Addition-Rearrangement of Ketenes with Lithium N- tert-Butanesulfinamides: Enantioselective Synthesis of α,α-Disubstituted α-Hydroxycarboxylic Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b01555

Addition of the lithium salts of chiral N-substituted tert-butanesulfinamides to ketenes and subsequent silylation initiates stereoselective [2,3]-rearrangement, which affords enantioenriched α,α-disubstituted α-sulfenyloxy carboxamides through a reaction

Full text of DOI:10.1021/acs.orglett.9b01555

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Addition−Rearrangement of Ketenes with Lithium N-tert-
Butanesulfinamides: Enantioselective Synthesis of α,α-Disubstituted
α‑Hydroxycarboxylic Acid Derivatives
Peng-Ju Ma,‡ Fan Tang,‡ Yun Yao,† and Chong-Dao Lu*,†,‡
†School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
‡Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011, China
S
* Supporting Information
ABSTRACT: Addition of the lithium salts of chiral N-
substituted tert-butanesulfinamides to ketenes and subsequent
silylation initiates stereoselective [2,3]-rearrangement, which
affords enantioenriched α,α-disubstituted α-sulfenyloxy carbox-
amides through a reaction that faithfully transfers the absolute
stereochemistry of the lithiated sulfinylamides to the α-carbon of
the amide products. This addition−rearrangement can be
performed together with ketene formation from acyl chloride
in a single flask, providing a new and practical synthetic route to
α-hydroxycarboxylic acid derivatives.
Scheme 1. Asymmetric Synthesis of α-Oxygenated
Carboxylic Acid Derivatives from Ketenes
nantioenriched α-hydroxycarboxylic acid derivatives are
important structural units in a range of biologically
E
relevant molecules and also serve as useful precursors in
organic synthesis.1 A straightforward path to these compounds
is asymmetric C−O bond formation at the α-position of acid
derivatives using suitable oxygen sources. This approach has
been well developed for enantioselective α-oxygen−function-
alization of α-unbranched2 and some α-branched acid
derivatives, primarily β-keto esters3 and cyclic carboxylic acid
derivatives.4 In contrast, asymmetric α-oxygen−functionaliza-
tion of common acyclic α,α-disubstituted carbonyls is
challenging. This reflects the difficulty with which these
compounds form the corresponding stereodefined enolates5 as
well as the sometimes poor enantio-discrimination between the
re and si faces of these enolates.6 Nevertheless, Davis6 and co-
workers achieved some success in such functionalizations using
double-asymmetric induction involving diastereoselective
oxidation of chiral acyclic, polysubstituted enolates with
chirality-matched camphorylsulfonyl oxaziridines. Subse-
quently, several examples of enantioselective construction of
tertiary α-hydroxy carbonyls7 via oxidation of stereodefined
acyclic enolates or their analogues have been reported.8−11
Enantioselective O,N-bifunctionalizations of ketenes12 have
recently been developed for asymmetric synthesis of α-hydroxy
carboxylic amide derivatives.13 Using chiral nucleophilic
catalysts, disubstituted ketenes react with nitrosoarene to
form enantioenriched 1,2-oxazetidin-3-ones,14 in which the
presence of an ortho electron-withdrawing group (CF3) on the
nitrosoarene is required for good regioselectivity and
diastereocontrol (Scheme 1a). In addition, [3 + 2] cyclo-
addition of disubstituted ketenes with oxaziridines proceeds via
Lewis base catalysis to give oxazolin-4-one derivatives with
high enantioselectivities (Scheme 1b).15 In both of these
protocols, only aryl alkyl ketenes have been examined for
simultaneous formation of C−O and amide C−N bonds, and
some of these substrates suffer from low yields15 and poor
enantioselectivities.14a
We hypothesized that disubstituted ketenes could be
efficiently O,N-bifunctionalized using a different approach.
Our previous studies demonstrated highly stereoselective
[2,3]-sigmatropic rearrangement of O-silyl N-tert-butanesulfin-
Received: May 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituted tert-butanesulfinamides to disubstituted ketenes,
followed by silylation, might give fully substituted O-silylated
enolates, which in turn might undergo rearrangement to give
tertiary α-sulfenyloxy carboxamides (Scheme 1c). This
addition−rearrangement is particularly appealing because of
the low molecular weight of Ellman’s tert-butanesulfinamide
and the commercial availability of its R and S enantiomers on a
kilogram scale at low cost.16
Scheme 2. Initial Results of Addition−Rearrangement of
Lithiated tert-Butanesulfinamide with Ketene
Initially, we examined the addition−rearrangement using
phenyl ethyl ketene (2a), the most commonly used
disubstituted ketene substrate. N-Lithiation of N-p-methox-
yphenyl (RS)-tert-butanesulfinamide (1a) with n-butyllithium
at −78 °C was followed by introduction of ketene 2a and
chlorotrimethylsilane at −78 °C. Keeping the reaction mixture
at −78 °C for 1.5 h led to formation of α-sulfenyloxy
carboxamide 3a in 69% yield with excellent enantioselectivity
(97.5:2.5 er), together with a small amount (∼13%) of acyl N-
tBS amide 4a (Scheme 2, entry 1). Elevating the reaction
temperature accelerated silylation−rearrangement while pre-
serving excellent enantioselectivity (entries 2 and 3). At 0 °C,
the reaction was complete within 30 min, affording the desired
product 3a in 77% yield with 96.5:3.5 er (entry 3).
yl (N-tBS) N,O-ketene aminals to α-sulfenyloxy carboxamides.
In this rearrangement, chiral information was transferred from
the sulfur atom in the sulfinyl group to the α-position in the
amide products.16 Consequently, Ellman’s tert-butanesulfina-
mide,17 commonly used as a chiral ammonia equivalent, works
well as a latent chiral hydroxyl group. We envisaged that aza-
Mislow−Evans rearrangement18 could lead to O,N-bifunction-
alization of disubstituted ketenes: addition of lithiated N-
The addition−protonation product 4a was obtained in 85%
isolated yield with ∼3:1 dr when the reaction of 1a and 2a was
quenched with an aqueous solution of ammonium chloride
rather than TMSCl.19 This indicates that the chiral sulfinyl
a
Table 1. Substrate Scope
b
c
entry
sulfinyl amide (R)
ketene (Ar, R′)
product
yield (%)
er
d
d
1
2
3
4
5
6
7
8
1a (PMP)
1b (Ph)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2a (Ph, Et)
2b (Ph, Me)
2c (Ph, iPr)
2d (Ph, cyclopentyl)
2e (4-MeC6H4, Et)
2f (3-MeC6H4, Et)
2g (2-MeC6H4, Et)
2h (4-FC6H4, Et)
2i (4-ClC6H4, Et)
2j (PMP, Et)
ent-2a (Ph, Et)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
77 (77)
97:3 (97.5:2.5)
99:1
77
61
80
84
57
83
78
56
79
66
76
77
80
77
75
23
64
68
74
74
1c (4-MeC6H4)
1d (3-MeC6H4)
1e (2-MeC6H4)
1f (4-FC6H4)
1g (2-naphthyl)
1h (4-MeSC6H4)
1i (4-MeO2CC6H4)
1j (Bn)
1k (nBu)
1a (PMP)
1a (PMP)
1a (PMP)
1a (PMP)
1a (PMP)
1a (PMP)
1a (PMP)
1a (PMP)
1a (PMP)
ent-1a (PMP)
98.5:1.5
99:1
99:1
99:1
99:1
97.5:2.5
98.5:1.5
87:13
79.5:20.5
97.5:2.5
92:8
95.5:4.5
97:3
97.5:2.5
82.5:17.5
99:1
9
10
11
12
13
14
15
16
17
18
19
20
3s
3t
ent-3a
98:2
97:3
f
21
4.5:95.5
a
Reaction conditions: 1 (0.40 mmol) and nBuLi (0.48 mmol) were stirred in anhydrous THF (4.0 mL) at −78 °C for 15 min before addition of
ketene (0.60 mmol). After the mixture was maintained at −78 °C for 15 min, chlorotrimethylsilane (0.80 mmol) was added at −78 °C, and the
reaction mixture was then warmed to 0 °C and stirred for 0.5 h before quenching with a saturated solution of NH4Cl. Isolated yield after silica gel
chromatography. Enantiomeric ratios were determined using HPLC and a chiral stationary phase. On a 1.4 g scale. The (S)-enantiomer of N-
tert-butanesulfinamide was used.
b
c
d
f
B
DOI: 10.1021/acs.orglett.9b01555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In contrast, use of N-benzylsulfinamide (3j) dramatically
reduced enantioselectivity (entry 10, 87:13 er), and using
sulfinamides bearing less hindered linear alkyl groups on the
nitrogen atom reduced enantioselectivity even further (entry
11, 79.5:20.5 er). A range of aryl alkyl disubstituted ketenes
3b−j were used to react with lithiated sulfinamide 1a to
construct enantioenriched α,α-disubstituted α-hydroxycarbox-
ylic amides 3l−t (entries 12−20). Ketenes containing linear or
branched aliphatic groups such as methyl (entry 12), isopropyl
(entry 13), and cyclopentyl (entry 14) were suitable substrates,
as were aryl ethyl ketenes bearing phenyl groups with methyl
(ortho, meta, or para), halogen, or methoxy substitutions
(entries 15−20). Most of these reactions showed good yields
and excellent enantioselectivities. An exception was the
reaction of ortho-substituted aryl ketene 2g (entry 17), for
which the yield was only 23% and the er was only 82.5:17.5.
The low yield was attributed to the formation of a substantial
amount of uncharacterized byproducts, but the reasons for the
relatively low stereocontrol remain unclear.
Table 2. Synthesis of α,α-Disubstituted α-Sulfenyloxy
Carboxamides using Acyl Chlorides as Starting Materials
a
b
sulfinyl amine
acid chloride
(RL, RS)
yield
(%)
c
entry
(R)
product
er
1
2
3
1a (PMP)
1a (PMP)
1a (PMP)
5a (Ph, Et)
5b (Ph, Me)
5c (4-MeC6H4,
Et)
3a
3l
3o
73
72
64
96:4
98:2
95:5
4
5
1a (PMP)
1a (PMP)
5d (4-FC6H4, Et)
5e (4-ClC6H4,
Et)
3r
3s
61
65
96:4
97.5:2.5
6
7
8
9
1a (PMP)
1a (PMP)
1a (PMP)
1a (PMP)
5f (Ph, nBu)
5g (iPr, Me)
5h (nBu, Me)
5i (Et, Me)
5i (Et, Me)
3u
3v
3w
3x
3y
67
37
74
78
63
94.5:5.5
89.5:10.5
81:19
75:25
73:27
This approach for O,N-bifunctionalization of ketenes proved
robust and was easily scaled up to 1 g without loss of yield or
enantioselectivity (Table 1, entry 1). It also allowed easy
preparation of both enantiomers of α-tertiary α-hydroxyl
amides with high enantiopurity when the corresponding
enantiomers of tert-butanesulfinamide were used (Table 1,
entries 1 and 21).
10
1e
(2-MeC6H4)
a
Reaction conditions: 5 (1.2 mmol), Et3N (2.4 mmol), lithiated
amide (0.4 mmol), and chlorotrimethylsilane (3.6 mmol) were used.
b
c
Preparing the pure ketenes usually involves several tedious
operations, including filtration, concentration, and high-
vacuum distillation under an inert atmosphere.22 Therefore,
we examined whether we could use a crude ketene solution
directly, which we generated by mixing acyl chlorides and
triethylamine in THF. We found that using 3 equiv of α-
branched acyl chlorides and 6 equiv of triethylamine gave the
desired products in yields and enantiomeric ratios comparable
to those obtained using the corresponding purified ketenes
(entry 1 in Table 2 vs entry 1 in Table 1, entry 2 in Table 2 vs
entry 12 in Table 1, entry 3 in Table 2 vs entry 15 in Table 1,
entry 4 in Table 2 vs entry 18 in Table 1, and entry 5 in Table
2 vs entry 19 in Table 1). In particular, this one-pot reaction
starting from acyl chloride was applicable for ketenes bearing
two linear alkyl groups (entries 7−10), which are rarely used in
organic synthesis.23 The moderate stereocontrol observed with
ketenes bearing two linear alkyl groups is not entirely
surprising, since the two aliphatic groups do not differ enough
in bulkiness to generate stereodefined enolate intermediates
during addition of lithiated N-tBS sulfinamide. Extending the
reaction to common α-linear acid chloride such as propionyl
chloride is not feasible. Common monosubstituted ketenes
generated from the corresponding α-linear acid chlorides are
often formed in the presence of reaction partners in order to
capture the ketenes in situ as soon as they formed, which is not
applicable in our addition−rearrangement process.
Isolated yield after silica gel chromatography. Enantiomeric ratios
were determined using HPLC and a chiral stationary phase.
Scheme 3. Manipulations of α-Sulfenyloxy Carboxamide 3a
and Assignment of Absolute Configuration
Scheme 4. Rationalization of Observed Absolute
Stereochemistry
group in the enolate intermediate does not provide good
stereocontrol during enolate protonation, which is consistent
with the poor 1,4-asymmetric induction observed in reactions
of ketenes with optically active amines.20,21
Next we examined the substrate scope of diastereoselective
addition−rearrangement of ketenes with chiral lithium N-tert-
butanesulfinamide (Table 1). N-tert-Butanesulfinamides bear-
ing diverse N-aryl substitutions (R = Ar) smoothly underwent
a cascade of lithiation−addition−silylation rearrangement to
give the corresponding α-sulfenyloxy carboxamides 3a−i
(entries 1−9) in good yields (56−84%) with excellent
enantioselectivities (96.5:3.5−99:1 er). The cascade was
compatible with ortho-, meta-, and para-substituted aryl groups.
Treating tertiary α-sulfenyloxy carboxamide 3a with
thiophile P(OMe)3 at room temperature efficiently cleaved
the S−O bond24 to afford the corresponding α-hydroxy amide
6 (Scheme 3). Heating the mixture of amide 6 and KOH in
ethylene glycol resulted in formation of tertiary α-hydrox-
ycarboxylic acid 7.25 Comparison of the optical rotation of
synthesized 7 with the literature26 indicated an absolute
configuration of R.
During addition−rearrangement, lithiated (RS)-tert-butane-
sulfinamide generates a stereocenter in the R configuration,
which can be rationalized by postulating the rearrangement of
C
DOI: 10.1021/acs.orglett.9b01555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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O-silylated cis-enolate via an exo transition state (Scheme
4).16,27 The cis-enolate forms preferentially to minimize steric
interaction between the bulky N-substituted sulfinamide group
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α-position in the cis-enolate. Replacing the Ar group with a
linear alkyl group makes the R and alkyl groups sterically
similar, reducing the ratio of cis- to trans-enolate and thereby
the enantiomeric ratio for the corresponding rearrangement
products (Table 2, entries 8−10).
In summary, we have developed an efficient method to
construct α-tertiary α-hydroxy acid derivatives. The process
involves addition of N-lithiated chiral tert-butanesulfinamide to
disubstituted ketene, followed by O-silylation. Stereoselective
aza-Mislow−Evans rearrangement allows enantioselective
installation of a sulfenyloxy group at the α-position of the
carbonyl group. This addition−rearrangement can be con-
ducted in a single flask using acid chlorides as starting
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01555.
Experimental details, characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: clu@ms.xjb.ac.cn; clu@ynu.edu.cn.
ORCID
́
J. Am. Chem. Soc. 2003, 125, 10808−10809. (d) Sunden, H.; Engqvist,
́
M.; Casas, J.; Ibrahem, I.; Cordova, A. Angew. Chem., Int. Ed. 2004,
43, 6532−6535.
(10) For asymmetric dihydroxylation of substituted enol derivatives,
see: (a) Debergh, J. R.; Spivey, K. M.; Ready, J. M. J. Am. Chem. Soc.
2008, 130, 7828−7829. (b) Gourdet, B.; Lam, H. W. Angew. Chem.,
Int. Ed. 2010, 49, 8733−8737.
Chong-Dao Lu: 0000-0001-8968-0134
Notes
The authors declare no competing financial interest.
(11) For phase-transfer-catalyzed enantioselective α-hydroxylation
of acyclic ketones, see: Sim, S.-B. D.; Wang, M.; Zhao, Y. ACS Catal.
2015, 5, 3609−3612.
ACKNOWLEDGMENTS
■
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Tetrahedron 1986, 42, 2587−2613. (b) Paull, D. H.; Weatherwax, A.;
Lectka, T. Tetrahedron 2009, 65, 6771−6803. (c) Allen, A. D.;
Tidwell, T. T. Chem. Rev. 2013, 113, 7287−7342.
This work was supported by the National Natural Science
Foundation of China (21871292).
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Synth. 2017, 94, 1−15.
̈
(23) Hertenstein, U.; hunig, S.; Reichelt, H.; Schaller, R. Chem. Ber.
1982, 115, 261−287.
(24) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147−155.
(25) The enantiomeric ratio for acid 7 was determined by chiral
HPLC analysis after conversion of 7 to its methyl ester. For a reported
method for enantiopurity analysis of 7, see: Yamanaka, M.; Inaba, M.;
Gotoh, R.; Ueki, Y.; Matsui, K. Chem. Commun. 2017, 53, 7513−
7516.
24
(26) The optical rotation for 7 was [α]D = −32.5 (c = 0.20,
24
EtOH). The literature indicated [α]D = −32.3 (c 1.77, EtOH) for
(R)-α-ethyl phenylacetic acid with 97% ee. See: Basavaiah, D.;
Krishna, P. R. Tetrahedron 1995, 51, 12169−12178.
(27) The presence of a bulky substituent such as Me3SiO at the C2
position in the allylic system of the precursor used for aza-Mislow−
Evans rearrangement destabilizes the endo transition state, facilitating
exo rearrangement. See: (a) Hoffmann, R. W.; Goldmann, S.; Gerlach,
R.; Maak, N. Chem. Ber. 1980, 113, 845−855. (b) Goldmann, S.;
Hoffmann, R. W.; Maak, N.; Geueke, K.-J. Chem. Ber. 1980, 113,
831−844.
E
DOI: 10.1021/acs.orglett.9b01555
Org. Lett. XXXX, XXX, XXX−XXX