Enantioselective α-arylation of O-carbamates via sparteine-mediated lithiation and Negishi cross-coupling

Article abstract of DOI:10.1021/acs.orglett.6b03472

A general and highly enantioselective arylation of carbamates derived from primary alcohols was developed by combining Hoppe's sparteine-mediated asymmetric lithiation with Negishi cross-coupling. Coupled with Aggarwal's lithiation-borylation sequence, the current method provides a short and divergent access to a variety of enantioenriched secondary and tertiary benzylic alcohols.

Full text of DOI:10.1021/acs.orglett.6b03472

Letter
pubs.acs.org/OrgLett
Enantioselective α‑Arylation of O‑Carbamates via Sparteine-
Mediated Lithiation and Negishi Cross-Coupling
Titouan Royal, Yann Baumgartner, and Olivier Baudoin*
University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
S
* Supporting Information
ABSTRACT: A general and highly enantioselective arylation of
carbamates derived from primary alcohols was developed by
combining Hoppe’s sparteine-mediated asymmetric lithiation with
Negishi cross-coupling. Coupled with Aggarwal’s lithiation−boryla-
tion sequence, the current method provides a short and divergent
access to a variety of enantioenriched secondary and tertiary benzylic
alcohols.
he asymmetric lithiation of carbamates derived from
aliphatic alcohols with s-BuLi and (−)-sparteine [(−)-sp]
stereoretentive Li → Zn → Pd transmetalations. The method
T
was first optimized in racemic mode using s-BuLi/TMEDA for
the lithiation step and previously reported conditions as a
starting point for the transmetalation and Negishi coupling
(Table 1).4,10,11 For the latter, p-bromoanisole was used as the
electrophile. The optimal conditions involved deprotonation
with s-BuLi and TMEDA in diethyl ether at −78 °C, followed
by transmetalation with zinc acetate, which proved superior to
zinc chloride, and Negishi coupling employing Pd2dba3/
RuPhos12 as the catalyst (3.5 mol % vs the carbamate reactant),
and gave rise to ( )-5a in 71% yield (entry 1). A 1.4-fold excess
of carbamate vs the aryl bromide was found to be optimal for
achieving good yields. Gratifyingly, the enantioselective
arylation, which involved initial deprotonation with (−)-sp
for 5 h instead of TMEDA for 1 h, under otherwise identical
conditions, furnished compound 5a in 51% yield and 98:2 er
(entry 1). Interestingly, the aminal-derived Cbx (2a)13 and Cby
(3a)14 carbamates, which were introduced by Hoppe as
efficient and removable directing groups in asymmetric
lithiations, gave improved yields and er with both TMEDA
and (−)-sp (entries 2 and 3). In addition to carbamates 1a−3a,
2,4,6-triisopropylbenzoate (TIB) 4a proved to be a competent
reaction partner with both TMEDA and (−)-sp,15 albeit with
reduced yields and er (entry 4). Finally, the aryl iodide and
triflate instead of the corresponding bromide also gave rise to
the coupling product, albeit in reduced yields (entries 5 and 6).
Moreover, the reaction of the corresponding aryl chloride was
low yielding (entry 7).
has been extensively studied by Hoppe and co-workers
(Scheme 1a).1 Upon trapping the configurationally stable
organolithium intermediate with a suitable electrophile, a
variety of highly enantioenriched secondary alcohols are
accessed. Both enantiomers of sparteine are commercially
available or readily prepared from the seeds of Lupinus albus,2
thereby making this method highly practical and versatile
despite the use of stoichiometric chiral reagent. However, to
our knowledge, the Hoppe method has been limited to
nonaromatic electrophiles. On the other hand, Campos and co-
workers have been able to combine Beak’s asymmetric
lithiation of Boc-amines3 with s-BuLi/(−)-sp with stereo-
retentive Li → Zn transmetalation and Negishi cross-coupling,4
but high enantioselectivities could be achieved only with Boc-
pyrrolidines (Scheme 1b).5 The current work demonstrates
that the combination of Hoppe’s asymmetric lithiation with
Negishi cross-coupling allows access to α-arylcarbamates with
high enantioselectivities (Scheme 1c). These products are
precursors of a great variety of enantioenriched secondary and
tertiary benzylic alcohols via Aggarwal’s lithiation−borylation
method.6 Both types of alcohols, which are traditionally
synthesized by enantioselective reduction, addition of organo-
metallics to carbonyl compounds, or enzymatic resolution,7 find
widespread use as chiral building blocks for the synthesis of
active pharmaceutical ingredients, such as the blockbuster
antidepressants fluoxetine and escitalopram8 (Scheme 1,
bottom).
The Cby carbamate and aryl bromides were thus selected as
the optimal directing group and electrophiles, respectively, for
the study of the reaction scope and limitations (Scheme 2).
First, a variety of aryl bromides were found to be compatible
with both racemic and enantioselective protocols, including
unsubstituted (7b), para- (7a,c−h), meta- (7i), ortho- (7j−k),
We set out to explore the α-arylation of diisopropylcarba-
mate (Cb) 1a (Table 1). From similar substrates and through
trapping with various nonaromatic electrophiles, Nakai, Taylor,
and co-workers had already reported that, following the
lithiation step, the Li → Zn transmetalation occurs with
retention of configuration.9 These, as well as the aforemen-
tioned literature reports on N-carbamates,4 provided us with a
sound basis for the development of a stereoretentive Negishi
coupling of O-carbamates, which would involve similar
Received: November 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03472
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Asymmetric Lithiation of Carbamates Using s-
BuLi/(−)-Sparteine and Negishi Arylation: State-of-the-Art
and Current Work
Table 1. Study of the Directing Group and Optimized
Reaction Conditions
a
b
yield (%)
c
entry
product
C(O)R
TMEDA
(−)-sp
er
1
2
3
4
5a
6a
7a
8a
7a
7a
7a
Cb
71
87
81
47
70
41
7
51
70
86
62
nd
nd
nd
98:2
99.5:0.5
99.5:0.5
92.5:7.5
nd
Cbx
Cby
TIB
Cby
Cby
Cby
d
5
e
6
f
nd
7
nd
a
Reaction conditions: (i)1a−4a (1.0 equiv), s-BuLi (1.3 equiv),
diamine (1.3 equiv), Et2O, −78 °C, 1 h (TMEDA) or 5 h [(−)-sp];
(ii) Zn(OAc)2 (1.4 equiv), −78 °C, 30 min, then 20 °C, 30 min, then
evaporation of volatiles; (iii) p-MeOC6H4Br (0.7 equiv), Pd2dba3
(1.75 mol %), RuPhos (3.5 mol %), toluene, 80 °C, 18 h. Yield of the
isolated product. Measured by HPLC using a chiral phase. p-
b
c
d
e
MeOC6H4I was used as the electrophile. p-MeOC6H4OTf was used
as the electrophile. p-MeOC6H4Cl was used as the electrophile.
f
TMEDA = N,N,N′,N′-tetramethylethylenediamine.
as well as polysubstituted (7l−n) arenes. In addition, the
Negishi coupling step was mild enough to tolerate sensitive
functional groups such as a methyl ketone (7e), nitrile (7f),
nitro (7g) and methyl ester (7h). Excellent enantioselectivities
were achieved in all cases (7a−n) with (−)-sp (7a−n) as the
diamine. In addition to bromoarenes, 3-bromopyridine reacted
successfully in both TMEDA and sp-mediated protocols (7o).
In contrast, the 2-bromo isomer failed to react in an
enantioselective reaction (7p). Other heteroaryl (e. g.,
thiophene-2-yl, furan-3-yl), alkenyl, or alkynyl electrophiles
gave low coupling yields and were not further explored. The
absolute configuration of compound 7f was determined to be R
by X-ray diffraction analysis, and the configurations of other
products were ascribed by analogy. This result is consistent
with previous work showing that the Li−Zn transmetalation
and Pd-catalyzed Negishi coupling are both stereoretentive4,9
and that the configuration of the carbamate is fixed in the initial
(−)-sp-mediated lithiation.
Next, the scope with respect to the carbamate reactant was
investigated using p-bromotoluene as the electrophile (Scheme
3). Moderate-to-very good yields were obtained for both
protocols, and excellent er were achieved using (−)-sp for
carbamates bearing a secondary carbon at the β position (7q,t−
u,w−z). Lower yields and enantioselectivities were observed
with (−)-sp for carbamates containing a more crowded tertiary
β carbon (7r−s). Since the (−)-sp-mediated lithiation of the
carbamate precursor of 7r was reported to occur with er
>97.5:2.5,16 the lower er observed for 7r,s likely arises from the
partial racemization of the corresponding organozinc or
organopalladium intermediate. A variety of useful functional
groups were tolerated, such as a benzene ring (7t,w), an olefin
(7u), a TBS-protected alcohol (7x), and a bis-benzyl-protected
amine (7z). Interestingly, bis-carbamate 7y17 also underwent
efficient enantioselective monoarylation. Importantly, as shown
with compound 7v, the reaction could be performed on a 5-fold
scale (3 mmol, 474 mg of product) and with the (+)
enantiomer of sparteine with equally good performance (74%
yield, er 99:1).
To demonstrate the versatility and utility of the current
arylation method to synthesize scalemic secondary and tertiary
alcohol building blocks, a series of reactions were performed
from both enantiomers of arylated Cby carbamate 7a by
adapting the protocols reported by Aggarwal and co-workers
with diisopropyl (Cb) carbamates (Scheme 4). A first
lithiation/borylation/oxidation sequence was performed with
HB(pin)18 from carbamate (R)-7a, obtained using (−)-sp, to
give 2° alcohol (R)-9a in good yield and enantiospecificity (es
94%).19 It is important to note that methods described by
Hoppe and co-workers to cleave the Cby group by treatment
with a metal hydride1b or with methanesulfonic acid14 failed,
presumably due to the steric hindrance and acid sensitivity,
respectively, of the current benzylic carbamate. Similarly, the
(S) enantiomer of 7a was obtained with 99:1 er using (+)-sp in
B
DOI: 10.1021/acs.orglett.6b03472
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the Racemic and Enantioselective α-
Arylation Reactions in Aryl Bromide
Scheme 3. Scope of the Racemic and Enantioselective α-
Arylation Reactions in Carbamate
a
a
a
For each product, A shows the yield obtained with TMEDA and B
shows the yield and er obtained with (−)-sp. Reaction conditions are
identical to those in Table 1 with 1.4 equiv of s-BuLi and diamine
b
c
instead of 1.3 equiv. With PhBr instead of p-TolBr. Reaction
d
performed with (+)-sp instead of (−)-sp on a 3 mmol scale. With 2
equiv of sec-BuLi/diamine.
Scheme 4. Synthesis of Enantioenriched Secondary and
Tertiary Alcohols via Aggarwal’s Lithiation−Borylation
Methods
a
For each product, A shows the yield obtained with TMEDA and B
shows the yield and er obtained with (−)-sp. Reaction conditions: see
b
Table 1. X-ray structure of 7f showing the absolute configuration
(shown with 30% probability ellipsoids, only one H atom is displayed
c
a
for clarity). Reaction performed with (+)-sp instead of (−)-sp.
Arylation reaction performed on a 3 mmol scale.
d
Reaction performed at 110 °C.
the asymmetric lithiation/Negishi coupling, which was
performed on a 3 mmol scale (542 mg of product). The
lithiation/borylation/oxidation of (S)-7a using HB(pin)
furnished (S)-9a with excellent enantiospecificity (es 96%).
Alternatively, using organoboronates EtB(pin) and PhB(pin)20
instead of pinacolborane provided (R)-configured 3° alcohols
9b,c in good yield and excellent preservation of the optical
purity (er 97:3, es 96%). It is remarkable to notice that the
configuration of 2° and 3° alcohols 9a−c is controlled by the
initial sparteine-mediated lithiation of the 1° carbamate 3a
followed by a sequence of five discrete stereospecific steps (Li−
Zn transmetalation, Negishi coupling furnishing 7a, then
lithiation, borylation, and oxidation).
In conclusion, a versatile and highly enantioselective
arylation of carbamates derived from primary alcohols was
designed by combining Hoppe’s sparteine-mediated asymmet-
ric lithiation with Negishi cross-coupling. This method, when
coupled to Aggarwal’s lithiation/borylation/oxidation sequence,
provides a concise and divergent access to enantioenriched
secondary and tertiary benzylic alcohols that complements
other enantioselective methods.
C
DOI: 10.1021/acs.orglett.6b03472
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) Deprotonation of TIBs with s-BuLi/TMEDA: (a) Beak, P.;
McKinnie, B. G. J. Am. Chem. Soc. 1977, 99, 5213. (b) Beak, P.;
Baillargeon, M.; Carter, L. G. J. Org. Chem. 1978, 43, 4255.
Deprotonation with s-BuLi/(−)-sp (c) Larouche-Gauthier, R.;
Fletcher, J. C.; Couto, I.; Aggarwal, V. K. Chem. Commun. 2011, 47,
12592.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03472.
■
S
(16) Wurthwein, E.-U.; Behrens, K.; Hoppe, D. Chem. - Eur. J. 1999,
̈
Full characterization of all new compounds, detailed
experimental procedures, and copies of NMR spectra
(PDF)
5, 3459.
(17) Paetow, M.; Ahrens, H.; Hoppe, D. Tetrahedron Lett. 1992, 33,
5323.
(18) Roesner, S.; Brown, C. A.; Mohiti, M.; Pulis, A. P.; Rasappan, R.;
Blair, D. J.; Essafi, S.; Leonori, D.; Aggarwal, V. K. Chem. Commun.
2014, 50, 4053.
(19) es = [ee (product)/ee (substrate)] × 100.
(20) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778.
X-ray crystal structure data for compound 7f (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: olivier.baudoin@unibas.ch.
ORCID
Olivier Baudoin: 0000-0002-0847-8493
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Agence National de la
Recherche (ANR-14-CE06-0001) and by the University of
Basel.
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D
DOI: 10.1021/acs.orglett.6b03472
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