Enantio- and Diastereoselective 1,2-Additions to α-Ketoesters with Diborylmethane and Substituted 1,1-Diborylalkanes

Article abstract of DOI:10.1002/anie.201603465

The catalytic enantioselective synthesis of boronate-substituted tertiary alcohols through additions of diborylmethane and substituted 1,1-diborylalkanes to α-ketoesters is reported. The reactions are catalyzed by readily available chiral phosphine/copper(I) complexes and produce β-hydroxyboronates containing up to two contiguous stereogenic centers in up to 99:1 e.r. and greater than 20:1 d.r. The utility of the organoboron products is demonstrated through several chemoselective functionalizations. Evidence indicates the reactions occur via an enantioenriched α-boryl-copper-alkyl intermediate.

Full text of DOI:10.1002/anie.201603465

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603465
German Edition: DOI: 10.1002/ange.201603465
Enantioselectivity
Enantio- and Diastereoselective 1,2-Additions to a-Ketoesters with
Diborylmethane and Substituted 1,1-Diborylalkanes
Stephanie A. Murray+, Jacob C. Green+, Sanita B. Tailor, and Simon J. Meek*
Abstract: The catalytic enantioselective synthesis of boronate-
substituted tertiary alcohols through additions of diborylme-
thane and substituted 1,1-diborylalkanes to a-ketoesters is
reported. The reactions are catalyzed by readily available
chiral phosphine/copper(I) complexes and produce
b-hydroxyboronates containing up to two contiguous stereo-
genic centers in up to 99:1 e.r. and greater than 20:1 d.r. The
utility of the organoboron products is demonstrated through
several chemoselective functionalizations. Evidence indicates
the reactions occur via an enantioenriched a-boryl-copper-
alkyl intermediate.
preparation of secondary alcohols bearing a vicinal boron-
containing stereogenic center (Scheme 1).[5] We proposed that
a similar strategy could be employed for the synthesis of
tertiary alcohols containing 1,2-hydroxyboronates by addition
to a-ketoesters. The difficulty of such a catalytic method
ꢀ
arises from the ability to efficiently form a new C C bond
between sterically congested vicinal C(sp3) stereogenic cen-
ters.
T
ertiary alcohols are valuable functional groups found within
many biologically active organic molecules. As a result, the
development of efficient and selective methods for their
preparation is an important challenge in organic chemistry.[1,2]
The catalytic addition of sp3-carbon-based nucleophiles to
ketones provides one of the most efficient strategies to access
enantiomerically enriched tertiary alcohols.[3] Nevertheless,
despite recent progress in this area, a number of challenges
still remain to be addressed. Of particular significance are
protocols which deliver nonracemic tertiary alcohols and
incorporate chemically versatile functional groups, such as
alkyl boronic esters, for further manipulation.[4] Stereoselec-
tive synthesis of b-boryl alcohols by the 1,2-addition of
a-boryl alkyl nucleophiles provides a direct approach for the
generation of such versatile chemical motifs.[5] Catalytic
methods of incorporating boronate esters by carbon–carbon
bond-formation remain limited, as current stoichiometric
protocols involve the use of cuprate reagents[6] and alkylation
of reactive dimesityl boron stabilized a-boryl carbanions.[7]
More recently, 1,1-organodiboronate esters have been devel-
oped as a-boryl carbanions in stereoselective deborylative
carbon–carbon bond forming reactions.[8] Furthermore, cata-
lytic enantioselective reactions which employ substituted 1,1-
diborylalkanes are scarce.[5a,8d–e,h]
Scheme 1. a) Previous work: Catalytic enantio- and diastereoselective
1,2-addition of 1,1-diborylethane to aldehydes. b) This work: Catalytic
enantio- and diastereoselective 1,2-addition of 1,1-diborylmethane and
functionalized 1,1-diborylalkanes to a-ketoesters.
Herein, we report the catalytic enantio- and diastereose-
lective synthesis of b-boryl tertiary alcohols through the
copper-catalyzed additions of
a-boryl nucleophiles to a-ketoesters. The utility of the
products is illustrated through further alkyl boronate ester
functionalizations (e.g., homologation, oxidation, and iodo-
etherification). Moreover, addition to a symmetrical ketone
demonstrates the reaction occurs by the formation of a non-
racemic a-borylalkyl-copper intermediate.
We initiated our studies by evaluating the copper-cata-
lyzed enantioselective addition of unsubstituted 1,1-diboryl-
methane (5) to different a-ketoesters (4a–c; Table 1). We first
examined the ability of the chiral copper complex derived
from the commercially available monodentate L1, which had
emerged as the optimal ligand for 1,2-additions involving
aldehydes.[5] We found that, with 5 mol% [Cu(NCMe)4]PF6,
10 mol% L1, and 2.05 equivalents of LiOtBu in THF at 228C,
the reaction proceeds to afford 43% of 6a (91:9 e.r.) in
24 hours and 24% of the elimination product 7 (entry 1). At
lower temperatures formation of 7 is suppressed, and the
conversion into, and enantioselectivity of, 6a increases. For
example, 6a is generated in 92:8 e.r. and 96:4 e.r. at 4 and
ꢀ108C, respectively (entries 2 and 3).[9] As illustrated in
entry 4, the copper(I)-catalyzed reaction is less efficient at
We have shown that a-boryl/Cu species can be accessed
through stereoselective deborylative transmetalation of 1,1-
diboron compounds with copper-based catalysts. We recently
demonstrated that such catalytically generated intermediates
engage in 1,2-additions for the enantio- and diastereoselective
[*] S. A. Murray,[+] J. C. Green,[+] S. B. Tailor, Prof. S. J. Meek
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
E-mail: sjmeek@unc.edu
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603465.
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Table 1: Initial examination of chiral copper complexes.[a]
We began exploring the scope of the catalytic reaction by
synthesizing various unsubstituted hydroxyboronates.
Because of the varying stability of unsubstituted hydroxybor-
onates (e.g., 6a), the products were oxidized to the corre-
sponding diol. Isolation and non-oxidative workup of the
primary alkylboron products can be achieved through hy-
droxy protection. By using the optimal reaction conditions in
Table 1, the catalytic transformations can be performed with
various aryl-substituted a-ketoesters (Table 2), including
Table 2: Copper(I)-catalyzed 1,2-addition of 1 to aryl a-ketoesters.[a]
Entry
R
Base
T [8C]
Yield [%][b,c]
e.r.[d]
4b
6a
7
6a
1
2
3
4
Et
Et
Et
Et
tBu
Me
Et
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
NaOtBu
22
4
<2
<2
<2
35
<2
<2
18
43
60
74
51
63
70
26
37
24
12
91:9
92:8
96:4
95:5
94:6
93:7
91:9
81:19
ꢀ10
ꢀ25
ꢀ10
ꢀ10
ꢀ10
ꢀ10
<2
<2
<2
<2
8
5[e]
6
Entry
Product
6
8
e.r.[e]
Yield [%][b,c]
Yield [%][d]
7[e]
8
Et
32
<2
1
2
3
4
5
6
7
8
9
8a; Ar=Ph
74
72
80
77
62
58
76
82
81
70
43
72
65
60
64
70
46
54
63
62
64
62
27
36
96:4
85:15
97:3
92:8
94:6
97:3
96:4
96:4
97:3
96:4
66:34
97:3
[a] Reactions performed under N2 atm. [b] In all cases >98% conv. of
a-ketoester starting material. [c] Determined by 1H NMR analysis of
unpurified mixtures, with DMF as an internal standard, at either 400 or
600 MHz. [d] Determined by NaBO3·4H2O oxidation to diol and HPLC
analysis; see the Supporting Information for details. [e] One equivalent
of LiOtBu was used. DMF=N,N-dimethylformamide, THF=tetrahy-
drofuran.
8b; Ar=p-OMeC6H4
8c; Ar=p-ClC6H4
8d; Ar=p-tBuC6H4
8e; Ar=p-NO2C6H4
8 f; Ar=p-CF3C6H4
8g; Ar=m-MeC6H4
8h; Ar=m-OMeC6H4
8i; Ar=m-ClC6H4
8j; Ar=2-napthyl
8k; Ar=o-MeC6H4
8l; Ar=3-pyridyl
10
11
12
[a] Reactions performed under N2 atm. [b] In all cases >98% conv. of
a-ketoester starting material. [c] Determined by 1H NMR analysis of
unpurified mixtures, with DMF as an internal standard, at either 400 or
600 MHz. [d] Yield of the purified diol (average of two runs). [e] Deter-
mined by HPLC analysis; see the Supporting Information for details.
those which carry para (8a–f) and meta (8g–i) substituents.
Transformations with electron-donating and electron-with-
drawing groups proceed with similar 1H NMR yields (58–
82%) and high enantioselectivities (92:8–97:3 e.r.) within
24 hours at ꢀ108C. Only in the presence of p-methoxy-
substituted phenyl a-ketoesters is a diminution in enantiose-
lectivity observed. The tertiary alcohol 8b (entry 2), is formed
in 72% yield (1H NMR) and 85:15 e.r.[14] The transformation
is sensitive to sterically congested a-ketoesters as 2-naphthyl
proceeds to 70% and 96:4 e.r. (entry 10), while the ortho-
methyl-substituted tertiary alcohol 8k is generated in 43%
and 66:34 e.r. (entry 11). Synthesis of pyridyl-substituted
product 8l demonstrates that N-heterocyclic a-ketoesters can
serve as effective substrates, albeit oxidation to the corre-
sponding diol proceeds with lower efficiency (entry 12).
Access to the b-boryl substituted products 6, can be easily
achieved by protection of the tertiary alcohol as the silyl ether
product prior to purification. The conversion of 4a into 9 in
Equation (1) (TMS = trimethylsilyl) is representative. Treat-
ment of the crude product 6a (70% conv) with (Me)3SiCl and
imidazole (DMF, 228C, 14 h) affords the alkylboronate 9 in
ꢀ258C, thus furnishing 6a in 51% conversion and in 95:5
e.r.[10] Remarkably, reaction of both the tert-butyl and methyl
a-ketoesters 4b and 4c, respectively, afford 6a with similar
conversions (63% and 70%) and similar enantioselectivities
(94:6 and 93:7 e.r.). These data indicate that 1) transesterifi-
cation of 4a and 4c, or the Et and Me ester products, occurs
faster than 1,2-addition (entries 3 and 6 versus 5),[9] and
ꢀ
2) C C bond formation occurs primarily via 4b (entry 3
versus 6).[11–12] This proposal is further supported by the
reaction of 4a with one equivalent of LiOtBu (entry 7),
wherein it proceeds to greater than 98% conversion of 4a to
afford 6a (26%, 91:9 e.r.), and 4b (18%).[13] Use of NaOtBu
results in a less efficient transformation (entry 8) as 6a is
formed in 37% yield (NMR) and 81:19 e.r. Further reaction
optimization using various mono- and bidentate chiral
phosphines did not result in a more efficient or stereoselective
process (see Table 1). As there is minimal difference in
reaction efficiency between 4a–c, ethyl a-ketoesters were
used for the remainder of the study because of their ready
availability.
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to the presence of acidic a-protons.[15] Increasing the size of
the substituent proximal to the 1,1-diboron group also results
in decreased reactivity. Under optimal reaction conditions the
phenethyl-containing 11g is generated in 55% yield (4:1 d.r.,
98:2 e.r.). The lack of formation (< 5% conv) of the benzyl-
substituted 11h highlights the sensitivity of the copper-
catalyzed protocol to increased steric demand of the sub-
stituted nucleophilic components. The absolute and relative
stereochemistry of the 1,2-hydroxyboronates synthesized
through the copper-catalyzed protocol was determined by
X-ray crystallographic analysis of tertiary alcohol 11b
(Scheme 2). The stereochemical assignment of 11b is (R,R)
with an anti relationship between the hydroxy and B(pin)
units, thus corresponding to the addition of an R-alkyl copper
species to the Si face of the a-ketoester.[16]
46% overall yield and 96:4 e.r. after silica gel chromatog-
raphy.
The copper-catalyzed protocol can be extended to more
challenging processes which utilize substituted alkyl 1,1-
diboron reagents to afford congested contiguous tertiary and
secondary stereogenic centers. Reactions require 5–10 mol%
of the copper catalyst derived from either L1 or L2 at 228C to
proceed to good conversion and high enantioselectivity.
Notably, the secondary alkyl hydroxyboronate products are
stable to silica gel column chromatography. For example,
b-boryl tertiary alcohols containing silyl ether (11a), alkyl
(11b,c), and alkenyl (11d,e) functional groups are isolated in
up to 64% yield, greater than 20:1 d.r., and 99:1 e.r.
(Scheme 2). The reaction is easily performed on a gram
scale as subjection of 1.0 gram of 4a to 10b led to the
formation of 11b in 75% conversion, 60% yield, greater than
20:1 d.r., and 98:2 e.r. The reaction of a gem-diboron reagent
which contains an ester (e.g., 11 f), although remarkably
diastereo- (> 20:1 d.r.) and enantioselective (94:6 e.r.), results
in only 40%yield (1H NMR) after 24 hours and is likely due
The substituted organoboron compounds formed by the
reported catalytic reaction can be transformed to afford
a number of valuable enantio- and disastereoenriched
molecules (Scheme 3a–d). Boron oxidation of 11a delivers
Scheme 3. Representative functionalizations of a-boryl tertiary alco-
hols. TBS=tert-butyldimethylsilyl.
the trans diol 12 in 91% yield, and is equivalent to the
dihydroxylation of a stereodefined trisubstituted alkene.
While the secondary alkyl B(pin) functional groups synthe-
sized through the copper-catalyzed protocol (e.g., 13) proved
to be unsuitable reagents for palladium-catalyzed cross-
coupling,[17] they readily participate in metal-free homologa-
tions. The sterically hindered secondary alkyl B(pin) silyl
Scheme 2. Enantio- and diastereoselective addition of substituted 1,1-
diboronates to a-ketoesters. Reactions performed under N2 atm. In all
cases >98% conv. of a-ketoester starting material. The e.r. values
were determined after oxidation with NaBO3·4H2O to the diol by
HPLC analysis; see the Supporting Information for details.
[a] Cu(NCMe)4PF6 (5 mol%), L1 (10 mol%). [b] Yield determined by
1H NMR spectroscopy.
ꢀ
ether 13 (formed in 60% yield) undergoes stereospecific C B
ꢀ
to C C conversion, to afford the primary alkylboron tertiary
silyl ether 14 in 50% yield. The functional-group-rich organo-
boron molecules can also be chemoselectively functionalized
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3
ꢀ
leaving the C(sp ) B bond intact. As illustrated in Scheme 3c,
the allyl substituted hydroxyboronate 11c undergoes efficient
cross-metathesis.[18] In the presence of 10 mol% of the
ruthenium catalyst 17 and 2 equivalents of the cis-alkene 15,
the allylic alcohol 16 is formed in 63% yield and 16:1 E/Z.
Additionally, the prenyl-substituted b-boryl tertiary alcohols
can be readily converted into tetrahydropyrans by iodoether-
ification[19] without loss of the B(pin) unit. Treatment of 11d
with I2 and NaHCO3 at ꢀ358C in MeCN for 2 hours furnishes
the substituted tetrahydropyran 18 in 56% conversion and 3:1
d.r., and silica gel purification delivers 18 as a single
diastereoisomer in 45% yield.
In summary, we present the first catalytic protocol for the
enantio- and diastereoselective synthesis of b-boryl tertiary
alcohols. The approach is applicable to diboroylmethane and
other readily accessible substituted 1,1-diborylalkanes and
a-ketoesters. Reactions are promoted by a phosphine/Cu
complex and proceed by 1,2-addition of a-boryl nucleophiles
to generate up to two contiguous stereogenic centers. The
versatility of the b-boryl tertiary alcohol products synthesized
is underlined by representative stereospecific and chemo-
selective functionalizations to provide useful chemical frag-
ments. Further mechanistic studies, application to multistep
complex molecule syntheses, and the development of related
stereoselective catalytic reactions are in progress.
A proposed catalytic reaction sequence for the copper-
catalyzed process is outlined in Scheme 4. Enantioselective
Acknowledgments
Financial support was provided by the United States National
Institutes of Health, Institute of General Medical Sciences
(GM-116987) and the University of North Carolina at Chapel
Hill.
Keywords: asymmetric catalysis · boron · copper ·
enantioselectivity · reaction mechanisms
Scheme 4. Working catalytic cycle for copper-catalyzed 1,2-addition.
[1] a) Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH,
Weinheim, 2006.
[2] For recent reviews on catalytic enantioselective additions to
ketones, see: a) O. Riant, J. Hannedouche, Org. Biomol. Chem.
2007, 5, 873; b) M. Shibasaki, M. Kanai, Chem. Rev. 2008, 108,
2853 – 2873.
transmetalation between a copper alkoxide (A) and the 1,1-
diboron 1, generates the chiral a-boryl-alkyl-copper B.
Stereoselective 1,2-addition to the a-ketoester 2 affords the
copper alkoxide C, containing two contiguous stereogenic
centers. Reaction with LiOtBu furnishes the lithium alkoxide
product D, which is converted into 3 after acid workup, and
regenerates A. While the chiral phosphine/copper catalyst
controls addition of the a-boryl/Cu intermediate to the Si face
of the a-ketoester (B!C) for diborylmethane, and substi-
tuted variants, it is unclear if substituted 1,1-diborons react
through an enantioenriched (R)-a-boryl-copper-alkyl nucle-
ophile (e.g., B R = Me; Scheme 4). To gain insight into the
formation of an enantioenriched a-boryl-copper-alkyl inter-
mediate we examined the copper-catalyzed 1,2-addition of
10b to a symmetrical carbonyl electrophile [Eq. (2)]. Treat-
ment of benzophenone (19) with 10b under optimal reaction
conditions (Scheme 2; 10 mol% Cu), affords (R)-20 in 42%
yield (1H NMR) and 97:3 e.r.[20] This result indicates that the
sterocenter of the a-boryl-copper-alkyl nucleophile is formed
with a high e.r., and that the catalyst functions to control both
the formation of the copper alkyl and the facial selectivity.[21]
[3] For representative examples of catalytic enantioselective addi-
tions of sp3-carbon-based nucleophiles to ketones, see: a) C.
Garcꢀa, L. K. LaRochelle, P. J. Walsh, J. Am. Chem. Soc. 2002,
124, 10970 – 10971; b) E. F. DiMauro, M. C. Kozlowski, J. Am.
Chem. Soc. 2002, 124, 12668 – 12669; c) K. Funabashi, M.
Jachmann, M. Kanai, M. Shibasaki, Angew. Chem. Int. Ed.
2003, 42, 5489 – 5492; Angew. Chem. 2003, 115, 5647 – 5650;
d) J. M. Betancort, C. Garcꢀa, P. J. Walsh, Synlett 2004, 5, 749 –
760; e) J. Siewert, R. Sandmann, P. von Zezschwitz, Angew.
Chem. Int. Ed. 2007, 46, 7122 – 7124; Angew. Chem. 2007, 119,
7252 – 7254; f) M. Hatano, T. Miyamoto, K. Ishihara, Org. Lett.
2007, 9, 4535 – 4538; g) D. K. Friel, M. L. Snapper, A. H.
Hoveyda, J. Am. Chem. Soc. 2008, 130, 9942 – 9951; h) A. V. R.
Madduri, S. R. Harutyunyan, A. J. Minnaard, Angew. Chem. Int.
Ed. 2012, 51, 3164 – 3167; Angew. Chem. 2012, 124, 3218 – 3221;
i) J. Rong, T. Pellegrini, S. R. Harutyunyan, Chem. Eur. J. 2016,
22, 3558 – 3570.
[4] a) S. M. Winbush, W. R. Roush, Org. Lett. 2010, 12, 4344 – 4347;
b) T. P. Blaisdell, T. C. Caya, L. Zhang, A. Sanz-Marco, J. P.
Morken, J. Am. Chem. Soc. 2014, 136, 9264 – 9267; c) T. P.
Blaisdell, J. P. Morken, J. Am. Chem. Soc. 2015, 137, 8712 – 8715;
for a recent in direct approach to 1,2-hydroxyborons, see: d) D.
Chen, X. Zhang, W.-Y. Qi, B. Xu, M.-H. Xu, J. Am. Chem. Soc.
2015, 137, 5268 – 5271.
[5] a) M. V. Joannou, B. S. Moyer, S. J. Meek, J. Am. Chem. Soc.
2015, 137, 6176 – 6179; b) M. V. Joannou, B. S. Moyer, M. J.
Goldfogel, S. J. Meek, Angew. Chem. Int. Ed. 2015, 54, 14141 –
14145; Angew. Chem. 2015, 127, 14347 – 14351.
4
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Chemie
[6] a) P. Knochel, J. Am. Chem. Soc. 1990, 112, 7431 – 7433; b) M.
5 mol% [Cu(NCMe)4]PF6, and 10 mol% L1) at ꢀ108C for 2.5 h
Sakai, S. Saito, G. Kanai, A. Suzuki, N. Miyaura, Tetrahedron
1996, 52, 915 – 924.
[7] A. Pelter, S. Peverall, A. Pitchford, Tetrahedron 1996, 52, 1085 –
1094.
results in > 98% conversion of 4a but only 70% to 6.
[12] For an example of copper(I)-catalyzed transesterification, see:
C. Munro-Leighton, S. A. Delp, E. D. Blue, T. B. Gunnoe,
Organometallics 2007, 26, 1483 – 1493.
[8] a) K. Endo, T. Ohkubo, M. Hirokami, T. Shibata, J. Am. Chem.
Soc. 2010, 132, 11033 – 11035; b) K. Endo, T. Ohkubo, T. Shibata,
Org. Lett. 2011, 13, 3368 – 3371; c) K. Endo, T. Ohkubo, T.
Ishioka, T. Shibata, J. Org. Chem. 2012, 77, 4826 – 4831; d) C.
Sun, B. Potter, J. P. Morken, J. Am. Chem. Soc. 2014, 136, 6534 –
6537; e) B. Potter, A. A. Szymaniak, E. K. Edelstein, J. P.
Morken, J. Am. Chem. Soc. 2014, 136, 17918 – 17921; f) K.
Hong, X. Liu, J. P. Morken, J. Am. Chem. Soc. 2014, 136, 10581 –
10584; g) J. R. Coombs, L. Zhang, J. P. Morken, J. Am. Chem.
Soc. 2014, 136, 16140 – 16143; h) H. Y. Sun, K. Kubota, D. G.
Hall, Chem. Eur. J. 2015, 21, 1 – 10; i) J. Kim, S. Park, J. Park,
S. H. Cho, Angew. Chem. Int. Ed. 2016, 55, 1498 – 1501; Angew.
Chem. 2016, 128, 1520 – 1523; j) Y. Shi, A. H. Hoveyda, Angew.
Chem. Int. Ed. 2016, 55, 3455 – 3458; Angew. Chem. 2016, 128,
3516 – 3519; k) Z.-Q. Zhang, B. Zhang, X. Lu, J.-H. Liu, X.-Y.
Lu, B. Xiao, Y. Fu, Org. Lett. 2016, 18, 952 – 955; l) J. Park, Y.
Lee, J. Kim, S. H. Cho, Org. Lett. 2016, 18, 1210 – 1213; m) M.
Zhan, R.-Z. Li, Z.-D. Mou, C.-G. Cao, J. Liu, Y.-W. Chen, D. Niu,
ACS Catal. 2016, 6, 3381 – 3386; for recent syntheses of 1,1-
alkylbisboronate esters, see: n) Z.-Q. Zhang, C.-T. Yang, L.-J.
Liang, B. Xiao, X. Lu, J.-H. Liu, Y.-Y. Sun, T. B. Marder, Y. Fu,
Org. Lett. 2014, 16, 6342 – 6345; o) A. S. Batsanov, J. A. Cabeza,
M. G. Crestani, M. R. Fructos, P. Garcꢀa-ꢁlvarez, M. Gille, Z.
Lin, T. B. Marder, Angew. Chem. Int. Ed. 2016, 55, 4707 – 4710;
Angew. Chem. 2016, 128, 4785 – 4788; p) A. K. Cook, S. D.
Schimler, A. J. Matzger, M. S. Sanford, Science 2016, 351, 1421 –
1424; q) K. T. Smith, S. Berritt, M. Gonzꢂlez-Moreiras, S. Ahn,
M. R. Smith III, M.-H. Baik, D. J. Mindiola, Science 2016, 351,
1424 – 1427.
[13] The decreased e.r. value is likely due to reaction with LiOEt.
[14] The lower enantioselectivity of 9b is not due to partial
racemization during purification. Re-subjection of 9b to silica
column chromatography affords 9b in 85:15 e.r.
[15] Increasing the equivalents of LiOtBu or decreasing the reaction
temperature does not improve conversion into 10e.
[16] For examples of stereoretentive reactions of organocopper
alkyls, see: a) M. J. Campbell, J. S. Johnson, Org. Lett. 2007, 9,
1521 – 1524; b) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2009,
131, 3160 – 3161; c) C. Zhong, S. Kunii, Y. Kosaka, M. Sawamura,
H. Ito, J. Am. Chem. Soc. 2010, 132, 11440 – 11442; d) N.
Matsuda, K. Hirano, T. Satoh, M. Miura, J. Am. Chem. Soc. 2013,
135, 4934 – 4937; e) T. Jia, P. Cao, B. Wang, Y. Lou, X. Yin, M.
Wang, J. Liao, J. Am. Chem. Soc. 2015, 137, 13760 – 13763; f) Y.
Yang, S.-L. Shi, D. Niu, P. Liu, S. L. Buchwald, Science 2015, 349,
62 – 66; for stereoinvertive reactions of organocopper alkyls, see:
g) Ref. [16c]; h) K. M. Logan, K. B. Smith, M. K. Brown,
Angew. Chem. Int. Ed. 2015, 54, 5228 – 5231; Angew. Chem. 2015,
127, 5317 – 5320.
[17] Steric hindrance of the primary and secondary alkyl boronic
esters likely inhibits reaction.
[18] S. J. Connon, S. Blechert, Angew. Chem. Int. Ed. 2003, 42, 1900 –
1923; Angew. Chem. 2003, 115, 1944 – 1968.
[19] S. Kumar, P. Kaur, A. Mittal, P. Singh, Tetrahedron 2006, 62,
4018 – 4026.
[20] 24% unreacted benzophenone. The e.r. value was determined
by conversion into the known corresponding diol (see the
Supporting Information for details).
[21] Studies to elucidate the boron enantiotopic group-selectivity
during transmetalation are ongoing.
[9] Absolute configuration of the tertiary alcohol 6a formed with
(R)-MonoPhos is R (see the Supporting Information).
[10] Reactions run for 48 h at ꢀ258C did not lead to an increase in
yield.
[11] Treatment of 4a with 2 equivalents of LiOtBu (no Cu or L1) at
ꢀ108C for 2.5 h results in > 98% conversion of 4a and 90%
conversion to 6. Treatment of 4a with 2 equivalents of LiOtBu,
Received: April 8, 2016
Revised: May 13, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Enantioselectivity
S. A. Murray, J. C. Green, S. B. Tailor,
S. J. Meek*
&&&& — &&&&
Enantio- and Diastereoselective 1,2-
Additions to a-Ketoesters with
Diborylmethane and Substituted 1,1-
Diborylalkanes
Catalytic enantioselective synthesis of
boronate-substituted tertiary alcohols is
possible through the title reaction. The
reactions are catalyzed by chiral phos-
phine/copper(I) complexes and produce
b-hydroxyboronates containing up to two
contiguous stereogenic centers. The util-
ity of the organoboron products is dem-
onstrated through several chemoselective
functionalizations. pin=pinacolato,
TMS=trimethylsilyl.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!