Synthesis of enantioenriched tertiary boronic esters by the lithiation/borylation of secondary alkyl benzoates

Article abstract of DOI:10.1021/ja409100y

Simple, secondary 2,4,6-triisopropyl benzoates (TIB esters) and secondary dialkyl N,N-diisopropyl carbamates have been reported to be resistant to deprotonation by strong bases. We have found that the combination of sBuLi (1.6 equiv) and TMEDA (6 equiv) in CPME at -60 C enables deprotonation of unactivated secondary dialkyl TIB esters, but not the carbamates. These carbanions were reacted with a range of neopentyl boronic esters which, after 1,2-metalate rearrangement and oxidation, gave a range of tertiary alcohols in high yield and universally high er. Further functional group transformations of the tertiary boronic esters were demonstrated (conversion to quaternary centers, C-tertiary amines) together with application of the methodology to the synthesis of the simplest unbranched hydrocarbon bearing a quaternary center, (R)-4-ethyl-4-methyloctane, validating the synthetic utility of the methodology.

Full text of DOI:10.1021/ja409100y

Communication
pubs.acs.org/JACS
Synthesis of Enantioenriched Tertiary Boronic Esters by the
Lithiation/Borylation of Secondary Alkyl Benzoates
Alexander P. Pulis, Daniel J. Blair, Eva Torres, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
S
* Supporting Information
proton that can be removed by strong base. Without enhanced
acidity, deprotonation cannot occur, as reported by Hoppe8 and
Beak9 on simple, unactivated isopropyl substrates (Scheme 2).
ABSTRACT: Simple, secondary 2,4,6-triisopropyl benzo-
ates (TIB esters) and secondary dialkyl N,N-diisopropyl
carbamates have been reported to be resistant to
deprotonation by strong bases. We have found that the
combination of sBuLi (1.6 equiv) and TMEDA (6 equiv)
in CPME at −60 °C enables deprotonation of unactivated
secondary dialkyl TIB esters, but not the carbamates.
These carbanions were reacted with a range of neopentyl
boronic esters which, after 1,2-metalate rearrangement and
oxidation, gave a range of tertiary alcohols in high yield
and universally high er. Further functional group trans-
formations of the tertiary boronic esters were demon-
strated (conversion to quaternary centers, C-tertiary
amines) together with application of the methodology to
the synthesis of the simplest unbranched hydrocarbon
bearing a quaternary center, (R)-4-ethyl-4-methyloctane,
validating the synthetic utility of the methodology.
Scheme 2. Deprotonation of Secondary Alkyloxy Substrates
Indeed, dialkyl α-oxy carbanions that are not mesomerically
stabilized are rare in the literature and have not previously been
prepared by deprotonation. Cohen reported the reductive
lithiation of Me2C(OMe)SPh to form the corresponding α-
lithio ether,10 and the cyclopropyl-OTIB has been deprotonated,
but this case benefits from the increased acidity of cyclopropyl
protons.11 Therefore, at the outset, it seemed that a general
synthesis of all-alkyl-substituted 3° boronic esters using
lithiation/borylation methodology of unactivated 2° carbamates
or benzoates was not achievable. In this Communication, we
report our success in finding conditions for deprotonating these
extremely reluctant substrates and show that simple 2° dialkyl
alcohols can now be converted into 3° alkylboronic esters (and
therefore 3° alcohols) in very high er.
he broad use and versatility of boronic esters in organic
Tsynthesis has fueled considerable interest in the develop-
ment of asymmetric methods for their synthesis.1 Of the different
classes of boronic esters, tertiary (3°) boronic esters are the most
difficult to prepare in high enantiomeric ratio (er) since they
cannot be accessed by commonly used methods such as
hydroboration. Nevertheless, a number of synthetic methods
have been developed, the most notable being asymmetric
nucleophilic β-borylation of Michael acceptors2 and allylic
carbonates3 (Scheme 1).
We began our studies by the preparation of the 2° benzoate 1a
and carbamate 2.12 As noted above, Hoppe8 and Beak9 reported
that isopropyl carbamate and benzoate could not be deproto-
nated (Scheme 2). Beak’s conditions (sBuLi/TMEDA in THF)
were tested using a lithiation/deuteration procedure so that the
Scheme 1. Methods To Synthesize Tertiary Boronic Esters
1
degree of lithiation could be readily assessed by H NMR.
However, in keeping with the literature, we found that <10%
deprotonation of either benzoate 1a or carbamate 2 occurred
(Table 1, entries 1 and 2). Lithiation at the benzylic position was
not observed in these or any subsequent reactions.13 Solvent and
additives can play a significant role in lithiation reactions, so we
tested benzoate ester 1a under a range of conditions.
We were gratified to find that simply switching from THF to
diethyl ether immediately gave a positive result (entry 3). The
extent of lithiation was increased further upon the use of
cyclopentyl methyl ether (CPME) as the solvent and by raising
the temperature to −50 °C (entries 4 and 5) without loss of er. A
Our own contributions have included the synthesis of 3°
benzylic,4 allylic,5 silyl-substituted,6 and propargylic7 boronic
esters using the lithiation/borylation reaction of the correspond-
ing carbamates, a process that is capable of delivering 3° boronic
esters with >99:1 er (Scheme 1). This broad-ranging method-
ology, however, has a significant limitation: the secondary (2°)
carbamate from which it is derived must have a sufficiently acidic
Received: September 3, 2013
Published: October 18, 2013
© 2013 American Chemical Society
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Communication
little deuterium incorporation was observed, indicating the
superiority of the TIB ester in promoting lithiation (entry 7 vs
9).14
Table 1. Optimization of Deprotonation Conditions
Having identified the optimum conditions for lithiation, we
tested the borylation reaction with EtB(pin) 3a (Table 2, entry
1). After addition of the boronic ester at −60 °C (this gave higher
yields than at −50 °C), the reaction mixture was heated at 50 °C
for 16 h, and subsequent oxidation gave the 3° alcohol in 72%
yield and 97:3 er. The slight erosion in er was investigated but was
not found to be due to reversibility in formation of the boronate
complex as determined by the two-electrophile test.15,16
Alternative boronic esters were therefore tested, and the
neopentyl boronic ester was found to give complete retention
of stereochemistry and high yield (entry 2).
Reaction with triethylborane was also examined, and it gave
the same alcohol 4aa with high er but in lower yield than the
corresponding boronic esters (entry 3). Interestingly, the
reaction occurred with complete retention of configuration.
This contrasts with reactions of 2° benzylic carbamates, where
reactions with boronic esters occurred with retention while those
with boranes occurred with inversion.4a Evidently, in the absence
of mesomeric stabilization, Li-1a retains its tetrahedral shape,
making retention the only available pathway in reactions with
both classes of electrophiles.
a
temp
sBuLi/TMEDA
time
(h)
1a /2-D
entry
X
(°C)
solv
(equiv)
(%D)
1
2
3
4
5
6
7
8
9
TIB
Cb
−78
−78
−78
−78
−50
−50
−50
−60
−50
THF
2/2
2/2
4
4
4
4
1
1
1
2
1
10
b
Et2O
<5
c
TIB
TIB
TIB
TIB
TIB
TIB
Cb
Et2O
2/2
60
CPME
CPME
CPME
CPME
CPME
CPME
2/2
70
74
92
89
87
2/2
2/6
1.6/6
1.6/6
1.6/6
d
10
a
b
Yield of 1a-D and recovered 1a was >90%. Yield of 2-D and
recovered 2 was 33%. Results with Et2O were found to be variable,
and the number given for %D is an average of three reactions (49%,
c
d
55%, 76%). Yield of 2-D and recovered 2 was 49%.
further enhancement was observed with excess TMEDA (6
equiv, entries 6 and 7). The analogous N,N-diisopropyl
carbamate 2 was tested under these optimum conditions, but
a
Table 2. Scope and Limitations of Lithiation/Borylation Reactions of Secondary Dialkyl-Substituted TIB Esters
a
Abbreviated procedure: (i) sBuLi (1.6 equiv) was added to a solution of 1 (0.5 mmol) and TMEDA (6 equiv) in CPME (3 mL) at −60 °C and
stirred for 2 h (lithiation time). (ii) A solution of 3 (2 equiv) in CPME (0.5 mL) was added and reaction stirred for 1 h at −60 °C (ate complex
formation). (iii) The reaction was heated at 50 °C (migration temperature) for 16 h. (iv) THF (3 mL) was added, reaction cooled to 0 °C, and
premixed NaOH/H2O2 added. Determined by chiral GC, HPLC, or SFC. Isolated yield. Migration temperature 20 °C for 4 h; 6 equiv of BEt3
used. Migration temperature 70 °C. MeOH (2 equiv) was added after ate complex formation. Without MeOH, 4ac formed in 54% yield and 88:12
er. TMSCl (6 equiv) was added after ate complex formation. Without TMSCl, 4ah formed in 68% yield and 84:16 er. With MeOD (2 equiv), 4ah
formed in 34% yield and 98:2 er, along with 45% of the protodeboronation product. Lithiation time 4 h. Lithiation time 8 h. Yield brsm.
b
c
d
e
f
g
h
i
j
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Communication
A range of boronic esters were then tested to map out the
scope of the reaction. In addition to primary alkyl boronic esters
(entry 2), more hindered 2° alkyl boronic esters worked
efficiently (entry 4) as well as more functionalized boronic
esters including propanoyl (entry 5), allyl (entry 6), E- and Z-
vinyl (entries 7 and 8), phenyl (entry 9), and pyridyl boronic
esters17 (entry 10). They all delivered 3° boronic esters, which
after oxidation gave 3° alcohols in high yields and ≥98:2 er.
Initially, the use of propanoyl boronic ester 3c and pyridyl
boronic ester 3h in the lithiation/borylation/oxidation reaction
gave reduced er in the product 3° alcohols (88:12 er for 4ac and
84:16 er for 4ah) under standard conditions. However, simply
adding MeOH or TMSCl18 after ate complex formation in the
reactions with propanoyl boronic ester 3c and pyridyl boronic
ester 3h, respectively, restored the high levels of selectivity
(≥98:2 er) achieved with other substrates (entries 5 and 10). The
erosion in er was again investigated but was not found to be due
to reversibility in formation of the boronate complex as
determined by the two-electrophile test.15,19 The exact role of
the additive in promoting high selectivity remains intriguing,
especially since transformations after ate complex formation
(1,2-migration and oxidation) are expected to be stereospecific.
The scope of the TIB ester component was also examined with
a range of synthetically useful functional groups. These included
a terminal alkene (entry 11), a THP-protected alcohol (entry
12), and, to examine steric effects, an α-ethyl substituent (instead
of methyl, entry 13). These more challenging substrates required
longer deprotonation times but nevertheless delivered 3°
boronic esters and 3° alcohols in good yields and high er’s.
We wished to demonstrate the synthetic utility of the
intermediate boronic esters by conversion to other function
groups, so we converted the unstable neopentyl boronic ester
5aa to the isolable pinacol ester 6aa (Scheme 3).20 Pinacol ester
Scheme 4. Synthesis of (R)-4-Ethyl-4-methyloctane
(99%),27 which was converted into the C-tertiary amine 11 in
84% and 99:1 er upon treatment with SiCl4 and benzyl azide.28
To demonstrate the generality of the methodology, we
decided to undertake a synthesis of the archetypal chiral
molecule, (R)-4-ethyl-4-methyloctane, the simplest unbranched
hydrocarbon bearing a quaternary center (Scheme 4).29 Our
synthesis began with a Mitsunobu reaction between TIBOH and
commercially available (R)-2-pentanol 12, which gave TIB ester
1e in high yield (77%) and 98:2 er. The key step utilizing 1e and
nBuB(neo) 3i, followed by in situ transesterification with
pinacol, afforded the desired trialkyl-substituted 3° boronic
ester 6ei in 35% yield (73% brsm) and excellent er (98:2).
Although lithiation was slow,30 a considerable amount of the TIB
ester 1e was recovered, thereby improving the efficiency of the
key step. Attempts to increase the extent of lithiation by
increasing time, temperature, or stoichiometry of reagents led to
lower overall yields. Finally, Zweifel olefination21,22 (75%, 98:2
er31) and hydrogenation (65%) gave 14 in just four steps,
providing the shortest and most selective synthesis of this
archetypal chiral molecule.
In conclusion, we have developed conditions for the first time
to deprotonate unactivated secondary alkyl TIB esters lacking
groups that acidify the adjacent proton. These carbanions were
reacted with a range of neopentyl boronic esters which, after 1,2-
metalate rearrangement and oxidation, gave a range of tertiary
alcohols32 in high yield and universally high er. Such compounds
are difficult to obtain in high er using current methods. Further
functional group transformations of the hindered tertiary boronic
esters were demonstrated together with the application of the
methodology to the shortest synthesis of the simplest
unbranched hydrocarbon bearing a quaternary center. This
addition to the methodology now enables essentially any
secondary alcohol to be converted into a tertiary boronic ester
with very high er.
Scheme 3. Functional Group Transformations of Tertiary
Boronic Esters
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
6aa was homologated under modified Zweifel olefination21,22
conditions with lithiated ethyl vinyl ether to give the quaternary
α-substituted ketone 7 in 81% and 99:1 er (Scheme 3). Pinacol
ester 6aa was also reacted with (3-chloroprop-1-en-1-yl)-
lithium23 (generated via tin−lithium exchange) to form the
corresponding 2° allylic boronic ester, which was oxidized to give
allylic alcohol 8 in high yield, 99:1 er, and with 1:1 dr (as
expected).24 One-carbon homologation using bromomethyl-
lithium22,25 (generated in situ from dibromomethane and nBuLi)
gave the desired primary alcohol 9 after oxidation in 35% yield.26
Similar yields were obtained with LiCH2Cl. We also transformed
6aa into its corresponding trifluoroborate salt 10 in high yield
AUTHOR INFORMATION
Corresponding Author
v.aggarwal@bristol.ac.uk
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank EPSRC and the European Research Council (ERC)
(FP7/2007-2013, ERC grant no. 246785) for financial support.
E.T. thanks the Spanish Ministerio de Ciencia e Innovacion
(FPU fellowship).
■
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readdition, and therefore lead to higher er. It would also give 1a-D. See
ref 4b.
REFERENCES
■
(1) (a) Brown, H. C.; Singaram, B. Acc. Chem. Res. 1988, 21, 287.
(b) Hall, D. G. In Boronic Acids: Preparation, Applications in Organic
Synthesis, Medicine and Materials, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, 2011; Vols. 1 and 2. (c) Hartmann, E.; Vyas, D. J.; Oestreich,
M. Chem. Commun. 2011, 47, 7917. (d) Scott, H. K.; Aggarwal, V. K.
Chem.Eur. J. 2011, 17, 13124. (e) Matteson, D. S. J. Org. Chem. 2013,
DOI: 10.1021/jo4013942.
(2) (a) O’Brien, J. M.; Lee, K.-s.; Hoveyda, A. H. J. Am. Chem. Soc.
2010, 132, 10630. (b) Feng, X.; Yun, J. Chem.Eur. J. 2010, 16, 13609.
(c) Chen, I.-H.; Kanai, M.; Shibasaki, M. Org. Lett. 2010, 12, 4098.
(3) Guzman-Martinez, A.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132,
10634.
(4) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778. (b) Bagutski, V.; French, R. M.; Aggarwal, V. K.
Angew. Chem., Int. Ed. 2010, 49, 5142.
(5) Pulis, A. P.; Aggarwal, V. K. J. Am. Chem. Soc. 2012, 134, 7570.
(6) Aggarwal, V. K.; Binanzer, M.; Ceglie, M. C. d.; Gallanti, M.;
(16) In this case no 1a-D was observed when MeOD was added in the
two-electrophile test, and there was no improvement in er.
(17) Watson, C. G.; Aggarwal, V. K. Org. Lett. 2013, 15, 1346.
(18) The use of MeOH as an additive for pyridyl boronic ester reaction
gave increased er but also significant amounts of protodeboronation of
the intermediate 3° boronic ester. Allyl bromide was also effective at
increasing the er in pyridyl boronic ester reaction, but TMSCl was
optimal. See SI for details.
(19) In the reactions of propanoate boronic ester 3c and pyridyl
boronic ester 3h, no 1a-D was observed when MeOD was added in the
two-electrophile test, but a substantial improvement in the er was
observed for both cases. See SI for details.
(20) Direct transesterification of the neopentyl boronic ester by
pinacol alone was unsuccessful. However, using water and pinacol,
transesterification was achieved in high yield. The reaction is assumed to
occur via the boronic acid or the partially hydrolyzed neopentyl ester.
(21) (a) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. J. Am. Chem.
Soc. 1967, 89, 3652. (b) Evans, D. A.; Crawford, T. C.; Thomas, R. C.;
Walker, J. A. J. Org. Chem. 1976, 41, 3947.
(22) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier,
R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50, 3760.
́
(23) Belanger, G.; Deslongchamps, P. J. Org. Chem. 2000, 65, 7070.
(24) For related reactions of 3-chloropropenylboranes and boronic
esters, see: (a) Zweifel, G.; Horng, A.; Snow, J. T. J. Am. Chem. Soc. 1970,
92, 1427. (b) Lombardo, M.; Morganti, S.; Tozzi, M.; Trombini, C. Eur.
J. Org. Chem. 2002, 2823. (c) Carosi, L.; Hall, D. G. Angew. Chem., Int.
Ed. 2007, 46, 5913. (d) Smith, K.; Elliot, M. C.; Jones, D. H. J. Org.
Chem. 2013, 78, 9526.
(25) (a) Michnick, T. J.; Matteson, D. S. Synlett 1991, 631. (b) Elliott,
M. C.; Smith, K.; Jones, D. H.; Hussain, A.; Saleh, B. A. J. Org. Chem.
2013, 78, 3057.
(26) Using Elliot et al.’s slow addition procedure (ref 25b) and with
either the pinacol ester 6aa or the crude 3° neopentyl boronic ester 5aa,
the alcohol 9 was obtained in 30−35% yield.
(27) Bagutski, V.; Ros, A.; Aggarwal, V. K. Tetrahedron 2009, 65, 9956.
(28) (a) Matteson, D. S.; Kim, G. Y. Org. Lett. 2002, 4, 2153.
(b) Bagutski, V.; Elford, T. G.; Aggarwal, V. K. Angew. Chem., Int. Ed.
2011, 50, 1080.
(29) (a) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1980, 45, 2754.
(b) Fujita, T.; Obata, K.; Kuwahara, S.; Nakahashi, A.; Monde, K.;
Decatur, J.; Harada, H. Eur. J. Org. Chem. 2010, 6372. (c) Fujita, T.;
Obata, K.; Kuwahara, S.; Miura, N.; Nakahashi, A.; Monde, K.; Decatur,
J.; Harada, N. Tetrahedron Lett. 2007, 48, 4219. (d) Simaan, S.;
Goldberg, A. F. G.; Rosset, A.; Marek, I. Chem.Eur. J. 2010, 16, 774.
(e) Seiser, T.; Cramer, N. J. Am. Chem. Soc. 2010, 132, 5340.
(30) It is intriguing that 1e is much slower at undergoing
deprotonation than the related compound 1a bearing an aromatic
ring. The aromatic ring must play a subtle role in promoting lithiation,
by π-coordination to lithium and stabilization of either the pre-lithiation
complex or Li-1a itself. For studies of Li−π interaction, see: Monje, P.;
Paleo, M. R.; García-Río, L.; Sardina, F. J. J. Org. Chem. 2008, 73, 7394.
(31) The er of 13 was determined by chiral GC after oxidative cleavage
of the double bond to the corresponding carboxylic acid. The er of 14 is
assumed to be the same as for 13.
Glasspoole, B. W.; Kendrick, S. J. F.; Sonawane, R. P.; Vaz
A.; Webster, M. P. Org. Lett. 2011, 13, 1490.
(7) Partridge, B. M.; Chausset-Boissarie, L.; Burns, M.; Pulis, A. P.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2012, 51, 11795.
́
quez-Romero,
(8) (a) Hoppe, D.; Marr, F.; Bruggemann, M. Enantioselective
̈
Synthesis by Lithiation Adjacent to Oxygen and Electrophile
Incorporation. In Organolithiums in Enantioselective Synthesis;
Hodgson, D. M., Ed.; Springer: London, 2003; Vol. 5, p 73. For
asymmetric lithiation of primary alkyl carbamates with sBuLi/
(−)-sparteine, see: (b) Hoppe, D.; Hintze, F.; Tebben, P. Angew.
Chem., Int. Ed. Engl. 1990, 29, 1422.
(9) (a) Beak, P.; Carter, L. G. J. Org. Chem. 1981, 46, 2363. For
lithiation of primary alkyl benzoates with sBuLi/TMEDA, see: (b) Beak,
P.; Baillargeon, M.; Carter, L. G. J. Org. Chem. 1978, 43, 4255. For
asymmetric lithiation of primary alkyl benzoates with sBuLi/
(−)-sparteine, see: (c) Larouche-Gauthier, R.; Fletcher, C. J.; Couto,
I.; Aggarwal, V. K. Chem. Commun. 2011, 47, 12592.
(10) Cohen, T.; Matz, J. R. J. Am. Chem. Soc. 1980, 102, 6900.
(11) Gadwood, R. C.; Rubino, M. R.; Nagarajan, S. C.; Michel, S. T. J.
Org. Chem. 1985, 50, 3255.
(12) Secondary TIB esters were prepared from the corresponding
enantioenriched 2° alcohol by Mitsunobu reaction with HOTIB. The 2°
alcohols were prepared by asymmetric reduction of the corresponding
enone [see: (a) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.;
Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529] followed by
hydrogenation. They were also prepared by ring-opening of
commercially available enantiopure epoxides [for details, see:
(b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 1307]. For reviews on the synthesis of enantioenriched
dialkyl 2° alcohols, see: (c) Ghanem, A.; Aboul-Enein, H. Y.
Tetrahedron: Asymmetry 2004, 15, 3331. (d) Nakamura, K.;
Yamanaka, R.; Matsuda, T.; Harada, T. Tetrahedron: Asymmetry 2003,
14, 2659. (e) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226.
(f) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757. (g) Binder, C. M.;
Singaram, B. Org. Prep. Proced. Int. 2011, 43, 139.
(13) Efficient benzylic lithiation has been reported on related
substrates with one fewer atom linking the directing group and the
benzylic hydrogen (PhCH2CH2NHC(O)R) [(a) Simig, G.; Schlosser,
M. Tetrahedron Lett. 1991, 32, 1693] or two fewer atoms
(PhCH2CH2C(O)NHR) [(b) Laumer, J. M.; Kim, D. D.; Beak, P. J.
Org. Chem. 2002, 67, 6797 (c) Pippel, D. J.; Curtis, M. D.; Du, H.; Beak,
P. J. Org. Chem. 1998, 63, 2].
(32) For alternative syntheses of trialkyl 3° alcohols, see: (a) Jeon, S.-J.;
Li, H.; García, C.; LaRochelle, L. K.; Walsh, P. J. J. Org. Chem. 2005, 70,
448. (b) Teo, Y. T.; Goh, J. -D.; Loh, T. -P. Org. Lett. 2005, 7, 2743.
(c) Hatano, M.; Ishihara, K. Synthesis 2008, 1647. For reviews, see ref
́
12g and the following: (d) Ramon, D. J.; Yus, M. Alkylation of carbonyl
and imino groups.. In Science of Synthesis, Stereoselective Synthesis;
Molander, G. A., Ed.; Georg Thieme Verlag: Stuttgart, 2011; Vol. 2, pp
349−400. (e) Suga, S.; Kitamura, M. In Asymmetric 1,2-Addition of
Organometallics to Carbonyl and Imine Groups. Synthetic Methods III
Catalytic Methods: C−C Bond Formation, Comprehensive Chirality;
Yamamoto, H., Carreira, E. M., Eds.; Elsevier Science; Oxford, 2012; pp
328−342.
(14) See Supporting Information for further optimization.
(15) Reversion of the ate complex to the starting lithiated TIB ester
and boronic ester at elevated temperatures followed by racemization of
the lithiated species before readdition could cause reduced er in the
product. Addition of a second, more reactive electrophile (in this case
MeOD) after ate complex formation at −60 °C would trap any lithiated
species formed in the reverse reaction, preventing racemization and
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