Enantioselective synthesis of tertiary α-chloro esters by non-covalent catalysis

Article abstract of DOI:10.1016/j.tetlet.2015.01.124

We report an enantioselective approach to tertiary α-chloro esters through the reaction of silyl ketene acetals and N-chlorosuccinimide. The reaction is promoted by a chiral squaramide catalyst, which is proposed to engage both reagents exclusively throug

Full text of DOI:10.1016/j.tetlet.2015.01.124

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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Enantioselective synthesis of tertiary a-chloro esters by non-covalent
catalysis
⇑
Richard Y. Liu, Masayuki Wasa, Eric N. Jacobsen
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an enantioselective approach to tertiary
a-chloro esters through the reaction of silyl ketene
Received 4 December 2014
Revised 16 January 2015
Accepted 19 January 2015
Available online xxxx
acetals and N-chlorosuccinimide. The reaction is promoted by a chiral squaramide catalyst, which is pro-
posed to engage both reagents exclusively through non-covalent interactions. Application of the tertiary
chloride products in stereospecific substitution reactions is demonstrated.
Ó 2015 Elsevier Ltd. All rights reserved.
Dedicated to the memory and legacy of
Harry Wasserman
Keywords:
Asymmetric catalysis
Organocatalysis
Hydrogen bonding
Chlorination
Non-covalent interactions
hydrogen
The development of new methods for enantioselective
nation is motivated primarily by the utility of -chloro carbonyl
compounds as synthetic intermediates.1,2 While construction of
a-chlori-
cation-π
bonding
‡
a
chiral backbone
OTMS
R2
N
H
N
H
R1O
O
OTMS
R2
R3
δ-
Ar
O
*
Cl
a
-secondary
a
-chloro stereocenters has been explored extensively
catalyst
NCS
O
R3
R2
Cl
R1O
OTMS
R2
δ+
R1O
R1O
using strategies such as enamine catalysis,3 few successful
methods have been reported for enantioselective catalytic
*
N
R3
N
O
Cl
R3
a
-chlorination at tertiary centers.4–7 In the context of our studies
O
of enantioselective reactions promoted through non-covalent
Scheme 1. Catalytic strategy for
a-chlorination reaction.
catalysis,8 we envisioned that electrophilic chlorination of
a-tertiary silyl enolates might be promoted by a chiral hydrogen
bond donor with ancillary functionality capable of positioning
the reacting partners in a specific orientation (Scheme 1).
reaction ee on the expanse and orientation of the aromatic compo-
nent.11 The 9-phenanthryl derivative afforded the highest enanti-
oselectivities, with smaller (e.g., 2-naphthyl, entry 7) and larger
(e.g., pyrenyl, entry 8) substituents affording substantially poorer
results.
Catalytic chlorination reactions with squaramide 5a were found
to be quite sensitive to reaction conditions (Table 2). Reactions car-
ried out in dichloromethane (DCM)) afforded racemic product
(entry 1), as NCS is fully soluble in that medium and the chlorina-
tion reaction appears to occur entirely through an uncatalyzed
pathway. In contrast, NCS is only sparingly insoluble in toluene
and ethereal solvents, and measurable levels of enantioselectivity
are obtained in those solvents (entries 2–4). This suggests that
one role of the squaramide catalyst may be to solubilize NCS, pre-
sumably through hydrogen binding interactions. Based on this
The chlorination of cyclic silyl ketene acetal 1a with N-chloro-
succinimide (NCS) was investigated as a model reaction (Table 1).10
Among the various subclasses of chiral dual hydrogen bond donors
that have been developed over the past decade, tert-leucine-aryl-
pyrrolidine derivatives with the general structure in 3–5 have pro-
ven remarkably effective in a wide range of enantioselective
catalytic reactions. Whereas promising results were observed with
thiourea catalyst 3, substantially higher reactivity and enantiose-
lectivity were obtained with the analogous urea and squaramide
derivatives 4 and 5a (entries 1–3). A systematic evaluation of aryl-
pyrrolidino-squaramide catalysts revealed a strong dependence of
⇑
Corresponding author. Tel.: +1 617 496 3688; fax: +1 617 496 1880.
E-mail address: jacobsen@chemistry.harvard.edu (E.N. Jacobsen).
http://dx.doi.org/10.1016/j.tetlet.2015.01.124
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Liu, R. Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.01.124

2
R. Y. Liu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
Table 3
Evaluation of catalyst structurea
Scope of silyl enolate substratea
catalyst (10 mol%)
5e
OM
catalyst
NCS
O
OTMS
O
O
NCS
Cl
*
Cl
O
O
O
R
R
*
MTBE
10% hexanes/MTBE
–
30 °C, 18 h
–30 °C, 12 h
1a
2a
1a-j
2a-h
Yieldb (%)
eec (%)
Entry
Catalyst
Ar
Yieldb (%)
eec (%)
Substrate
Product
M
R
1
2
3
4
5
6
7
8
9
3
4
9-Phenanthryl
9-Phenanthryl
9-Phenanthryl
1-Phenanthryl
3-Phenanthryl
Phenyl
2-Naphthyl
4-Pyrenyl
3-(N-Methylcarbazolyl)
CF3
78
56
81
86
33
84
34
47
62
47
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2a
2a
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TMS
TES
C6H5
91
90
94
96
94
95
84
88
90
79
90
92
92
94
82
11
80
58
86
83
>95
>95
>95
>95
>95
>95
>95
>95
CF3
2-Naphthyl
4-Br-C6H4
4-Cl-C6H4
4-CH3-C6H4
4-CH3O-C6H4
3-CH3O-C6H4
3-Thienyl
C6H5
5a
5b
5c
5d
5e
5f
5g
1j
TBS
C6H5
O
O
t-Bu
E
t-Bu
a
Data represent the average of two experiments. Conditions: silyl enolate
N
N
N
H
N
H
CF3
N
N
H
CF3
(0.2 mmol), NCS (0.4 mmol), 5e (0.02 mmol) in MTBE (3 mL), and hexanes (0.3 mL)
under nitrogen at À30 °C for 12 h.
H
Ar
Ar
O
O
3
5a-g
: E = S
4: E = O
b
Isolated yield of purified product.
c
Enantiomeric excess determined by HPLC analysis on commercial chiral
a
columns.
Conditions: 1a (0.05 mmol), NCS (0.0375 mmol), catalyst (0.005 mmol) in MTBE
(3 mL) under nitrogen at À30 °C for 18 h.
b
Yield based on NCS determined by 1H NMR analysis of crude reaction mixture.
Enantiomeric excess determined by HPLC analysis on commercial chiral
c
columns.
O
i) NaN3, CH3CN
O
*
RT, 4 h
N3
6, 95% yield
Table 2
85% ee
Optimization of reaction parametersa
O
O
5a
catalyst
NCS
OTMS
O
ii) PhSNa, CH3CN
90 °C, 12 h
Cl
*
O
*
O
Cl
O
O
SPh
*
solvent
7, 66% yield
86% ee
2a
90% ee
temperature, 18 h
1a
2a
O
iii) CsF, 18-crown-6,
Entry
Solvent
Temperature (°C)
Yieldb (%)
eec (%)
t-BuOH
O
*
1
2
3
4
5
6
7
8
9
DCM
Toluene
Methyl cyclopentyl ether
MTBE
MTBE
0
0
0
ND
ND
ND
>95
>95
>95
>95
64
0
60
74
80
86
46
90
30
0
F
60 °C, 12 h
8
, 25% yield
90% ee
0
Scheme 2. Substitution reactions of 2aa,b,c. Reagents and conditions: (a) (i) 2a
(0.5 mmol), sodium azide (1.0 mmol) in acetonitrile (4 mL) at room temperature for
4 h. (ii) 2a (0.5 mmol), thiophenol sodium salt (1.0 mmol) in acetonitrile (0.5 mL) at
90 °C for 12 h. (iii) 2a (0.1 mmol), cesium fluoride (0.3 mmol), 18-crown-6
(0.1 mmol) in tert-butanol at 60 °C for 12 h. (b) Isolated yield of purified product.
(c) Enantiomeric excess determined by HPLC analysis on commercial chiral
columns.
À30
À78
À30
À30
À30
MTBE
10% Hexanes in MTBE
25% Hexanes in MTBE
Hexanes
18
a
Conditions: 1a (0.05 mmol), NCS (0.0375 mmol), 5a (0.005 mmol) in solvent
(3 mL) under nitrogen at indicated temperature for 18 h.
Yield based on NCS determined by 1H NMR analysis of crude reaction mixture.
b
c
Enantiomeric excess determined by HPLC analysis on commercial chiral
ee is slightly sensitive to the identity of the silyl group (substrates
1a vs 1i vs 1j, Table 3), suggesting that the silyl group is still
associated to the substrate in the enantiodetermining transition
structure.
columns.
a
-Halocarbonyl compounds are excellent substrates for SN2
pathways,12 so we explored the possibility of effecting stereospe-
cific substitution reactions at the tertiary -position of product
hypothesis, we evaluated the addition of hexanes as an additive to
further reduce solubility of NCS and thereby suppress the back-
ground reaction. Optimal results were obtained at À30 °C with
the introduction of 10% hexanes (entries 5 vs 7). Further increase
in proportion of hexanes had a deleterious effect on both yield
and enantioselectivity, most likely due to the insolubility of
catalyst 5a in these solvent mixtures (entries 8 and 9).
The optimized enantioselective chlorination protocol was
applied to several silyl ketene acetals derived from 2-arylbutyro-
lactones (Table 3). High ee’s were observed with substrates bearing
neutral or slightly electron-withdrawing substituents on the aryl
group (1a–1e, 1g), but electron-donating substituents underwent
chlorination with significantly poorer enantiocontrol (e.g., 1f, 1h).
Low enantioselectivities were also observed with other classes of
silyl enolate substrates (see Supporting information). The product
a
2a (Scheme 2). Treatment of 2a with sodium azide cleanly effected
the desired substitution reaction in nearly quantitative yield and
with high stereospecificity. Likewise, substitution with phenylthi-
olate was accomplished at elevated temperatures, in moderate
yield, and similar stereospecificity (66% yield, 86% ee). Finally,
reaction of 2a with cesium fluoride and crown ether successfully
yielded tertiary
90% ee). Together, these represent two-step asymmetric net C–N,
C–S, and C–F bond forming reactions of -tertiary silyl enolates.
a-fluoride 8, albeit in moderate yield (25% yield,
a
Previous studies of uncatalyzed reactions of silyl enol ethers
with NCS have pointed to rate-determining formation of an ionic
intermediate by Cl+ transfer from NCS to the silyl enolate.9 In the
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R. Y. Liu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
NCS
catalyst
O
References and notes
OTMS
R
R
Cl
*
O
O
N
1. For recent reviews on enantioselective
a
-halogenation reactions including
chlorination, see: (a) Oestreich, M. Angew. Chem., Int. Ed. 2005, 44, 2324–2327;
(b) France, S.; Weatherwax, A.; Lectka, T. Eur. J. Org. Chem. 2005, 475–479; (c)
Mitsuhiro, U.; Taichi, K.; Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005–2012;
(d) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111, 1637–1656; (e) Guillena, G.;
Ramon, D. J. Curr. Org. Chem. 2011, 15, 296–327; (f) Shibatomi, K.; Narayama, A.
Asian J. Org. Chem. 2013, 2, 812–823.
TMSO
N
desilylation
O
‡
O
t-Bu
N
O
N
O
N
O
t-Bu
O
Ar
Hhydrogen
Ar
N
H
O
N
δ-
H
H
2. De Kimpem, N.; Verhe, R. The Chemistry of
-Haloimines; Wiley: New York, 1988.
a-Haloketones, a-Haloaldehydes, and
Ar
O
Ar
O
bonding
cation-π OTMS
a
OTMS
δ+
N
3. For leading references, see: (a) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2004, 126, 4108–4109; (b) Halland, N.; Braunton, A.; Bachmann,
S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4108–4109; (c)
Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem., Int.
Ed. 2009, 48, 5121–5124; (d) Wang, L.; Cai, C.; Curran, D. P.; Zhang, W. Synlett
2010, 433–436.
O
R
R
N
*
O
Cl
Cl
O
O
Scheme 3. Proposed mechanism of chlorination reaction.
4. To our knowledge, aside from the few examples cited in Refs. 5–7, the only
catalytic
a-chlorination reactions producing enantioenriched tertiary alkyl
enantioselective, squaramide-catalyzed reaction described here,
we propose that the polarized transition state leading to the ion
pair intermediate may be stabilized by hydrogen bonding to the
succinimide, with simultaneous stabilization of the developing
chlorides employ 1,3-dicarbonyl and 1,3-ketophosphonate substrates. For
representative references, see: (a) Hintermann, L.; Togni, A. Helv. Chem. Acta
2000, 83, 2425–2435; (b) Marigo, M.; Kumaragurubaran, N.; Jørgensen, K. A.
Chem. Eur. J. 2004, 10, 2133–2137; (c) Shibata, N.; Kohno, J.; Takai, K.; Ishimaru,
T.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem., Int. Ed. 2005, 44, 4024–
4207; (d) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Angew. Chem., Int. Ed. 2005, 44, 6219–6222; (e) Bernardi, L.;
Jørgensen, K. A. Chem. Commun. 2005, 1324–1326; (f) Kawatsura, M.; Hayashi,
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positive charge on silyl ketene acetal through a cation–
p interac-
tion with the arylpyrrolidine (Scheme 3). The profound effect of
the arene substituent size and orientation on reaction enantiose-
lectivity (Table 1) is consistent with the crucial role of such an
attractive interaction in defining the transition structure geometry.
An alternative mechanism involving formation and reaction of a
squaramide-bound enolate is unlikely given the observed depen-
dence of ee on identity of the silyl group (see above).
5. Enantioselective chlorination at C3 of 3-substituted oxindoles has been
reported. For representative references, see: (a) Zhao, M.-X.; Zhang, Z.-W.;
Chen, M.-X.; Tang, W.-H.; Shi, M. Eur. J. Org. Chem. 2011, 3001–3008; (b) Zheng,
W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc. 2011, 133, 3339–3341;
(c) Wang, D.; Jiang, J.-J.; Zhang, R.; Shi, M. Tetrahedron: Asymmetry 2011, 22,
1133–1141.
In summary, we have developed a method for the enantioselec-
tive a-chlorination of a-tertiary silyl ketene acetals with NCS. The
reaction is promoted by a chiral arylpyrrolidino squaramide cata-
lyst that binds and activates the reactants through a network of
non-covalent interactions. Synthetic application of these products
in stereospecific substitution at the tertiary carbon was demon-
strated. Identification and mechanistic characterization of related
types of enantioselective catalytic ion-pairing pathways are the
subject of ongoing work in our laboratory.
6. Enantioselective synthesis of alkyl chlorides from ketenes has been reported.
For representative references, see: (a) Wack, H.; Taggi, A. E.; Hafez, A. M.;
Drury, W. J.; Lectka, T. J. Am. Chem. Soc. 2001, 123, 1531–1532; (b) France, S.;
Wack, H.; Taggi, A. E.; Hafez, A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C. L.;
Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245–4255; (c) Lee, E. C.; McCauley, K. M.;
Fu, G. C. Angew. Chem., Int. Ed. 2007, 119, 995–997.
7. For an example of enantioselective
a-chlorination using Lewis acid catalysis
with a chiral chlorinating reagent, see: Zhang, Y.; Shibatomi, K.; Yamamoto, H.
J. Am. Chem. Soc. 2004, 126, 15038–15039.
8. For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520–1543; (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743;
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(d) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2012, 52, 534–561.
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K.; Mase, M.; Akiba, K.-Y. J. Chem. Soc., Chem. Commun. 1987, 1727–1728.
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Acknowledgments
The authors gratefully acknowledge the National Institutes of
Health (GM-43214) for financial support. R. Y. L. thanks Pfizer,
Inc. and the American Chemical Society for a Summer Undergrad-
uate Research Fellowship. M. W. thanks the Japan Society for the
Promotion of Science for a postdoctoral fellowship.
11. For examples of reactions where cation–
p interaction is proposed to be
involved in selectivity and correlated with size of catalyst arene, see: (a)
Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 5030–5032;
(b) Lin, S.; Jacobsen, E. N. Nat. Chem. 2012, 4, 817–824; (c) Brown, A. R.; Uyeda,
C.; Brotherton, C. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2013, 135, 6747–6749.
12. For examples of stereospecific substitution reactions on
a-chloro-1,3-
Supplementary data
dicarbonyl compounds, see Ref. 4g. For studies of stereospecific substitution
on tertiary halides, see: (a) Winstein, S.; Smint, S.; Darwish, D. Tetrahedron Lett.
1959, 1, 24–31; (b) Edwards, O. E.; Greico, C. Can. J. Chem. 1974, 52, 3561–3562;
(c) Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem. Soc. 2003, 125,
10538–10539; (d) Mascal, M.; Hafezi, N.; Toney, M. D. J. Am. Chem. Soc. 2010,
132, 10662–10664; (e) Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. Nature 2013,
501, 195–199.
Supplementary data (experimental procedures, characteriza-
tion of compounds, and reproductions of spectra and HPLC traces)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.01.124.
Please cite this article in press as: Liu, R. Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.01.124