Design and synthesis of chiral oxathiozinone scaffolds: Efficient synthesis of hindered enantiopure sulfinamides and sulfinyl ketimines

Article abstract of DOI:10.1002/anie.201301676

Is that S-O? The title scaffolds have a highly active and properly differentiated S-O bond for the efficient synthesis of enantiopure sulfinamides. The method is practical, green, and has the potential to provide an economical commercial process for the synthesis of bulky sulfinamides. Copyright

Full text of DOI:10.1002/anie.201301676

Angewandte
Chemie
DOI: 10.1002/anie.201301676
Synthetic Methods
Design and Synthesis of Chiral Oxathiozinone Scaffolds: Efficient
Synthesis of Hindered Enantiopure Sulfinamides and Sulfinyl
Ketimines
Zhengxu S. Han,* Melissa A. Herbage, Hari P. R. Mangunuru, Yibo Xu, Li Zhang,
Jonathan T. Reeves, Joshua D. Sieber, Zhibin Li, Philomen DeCroos, Yongda Zhang,
Guisheng Li, Ning Li, Shengli Ma, Nelu Grinberg, Xiaojun Wang, Navneet Goyal,
Dhileep Krishnamurthy, Bruce Lu, Jinhua J. Song, Guijun Wang, and Chris H. Senanayake
Chiral-sulfinamide-mediated (1; see Scheme 1) chemistry has
become one of the most employed approaches for the
synthesis of compounds containing chiral amine functional-
ities.[1] Moreover, their utility has been extended to being used
as chiral ligands for many catalytic asymmetric transforma-
tions.[2] Although the potential of chiral sulfinamides has long
been recognized, only a few methods have been developed for
their synthesis. Among the prominent works are the method
reported by Davis et al.[3a] for the synthesis of p-toluenesul-
finamide (pTSA) from Andersonꢀs reagent, the method
reported by Ellman and co-workers[3b] for the synthesis of
tert-butanesulfinamide (tBSA) from tert-butyl tert-butane-
thiosulfinate, and others.[3c–e] However, these methods cannot
meet the demand for accessing sulfinamides with diverse
structures, which are required to fine-tune stereoselectivities
in asymmetric synthesis. To meet this need, soon after the
report from the group of Ellman, we designed and developed
a versatile cyclic-oxathiozolidinone-based chiral sulfinyl-
transfer agents which provide access to a range of sulfin-
amides with diverse structures (Scheme 1).[4]
The success of this method hinged on the recognition that
the reactivity of the cyclic oxathiozolidinone 2 could be
activated by an electron-withdrawing substituent on the
nitrogen atom (3), thus allowing for the facile cleavage of
Scheme 1. Approaches for the synthesis of sulfinamides. Ts=4-
toluenesulfonamide.
ꢀ
the S N bond to provide the desired sulfinate intermediate
4.[4a] However the reaction conditions required for the
ꢀ
cleavage of the S O bond in 4 to liberate the desired
sulfinamides relied heavily on the steric bulk of the R sub-
sulfinamides, in the case of hindered substrates [e.g. R = tBu
or triisopropylphenyl (TIPP)], the use of excess NH2Li/NH3
(Li/NH3) was required to incorporate the amino group.
Currently, NH2Li/NH3 is prepared in situ by portionwise
addition of a large excess of solid Li metal to anhydrous NH3
at reaction temperatures of less than ꢀ708C.[4] These reaction
conditions, in addition to the safe handling and disposal of
waste generated by using NH2Li/NH3, have limited our ability
to produce these important sulfinamides on large scale.
Therefore, the efficient and practical synthesis of sterically
hindered sulfinamides remained an unsolved problem in the
field.
stituent.[4c] While the S O bond could be readily cleaved with
LHMDS at 08C to room temperature to generate some
ꢀ
[*] Dr. Z. S. Han, Dr. M. A. Herbage, Y. Xu, L. Zhang, Dr. J. T. Reeves,
Dr. J. D. Sieber, Dr. Z. Li, Dr. P. DeCroos, Dr. Y. Zhang, Dr. G. Li, N. Li,
Dr. S. Ma, Dr. N. Grinberg, Dr. X. Wang, Dr. N. Goyal,
Dr. D. Krishnamurthy, Dr. B. Lu, Dr. J. J. Song, Dr. C. H. Senanayake
Department of Chemical Development
Boehringer Ingelheim Pharmaceuticals Inc.
900 Old Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877 (USA)
E-mail: steve.han@boehringer-ingelheim.com
H. P. R. Mangunuru, Dr. G. Wang
Considering that the steric environment provided by the
bulky alkyl (e.g. tBu) or aryl (e.g. TIPP) substituents of the
sulfinamides is critical for obtaining high stereoselectivi-
ties,[6,7] it was highly desirable to develop a more practical and
cost-effective process for their synthesis by replacing NH2Li/
Department of Chemistry and Biochemistry
Old Dominion University
4541 Hampton Boulevard, Norfolk, VA 23529-0126 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301676.
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Table 2: Conditions surveyed for the synthesis of 7.[a]
NH3 with a safer and greener reagent such as LHMDS for the
[4d,e]
ꢀ
final S O bond cleavage.
We envisioned that this goal
ꢀ
could be achieved by tuning the S O bond reactivity in our
cyclic oxathiozolidinone templates. Herein, we report a new
ꢀ
chiral sulfinyl-transfer agent containing a more activated S O
bond, from which both sterically hindered enantiopure
sulfinamides and sulfinyl ketimines were prepared under
mild reaction conditions.
Entry
6
R’
Base
T [8C]
7
d.r.[b]
ꢀ
To identify a template with a more reactive S O bond, the
reaction between the tert-butanesulfinates 5 and LHMDS was
1
2
3
4
5
6
6a
6a
6a
6b
6b
6b
H
H
H
Cl
Cl
Cl
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
ꢀ40
ꢀ15
0
ꢀ40
ꢀ10
0
7a
7a
7a
7b
7b
7b
98:2
98:2
97:3
99:1
98:2
98:2
ꢀ
first investigated (Table 1). It is clear that S OR bond
Table 1: Reactivity of the sulfinates 5 toward LHMDS.[a]
[a] Reactions were performed in THF with full conversion. Refer to the
Supporting Information for further details. [b] The d.r. was determined by
1H NMR analysis.
Entry
5
R
pKa[b] t [h]
Conversion [%][c]
1
2
3
4
5a
5b
5c
Et
PhCH2
Ph
16
15.4
9.95
9.95
>12
>12
0
0
1.5 99
1.5 99
(20% ee)
<1
4–5
ꢀ408C provided the desired product with excellent selectivity
(entry 1). Notably, the reaction temperature has negligible
effect on the selectivity, with minimal erosion of the d.r. value
noted when the reaction temperature was increased from
ꢀ408C to 08C (entries 2 and 3). Despite the promising profile
of this chiral template, crystallization of 7a to diastereomeri-
cally pure material proved highly challenging. Modification of
the sulfonyl group on the nitrogen atom did not improve the
crystallinity of 7a.[10c] The para-chloro-substituted phenol
derivative 6b that has been used successfully in the synthesis
of P-chiral phosphine oxides[10a] was subsequently examined.
Analogous reaction conditions afforded 7b with equally high
selectivity (entry 4). Again, raising the temperature did not
adversely affect the selectivity (entries 5 and 6). In contrast to
7a, 7b was readily obtained by recrystallization from EtOAc/
heptanes in diastereomerically pure form (> 99.5:0.5 d.r.).
From a process control point of view, scale-up was conducted
at ꢀ108C to yield 7b (2.0 kg) in 87% yield and 99.6:0.4 d.r.
with an S configuration at the sulfur center as confirmed by
a single-crystal X-ray structure.
5c*
Ph
(20% ee)[d]
5
6
5d
5e
4-ClC6H4
4-MeOC6H4 10.2
9.38
99
95
[a] Reactions were conducted in THF by adding LHMDS at 08C, stirring
for 30 min, and then warming to ambient temperature. [b] See reference
[8] for the pKa values of ROH. [c] Based on HPLC analysis. [d] Based on
HPLC analysis using a chiral stationary phase. THF=tetrahydrofuran.
reactivity is affected by the basicity of the leaving group or
the pKa value of the corresponding ROH (that is, the
reactivity increases as the pKa value of ROH[8] decreases).
ꢀ
In general, good correlation between the S O bond strength
and the electronegativity of the oxygen atom, as predicted
based on the pKa values of the selected alcohol substrates
from which the sulfinates were synthesized, was observed. For
example, no reaction was observed for the sulfinates derived
from ethanol or benzyl alcohol (entries 1 and 2), however, the
reaction of 5c, derived from phenol, was complete in
1.5 hours, thus providing the desired product in quantitative
yield (entry 3). The presence of an electron-withdrawing
substituent on the phenol ring (5d) increased the reactivity
(entry 5), whereas the reactivity was attenuated with an
With sufficient quantities of the chiral template 7b, the
evaluation of the synthesis of (R)-tBSA (1a) by cleavage of
ꢀ
the S N bond with tert-butylmagnesium chloride and sub-
ꢀ
sequent cleavage of the S O bond upon addition of LHMDS
was initiated (Table 3). Addition of tBuMgCl to 7b in THF at
ꢀ
electron-donating group (5e; entry 6). The effect of sterics on
ꢀ308C selectively cleaved the S N bond, thus providing the
[8f]
ꢀ
the reactivity of the S O bond was also observed.
diastereomerically pure, stable, and crystalline sulfinate ester
Application of a chiral sulfinate (5c*, 20% ee)[9] in this
transformation demonstrated that no erosion of enantiomeric
purity occurred under the present reaction conditions
(entry 4).
8a in 91% yield. Gratifyingly, treatment of 8a with LHMDS
ꢀ
in THF at ꢀ108C!08C cleaved the S O bond effectively in
quantitative conversion. After quenching the reaction with
aqueous NH4Cl solution, enantiopure (R)-tBSA (1a) was
isolated in 90% yield and 99.7:0.3 e.r. Temperatures up to
ꢀ108C for the Grignard addition and 08C for the LHMDS
addition did not result in any erosion of the enantiomeric
purity of 1a.
ꢀ
With successful identification of a more reactive S O
bond derived from a phenol-based template, the sulfinyl-
transfer agent benzoxathiazine 2-oxide 7 (Table 2) was
designed. It was envisioned that optically pure 7 could be
efficiently accessed on large scale from the simple and
commercially available chiral aminophenol 6.[10a] After
screening several reaction conditions,[10b] it was found that
slow addition of pyridine to a solution of 6a and SOCl2 at
This efficient and simple method was further demon-
strated in the synthesis of other sterically hindered sulfin-
amides (Table 3). A variety of structurally diverse and
sterically hindered alkyl and aryl sulfinamides were readily
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Table 3: Synthesis of sterically hindered sulfinamides.[a]
Table 4: Synthesis of sterically hindered chiral ketimines and amines.
Entry RMgX
8
1
Yield e.r.[b]
[%]
Yield [%]
1
2
3
4
91 (8a)
85 (8b)
75 (8c)
88 (8d)
90
84
73
91
99.7:0.3
Entry
R
9
Yield [%]
e.r.[a]
10 Yield [%]
d.r.[b]
93:7
94:6
1
2
9a
9c
85
91
99.1:0.9 10a
99.5:0.5 10c
99
95
98.8:1.2
98.8:1.2
99:1
3
4
9d
9e
78
71
98.4:1.6 10d
98.4:1.6 10e
98
97
95:5
>99:1[c]
[a] Based on HPLC analysis using chiral stationary phase. [b] Based on
1H NMR analysis. [c] Only one diastereomer was observed.
5
56 (8e)[d]
83
99.9:0.1
[a] Refer to the Supporting Information for detailed reaction conditions.
[b] Enantiomeric ratios were determined by HPLC analysis using a chiral
stationary phase. [c] With 0.5 equiv of MgBr2·OEt2 added. [d] Reaction
conducted in CH2Cl2 in the presence of bis[2-(N,N-dimethylamino)-
ethyl]ether.[13] [e] With 0.2 equiv of MgBr2·OEt2 added.
enantiopurity (that is, 90:10 e.r. for 9a at ꢀ408C). Conversely,
under the same reaction conditions, the synthesis of 9a using
the sulfinate 11 failed to provide the desired product and no
reaction was observed [Eq. (1)]. This result clearly demon-
ꢀ
strates the higher reactivity of the S O bond in the phenol
backbone.
synthesized in high yields and e.r. values. Notably, the chiral
sulfinamide 1d has never been previously prepared
(entry 4).[12] In the case of 1d and 1e, a slight decrease in
enantiopurity was observed when the LHMDS addition was
performed at higher temperature. An excellent e.r. value
(99:1) was obtained if the addition was started at ꢀ788C or by
addition of 0.2 equivalents of MgBr2·OEt2 (entry 5). Addi-
tionally, it has been demonstrated that the double nucleo-
philic substitution can be carried out by a one-pot protocol.[13]
To highlight the utility of this new process, the scope of
this chemistry was extended to the direct synthesis of
sterically hindered chiral sulfinyl ketimines (9) by addition
of an imine nucleophile to the sulfinate ester 8 (Table 4).
Sulfinyl ketimines are key intermediates in the synthesis of
chiral amine compounds and their synthesis has been carried
out by condensation of a ketone with sulfinamide in the
presence of a Lewis acid, such as tetraalkoxytitanium.[1c,d]
However, when sterically hindered ketones are employed, the
yield decreases even under forcing reaction conditions.[14]
Therefore, the synthesis of 9 from 8 would allow for an
efficient and direct synthesis of sterically hindered sulfinyl
ketimines.
As presented in Table 4, a variety of hindered ketimines
were prepared by following this sequence. Ketimines with
different alkyl functionalities (9a,c,d) were prepared in good
yields and excellent selectivities. The ketimine 9e, containing
a hindered aryl group, was also prepared in good yield and
98:2 e.r. (Table 4, entry 4). For comparison, only 20% yield
was obtained from the condensation reaction between TIPP
sulfinamide (TIPPSA) and the ketone. It is worth pointing out
that ketimines with different sulfinyl groups would provide an
avenue for fine-tuning the stereoselectivity in the synthesis of
chiral amines by either reduction or nucleophilic addition.
While direct synthesis of nonhindered chiral ketimines using
Andersonꢀs reagent was previously reported, our newly
developed chiral template allows an efficient and direct
synthesis of structurally diverse bulky chiral sulfinyl ketimines
by stereoselective substitution of a chiral sulfinate.[15]
The synthesis of (S)-N-(tert-butyl-phenylmethylidene)-2-
tert-butane-2-sulfinamide (9a) was first explored. Addition of
tBuLi at ꢀ788C to benzonitrile in THF generated the lithium
imide, which was then slowly added to 8a in THF at ꢀ788C.
The reduction of 9 in the synthesis of the chiral amine 10
was initially studied to understand the effect of the alkyl and
arylsulfinyl groups on the stereoselectivity. Reduction of 10a
with different reducing reagents was first investigated.
Among the reagents examined (e.g. NaBH4, L-selectride,
and 9-BBN), NaBH4 in THF gave the best selectivity, thus
ꢀ
This hindered lithiumimide readily cleaves the S O bond to
yield sulfinyl ketimine 9a in good yield upon isolation and
greater than 99:1 e.r., exclusively as one E/Z isomer (Table 4,
entry 1). Increasing the reaction temperature led to decreased
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providing 10a in 93:7 d.r.[16] and almost quantitative yield
(Table 4, entry 1). The same reaction conditions were then
applied to other substrates. Similar selectivities were
observed when other alkylsulfinyl groups were used (10c,d;
entries 2 and 3). However, better selectivity was observed
when the TIPP sulfinyl group was used, and only one
diastereomer of 10e was observed. The effect of the sulfinyl
group on the selectivity is obvious and the application of this
method in the synthesis of other chiral amines under different
reactions conditions is under further exploration.
The potential of this powerful method for the large scale
synthesis of (R)-tBSA was also demonstrated. The prelimi-
nary process has been conducted on 100 g scale as shown in
Scheme 2. Reaction of 7b with tBuMgCl at ꢀ158C gave 8a in
up to 90% yield upon isolation. Treatment of 8a with
Received: February 26, 2013
Revised: March 28, 2013
Published online: May 15, 2013
Keywords: amines · asymmetric synthesis · chirality · sulfur ·
.
synthetic methods
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Scheme 2. Practical process for large scale synthesis of (R)-tBSA.
LHMDS at ꢀ10!158C and subsequent quenching with 25%
phosphoric acid resulted in a mixture of 6b and (R)-tBSA.
After switching the solvent to water, 6b and (R)-tBSA were
effectively separated by crystallizing out 6b while leaving (R)-
tBSA in the aqueous phase. The auxiliary 6b was recovered in
99% yield and can be used in the next production cycle. The
(R)-tBSA was then extracted using CH2Cl2 in 85% yield and
99.5:0.5 e.r. Clearly, this protocol is operationally simple,
mild, and practical, and is commercially feasible for the
synthesis of (R)-tBSA on large scale.
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ꢀ
In summary, through the studies of S O bond reactivities
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synthesis of chiral amines; b) Refer to Table 2 in the Supporting
derived from different alcohols, we have developed a chiral
amine template based on a phenol backbone (6), from which
the optically pure chiral sulfinyl-transfer agent benzo-
[1,3]oxathiozin-2-one 7 was prepared effectively. The inter-
ꢀ
ꢀ
mediate 7 contains S N and S O bonds with differentiated
reactivities that allow the synthesis of sterically hindered
chiral sulfinamides and sulfinyl ketimines under mild reaction
conditions. This method is practical, efficient, green, and has
the potential to provide an economical commercial process
for the synthesis of enantiopure bulky sulfinamides, such as
tBSA and TIPPSA.
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Information for detailed information; c) 4-chlorophenyl-, 2-
mesityl-, and 2-methylphenylsulfonyl groups were investigated.
[11] (R)-tBSA was obtained from the reaction of 7a with tBuMgCl
and subsequent addition of LHMDS. The S configuration
depicted was based on double inversion at sulfur atom for
nucleophilic substitution.
[12] The reaction for the synthesis of 1d was conducted in the
presence of 0.5 equivalents of MgBr2·OEt2 to improve the
selectivity.
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[17] See the Supporting Information for crystallographic data of 7b.
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