Enantioselective synthesis of allylboronates bearing a tertiary or quaternary B-substituted stereogenic carbon by NHC-Cu-catalyzed substitution reactions

Article abstract of DOI:10.1021/ja104254d

Allylic substitutions that afford α-substituted allylboronates bearing B-substituted tertiary or quaternary carbon stereogenic centers are presented. C-B bond-forming reactions, catalyzed by chiral bidentate Cu-NHC complexes, are performed in the presence of commercially available bis(pinacolato)diboron. Transformations proceed in high yield (up to >98%) and site selectivity (>98% S_N2′), and in up to >99:1 enantiomer ratio. Trans- or cis-disubstituted alkenes can be used; alkyl- (linear as well as branched) and aryl-trisubstituted allylic carbonates serve as effective substrates. Allylboronates that bear a quaternary carbon center are air-stable and can be easily purified by silica gel chromatography; in contrast, secondary allylboronates cannot be purified in the same manner and are significantly less stable. Oxidation of the enantiomerically enriched products furnishes secondary or tertiary allylic alcohols, valuable small molecules that cannot be easily obtained in high enantiomeric purity by alternative synthesis or kinetic resolution approaches.

Full text of DOI:10.1021/ja104254d

Published on Web 07/15/2010
Enantioselective Synthesis of Allylboronates Bearing a Tertiary or Quaternary
B-Substituted Stereogenic Carbon by NHC-Cu-Catalyzed Substitution Reactions
Aikomari Guzman-Martinez and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received May 17, 2010; E-mail: amir.hoveyda@bc.edu
Table 1. Evaluation of Chiral NHC Complexesa
Abstract: Allylic substitutions that afford R-substituted allylboronates
bearing B-substituted tertiary or quaternary carbon stereogenic
centers are presented. C-B bond-forming reactions, catalyzed by
chiral bidentate Cu-NHC complexes, are performed in the presence
of commercially available bis(pinacolato)diboron. Transformations
proceed in high yield (up to >98%) and site selectivity (>98% SN2′),
and in up to >99:1 enantiomer ratio. Trans- or cis-disubstituted
alkenes can be used; alkyl- (linear as well as branched) and aryl-
trisubstituted allylic carbonates serve as effective substrates. Allyl-
boronates that bear a quaternary carbon center are air-stable and
can be easily purified by silica gel chromatography; in contrast,
secondary allylboronates cannot be purified in the same manner
and are significantly less stable. Oxidation of the enantiomerically
enriched products furnishes secondary or tertiary allylic alcohols,
valuable small molecules that cannot be easily obtained in high
enantiomeric purity by alternative synthesis or kinetic resolution
approaches.
Allylboronates are used as nucleophiles for additions to carbonyls
or imines and can be converted to valuable allylic alcohols or amines.1
Design of efficient catalytic protocols for enantioselective preparation
of such B-containing unsaturated molecules thus represents a compel-
ling objective in chemical synthesis. In their notable disclosure, Ito
and Sawamura outlined an enantioselective protocol for synthesis of
R-substituted allylboronates that contain a B-substituted tertiary carbon;
this was accomplished by reactions of allylic carbonates with bis(pina-
colato)diboron (1), catalyzed by a chiral copper-phosphine complex.2,3
Use of Z-allylic carbonates bearing a linear alkyl substituent was
a Reactions performed under N2 atm; >98% site selectivity in all
necessary, however, since enantioselectivity diminished substantially
with E isomers; furthermore, boronate substitution was not observed
with substrates containing a sterically hindered alkyl (e.g., cyclohexyl)
or an aryl unit. Herein, we report methods for synthesis of an
cases (e.g., <2% SN2 product). b Values determined by analysis of 400
MHz 1H NMR spectra of unpurified mixtures. c Yields of purified
products. d By GLC analysis; see the Supporting Information for details.
assortment of R-substituted allylboronates through reactions promoted
by bidentate NHC-Cu complexes developed in these laboratories (eq
1).4 Transformations proceed with 1 and various allylic carbonates,
delivering allylboronates carrying a tertiary or s for the first time s a
quaternary R carbon stereogenic center,5 in >98% site selectivity and
up to 99:1 enantiomer ratio (er). E-Disubstituted allylic carbonates as
well as trisubstituted alkyl (linear or branched) or aryl alkenes are
effective substrates. Subsequent oxidation furnishes enantiomerically
enriched carbinols,6 including tertiary allylic alcohols, valuable entities
not easily accessible by other synthesis7 or kinetic resolution strategies.8
We began by examining the reaction of an E-disubstituted alkene
in the presence of a representative set of chiral NHC-Cu complexes,
generated in situ from treatment of an imidazolinium salt with a
sodium alkoxide and Cu(OTf)2; initial screening had indicated that,
somewhat surprisingly, high reactivity and selectivity can be
obtained with the Cu(II) salt.9 Representative findings emerging
from initial catalyst screening are summarized in Table 1. Reactions
with complexes derived from bidentate hydroxyl-containing 2 or 3
are inefficient (e22% conv). In contrast, sulfonates 4a,b and 5a-c
give rise to significantly more effective catalysts: substantial
conversion (34-81%) is observed despite reactions being performed
at -30 °C (vs 22 °C for entries 1 and 2). Among the bidentate
sulfonate-NHC-Cu complexes probed, 5c, bearing a di-isopropyl-
phenyl moiety, promotes the most enantioselective transformation
(94:6 er). It should be noted that, although the reaction in the
presence of 5c proceeds to 69% conversion, the desired allylic
alcohol S-9 is isolated in 68% yield after purification (including
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C O M M U N I C A T I O N S
Table 2. NHC-Cu-Catalyzed Enantioselective Synthesis of
the follow-up oxidation procedure); the allylic substitution thus
proceeds without generating significant amounts of byproducts. As
indicated in entries 8 and 9 of Table 1, C1- or C2-symmetric
monodentate Cu complexes of 6 and 710 are relatively ineffective
catalysts (63:37 and 61:39 er, respectively).
Alkyl-Substituted Tertiary Allylboronates and Alcoholsa-d
Subsequent optimization studies indicated that use of dme (vs
thf used in Table 1) and excess amounts of NaOMe (80 vs 20 mol
% NaOt-Bu) leads to significant improvement in reaction ef-
ficiency.11 As shown in Scheme 1, under the new conditions, allylic
alcohol S-9 is isolated in 90% yield (>98% conv) and 95:5 er from
reaction of E-8; the related transformation involving Z-8 furnishes
R-9 in 94% yield and with identical enantioselectivity (95:5 er).
Cu-catalyzed allylic boronate substitutions involving substrates that
bear a ꢀ- or an R-branched alkyl substituent proceed readily; the
allylic carbonate precursor to 11 is unreactive with the previously
reported chiral copper-phosphine catalysts.2 Allylic alcohols 10
and 11 (Scheme 1) are obtained from reactions of the corresponding
E-disubstituted allylic carbonates in 71% and 93% yield and 91.5:
8.5 and 97:3 er, respectively. In all cases, none of the achiral
products derived from the SN2 mode of C-B bond formation are
detected (see below for more details regarding this selectivity issue).
a-d See Table 1. e Enantioselectivity does not improve at -30 °C.
alkenes as well (see S-9, 10, and 11, Scheme 1). In further contrast
to the less substituted alkenes, reactions of Z-trisubstituted allylic
carbonates are less efficient and relatively nonselective. As an
example, when the Z isomer of the substrate in entry 1 of Table 2
is used with the Cu complex of 4a under the conditions shown in
Table 2, (+)-linalool is isolated in 88% yield (>98% conv at 22
°C) and 76:24 er (vs >98% conv, 97% yield, and 95:5 er with the
E isomer in entry 1 of Table 2).
Scheme 1. NHC-Cu-Catalyzed Boronate Additions to Disubstituted
Allylic Carbonatesa
Transformations of aryl-substituted alkenes, which pose a
noteworthy mechanistic question, were subsequently investigated.
We have reported that NHC-Cu complexes in the presence of
B2(pin)2 promote boron-copper additions with disubstituted aryl
olefins (vs those in Table 1 and Scheme 1) with high site selectivity,
affording benzylic C-Cu bonds exclusively (I, Figure 1). Reaction
of an allylic carbonate (R ) CH2OCO2Me in I), bearing a
disubstituted olefin, was found to afford only a homobenzylic C-B
bond (>98% R to C-O).14 Such preferences were attributed to the
stabilization of the developing electron density at the carbon of
the benzylic C-Cu bond (I). The above considerations offer a
rationale for the site selectivity in NHC-Cu-catalyzed reactions of
alkyl-substituted carbonates discussed above: the intermediate
C-Cu is likely stabilized by the adjacent C-O. With an aryl-
containing trisubstituted allylic carbonate, C-Cu bond formation
may be electronically favored at either the benzylic or the
homobenzylic position (stabilization by aryl group or C-O,
respectively). Partial positive charge developed at the site of the
C-B bond formation, however, should be better accommodated at
the more substituted benzylic carbon (II) and disfavored adjacent
to the electron-withdrawing carbonate, thus culminating in site-
selective allylic substitution.15
a All >98% conversion by analysis of 400 MHz 1H NMR spectra of
unpurified mixtures; >98% SN2′ in all cases. Er determined by GLC analysis
(see the SI for details).
With an effective procedure for reactions of E- and Z-disubsti-
tuted allylic carbonates established, we turned to the more chal-
lenging issue of enantioselective synthesis of allylboronates with
an R B-substituted quaternary carbon stereogenic center. The
findings summarized in Table 2 illustrate that, in the presence of
6.0 mol % chiral imidazolinium salt 4a, alkyl-bearing trisubstituted
allylic carbonates, including those that contain a sterically hindered
substituent (e.g., entry 7), efficiently undergo reaction to afford the
derived allylboronates in up to 98:2 er (86 to >98% conv, 81-97%
yield of tertiary allylic alcohol).12 Preliminary studies indicated that
the reaction in entry 1 of Table 2 in the presence of 5c (22 °C),
used in the case of disubstituted alkenes,13 affords the desired
product with somewhat lower enantioselectivity (89:11 er vs 95:5
er with 4a).
Reaction rates and enantioselectivities can be sensitive to
substrate structure. The more facile processes can be performed at
-30 °C so that higher er values can be achieved; the representative
comparison in entries 1 and 2, where (-)-linalool can be obtained
in 82% yield and 97:3 er, illustrate this point. The lowest er value
(81:19 er in entry 6, Table 2) corresponds to a substrate that contains
a ꢀ-branched alkyl, a trend observed with reactions of disubstituted
Figure 1. Effect of alkene substitution on selectivity of Cu-B addition to
an aryl alkene.
As the data in Table 3 indicate, in sharp contrast to their
disubstituted counterparts,13 aryl-containing carbonates containing
a trisubstituted alkene undergo Cu-catalyzed boronate substitution
with the opposite sense of site selectivity, in favor of benzylic C-B
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C O M M U N I C A T I O N S
Table 3. NHC-Cu-Catalyzed Enantioselective Synthesis of
Scheme 2. Stability of Enantiomerically Enriched Allyl Boronates
Aryl-Substituted Tertiary Allylboronates and Alcoholsa-d
entry
aryl
temp (°C)
conv (%)b
R:ꢀb
yield (%)c
erd
1
2
3
4
5
6
7
8
Ph
22
22
22
22
22
-30
-30
22
>98
>98
>98
86
>98
86
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
95
91
96
84
88
77
72
90:10e
94.5:5.5e
99:1
99:1
98:2
Identification of effective catalysts that promote reactions of sterically
congested allylboronates (e.g., 14 and 15) to a wide range of
electrophilic substrates and introduction of effective procedures leading
to efficient and stereoselective conversion of hindered C-B to C-N19
and C-C bonds are among such challenges. Investigations along these
lines, mechanistic studies, development of more effective chiral
catalysts, and application of the NHC-Cu-catalyzed C-B bond
formation to other substrate classes are in progress.
1-naphthyl
o-ClC6H4
o-BrC6H4
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-CF3C6H4
93:7
92:8
74
<2
a-d See Table 1. e Enantioselectivity does not improve at -30 °C.
Acknowledgment. Support was provided by the NSF (CHE-
0715138). A.G.-M. is an NIH Postdoctoral Fellow (GM-47480).
We are grateful to B. Maybury-Lewis for experimental assistance
and to Frontier, Inc. for gifts of reagent 1. Mass spectrometry
facilities at Boston College are supported by the NSF (DBI-
0619576).
bond. Reactions afford the corresponding tertiary allylic alcohols
(after oxidative workup) with >98% site selectivity and 72-96%
yield. The desired allylboronates can be obtained in 90:10-99:1
er, with the highest selectivities being observed with the more
sterically demanding aryl units; lower temperature can lead to
improved enantioselectivity (entries 6 and 7 >98% conv and 89:11
er for both cases at 22 °C). The lack of reactivity with p-
trifluoromethyl substrate (entry 8) supports the aforementioned
scenario (cf. II, Figure 1); reaction via I could be energetically
inaccessible, or MeOH may be required for effective turnover with
such a mode of addition.13
Supporting Information Available: Experimental procedures and
spectral and analytical data for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
A limitation of the present class of reactions is worthy of note.
Cu-catalyzed reaction of Et-substituted alkene 12 (eq 2) delivers
13 in 62% yield and 80:20 er. Particularly noteworthy is that the
reaction leads to s unlike all previous cases s the formation of the
primary C-B bond (20% SN2 addition). Generation of the achiral
byproduct suggests the intermediacy of π-allylcopper complexes
in reactions promoted by boronate-containing NHC-cuprates (vs
neutral copper boronates) and, at least in certain instances, the
intermediacy of Cu(III) complex (oxidative addition), followed by
B-alkyl reductive elimination (vs Cu-B addition to the alkene
proposed for neutral Cu complexes2). The above findings point to
the need for still more effective chiral catalysts for transformations
of highly congested alkenes.
(1) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany, 2000.
(2) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem.
Soc. 2007, 129, 14856.
(3) For catalytic enantioselective synthesis of R-substituted allyl boronates (tertiary
C-B), see: (a) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 9308. (b)
Pelz, N. F.; Woodward, A. R.; Burks, H. E.; Sieber, J. D.; Morken, J. P. J. Am.
Chem. Soc. 2004, 126, 16328. (c) Gerdin, M.; Moberg, C. AdV. Synth. Catal.
2005, 347, 749. (d) Carosi, L.; Hall, D. G. Angew. Chem., Int. Ed. 2007,
46, 5913. (e) Peng, F.; Hall, D. G. Tetrahedron Lett. 2007, 48, 3305. For
related auxiliary-based methods, see: (f) Fang, G. Y.; Aggarwal, V. K. Angew.
Chem., Int. Ed. 2007, 46, 359, and references cited therein.
(4) For example, see: (a) Larsen, A. O.; Leu, W.; Oberhuber, C. N.; Campbell,
J. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130. (b) Van
Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 6877. (c) Brown, M. K.; May, T. L.; Baxter, C. A.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 1097. (d) May, T. L.;
Brown, M. K.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2008, 47, 7358. (e)
Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 12904.
(5) To the best of our knowledge, there is only a limited number of reported
examples involving a chiral, enantiomerically enriched substrate (non-
catalytic) for enantioselective synthesis of an R-substituted allyl boronate
with a quaternary carbon stereogenic center. See: (a) Stymiest, J. L.;
Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778. (b)
Bagutski, V.; Ros, A.; Aggarwal, V. K. Tetrahedron 2009, 65, 9956.
(6) For representative recent catalytic enantioselective protocols that afford
secondary allylic alcohols, see: (a) Tomita, D.; Wada, R.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 4138. (b) Kirsch, S. F.;
Overman, L. E. J. Am. Chem. Soc. 2005, 127, 2866. (c) Lyothier, I.;
Defieber, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2006, 45, 6204. For
additional cases, see the Supporting Information.
Unlike the less substituted tertiary derivatives, allylic carbonates
with a B-substituted quaternary carbon are sufficiently robust to
be purified by silica gel chromatography. Alkyl- or aryl-substituted
quaternary allylboronates can be obtained in high yields and er
(Scheme 2). Such stability is likely the result of steric congestion
at the B center, rendering it less susceptible to nucleophilic attack.
Nonetheless, quaternary carbon-containing allyl boronates obtained
by the present protocol do serve as nucleophilic reagents. Treatment
of 14 with benzaldehyde (22 °C) affords the desired homoallylic
alcohol in 98% yield and 97:3 er but as an equal mixture of alkene
isomers (improvement not observed at -78 °C).
We put forth protocols for enantioselective synthesis of allyl
boronates and allylic alcohols that were not easily attainable
previously16 and further underline the special utility of sulfonate-
bearing NHC-Cu catalysts.17 These studies, and a small number of
other disclosures,18 underline the need for certain future developments.
(7) For example, see: (a) Uenishi, J.; Kubo, Y. Tetrahedron Lett. 1994, 35,
6697. (b) Wu, Y.-K.; Liu, H.-J.; Zhu, J.-L. Synlett 2008, 621. A tertiary
allylic alcohol has been prepared by Cu-catalyzed enantioselective vinyl
addition to an R-ketoester. See ref 6a.
(8) Tertiary allylic alcohols cannot be effectively resolved through Ti-catalyzed
epoxidation: Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: Weinheim, Germany, 1993; p 103.
(9) For details of Cu screening, see the Supporting Information. It is noteworthy
that a Cu(II) salt is reduced to the catalytic active Cu(I) complex by 1. All
previous Cu-catalyzed C-B bond-forming reactions involve use of a Cu(I)
salt (e.g., refs 2, 13, and 18b). Related mechanistic details will be discussed
in the full account of this work.
(10) For use of C1-symmetric chiral NHC-Cu complexes in enantioselective
synthesis, see: (a) Lee, K-s.; Hoveyda, A. H. J. Org. Chem. 2009, 74, 4455.
(b) Lee, K-s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 2898.
(11) The exact reason for improvement in reaction efficiency due to use of larger
excess of NaOMe is not clear, but may be partly the result of more efficient
imidazolinium salt deprotonation and Cu-NHC complex formation.
(12) The stereochemical outcome of reactions in Table 2 (determined on the
basis of formation of (-)-linalool in entry 1) differs from E-disubstituted
9
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alkenes (see Scheme 1). The origin of this difference is difficult to establish
in the absence of mechanistic data (identity of turnover-limiting step).
(13) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160.
(14) When alkyl-containing (vs aryl) disubstituted olefins are subjected to Cu-
NHC-catalyzed boron-copper additions (in the presence of MeOH), <2%
hydroboration product is generated. See ref 13.
(15) It is possible that boron-copper addition is reversible and only when mode
of addition II occurs, copper-alkoxide elimination leads to the formation
of the allylic substitution product. Studies carried out with products from
additions to alkynes suggest that the boron-copper addition process is
largely irreversible (Lee, Y.; Hoveyda, A. H., unpublished results); similar
investigations corresponding to alkene substrates are in progress.
(16) Reactions with the less air-sensitive Cu(OAc)2 ·H2O, although at times less
efficient, deliver similar enantioselectivities. For example, 9 and the product
from the reaction in entry 3 of Table 2 are obtained in 52% yield, 94:6 er
and 96% yield, 97:3 er, respectively, with the latter Cu salt.
(17) For another example, see: Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown,
M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 446.
(18) (a) Lee, K-s.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009,
131, 7253. (b) Chen, I.-H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 11664.
(19) Primary or secondary benzylic C-B bonds have been converted to C-N
bonds. For representative cases, see: Fernandez, E.; Maeda, K.; Hooper,
M. W.; Brown, J. M. Chem.sEur. J. 2000, 6, 1840. However, application
of such procedures to compounds bearing a B-substituted quaternary carbon
has not been disclosed.
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