Sulfinylimidates as chiral amide equivalents for irreversible, asymmetric aldol reactions

Article abstract of DOI:10.1021/ol500520h

A highly selective N-sulfinylimidate aldolization has been developed under mildly basic conditions leading to diastereopure products of high synthetic potential. The innate reversibility of this aldolization was suppressed by the use of titanium as the Lewis acid. An application of this methodology via the synthesis of a potential neurotransmitter reuptake inhibitor is illustrated.

Full text of DOI:10.1021/ol500520h

Letter
pubs.acs.org/OrgLett
Sulfinylimidates as Chiral Amide Equivalents for Irreversible,
Asymmetric Aldol Reactions
Hannah E. Bartrum, Audrey Viceriat, Sebastien Carret, and Jean-Franco̧ is Poisson*
́
́ ́ ́
Departement de Chimie Moleculaire (SERCO) UMR 5250, ICMG FR-2607, CNRS-Universite Joseph Fourier, BP 53, 38041
Grenoble Cedex 09, France
S
* Supporting Information
ABSTRACT: A highly selective N-sulfinylimidate aldolization has been
developed under mildly basic conditions leading to diastereopure products of
high synthetic potential. The innate reversibility of this aldolization was
suppressed by the use of titanium as the Lewis acid. An application of this
methodology via the synthesis of a potential neurotransmitter reuptake inhibitor is
illustrated.
tert-Butanesulfinamide, a chiral ammonia equivalent, exhibits
very high levels of diastereocontrol in the addition of a large
variety of nucleophiles to tert-butylsulfinylimines, which has led
to numerous synthetic applications.1 Conversely, the α-
functionalization of tert-butylsulfinylimines has been less
successful. Indeed, N-sulfinylaldimines are unsuitable for this
transformation due to competing autocondensation during the
deprotonation step.2 This limitation was partially overcome
using N-sulfinylimidates which undergo highly diastereoselec-
tive α-functionalization, so far limited to alkylation, Mannich-
type, and Michael addition reactions under strong basic
conditions.3 Strikingly, the obvious and much more applicable
condensation with an aldehyde has not been reported to date,
despite the potential of these compounds as chiral amide
equivalents to be complementary to e.g. chiral oxazolidinones
(Figure 1).4 The functionalized imidates produced from such a
heterocycle synthesis.7 Herein the development of a highly
diastereoselective N-sulfinylimidate aldolization under mild
conditions is reported.
Initially, the reaction of methyl (Rs)-N-tert-butylsulfinyl-2-
phenylethanimidate8 1a with benzaldehyde was studied.
Deprotonation of the imidate 1a with LiHMDS followed by
the addition of benzaldehyde at low temperature gave very low
conversion (Table 1, entry 1). Longer reaction times had no
influence on the conversion, and raising the temperature
resulted in complete recovery of the starting imidate 1a (Table
1, entry 2). A range of different bases were then employed
(KHMDS, n-BuLi, DBU, Et3N, entries 3−6), but no improve-
ment was observed. It was apparent at this stage that
development of an N-sulfinylimidate aldolization would not
be possible by simple extension of previous work.3 The innate
reversibility of the reaction and need for efficient control in the
formation of two new stereocenters render it a significant
challenge. Attempts to improve the nucleophilicity of the
metalloenamine (DMPU, Table 1, entry 7), or the electro-
philicity of the aldehyde (BF3·OEt2, Table 1, entry 8), were
unsuccessful. To prevent the reversibility of the reaction,
stabilization of the aldol product by coordination to an
oxophilic center was investigated: use of TMSOTf resulted
only in degradation (Table 1, entry 9), but when TiCl4 was
employed trace formation of the desired product was observed
(Table 1, entry 10). This titanium-promoted reaction turned
out to be very sensitive to the amine base, and significant
improvement in the efficiency of the reaction was gained by
employing a milder base (triethylamine, Table 1, entry 11).
Under these conditions the reaction proceeded with moderate
diastereoselectivity to give two diastereoisomers (out of a
potential four) in a 66% combined yield. The yield was further
improved when TiCl2(Oi-Pr)2 was utilized in the place of TiCl4
Figure 1. Context of this work.
reaction would represent versatile synthetic intermediates,
readily converted into the corresponding esters or amides.
Derivatives of this type of product are currently of significant
interest for their potential activity as selective neurotransmitter
reuptake inhibitors.5 In addition, oxidation of the N-sulfinyl
group yields N-sulfonylimidates, potentially useful pro-drugs,6
and N-deprotection gives chiral imidate intermediates used in
Received: February 18, 2014
Published: March 19, 2014
© 2014 American Chemical Society
1972
dx.doi.org/10.1021/ol500520h | Org. Lett. 2014, 16, 1972−1975

Organic Letters
Letter
a
Table 1. Initial Aldol Reaction Attempts
Table 2. Optimization of the Reaction Diastereoselectivity
b
c
a
PhCHO
(equiv)
Ti
conv
(yield)
dr (2a/
entry
base
additive (equiv)
t (°C)
−78
−78 to rt
−78 to rt
−78 to rt
rt
result
entry
1
(equiv)
solvent
THF
t (h)
2a′)
1
LiHMDS
LiHMDS
KHMDS
n-BuLi
−
−
−
−
−
−
b
f
f
f
f
f
f
4
2
18
100%
(90%)
57:43
2
NR
NR
NR
NR
NR
NR
3
2
3
3
THF
18
100%
(94%)
91:9
4
c
d
d
5
DBU
3
4
5
″
″
″
″
″
″
Et2O
1
1
1
100%
86:14
89:11
91:9
d
6
Et3N
rt
toluene
CH2Cl2
100%
100%
7
LiHMDS
LiHMDS
LiHMDS
LiHMDS
DMPU (1)
BF3·OEt2 (1.3)
TMSOTf (2)
TiCl4 (1.5)
TiCl4 (2)
TiCl2(Oi-Pr)2 (2)
−78 to rt
−78 to rt
−78 to rt
−78
(96%)
8
degradation
e
6
″
″
1.5
″
″
3
CH2Cl2
4
100%
91:9
91:9
97:3
9
degradation
f
7
CH2Cl2 2 + 1 100%
CH2Cl2 100%
(94%)
10
11
12
trace product
66%, 60:40 dr
90%, 57:43 dr
e
8
2
Et3N
0 to rt
e
Et3N
rt
a
All reactions run with 5.0 equiv of Et3N except for entry 8, which was
run with 4.0 equiv. Ti = TiCl2(Oi-Pr)2. Determined by H NMR
a
Unless otherwise indicated reactions employed 1.5 equiv of base.
20% conversion after 4 h; presumably a mixture of the four
b
c
1
b
d
analysis of the crude reaction mixture. Presence of four
c
d
diastereoisomers (4:2:2:1). 0.05 equiv and 1.5 equiv of base tested. 3
diastereoisomers in 1H NMR spectrum of the crude reaction mixture;
dr refers to major diastereoisomer/combined minor diastereoisomers.
e
f
equiv of base. 4 equiv of base. No reaction, recovery of the starting
imidate.
e
f
Reaction performed at 0 °C. Slow addition of a dichloromethane
solution of TiCl2(Oi-Pr)2 and PhCHO via syringe pump over 2 h.
(Table 1, entry 12), although the moderate diastereoselectivity
was unaltered.
toluene, or dichloromethane (complete conversion after 1 h,
Table 2, entries 3−5) than in tetrahydrofuran (complete
conversion after 18 h, Table 2, entry 2). The reaction in
dichloromethane gave the best selectivity, comparable to that of
the reaction in tetrahydrofuran. Performing the reaction at 0
°C, or undertaking a slow addition of the aldehyde/TiCl2(Oi-
Pr)2 solution, resulted in no further improvement in the
selectivity (Table 2, entries 6 and 7). Finally, the best results
were obtained in dichloromethane using a 2:1 ratio of
TiCl2(Oi-Pr)2/PhCHO (Table 2, entry 8), which resulted in
high diastereoselectivity (97:3) and enabled isolation of the
major diastereoisomer in a 94% yield. Attempts to reduce the
triethylamine, or TiCl2(Oi-Pr)2, to stoichiometic or substoi-
chiometric quantities were unsuccessful, resulting in incomplete
conversion of the starting imidate 1a.
Separation of the two crystalline diastereoisomers by column
chromatography allowed assignment of their relative config-
uration by X-ray crystallography (Figure 2).9 This analysis
The scope of the reaction was next investigated (Table 3).
Variation of the imidate8 (R1 or R2) was successfully tolerated,
and reactions with ethyl imidate 1b (R1 = Et), imidate 1c (R2 =
p-MeO-C6H4), and imidate 1d (R2 = p-F-C6H4) proceeded
with similar diastereoselectivities to those obtained with the
methyl imidate 1a to give comparable yields of the desired
products 2 (Table 3, entries 2−6). The chloroalkylsubstituted
imidate 1e (R2 = Cl) also reacted efficiently, with high
diastereoselectivity,12 although the formation of three diaster-
eoisomers was observed (Table 3, entries 4, 10, and 13). The
relative stereochemistry of 2c was secured by X-ray analysis, as
variation of the facial selectivity has been reported in the
alkylation of α-alkyl and α-chloro imidates.3b,d A range of
aldehydes were also well tolerated: reactions with aromatic
aldehydes containing electron-withdrawing or -donating groups
proceeded equally efficiently and with high diastereoselectivities
(Table 3, entries 7−14). More sterically hindered aromatic
aldehydes, bearing ortho substituents on the ring, were good
substrates (Table 3, entries 14−16) as were those bearing
halogens (Table 3, entries 17−21). Heterocyclic aldehydes
Figure 2. ORTEP of E-N-sulfinylimidate adduct 2a.
indicated that the reaction proceeded with complete control of
the face of attack of the imidate, as diastereoisomers 2a and 2a′
possess the same configuration at the center α to the CN
bond. Interestingly, the X-ray analysis also showed an E-
configuration for the sulfinylimidate, which has been shown as a
Z-isomer in previous reports.10 To the best of our knowledge,
this is the first crystal structure of a N-sulfinylimidate
derivative.11
Systematic optimization of the reaction parameters was
undertaken in order to improve the diastereocontrol of the
reaction (Table 2). The ratio of TiCl2(Oi-Pr)2 to benzaldehyde
was highly important: changing from a 1:2 to 1:1 ratio
substantially improved the diastereomeric ratio from 57:43 to
91:9 (Table 2, entries 1 and 2). Solvent screening revealed that
the transformation proceeded at a faster rate in diethyl ether,
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dx.doi.org/10.1021/ol500520h | Org. Lett. 2014, 16, 1972−1975

Organic Letters
Letter
Table 3. Scope of the Sulfinylimidate Aldolization
a
entry
1
R1
R2
R3
dr
yield
2
Me
Me
Et
Ph
Ph
Ph
Cl
Ph
Ph
Ph
Ph
Ph
Ph
97:3
97:3
97:3
93:7
96:4
95:5
96:4
96:4
97:3
94:6
>98:2
>98:2
92:8
>98:2
95:5
94:6
93:7
93:7
96:4
97:3
94:6
95:5
91:9
92:8
89:11
>98:2
>98:2
94%
92%
2a
b
2
ent-2a
2b
c
3
92%
b
cd
,
4
Me
Me
Me
Me
Me
Et
96%
91%
90%
96%
92%
97%
94%
96%
91%
96%
94%
93%
89%
91%
89%
92%
89%
90%
85%
85%
90%
84%
98%
96%
ent-2c
2d
5
6
7
p-MeO-Ph
Figure 3. Stereochemical rationalization.
p-F- Ph
Ph
2e
m-MeO-Ph
m-MeO-Ph
m-MeO-Ph
m-MeO-Ph
p-NO2-Ph
p- NO2-Ph
p- NO2-Ph
o- NO2-Ph
o-Me-Ph
o-Me-Ph
m-Br-Ph
p-Br-Ph
2f
the dideuterated analogue after 3 h. The aldol reaction of the
same imidate 1a with benzaldehyde was complete in only half
that time, strongly suggesting that the titanium facilitates
deprotonation of the imidate 1a. Assuming that 1 equiv of the
titanium is also required to activate the aldehyde, this would
explain the necessity for a 2:1 ratio of TiCl2(Oi-Pr)2 to
benzaldehyde.
In addition to its role in templating the reaction, it is of
course highly likely that the titanium remains coordinated to
the final product, preventing the retro-aldol reaction. Indeed,
treatment of the aldol product 2a with triethylamine at rt
resulted in 10% retro-aldolization, whereas treatment with DBU
or LiHMDS resulted in complete reversal of the reaction
(Scheme 1).15
b
8
Ph
ent-2f
2g
9
Ph
b
c
c
,
,
d
d
10
Me
Me
Et
Cl
ent-2h
2i
11
12
Ph
Ph
2j
b
13
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Cl
ent-2k
2l
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ph
Ph
2m
2n
p-F- Ph
Ph
2o
Ph
2p
Ph
m-F-Ph
2q
p-MeO-Ph
Ph
m-F-Ph
2r
p- F-Ph
2s
c
Ph
1-napthyl
2-furyl
2t
Scheme 1. Retroaldolization in the Presence of Strong or
Weak Base
Ph
2u
Ph
2-thiophene
PhCHCH
t-Bu
2v
Ph
2w
2x
Ph
Ph
t-Bu
2y
a
b
Yield refers to a single isolated diastereoisomer (>99:1). Ss
c
enantiomer of N-sulfinylimidate used. Yield refers to a mixture of
the diastereoisomers. Three diastereoisomers observed; major
d
diastereoisomer: combined minor diastereoisomers.
The synthesis of amine 3 was next undertaken. This
molecule (and a number of similar compounds) has recently
been patented for its potential use as a selective neuro-
transmitter reuptake inhibitor. The current synthetic method
suffers from low yields, and poor diastereoselectivities, and
access to enantiopure versions relies on optical resolution of the
racemate.5 From the diastereomerically and enantiomerically
pure product 2s (Table 3, entry 21), amine 3 was obtained in
only four steps in excellent yield (89%). Quantitative protection
of the free hydroxyl group as a triethylsilyl ether followed by
reduction gave the sulfinamide, which was N-methylated, and
the protecting groups were then removed concurrently to give
the desired amine hydrochloride 3 (Scheme 2). This novel
imidate aldol reaction can thus provide an efficient entry to a
range of compounds of this type in enantiopure form.
In summary, we have developed a mild and efficient method
for the unprecedented and challenging aldol reaction of a
variety of N-sulfinylimidates with a range of aldehydes. In most
cases, the transformation affords diastereomerically and
enantiomerically pure products 2a−y in excellent yields. This
method allows access to anti-aldol imidate derivatives
containing both α- and β-aromatic groups, which are not
readily available by other methods. Further investigations are
were also compatible with the reaction conditions in addition to
α,β-unsaturated aldehydes (Table 3, entries 23−25) and
pivaldehyde (Table 3, entries 26 and 27), but not enolizable
aldehydes.
In all cases, the same complete facial selectivity of the imidate
is observed, regardless of the α-substituent of the imidate. This
feature can be explained by the selective formation of an E-
enolate upon deprotonation of the N-sulfinylimidate with
triethylamine (with the bulky NSOt-Bu group and the R2 group
at opposite sides of the C−C bond).11 Steric shielding of the
face of the enolate occupied by the bulky tert-butylsulfinyl
group forces the reaction with the aldehyde to occur from the
opposite face.14 Given the steric repulsion between the R3
group of the aldehyde and both the R2 group of the imidate and
the OR1 group of the imidate in transition state B, it is
proposed that the reaction proceeds via transition state A,
giving the desired anti product (Figure 3). Although a complete
mechanistic understanding of the reaction is not yet possible,
some insight into the role of the titanium, which must be
important in templating the reaction, has been gained. For
example, treatment of N-sulfinylimidate 1a with triethylamine
in the presence of MeOD resulted in its complete conversion to
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dx.doi.org/10.1021/ol500520h | Org. Lett. 2014, 16, 1972−1975

Organic Letters
Letter
D. J.; Lacey, P. M.; McCarthy, M.; Saunders, C. P.; Carroll, A.-M.;
Goddard, R.; Guiry, P. J. J. Org. Chem. 2004, 69, 6572. (c) Iso, Y.;
Kozikowski, A. P. Synthesis 2006, 243. (d) Smith, T. E.; Kuo, W.-H.;
Balskus, E. P.; Bock, V. D.; Roizen, J. L.; Theberge, A. B.; Carroll, K.
A.; Kurihara, T.; Wessler, J. D. J. Org. Chem. 2008, 73, 142.
(e) Cannon, J. S.; Olson, A. C.; Overman, L. A.; Solomon, N. S. J. Org.
Chem. 2012, 77, 1961.
Scheme 2. Transformation of Aldol Product 2s into
Potential Neurotransmitter Reuptake Inhibitor 3
(8) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.
(9) Crystal data for 2a: C20H25NO3S, Mr: 359.47 g·mol−1, crystal
dimensions (mm3): 0.38 × 0.36 × 0.35, crystal system: monoclinic,
space group: P21, unit-cell dimensions and volume: a = 11.057(2) Å, b
= 7.2132(14) Å, c = 13.515(3) Å, β = 106.23(3)°, V = 1035.0(4) Å3,
ongoing to expand the scope of this transformation and will be
reported in due course.
no. of formula units in the unit cell Z = 2, calculated density rcalcd
:
1.153 mg/m3, linear absorption coefficient m: 0.173 mm−1, radiation
and wavelength: l Mo Kα = 0.71073 Å, temperature of measurement:
296.0 K, 2 Qmax 60°, no. of measured and independent reflections:
14674 and 5480 (including Friedel pairs), Rint: 0.0313, R = 0.0463, wR
= 0.1027, residual electron density: 0.305. The crystallographic
information file (CIF) has been deposited at the Cambridge
Crystallographic Data Centre as CCDC 981802. For the ORTEP of
2a and 2a′ (CCDC 981801), see the Supporting Information.
(10) Previous reports of both alkylation and Mannich-type reaction
of N-sulfinylimidates have suggested a Z-configuration; however
crystal structures of the products were not provided: see ref 3.
(11) The crystal structure of a compound derived from a Mannich
reaction of a N-sulfonylimidate reveals a similar E-configuration:
Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130,
1804.
ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization data, full experimental procedures, copies of
1H and 13C NMR spectra for all new compounds, and
crystallographic data for compounds 2a, 2a′, and 2c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jean-francois.poisson@ujf-grenoble.fr.
Notes
(12) X-ray crystallographic analysis confirmed the stereochemistry of
the major diastereoisomer 2c (CCDC 981803). The ORTEP is
included in the Supporting Information.
The authors declare no competing financial interest.
(13) It has been postulated that the α-substituent of the imidate can
influence the E/Z ratio of the corresponding enolate, and this could
explain the presence of the third diastereoisomer: see ref 3d.
(14) The observed facial selectivity is in agreement with that
previously observed for the alkylation of N-sulfinylimidates: see ref 3a.
(15) Treatment of the aldol product 2s derived from the reaction of
p-fluorobenzaldehyde with triethylamine under the same conditions
resulted in 30% retro-aldolization.
ACKNOWLEDGMENTS
■
We thank the ANR (Project Lycomet ANR-11-JS-07-006-01)
for financial support. H.E.B. acknowledges the Marie Curie
program for a postdoctoral fellowship (Project Metalk), and
A.V., the Universite de Grenoble for a PhD fellowship. Dr C.
́
Philouze (ICMG-DCM-UJF) is gratefully thanked for X-ray
analysis.
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dx.doi.org/10.1021/ol500520h | Org. Lett. 2014, 16, 1972−1975