Enantioselective Synthesis of Carbo- and Heterocycles through a CuH-Catalyzed Hydroalkylation Approach

Article abstract of DOI:10.1021/jacs.5b07061

The enantioselective, intramolecular hydroalkylation of halide-tethered styrenes has been achieved through a copper hydride-catalyzed process. This approach allowed for the synthesis of enantioenriched cyclobutanes, cyclopentanes, indanes, and six-membered N- and O-heterocycles. This protocol was applied to the synthesis of the commercial serotonin reuptake inhibitor (ˉ)-paroxetine.

Full text of DOI:10.1021/jacs.5b07061

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Enantioselective Synthesis of Carbo- and Heterocycles
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Yi-Ming Wang, Nicholas C. Bruno, Ángel L. Placeres, Shaolin Zhu, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
ABSTRACT: The enantioselective, intramolecular
hydroalkylation of halide-tethered styrenes has been
achieved through a copper hydride-catalyzed pro-
cess. This approach allowed for the synthesis of en-
antioenriched cyclobutanes, cyclopentanes, indanes,
and six-membered N- and O-heterocycles. This pro-
tocol was applied to the synthesis of the commercial
serotonin reuptake inhibitor (–)-paroxetine.
Our group’s recent work on copper hydride (CuH)
catalyzed enantioselective alkene hydroamination
5
suggested that hydrocupration of an olefin could
provide a general approach for the formation of an
enantioenriched organocopper species under
catalytic conditions (Figure 1). In this context, we
posited that an olefin bearing an alkyl
(pseudo)halide tether (II, Figure 2) would undergo a
formal intramolecular hydroalkylation in the
presence of a catalytically generated L*CuH species
6
The formation of carbon-carbon (C–C) bonds has
long been recognized as a central process in organic
synthesis and remains a fundamental objective in the
field. In particular, the construction of C–C bonds
(I) to furnish enantioenriched, cyclized products.
Although the analogous borocupration/ring closure
4
a-d
sequence has previously been disclosed,
competititive reduction of alkyl (pseudo)halides by
3
7
between sp centers represents a strategically
CuH
hydrocupration/ring closure process nontrivial to
execute. Nevertheless, we felt that if suitable
complexes
renders
the
proposed
important approach for the introduction of
stereochemical information. A diverse array of
catalytic and stoichiometric approaches have been
conditions could be identified, this strategy would
constitute a flexible approach for the synthesis of a
variety of 4-, 5-, and 6-membered rings, which are
featured prominently in biologically active natural
3
3
developed for the construction of C(sp )–C(sp )
1
bonds with high stereoselectivity. However, the
majority of these methods rely on the presence of
nearby reactive functional groups in the target
compound. The formation of stereochemically well-
8
products and pharmaceuticals (Figure 2). Herein,
we report the implementation of this strategy for the
enantioselective synthesis of several classes of
compounds, including substituted cyclobutanes,
cyclopentanes, indanes, and saturated heterocycles.
3
3
defined sp -sp C–C bonds in the absence of such
functional groups remains a formidable synthetic
2
challenge.
Figure 1. Hydroalkylation as a strategy for the
3
3
construction of unfunctionalized C(sp )-C(sp )
bonds.
3
The Corey–Posner–Whitesides–House reaction
between an organocuprate and alkyl halide serves as
a prototypical method for the generation of bonds
between unfunctionalized saturated carbon atoms.
Subsequent work has shown that organocopper
3c,4
species generated under catalytic conditions
similarly react with alkyl halides to form C–C bonds.
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terms of reactivity (entries 9-11). Finally, the use of
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dimethoxymethylsilane as the stoichiometric hydride
source, as well as further optimization of
concentration and temperature, allowed the desired
cyclobutane product to be obtained in high yield and
excellent enantioselectivity (entry 12).
Under these optimized conditions, we explored the
substrate scope of this copper hydride-catalyzed pro-
cess. Substrates bearing electron-poor aryl substitu-
ents reacted efficiently to provide the desired cyclo-
butane product (2c, 2g, 2h). Replacement of the me-
thyl substituent with a larger ethyl group was also
well-tolerated (2b). Substrates containing several
functional groups, including the t-butyl (2g) and
methyl (2h) esters, as well as a cis-dialkyl olefin (2e),
were also suitable substrates for the transformation.
Under these conditions, an alcohol substrate was
rapidly transformed to the corresponding silyl ether,
which underwent subsequent intramolecular hy-
droalkylation to furnish the desired cyclization
product (2f). Substrates containing heterocycles,
including a dibenzofuran (2i), a benzothiophene
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Figure 2. (A) Representative saturated 4-, 5-, and
6-membered rings found in pharmaceuticals
and natural products. (B) Proposed catalytic
cycle for the CuH-catalyzed enantioselective
hydroalkylation.
(2j), and a pyrrole (2k) also proved competent in the
We began our study by examining the reactivity of a
homoallylic methanesulfonate in the presence of a
DTBM-SEGPHOS-based copper catalyst with
diethoxymethylsilane as the hydride source (Table 1).
At the outset, we anticipated that the copper
cyclization. However, substrates containing an elec-
tron-rich aryl substituents tended to provide cycliza-
tion product in lower yields, as exemplified by the
preparation of 3,4,5-trimethoxyphenyl-substituted
11
cyclobutane 2d. Nevertheless, enantioselectivities
(
pseudo)halide species (IV, Figure 2) generated upon
C–C bond formation would be reluctant to undergo
transmetalation with the hydrosilane. We
were uniformly high (≥97% ee) in all cases examined,
1
with only one diastereomer (>20:1 dr) observed by H
NMR of the crude material. To demonstrate the
scalability of the procedure, we performed the syn-
thesis of 2g on a 4.0 mmol scale (1.30 g starting ma-
terial). The reaction proceeded at this scale without
envisioned that the use of an alkoxide base would
result in the formation of an intermediate copper
9
alkoxide species (V), which would more readily
transmetalate with hydrosilane to regenerate copper
hydride I. Thus during preliminary investigations, a
range of alkoxide bases were evaluated. Among
them, lithium methoxide was found to be uniquely
effective in promoting the desired transformation,
providing the cyclobutane product in excellent
enantioselectivity, albeit in low yield (entry 3). No
desired cyclization product was observed in the
absence of base, or when other common alkoxide
any deleterious effect on yield or enantioselectivity
12
(78% yield, 98% ee).
Table 1. Optimization of Reaction Conditions
10
bases were employed (entries 1, 2, and 4).
The effect of the leaving group was then probed in
this hydroalkylation protocol. In the presence of
additional LiOMe (4.0 eq), bromide was found to be
superior to methanesulfonate as the leaving group,
affording the desired cyclobutane product in
moderate yield and still excellent enantioselectivity
(entry 7 vs. entries 3 and 8). Our initial choice of
ligand, DTBM-SEGPHOS, was found to be superior
to other chiral bisphosphine ligands explored in
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tion conditions provided the corresponding cyclo-
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pentane product 2l in similarly high yield and enan-
tioselectivity. Notably, a highly electron-poor sub-
strate bearing a 4-trifluoromethyl-3-pyridyl substit-
uent could be used (2m), and a trifluoromethylthio
group was also tolerated (2n). As a further extension
of this process, we explored the use of substrates
with heteroatoms in the tether for the preparation of
enantioenriched, saturated heterocycles. Using this
approach, 3,4-disubstituted N-sulfonyl piperidines
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o and 2p, as well as tetrahydropyran 2r, could be
prepared in moderate to good yield and excellent
enantioselectivity. An aryl chloride functional group
was tolerated (2p), affording a product that is poten-
tially amenable to subsequent derivatization. The
connectivity and stereochemistry of 2o was deter-
mined by single crystal X-ray diffraction (Figure 3).
As expected, the relative stereochemistry (trans) was
consistent with syn-hydrocupration. The absolute
stereochemistry was consistent with the sense of ste-
reoinduction observed for the DTBM-SEGPHOS-
5a
CuH catalyzed hydroamination.
Next, we set out to explore the enantioselective syn-
thesis of other ring systems using this approach.
Subjection of a homologated substrate to the reac-
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a
Table 2. Substrate Scope
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a
Yields reported are average isolated yields of two runs (0.5 mmol scale). See the Supporting Information for detailed
experimental
procedures.
Subsequent deprotection of the sulfonyl group fur-
nished the target compound (Scheme 1). Spectro-
scopic and optical rotation data matched literature
values and further confirmed the stereochemical as-
signment based on X-ray diffraction (see the Sup-
porting Information).
Finally, we sought to expand the hydroalkylation
process to the synthesis of 1-alkylindanes through
the use of mono- and disubstituted styrenes sub-
strates bearing an alkyl bromide tethered at the or-
tho position. Indeed, subjection of 3a-3c to hydroal-
kylation conditions afforded 1-alkylindane products
with high synthetic efficiency, though enantioselec-
tivities were somewhat diminished compared to tri-
substituted alkene substrates. We note that when a
substrate containing both an alkyl chloride and bro-
mide was used, complete selectivity for cyclization at
the alkyl bromide was observed while the alkyl chlo-
ride remained inert under reaction conditions (4c).
Scheme 1. Synthesis of (–)-paroxetine
SO
N
2
Ph
H
N
1. Cu(OAc) , L
2
(
MeO)
63% yield, 99% ee
2
MeSiH, LiOMe
O
O
O
O
Br
O
O
2. SmI
2
, pyrrolidine, H
61% yield
(L = (S)-DTBM-SEGPHOS)
2
O
1
r
F
F
(−)-paroxetine
In summary, an intramolecular, enantioselective hy-
droalkylation of bromide-tethered styrenes was
achieved through a copper-catalyzed process. Cru-
cial to the success of this process was the use of lithi-
um methoxide to facilitate regeneration of the pro-
posed copper hydride species and the use of DTBM-
SEGPHOS as the supporting ligand. The method
presented here was amenable to gram-scale synthesis
and could be applied to the synthesis of the pharma-
ceutical product paroxetine. Importantly, the hy-
droalkylation process proved general to the synthesis
of several scaffolds, including cyclobutanes, cyclo-
pentanes, indanes, and saturated 6-membered het-
erocycles, all with complete diastereoselectivity and
good to excellent levels of enantioselectivity. Efforts
toward the development of an intermolecular hy-
droalkylation reaction are currently under way.
Figure 3. X-ray crystallographic structure of 2o
(
ellipsoids at 50% probability).
To demonstrate the potential applicability of this
process to the synthesis of biologically active mole-
cules, we prepared the commercial selective seroto-
nin reuptake inhibitor (–)-paroxetine in seven steps
from known starting materials. The key hydroalkyla-
tion step on bromide 1r proceeded smoothly to afford
the desired cyclization product in moderate yield
and excellent enantioselectivity as one diastereomer.
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ASSOCIATED CONTENT
Journal of the American Chemical Society
ens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (w)
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Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
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oselective C—C bond forming reactions applied to com-
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antioselective Chemical Synthesis; Academic Press: San
Diego, 2013.
Supporting Information. Experimental proce-
dures, characterization data for new compounds,
and crystallographic data for 2o (CIF). This material
is available free of charge via the Internet at
http://pubs.acs.org.
2. For examples of the enantioselective, catalytic generation
3
3
of C(sp )—C(sp ) bonds remote from reactive functional
groups, see: (a) Pino, P.; Cioni, P.; Wei, J. J. Am. Chem.
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AUTHOR INFORMATION
Corresponding Author
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* sbuchwal@mit.edu
Notes
3.
(a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89,
3
911. (b) Whitesides, G. M.; Fischer, W. P.; San Filippo, J.;
Bashe, R. W.; House, H. O. J. Am. Chem. Soc. 1969, 91,
871. For the copper-catalyzed coupling of alkyl halides
The authors declare no competing financial interest.
4
and Grignard reagents, see: (c) Fouquet, G.; Schlosser, M.
Angew. Chem. Int. Ed. Engl. 1974, 13, 82.
ACKNOWLEDGMENT
3
3
4. For the construction of C(sp )—C(sp ) bonds through
Cu-catalyzed alkene carboboration, see: (a) Ito, H.; Kosa-
ka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M. Angew.
Chem. Int. Ed. 2008, 47, 7424. (b) Ito, H.; Toyoda, T.;
Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990. (c)
Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J.
Am. Chem. Soc. 2010, 132, 11440. (d) Kubota, K.; Yamamo-
to, E.; Ito, H. J. Am. Chem. Soc. 2013, 135, 2635. (e) Yo-
shida, H.; Kageyuki, I.; Takaki, K. Org. Lett. 2013, 15, 952.
5. (a) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2013, 135, 15746. (b) Zhu, S.; Buchwald, S. L. J. Am.
Chem. Soc. 2014, 136, 15913. (c) Niljianskul, N.; Zhu, S.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2015, 54, 1638. (d).
Shi, S.; Buchwald, S. L. Nat. Chem. 2015, 7, 38. For the
independent development of a related system, see: (e)
Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem.
Int. Ed. 2013, 52, 10830. (f) Miki, Y.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2014, 16, 1498. For a CuH-catalyzed
C—C bond forming reaction resulting in the enantiose-
lective formation of indolines, see: (g) Ascic, E.; Buch-
wald, S. L. J. Am. Chem. Soc. 2015, 137, 4666.
6. Cu-catalyzed diene hydroalkylation: (a) Iwasaki, T.;
Shimizu, R.; Imanishi, R.; Kuniyasu, H.; Kambe, N. An-
gew. Chem. Int. Ed. 2015, 54, 9347. Cu-catalyzed hydroal-
kylation of alkynes: (b) Uehling, M. R.; Suess, A. M.;
Lalic, G. J. Am. Chem. Soc. 2015, 137, 1424. (c) Suess, A. M.;
Uehling, M. R.; Kaminsky, W.; Lalic, G. J. Am. Chem. Soc.
2015, 137, 7747. Pd-catalyzed intermolecular hydroalkyla-
tion: (d). Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc.
2009, 131, 18042. (e) DeLuca, R. J.; Sigman, M. S. Org. Lett.
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[60]fullerene: (f) Lu, S.; Jin, T.; Bao, M.; Yamamoto, Y. J.
Am. Chem. Soc. 2011, 133, 12842. (g) Lin, X.; Qing, F.-L.
Org. Lett. 2013, 15, 4478. Sc-catalyzed hydromethylation
of olefins: (h) Sadow, A. D.; Tilley, T. D. J. Am. Chem. Soc.
2003, 125, 7971. (i) Fontaine, F.-G.; Tilley, T. D. Organo-
metallics 2005, 24, 4340. Lewis acid catalyzed hydro-
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S.; Vol’pin, M. E.; Kursanov, D. N. J. Chem. Soc., Chem.
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Research reported in this publication was supported
by the National Institutes of Health under award no.
GM46059. The content is solely the responsibility
of the authors and does not necessarily represent
the official views of the National Institutes of
Health. Y.-M.W. thanks the National Institutes of
Health for a postdoctoral fellowship (GM112218).
Á.L.P. gratefully acknowledges the MIT Summer
Research Program. We thank Dr. Peter Mueller for
X-Ray crystallographic data and Drs. Michael Pirnot
and Aaron Sather for their advice on the preparation
of this manuscript.
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0. The use of other bases were found to be ineffective, in-
cluding LiOEt, LiOPh, NaOPh, NaO(2,6-t-Bu ),
1
2 6 3
C H
NaOBz, LiOBz, all of which provided <5% yield of the de-
sired cyclization product.
11. We attribute the poorer reactivity of electron-rich sub-
strates to a more difficult hydrocupration step. Reduc-
tion of the alkyl bromide to a terminal methyl group was
observed as the major side reaction.
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9
0
1
2
3
4
5
6
7
8
9
0
1
2. Preliminary experiments indicate that the corresponding
Z)-configured homoallylic bromides were unreactive in
the present catalyst system.
(
TOC graphic:
Het
Het
L*CuH
21 examples,
7 - 95% yield
20:1 dr
4
>
Z = -CH
-CH
-CH N(SO
2
-, -CH
OCH
R')CH
2
CH
-,
2
-,
Z
Z
Br
85 - 99% ee
2
2
R
2
2
2
-
R
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