Enantioselective rhodium-catalyzed arylation of cyclic N -sulfamidate alkylketimines: A new access to chiral β-alkyl-β-aryl amino alcohols

Article abstract of DOI:10.1021/ol501464e

The enantioselective rhodium-catalyzed 1,2-addition of arylboronates to cyclic N-sulfamidate alkylketimines was developed. With a rhodium/diene complex as catalyst, high enantioselectivity and broad functional group tolerance were observed. The resulting sulfamidates can easily be converted into chiral β-alkyl-β-aryl amino alcohols.

Full text of DOI:10.1021/ol501464e

Letter
pubs.acs.org/OrgLett
Enantioselective Rhodium-Catalyzed Arylation of Cyclic
N‑Sulfamidate Alkylketimines: A New Access to Chiral β‑Alkyl-β-aryl
Amino Alcohols
Ya-Jing Chen, Ya-Heng Chen, Chen-Guo Feng,* and Guo-Qiang Lin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: The enantioselective rhodium-catalyzed 1,2-
addition of arylboronates to cyclic N-sulfamidate alkylketimines
was developed. With a rhodium/diene complex as catalyst,
high enantioselectivity and broad functional group tolerance
were observed. The resulting sulfamidates can easily be
converted into chiral β-alkyl-β-aryl amino alcohols.
hiral β-amino alcohols constitute broadly useful building
1
Cblocks for the preparation of complex molecules as well
as ligands2 and auxiliaries3 for asymmetric synthesis. A variety
of methods have been developed for their asymmetric
synthesis,4 including asymmetic hydrogenation,5 asymmetric
nucleophilic addition to CN or CO double bonds,6
asymmetric aminohydroxylation,7 and catalytic asymmetric
ring-opening of epoxides.8 However, only limited success has
been achieved in the synthesis of β-alkyl-β-aryl amino alcohols,
which are the key intermediates for many bioactive molecules,
such as the opioid drug fedotozine (1)9 and β-secretase
(BACE) inhibitor (2) (Figure 1).10
butanesulfinyl arylketimines to achieve a broader substrate
scope (eq 3).10a Although the asymmetric catalytic version of
Figure 1. Representative bioactive chiral β-alkyl-β-aryl amino alcohol
derivatives.
this reaction is attractive, and the rapid development of
transition-metal-catalyzed addition of organometallic reagents
to imines affords an obvious choice to this end,14,15 the efficient
Previous synthetic methods mainly relied on a chiral auxiliary
strategy, in which reactive organomagnesium or -lithium
reagents were used in the addition to α-hydroxyl ketone
derived imines. For example, Spero and co-workers reported
the addition of phenylmagnesium bromide to hydroxyacetone-
derived chiral imine, affording the addition product in 50%
installation of such quaternary chiral centers is often quite
challenging because of the steric constraints of ketimines.15
Recently, the rhodium-catalyzed imine addition has been
greatly promoted by the introduction of chiral olefin ligands16
and reactive cyclic N-sulfonyl and N-sulfamidate imines. The
yield with 95% de (eq 1).11 Ellman and co-workers achieved
rhodium-catalyzed asymmetric alkenylation and allylation of
these cyclic imines catalyzed by rhodium/diene were achieved
improved reaction yield and similar diastereoselectivity by using
by Lam and co-workers,17 and the corresponding highly
enantioselective arylation reactions were reported by Nichi-
mura, Hayashi, and co-workers18 as well as Xu and co-
workers,19 using a rhodium/diene and rhodium/sulfur−olefin
a chiral tert-butanesulfinyl auxiliary (eq 2).12 Because of the
existence of steric hindrance and competing deprotonation at
the α-position of these ketimines, the use of arylmetallic
reagents may suffer from low reaction yields in this trans-
formation.13 Delgado, Fustero, and co-workers applied an
alternative synthetic approach, in which more reactive
alkylmagnesium bromide was used in the addition to tert-
Received: May 21, 2014
Published: June 12, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
c
entry
Ph[B]
catalyst
additive
solvent
yield (%)
ee (%)
1
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhB(OH)2 (4a1)
PhBF3K (4a2)
[RhCl(C2H4)2]2/L1
[RhCl(C2H4)2]2/L2
[RhCl(C2H4)2]2/L3
[RhCl(C2H4)2]2/L4
[RhCl(C2H4)2]2/L5
[RhCl(C2H4)2]2/L6
[RhCl(L1)]2
aq KF
aq KF
aq KF
aq KF
aq KF
aq KF
aq KF
aq KF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
11
5
92
81
2
3
13
3
−43
−39
−27
31
4
5
1
6
1
7
10
32
27
23
39
22
51
28
77
16
18
99
93
8
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
[Rh(OH)(L1)]2
91
9
92
10
11
12
13
14
15
16
17
92
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
92
89
PhBPin (4a3)
89
PhBPin (4a3)
93
PhBPin (4a3)
dioxane
dioxane
dioxane
dioxane
93
PhBPin (4a3)
92
PhBPin (4a3)
iPrOH
90
d
18
PhBPin (4a3)
MeOH
95
a
Reactions were carried out with 3a (0.1 mmol), 4a (0.2 mmol), [RhCl(C2H4)2]2 (0.0015 mmol) and chiral ligand (0.0033 mmol) or rhodium
b
complex (0.0015 mmol), and 0.2 M aq KF (0.02 mmol) or alcohol (0.4 mmol) in solvent (1 mL) at 80 °C for 24 h unless otherwise noted. Yields
were determined by H NMR spectroscopy using CH2Br2 as an internal standard. Determined by chiral HPLC analysis. Reaction time was
prolonged to 48 h. Isolated yield.
c
d
1
catalyst, respectively. Despite these advancements, most of
these reaction focused on the utilization of arylimines, and only
one single example with alkylimine was involved in Lam’s
rhodium-catalyzed allylation research.17b Inspired by our recent
success in the arylation of unstable alkylimines,20 we initiated
research on the arylation of cyclic N-sulfamidate alkylketimine
to provide a convenient access to chiral β-alkyl-β-aryl amino
alcohols.
Initially, we examined the addition of phenylboronic acid 4a1
to imine 3a in the presence of [RhCl(C2H4)2]2 and selected
ligands (Table 1). With bicyclo[3.3.0]octadiene L121 as a
ligand, the desired product was produced in high enantiose-
lectivity (92% ee) but only with 11% yield after 24 h reaction
(entry 1). The replacement of the phenyl groups on the double
bonds with two sterically more hindered 2-naphthyl groups
gave rise to the loss in not only reaction yield but also
enantioselectivity (entry 2). Chiral diene L322 bearing a
bicyclo[2.2.2]octadiene skeleton showed similar reactivity but
aroused significant loss in enantioselectivity (entry 3).
Phosphine-containing ligands, including phosphine−olefin
L4,23 bisphosphine L5, and phosphoramidite L6, gave only a
trace amount of product with low enantioselectivities (entries
4−6). As expected, the prepared rhodium complex [Rh(OH)-
(L1)]2 showed higher catalytic activity, affording a reaction
yield of 32% (entry 8). Considering the existence of the
protodeboronation,24 efforts to reduce this side reaction by
removal of base and a change of proton sources were
conducted. However, only a slightly improved reaction yield
was observed (entries 8−11), which prompted us to test more
stable arylboron reagents. To our delight, when phenylboronic
acid pinacol ester 4a3 was used, the reaction yield could be
improved to 51% (entry 13). Further reaction condition
screening revealed that dioxane was a better solvent, and a
prolonged reaction time is necessary to drive the reaction
toward completion, providing the desired product in 99%
isolated yield with 95% ee (entry 18).
Having identified optimized reaction conditions, we began to
explore the substrate scope. The results are summarized in
Scheme 1. In all cases, high enantioselectivities were observed
(92 → 99% ee). The reaction yield seemed to be sensitive to
the steric and electronic properties of both arylboronate esters
and imines and varied dramatically. While arylboronate ester
with an electron-donating group at the para position of the
phenyl ring gave moderate to excellent yields (5b−g), even the
introduction of a mild electron-withdrawing group such as Cl
or CO2Me resulted in a significant loss in reaction yield (5h−j).
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Organic Letters
Letter
uration of the product was determined by a single-crystal X-ray
analysis of enantiopure 5c as depicted in Figure 2.
Scheme 1. Reaction Scope for the Rhodium-Catalyzed
Asymmetric Arylation of Cyclic N-Sulfamidate Imines
a
Figure 2. X-ray crystal structure of product 5c.
The reaction products can easily be converted into the
corresponding chiral β-amino alcohol. For example, sulfamidate
5a was treated with LiAlH4 to afford the β-amino alcohol 6 in
quantitative yield and without any loss of optical purity (eq 5).
In summary, an enantioselective 1,2-addition of arylboronate
ester to cyclic N-sulfamidate alkylketimines was developed with
a chiral rhodium/diene complex as a catalyst. High
enantioselectivity and broad functional group tolerance were
observed in this reaction. The resulting sulfamidates can easily
be reduced, providing a convenient alternative to access
biologically interesting chiral β-alkyl-β-aryl amino alcohols.25
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
a
Reaction conditions: Reactions were carried out with 3 (0.1 mmol), 4
(0.2 mmol), [Rh(OH)(L1)]2 (0.0015 mmol), and MeOH (0.4 mmol)
AUTHOR INFORMATION
Corresponding Authors
■
in dioxane (1 mL) at 80 °C for 48 h. Yields refer to isolated product.
b
Enantiomeric excesses were determined by chiral HPLC analysis.
mmol reaction scale.
2
*E-mail: fengcg@sioc.ac.cn.
*E-mail: lingq@sioc.ac.cn.
Notes
Sterically more hindered meta-substituted boronate esters gave
moderate reaction yields (5k and 5l), but an ortho-MeO
substituted boronate ester failed to produce any observable
product (5m). Although replacing the methyl group would
increase the sterics of imine substrates and decrease their
reactivity, the reaction still proceeded to provide the desired
products in decent yields with higher enantioselectivities (5o−
t). It should be noted that a variety of functional groups could
be tolerated in this reaction, such as an alkyl bromide (5c), a
free benzyl alcohol (5h), and an ester group (5j), which may be
problematic functional groups in reactive metallic reagent
addition but are convenient handles for further functionaliza-
tion. A maintained high yield and improved enantioselectivity
(5b) were obtained with a larger reaction scale (2 mmol of 3a)
compared with a small-scale reaction. The absolute config-
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21232009, 21361162001), the Major
State Basic Research Development Program (2010CB833302),
and the Collaborative Innovation Center of Chemical Science
and Engineering (Tianjing) is acknowledged. We acknowledge
Mr. Jian-Kang Liu (SIOC) for his help in the preparation of this
manuscript.
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