Catalytic enantioselective protoboration of disubstituted allenes. Access to alkenylboron compounds in high enantiomeric purity

Article abstract of DOI:10.1021/ol5022417

Proto-boryl additions to 1,1-disubstituted allenes in the presence of 1.0-5.0 mol % of chiral NHC-Cu complexes, B₂(pin)₂, and t-BuOH proceed to afford alkenyl-B(pin) products in up to 98% yield, >98:2 site selectivity, and 98:2 er. T

Full text of DOI:10.1021/ol5022417

Letter
pubs.acs.org/OrgLett
Open Access on 08/25/2015
Catalytic Enantioselective Protoboration of Disubstituted Allenes.
Access to Alkenylboron Compounds in High Enantiomeric Purity
Hwanjong Jang,† Byunghyuck Jung,† and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Proto-boryl additions to 1,1-disubstituted allenes in the
presence of 1.0−5.0 mol % of chiral NHC−Cu complexes, B2(pin)2, and
t-BuOH proceed to afford alkenyl−B(pin) products in up to 98% yield,
>98:2 site selectivity, and 98:2 er. The enantiomerically enriched
alkenylboron products can be converted to otherwise difficult-to-access
alkenyl bromides, methyl ketones or carboxylic acids. What’s more, the
corresponding boronic acids may be used in highly stereoselective
NHC−Cu-catalyzed allylic substitution reactions.
llylmetal complexes occupy a prominent position in
organic chemistry;1 reactions of these nucleophilic agents
procedures.6 Herein, we report the realization of the above
plan.
We first established a practical method for preparation of 1,1-
disubstituted allenes (Scheme 2). Treatment of a propargylic
A
with carbonyl- and imine-containing compounds are a
cornerstone of chemical synthesis. Nonetheless, methods for
enantioselective protonation2 of allylmetal species are scarce.3
The difficulty in designing a catalytic enantioselective allyl
anion protonation arises from the identification of a Brønsted
acid that is compatible with the reaction conditions and
contains a counterion component that allows proper acidity to
be maintained while imparting sufficient bulk to cause
stereochemical differentation. We envisioned that if a 1,1-
disubstituted allene (i, Scheme 1) were to undergo selective
a
Scheme 2. Preparation of Allene Substrates
a
See the Supporting Information for details.
a
Scheme 1. Proposed Catalytic Cycle
phosphate, prepared in one step from the corresponding
alcohol, with 5.0 mol % CuCl and an arylaluminum compound,
accessed in situ by reaction of an aryllithium reagent and
AlMe2Cl, furnishes the desired allenes typically in >60% yield
with complete control of SN2′ selectivity. Transformations
proceed to completion in 5 min to 1 h (depending on the
scale).7
We began by investigating the possibility of a chiral Cu
catalyst promoting protoboration of 1a in a site-selective (2a vs
3a or 4a) and enantioselective fashion (Table 1). In our
previous studies involving Cu−B(pin) additions to monosub-
stituted allenes in the presence of aldehydes and ketones,8 a
chiral phosphine proved to be most effective (vs nonselective
chiral NHCs). Accordingly, we first examined the representa-
tive protoboration process under the same parameters.9
Reaction with bis-phosphine 5 (R-SEGPHOS) generated 2a
in 88:12 er along with 9% of 4a (entry 1, Table 1). Consistent
with earlier investigations, the reaction with imidazolinium salt
6a was much less enantioselective (63:37 er; entry 2), affording
14% of 3a as the byproduct. We reasoned that use of a more
sizable alcohol might exacerbate the steric interactions within
a
B(pin) = (pinacolato)boron.
reaction with a chiral Cu−B(pin) complex (pin = pinacolato),4
and the resulting allylcopper (ii) were to be γ-selectively and
enantioselectively protonated via iii,5 a Cu-catalyzed route to
versatile unsaturated organoboron compounds (iv) would be in
hand. The enantioselective C−H bond forming step would be
distinct from other catalytic protoborations (i.e., γ proton
transfer vs direct Cu−C bond protonation4c), affording entities
that cannot be accessed by traditional hydroboration
Received: July 31, 2014
© XXXX American Chemical Society
A
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Letter
a
imidazolinium salt 6b, which delivered some increase in
enantioselectivity (95:5 vs 93:7 er). As will be demonstrated
below, 6b, while requiring a longer synthesis route (6 vs 3
steps), in some cases delivers a better stereoselectivity profile.
Different 1,1-disubstituted allenes underwent catalytic
protoboration efficiently and with high enantioselectivity
(Scheme 4; for additional cases, see the Supporting
Table 1. Evaluation of Chiral Complexes
Scheme 4. Enantioselective Protoboration of Aryl-
a
Substituted Allenes
a
b
Reactions performed under a N2 atmosphere. By analysis of 1H
NMR spectra of the unpurified (for conv) or purified (for selectivity)
c
d
mixtures ( 2%). Yields of purified products ( 5%). By GC analysis.
the competing transition states for enantioselective protona-
tion, leading to a rise in enantioselectivity. We therefore
examined protoboration of 1a with t-BuOH (entries 3−4,
Table 1); this resulted in a substantial improvement in
enantioselectivity with bis-phosphine 5 (93:7 er). To our
surprise, catalytic protoboration promoted by the NHC−Cu
complex derived from 6a delivered the desired product not
only in a similarly high er but also in a significantly improved
yield (77% vs 53%) with superior site selectivity (98% vs 91%
2a and 3% 3a).
To account for the selectivity trends observed with the
NHC−Cu complex derived from 6a, as well as the positive
influence of a large alcohol reagent, we arrived at the
stereochemical models depicted in Scheme 3. We surmised
that two interactions could render III less favorable (vs II).
One is engendered by the tilt of the NAr, causing the ortho unit
of the NAr (blue sphere) to interact with the alcohol
substituent (R); III might be less favored because of steric
repulsion between the NAr’s para unit (red sphere) and the aryl
group of the allene. The latter point led us to prepare and study
a
Same conditions as those in Table 1; all conv = >98%, except
otherwise noted. Yields are of purified products (2 and 3; 5%). Site
selectivities determined by analysis of 1H NMR spectra of the
b
unpurified mixtures. Enantioselectivities determined by GC analysis.
Conv = 88%. Conv = 91%.
c
Scheme 3. Stereochemical Models
Information). Allenes containing an ortho-, meta-, or para-
substituted aryl group (2b−f) and those that bear a
heteroaromatic moiety (e.g., 2g) were suitable substrates.
Synthesis of 2h−j illustrates that reactions of allenes with larger
alkyl units (vs Me) are facile. The data for the Cu complexes
derived from bis-phosphine 5 as well as NHC ligands obtained
from 6a−b highlight the characteristics of each system and
illustrate that in all cases the NHCs are the ligands of choice. In
many instances, the phosphine−Cu complex generated
substantial amounts of inseparable isomeric products (i.e., 3
and 4); with methoxy-substituted 2c, the desired product
constituted only 5% of the mixture, and in reactions to generate
2h−j, the corresponding allylboron compounds (4h−j) were
formed. On several occasions, use of bis-phosphine 5 resulted
in low to moderate enantioselectivity (e.g., 33:67 er for 2c,
16:84 er for 2f, 21:79 er for 2g and 2j). While 6a−b were often
B
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similarly effective, in some cases, the latter afforded significantly
higher site selectivities in favor of 3 (cf. 2e and 2g). The general
effectiveness of the NHC−Cu species is in stark contrast to
additions of allylcopper species derived from Cu−B(pin)
additions to aldehydes and ketones, where bis-phosphines
such as 5 are optimal. These results underline the fundamental
steric and geometric distinctions between the transition states
involved in the reactions of B(pin)-substituted allylcopper
species with aldehydes or ketones vs those involving proton
addition.
synthesis of alkenyl bromides (cf. 9a−b), precursors to many
catalytic or noncatalytic C−C bond forming reactions; such
entities cannot be easily accessed by alternative protocols.12
Exceptional enantiospecificity (es) was observed for reactions
performed with CuBr2. The second set entails preparation of
enantiomerically enriched α,α′-disubstituted ketones (cf. 10a−
b).13 The mild oxidation process is complete in 30 min,
furnishing ketones with >97% es. The alternative catalytic
strategies (e.g., enantioselective alkylations) have not been
employed to prepare this type of α-substituted enantiomerically
enriched methyl ketones.14 We have also developed a catalytic
method15 for direct oxidation of enantiomerically enriched
alkenyl−B(pin) products to carboxylic acids (Scheme 6).16
Enantioselective synthesis of nonsteroidal anti-inflammatory
agent (S)-naproxen was carried out on 2.0 mmol scale with 1.0
mol % of 6b, affording the acid in 75% overall yield and 95:5 er
(94% es).
The examples in Scheme 5 show that reactions of exocyclic
1,1-disubstituted allenes are efficient as well as site selective and
a
Scheme 5
We then investigated the possibility of directly using the
alkenylboron compounds in stereoselective C−C bond
formation. We selected allylic substitutions, partly because, to
the best of our knowledge, chiral nucleophiles (enantiomeri-
cally enriched or otherwise) have not been utilized in this
reaction class.17 However, our attempts to effect allylic
substitutions involving 2a with various Cu-based complexes
(achiral or chiral) led to <2% conversion (Scheme 7).
Neopentyl glycol ester 12 and the trifluoroborate 13 were
equally ineffective.
a
Same conditions used as those indicated in Table 1 and Scheme 4.
stereoselective (cf. 7a−b).10 Similar efficiency and stereo-
selectivity levels were observed with substrates with an alkyl
and a silyl substituent (cf. 8).11
We subsequently prepared the less congested boronic acid R-
14 (NaIO4, NH4OAc;18 83% yield) and determined that, with
5.0 mol % NHC−Cu complex derived from 6c, it reacts to
The alkenyl−B(pin) products are versatile, as underscored by
the transformations in Scheme 6. The first category deals with
a
Scheme 7. Catalytic Allylic Substitution Reactions
a
,b
Scheme 6. Representative Functionalization Procedures
a
See the Supporting Information for experimental and analytical
b
details. Yield values correspond to conversion of alkyl-B(pin) to
ketones or alkenyl bromides; es = enantiospecificity (product
enantiomeric excess/substrate enantiomeric excess) × 100.
a
Ar = 2,4,6-(i-Pr)3C6H2.
C
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tetrasubstituted alkenyl-B(pin), 2% of the allyl-B(pin), and 46:54 er
for the first isomer (>98% conv, 47% yield, 22:76:2 and 48:52 er with
6b).
(11) Related B(pin)-substituted allylsilanes have been accessed by
Pd-catalyzed silaborations of monosubstituted allenes. See: Ohmura,
T.; Taniguchi, H.; Suginome, M. J. Am. Chem. Soc. 2006, 128, 13682.
(12) For conversion of C−B(pin) into C−Br bonds, see: (a) Murphy,
J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434. (b)
Reference 2.
afford 1,4-diene 15 in 62% yield with 98% SN2′ selectivity and
in 96:4 dr (>98% stereoselectivity). Cross-coupling with S-14
gave anti isomer 16 with similar site selectivity and efficiency
(i.e., nearly complete catalyst control); here, 6d proved to be
the more effective ligand. By comparison, when an achiral
NHC−Cu complex, such as that derived from 17, was used, site
selectivity (76:24 SN2′:SN2) and stereoselectivity (80:20 dr)
were substantially diminished.
Development of other catalytic proto-boryl additions and
further mechanistic investigations are in progress.
(13) For the catalytic enantioselective synthesis of acyclic α,α-
disubstituted ketones, see: Pd-based catalysts: (a) Chen, J.-P.; Ding,
C.-H.; Liu, W.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc. 2010, 132,
15493 and references cited therein. Ni-based catalysts: (b) Cherney,
A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135,
7442 and references cited therein.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(14) For enzyme-catalyzed enantioselective synthesis of 2-aryl-
substituted butanones, see: Rodríguez, C.; de Gonzalo, G.; Pazmino,
̃
D. E. T.; Fraaije, M. W.; Gotor, V. Tetrahedron: Asymmetry 2009, 20,
1168.
(15) For a related dihydroxylation process, see: Le, H.; Kyne, R. E.;
Brozek, L. A.; Morken, J. P. Org. Lett. 2013, 15, 1432.
(16) For recent catalytic enantioselective synthesis of α,α-
disubstituted carboxylic acids, see: (a) Bigot, A.; Williamson, A. E.;
Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778. (b) Harvey, J. S.;
Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2011, 133, 13782. (c) Huang, Z.; Liu, Z.; Zhou, J. J. Am. Chem.
Soc. 2011, 133, 15882.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: amir.hoveyda@bc.edu.
Author Contributions
†H.J. and B.J. contributed equally.
Notes
(17) For catalytic enantioselective allylic substitutions involving
alkenyl−B(pin) compounds, see: (a) Shintani, R.; Takatsu, K.; Takeda,
M.; Hayashi, T. Angew. Chem., Int. Ed. 2011, 50, 8656. (b) Gao, F.;
Carr, J. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2012, 51, 6613.
(c) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2013,
135, 994. (d) Gao, F.; Carr, J. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2014, 136, 2149.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NSF (CHE-136273) and
the NIH (GM-47480).
(18) Wang, H.-Y.; Anderson, L. L. Org. Lett. 2013, 15, 3362.
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(9) See the Supporting Information for additional details.
(10) Reactions with allenes that contain two alkyl groups are less
efficient and proceed with low site selectivity and enantioselectivity.
For example, reaction of Me- and Cy-substituted allene proceeds to
66% conversion (41% yield), affording a 57:41 ratio of di-/
D
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