion at 228C, it appeared that EAS with
the relatively more hindered vinylboron demands more
[*] F. Gao, Dr. J. L. Carr, 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) and the
NSF (CHE-1111074). F.G. was an AstraZeneca (2010–11) and is
a Bristol-Myers Squibb graduate fellow (2011–12). We are grateful to
Dr. B. Jung and Dr. F. Haeffner for helpful discussions, to Frontier
Scientific, Inc. for gifts of vinylboronic acid pinacol esters, and to
Boston College Research Services for providing access to compu-
tational facilities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202856.
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Table 2: Site- and enantioselective NHC–Cu-catalyzed EAS with aryl-
substituted substrates and alkenylboron 9.[a]
forcing conditions. Whether high site- and enantioselectivity
would be achievable under the latter circumstances remained
to be established.
There is reasonable efficiency (58–92% conv., ꢀ 60%
yield) and low to appreciable site and enantioselectivity with
monodentate and aryloxy- or alkoxy-bridged NHC–Cu com-
plexes (80–93% SN2’ and up to 80:20 e.r.; Table 1, entries 1–
Entry Substrate (Ar)
Imid. Conv. Yield SN2’:SN2[b]
salt
e.r.[d]
[%][b] [%][c]
Table 1: Initial examination of various chiral NHC–Cu complexes.[a]
1
2
3
4
5
7b (o-MeC6H4)
7c (o-BrC6H4)
7d (o-NO2C6H4)
7e (C6H5)
6b
6b
5a
6c
6b
87
87
82
>98
>98
82
85
50
90
>98
96:4
98:2
98:2
98:2
98:2
92:8
>98:2
87:13
86:14
84:16
7 f (p-ClC6H4)
[a] Reactions were performed under N2 atmosphere. [b] Determined
through analysis of 400 MHz 1H NMR spectra of unpurified mixtures.
[c] Yields of isolated purified products (Æ5%). [d] Determined by HPLC
analysis (Æ2%); see the Supporting Information for details.
Entry
Imid.
salt
Conv.
[%][b]
Yield
[%][c]
SN2’:SN2[b]
e.r.[d]
1
2
3
4
5
6
7
8
9
10
1
2
3
87
92
58
51
59
12
60
95
90
91
87
94
86
86:14
87:13
80:20
93:7
98:2
98:2
>98:2
>98:2
98:2
80:20
73:27
n.d.[e]
52:48
90:10
97:3
>98:2
73:27
>98:2
>98:2
4
89
The examples provided in Scheme 2 illustrate that the
NHC–Cu-catalyzed EAS can be performed with different
robust vinylboron reagents and allylic phosphates, including
those that contain an alkyl or a carboxylic ester unit. Thus,
(pinacolato)vinylboron species that carry a halogen atom (see
5a
5b
5c
6a
6b
6c
>98
>98
>98
95
>98
>98
98:2
[a] Reactions were performed under N2 atmosphere. [b] Determined
through analysis of 400 MHz 1H NMR spectra of unpurified mixtures.
[c] Yield of isolated and purified products. [d] Determined by HPLC
analysis (Æ2%); see the Supporting Information for details. [e] Enan-
tioselectivity not determined because of low yield of isolated product
(12%). n.d.=not determined.
Scheme 2. Products of NHC–Cu-catalyzed EAS of various trisubsti-
tuted allylic phosphates and different readily accessible vinylboron
reagents. All reactions were performed with 5.5 mol% 6b; see Table 2
for conditions and the Supporting Information for details.
8g) or an aryl group (see 8h, 10, and 11) can be utilized. As
before, high efficiency (75–98% yield) and exceptional site
selectivity (> 98% SN2’) is observed, and allylic phosphates
with ortho-substituted aryls are converted to products of
higher enantiomeric purity (> 98:2 vs. 85:15–87:13 e.r.).
The transformations discussed up to this point establish
the feasibility of using a readily accessible and robust class of
boron-based reagents. Next, we turned our attention to
4). Conversely, with sulfonate-bridged imidazolinium salts[15]
5a–c and 6a–c as catalyst precursors, transformations are
efficient, generating divinyl-substituted quaternary carbon
stereogenic centers with nearly complete site and enantiose-
lectivity (up to 95% yield, > 98% SN2’ and > 98:2 e.r.;
Table 1, entries 5–10).[16]
À
Catalytic EAS with vinylboron reagent 9 can be per-
formed with various aryl-substituted allylic phosphates (rep-
resentative cases in Table 2). Reactions with substrates that
contain an ortho-aryl group, although somewhat less facile
(82–87% conversion in entries 1–3 vs. > 98% conversion in
entries 4 and 5), are generally more enantioselective (87:13 to
> 98:2 e.r. vs. 84:16–86:14 e.r.). There is high site selectivity in
favor of the branched 1,4-diene isomer in every case (96–98%
SN2’).[17]
examining C C bond-forming processes in which use of
a vinylmetal is not possible. With ester-substituted vinylboron
compound 13, NHC–Cu-catalyzed EAS furnishes the desired
product with high selectivity (Scheme 3). Allylic substitutions
proceed in more than 98% SN2’ selectivity and 96:4 to more
than 98:2 e.r. (Scheme 3)[18] and the desired products are
obtained in 51–69% yield. It is possible that slower rate of
reaction (808C required vs. 608C for alkyl-substituted vinyl-
boron reagents) and moderate yields are because the
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treatment of the mixture with a suspension of silica gel for
one hour (228C) delivers enal 15a in 88% yield and more
than 98:2 e.r. (< 2% SN2 addition). Other examples in
Scheme 4 (15b–c and 17–18) demonstrate the generality of
the approach. Use of organoboron 16 offers the attractive
combination of furnishing the desired products in higher
yields (vs. 13), while allowing access to the more reactive a,b-
unsaturated aldehydes by a simple hydrolytic procedure. The
enantiomerically enriched acetals can be accessed through
chromatography with silica gel neutralized with Et3N (3% by
volume);[19] for example, the precursor to 15a is isolated in
86% yield and more than 98:2 e.r. The vinylaluminum species
corresponding to 16 or the aldehyde derived from it cannot be
prepared by hydroalumination procedures.
Scheme 3. NHC–Cu-catalyzed EAS with allylic phosphates and carbox-
ylic ester containing vinylboron 13. MOM=methoxymethyl.
electron-withdrawing ester substituent diminishes the facility
of the addition of the vinylcuprate to the allylic phosphate,
which is accompanied by the conversion of the CuI complex to
In connection with the synthesis of Pummerer ketones,
treatment of allylic phosphate 19 with the aforementioned
conditions delivers unsaturated aldehyde 20 in 77% yield,
more than 98% SN2’ selectivity, and 98:2 e.r. Subjection of the
enal to oxone in MeOH (228C, 18 h) delivers the methyl ester
concomitant with the removal of the methoxymethyl (MOM)
group, affording 21 in 83% yield.[20] The two-step sequence,
which commences with allylic phosphate 19 and culminates in
unprotected phenol 21 in high enantiomeric purity proceeds
in 64% overall yield (vs. 51% yield of methoxymethyl
(MOM) ether 14 in Scheme 3).
a CuIII intermediate; subsequent reductive elimination gen-
[5,7c]
À
erates the C C bond.
In spite of the appreciable reactivity and exceptional site-
and enantioselectivity in the latter processes, we decided to
search for a more efficient protocol for obtaining products
with carbonyl-containing vinyl units. We were especially
interested in identifying a higher yielding approach to the
enantioselective preparation of a,b-unsaturated ester 14, to
be incorporated in the projected Pummerer ketones synthesis
(see Scheme 1). We accordingly explored the possibility of
EAS with another commercially available vinylboron
reagent: the acetal-containing 16 (Scheme 4). Based on the
above-mentioned electronic effects regarding the slower rate
of transformations with vinylboron compound 13, we envi-
sioned that catalytic EAS with 16, which carries a less
electron-withdrawing substituent, would be more facile and
efficient. Reaction of allylic phosphate 7a with 16 in
combination with 5.5 mol% imidazolinium salt 6b, under
otherwise identical conditions (see above), followed by
With an efficient route for enantioselective synthesis of
a,b-unsaturated ester 21 outlined, we explored the possibility
of converting the EAS-derived product to the desired
benzofuran in a diastereoselective manner (see Scheme 1).
Because of the similar size of methyl and vinyl substituents at
the quaternary carbon center, high diastereoselectivity can
only be achieved if an effective chiral catalyst promotes the
cyclization. We thus considered the possibility that cinchona
alkaloids might catalyze the desired intramolecular phenol
conjugate addition[21] efficiently and stereoselectively. We
pursued the latter strategy with the knowledge that every
extant example thus far is for obtaining
a benzopyran.[21] Treatment of 21 with
10 mol% of commercially available and
inexpensive cinchonine (22) leads to the
formation of anti-23 in 87% yield and 89:11
diastereomeric ratio (d.r.; 08C, 2.0 h;
Scheme 5). Conversion to Weinreb amide
anti-25 proceeds efficiently (76% yield).
The latter reaction generates approximately
20% of the a,b-unsaturated amide 26 as
a by-product; however, the catalytic diaste-
reoselective benzofuran synthesis can be
performed with 26 to afford additional
amounts of anti-25 with similar efficiency
and stereoselectivity (92% yield, 88:12 d.r.;
Scheme 5).[22] Subsequent treatment with
vinylmagnesium bromide and ring-closing
metathesis catalyzed by Ru-based carbene
27[23] delivers the anti isomer of Pummerer
ketone in 80% yield (> 98:2 e.r.). Since the
À
stereochemical outcome of the C O bond
generation by the intramolecular conjugate
addition can be controlled by a chiral
Scheme 4. NHC–Cu-catalyzed EAS of allylic phosphates with acetal-containing alkenylboron
compound 16.
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Scheme 5. Syntheses of Pummerer ketone and its anti isomer involving NHC–Cu-catalyzed EAS, cinchona alkaloid catalyzed diastereoselective
intramolecular conjugate addition and Ru-catalyzed ring-closing metathesis.
catalyst, the alternative diastereomer can be obtained simply
through the use of 10 mol% cinchonidine (24, Scheme 5).
Benzofuran syn-23 is therefore generated in 89% yield and
90:10 d.r. and can be carried on to complete the enantiose-
lective synthesis of Pummerer ketone.[24]
The possibility of utilizing commercially available and/or
easily accessible (pinacolato)vinylboron reagents in Cu-
catalyzed enantioselective allylic substitution reactions
enhances the value of catalytic EAS reactions. Furthermore,
the high site- and enantioselectivities obtained in the trans-
formations detailed above provide further testimony to the
unique ability of sulfonate-bridged bidented NHC–Cu com-
plexes to serve as efficient catalysts for this important class of
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À
enantioselective C C bond-forming processes.
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1493.
Received: April 13, 2012
Published online: May 25, 2012
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Keywords: copper · enantioselective allylic substitution ·
.
enantioselective catalysis · N-heterocyclic carbenes ·
vinylboron reagents
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[16] For relevant stereochemical models, see Ref. [5].
[17] Catalysts prepared from 5b,c and 6b,c generate high enantio-
selectivity for substrates that contain an ortho-substituted aryl
substituent. However, only NHC–Cu complexes derived from
6b,c reliably deliver high e.r. values with other allylic phos-
phates.
[18] With the catalyst originating from 6b, 14 is isolated in 42% yield
(> 98% SN2’, 96:4 e.r.). The results obtained with 6b or 6c are
often similar but the outcome can be, at times, slightly different.
Currently, we cannot precisely predict the identity of the most
optimal complex for a particular application.
[19] See the Supporting Information for details.
[20] B. R. Travis, M. Sivakumar, G. O. Hollist, B. Borhan, Org. Lett.
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[22] Phenolic ester 21 undergoes intramolecular conjugate addition
to afford an equal mixture of syn- and anti-23 upon standing for
a few hours (228C), and is unstable under the conditions
required for its conversion to a Weinreb amide.
[23] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Am.
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[24] The catalytic RCM that affords Pummerer ketone must be
carried out for 46 h at 228C (vs. 508C and 20 h), because, in
contrast to its anti isomer, it is prone to racemization. When
RCM of enone derived from syn-25 is performed at 508C, under
otherwise identical conditions, the tricyclic enone is generated
with substantial loss of enantiomeric purity ( ꢁ 60:40 e.r.; > 98%
conv, 90% yield). See the Supporting Information for mecha-
nistic rationale and additional details.
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