Enantioselective bromolactonization using an S-alkyl thiocarbamate catalyst

Article abstract of DOI:10.1002/anie.201202079

The apple never falls far from the tree: S-alkyl thiocarbamate 1 (see scheme, NBP=N-bromophthalimide) was prepared in high yield through a synthetic sequence involving a Newman-Kwart rearrangement of the corresponding O-alkyl thiocarbamates. Compound 1 was used to catalyze bromolactonization, thus providing enantioenriched δ-lactones in excellent yield and enantioselectivity. Copyright

Full text of DOI:10.1002/anie.201202079

Angewandte
Chemie
DOI: 10.1002/anie.201202079
Asymmetric Catalysis
Enantioselective Bromolactonization Using an S-Alkyl Thiocarbamate
Catalyst**
Xiaojian Jiang, Chong Kiat Tan, Ling Zhou, and Ying-Yeung Yeung*
Asymmetric halofunctionalization and related electrophile-
promoted functionalization of unactivated olefins are power-
ful reactions in organic synthesis.[1] Despite the formidable
challenges associated with these reactions, recently, there has
been significant advancements using various organocatalysts;
enantioselective variants of reactions such as halolactoniza-
tion,[2] haloetherification,[3] haloaminocyclization,[4] haloami-
dation,[5] halocyclization of polyenes,[6] and others[7] have been
reported.
In these reactions, several strategies were used to activate
the electrophile. The use of promoters that contain Lewis
basic sulfur or selenium atoms is especially interesting,[8] and
Denmark et al. have reported an example of such a promoter,
a phosphoramide derived from 1,1’-binaphthyl-2,2’-diamine
(BINAM), which was used to catalyze thiofunctionalization.[9]
In addition, Snyder et al. reported the use of bromodiethyl-
sulfonium bromopentachloroantimonate (BDSB), a unique
sulfur-containing bromination reagent that shows promising
activity in mediating polyene cyclizations.[10]
Proline was chosen as a starting material for the prepa-
ration of catalysts in the study, because both the R and
S enantiomers are commercially available, and in our pre-
vious study, the use of a proline-derived catalyst gave
enantioenriched product.[11a] The diastereomeric prolinols
1a and 1a’ were synthesized from l-proline according to
literature procedures.[13] 1a was then treated with phenyl
isothiocyanate to give, exclusively and unexpectedly, S-alkyl
thiocarbamate 2a in excellent yield upon isolation; the
corresponding O-alkyl thiocarbamate was not detected
(Scheme 1). On the other hand, when 1a’ was treated with
phenyl isothiocyanate, the expected O-alkyl thiocarbamate
Recently, we reported the use of cinchona alkaloid
derived O-alkyl thiocarbamate catalysts in enantioselective
bromocyclization reactions.[11] A dual-activation mechanism,
which involves the activation of the bromine atom on the
reagent through interaction with the Lewis basic sulfur atom
on the catalyst, was proposed. Although the use of this class of
catalyst gave products with excellent ee values and yields,
a limitation was encountered during our research: although
the pseudo-enantiomeric pair of cinchona alkaloids are
available,[12] the corresponding enantiomeric products were
not formed with equally high ee value.[11]
Scheme 1. Synthesis of thiocarbamate catalysts 2 and 3. For the crystal
structure of 2a, thermal ellipsoids are shown at 50% probability.
To solve this problem, we initiated a program to search for
a new class of catalyst that satisfies two criteria: (1) the
enantiomeric catalysts should be inexpensive and readily
available; (2) the catalyst should contain readily modifiable
handles to facilitate adaption to different substrates. Herein
we report a synthetic route to an amino S-alkyl thiocarbamate
catalyst and its application to asymmetric bromolactoniza-
tion.
3a was obtained as the sole product in 85% yield. It is
plausible that S-alkyl thiocarbamate 2a forms through
a Newman–Kwart type rearrangement.[14] The structure of
catalyst 2a was confirmed by X-ray crystallographic analy-
sis.[15,16]
We then tested 2a for its ability to catalyze the bromo-
lactonization of substrate 4a. N-Bromophthalimide (NBP)
was used as the stoichiometric halogen source and the
reaction was conducted in toluene at À788C. Interestingly,
amino S-alkyl thiocarbamate 2a was able to catalyze the
reaction to give the product in 90% yield and 26% ee
(Table 1, entry 1). Notably, in a number of studies, catalysts
[*] X. Jiang, C. K. Tan, Dr. L. Zhou, Prof. Dr. Y.-Y. Yeung
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmyyy@nus.edu.sg
Homepage: http://www.chemistry.nus.edu.sg/people/academi-
c_staff/yeungyy.htm
=
=
that contain Lewis-basic oxygen in the form of C O and P O
moieties were not suitable for activating the halogen atom,
particularly the bromine atom, in electrophilic halofunction-
alization.[17]
[**] We thank the National University of Singapore (Grant No. 143-000-
509-112) for financial support. We acknowledge the receipt of both
an NUS Research Scholarship (to X.J.) and a President’s Graduate
Fellowship (to C.K.T.).
We then optimized the reaction by modifying the catalyst
structure. When the R group was changed from phenyl to
2-naphthyl, a significant drop in enantioselectivity was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202079.
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Table 1: Optimization of the S-alkyl thiocarbamate catalyst 2 for the
enantioselective bromolactonization of 4a.[a]
Table 2: S-Alkyl thiocarbamate 2g catalyzed halolactonization using
different halogen (X) sources.[a]
Entry
X source
X
t [days]
Yield [%][b]
ee [%]
1
2
3
4
5
NBA
NBS
DBH
NCS
NIS
Br
Br
Br
Cl
I
3.5
3.5
3.5
8
96
94
93
0
68
87
86
0
Entry
Catalyst
R
Ar
Yield [%][b]
ee [%]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
C6H5
C6H5
C6H5
C6H5
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-EtOC6H4
4-iPrOC6H4
90
87
84
86
89
90
97
91
26
6
2-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
33
40
29
87
88
77
8
63
75
[a] Reactions were carried out with acid 4a (0.05 mmol), catalyst 2g
(0.005 mmol), and X source (0.06 mmol) in toluene (1.5 mL) in the
absence of light. [b] Yield upon isolation.
2g
2h
[a] Reactions were carried out with acid 4a (0.05 mmol), catalyst 2
(0.005 mmol), and NBP (0.06 mmol) in toluene (1.5 mL) in the absence
of light. [b] Yield upon isolation.
Table 3: S-Alkyl thiocarbamate 2g catalyzed enantioselective bromolac-
tonization of 4.[a]
observed (Table 1, entry 2). In contrast, when the R group
was 1-naphthyl, that is, catalyst 2c, the desired product 5a was
obtained in 33% ee (Table 1, entry 3).
Entry Substrate
R
Product
t [days] Yield ee
[%][b] [%]
1
4a
4a
4b
4c
4d
4e
4 f
4g
4h
4i
C6H5
C6H5
2-naphthyl
4-MeC6H4
2,4-Me2C6H3 5d
4-MeOC6H4 5e
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
Me
5a
5a
5b
5c
3.5
3.5
3.5
3.5
3.5
2.5
5.5
4.5
4.5
8
97
96
97
95
97
95
99
99
95
96
97
96
99
98
92
92
92
90
81
19
91
88
91
70
78
85
82
88
2[c]
3
The effect of the nature of the N-aryl group in the S-alkyl
thiocarbamate catalyst on the bromolactonization was also
investigated. Unlike a previous investigation of O-alkyl
thiocarbamate catalysts, a study, wherein it was found that
the 2-MeO substituent on the aryl moiety was crucial for
obtaining a halocyclization product with high ee value,[11b] in
the study herein, the use of catalyst 2d, which contains the
N-2-methoxyphenyl moiety, resulted in only a slight increase
in enantioselectivity (Table 1, entry 4).
When the N-phenyl group was changed from
N-2-methoxyphenyl to N-3-methoxyphenyl, a slight drop in
enantioselectivity was observed (Table 1, entry 5). In sharp
contrast, changing the N-phenyl group to an N-4-methox-
yphenyl group, that is, catalyst 2 f, a dramatic increase in
enantioselectivity was observed (Table 1, entry 6). The steric
demand of the 4-alkoxy unit was found to affect the
enantioselectivity of the reaction. Although the use of catalyst
2g, which contains an N-4-ethoxyphenyl moiety, resulted in
enantioselectivity that was similar to that obtained when
using 2 f (Table 1, entry 7), the use of catalyst 2h, which
contains an N-4-isopropoxyphenyl moiety, resulted in a sharp
decrease in enantioselectivity (Table 1, entry 8).
With the optimized catalyst 2g in hand, we investigated
the scope of the halogen source. The use of N-bromoamides
other than NBP, including N-bromoacetamide (NBA),
N-bromosuccinimide (NBS), and 1,3-dibromo-5,5-dimethyl-
hydantoin (DBH) resulted in moderate to high enantioselec-
tivity (Table 2, entries 1–3). The use of N-iodosuccinimide
(NIS) gave the corresponding iodolactone with 75% ee
(Table 2, entry 5). However, no reaction was observed when
N-chlorosuccinimide (NCS) was used as a chlorine source
(Table 2, entry 4). An extensive survey of solvent was also
conducted and it was found that m-xylene/toluene (1:9) was
optimal (see the Supporting Information, Table S1).[16]
Next, the substrate scope was investigated (Table 3). In
general, most of the substrates gave the corresponding
4
5
6
7
8
9
10
11
12
13
14
5 f
5g
5h
5i
5j
5k
5l
4j
4k
4l
2
Et
2.5
3.5
3.5
isopropyl
cyclohexyl
4m
5m
15
3.5
95
86
[a] Reactions were carried out with acid 4 (0.05 mmol), catalyst 2g
(0.005 mmol), and NBP (0.06 mmol) in m-xylene/toluene (1:9) (1.5 mL)
in the absence of light. [b] Yield upon isolation. [c] The reaction was
conducted on a 1.0 mmol scale.
products with high yields and ee values. When the R group
on the alkene moiety is phenyl or 2-naphthyl, the correspond-
ing products were obtained in 92% ee (Table 3, entries 1 and
3). For substrates in which the R group is an electron-rich
phenyl group, the corresponding products were obtained in
good yield with high ee value, an exception being the
substrate 4e, which contains a 4-methoxyphenyl substituent
(Table 3, entries 4–6).[11]
Substrates 4 f—i, which contain electron-deficient aro-
matic substituents on the alkene moiety, gave the correspond-
ing products with high ee value, although relatively long
reaction times were required to obtain high yields of product
(Table 3, entries 7–10). Remarkably, substrates containing
aliphatic substituents on the alkene moiety also gave the
corresponding products with high ee value (Table 3,
2
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entries 11–14). The product derived from 3,3-dimethyl ole-
finic acid 4n was also obtained in good yield and with high
ee value (Table 3, entry 15). The absolute configuration of the
lactones 5 were assigned based on the X-ray crystal structure
of 5 f.[15,16]
Next, we examined the cyclization of the homologous
substrate 6 in the presence of the S-alkyl thiocarbamate
catalyst 2g. Unexpectedly, the cyclization of 6a in toluene,
a reaction catalyzed by 2g, gave the corresponding product
with a low ee value of 15% (Table 4, entry 1).[18] Further
with high yield and high enantiopurity (Table 4, entry 10).
Notably, when using the family of catalysts 3, the sense of
asymmetric induction is opposite that observed with the
family of catalysts 2; the absolute configuration of lactones 7
were determined based on the literature data.[11a] The reaction
was readily scalable without loss of enantioselectivity
(Table 4, entry 11).
Other derivatives of 6a were investigated as substrates
(Table 5). The catalytic protocol was suitable for the bromo-
lactonization of a range of sterically-hindered and electronic-
Table 4: Optimization of thiocarbamate catalysts 2 and 3 for the
enantioselective bromolactonization of 6a.[a]
Table 5: O-Alkyl thiocarbamate 3 f catalyzed enantioselective bromolac-
tonization of 6.[a]
Entry Substrate
R
Product t [h] Yield [%][b] ee [%]
1
2
3
4
5
6
7
8
6b
6c
6d
6e
6 f
6g
6h
6i
6j
6k
6l
6m
6n
6o
1-naphthyl
2-naphthyl
9-phenanthryl 7d
7b
7c
42
40
48
56
40
40
48
36
30
48
32
32
36
36
99
98
96
97
95
96
94
96
97
93
96
94
93
94
91
90
91
91
78
84
76
74
48
82
13
45
57
84
Entry
Catalyst
R
Yield [%][b]
ee [%]
1
2g
2g
2e
3b
3c
3d
3e
3 f
3g
3 f
3 f
–
–
–
Me
Et
nPr
Bn
allyl
93
94
96
95
94
93
95
93
92
95
98
15[c]
18[c]
41[c]
31
31
32
72
83
18
90
2[d]
1-pyrenyl
3-FC6H4
4-FC6H4
3,5-F2C6H3
4-CF3OC6H4
4-MeOC6H4
4-MeC6H4
Me
7e
7 f
7g
7h
7i
7j
7k
7l
3
4
5
6
7
8
9
9
10
11
12
13
14
isopropenyl
allyl
allyl
10[d]
11[d,e]
Et
7m
7n
7o
90
isopropyl
cyclohexyl
[a] Reactions were carried out with acid 6a (0.05 mmol), catalyst
(0.005 mmol), and NBP (0.06 mmol) in toluene (1.5 mL) in the absence
of light. [b] Yield upon isolation. [c] ent-7a was obtained as the major
enantiomer. [d] PhCl/toluene (1:9) (1.5 mL) was used as the solvent.
[e] The reaction was conducted on a 1.0 mmol scale. The reaction time
was 42 h.
[a] Reactions were carried out with acid 6 (0.05 mmol), catalyst 3 f
(0.005 mmol), and NBP (0.06 mmol) in PhCl/toluene (1:9) (1.5 mL) in
the absence of light. [b] Yield upon isolation.
deficient olefins 6 (Table 5, entries 1–8). The enantioselectiv-
ity was relatively low for the reactions of electronic-rich
substrates, a result that was also found in previous studies
(Table 5, entry 9).[11] For substrates containing alkyl substitu-
ents on the alkene moiety, the ee values of the resulting
products were moderate, although that of the product
obtained from 6l, which contains a methyl substituent, was
poor (Table 5, entries 11–14).
experiments led to the discovery that the use of catalyst 2e
gave product 7a with 41% ee, favoring the same enantiomer
that was observed when using catalyst 2g (Table 4, entry 3;
see the Supporting Information, Table S2).[16] We ultimately
identified the O-alkyl thiocarbamate catalyst 3 as being
suitable for mediating the cyclization of olefinic acid 6 (see
the Supporting Information, Table S3).[19] An investigation of
the effect of catalyst structure on reaction outcome led to the
conclusion that an O-alkyl thiocarbamate catalyst containing
a 1-naphthyl substituent at the carbinol carbon atom and a
N-4-ethoxyphenyl substituent at the carbamyl moiety is
optimal for the bromolactonization of 6. These structural
features were previously found to be optimal for the S-alkyl
thiocarbamate catalyst 2.[16] In addition, the identity of the
substituent on the nitrogen atom of the pyrrolidine moiety
was found to affect the enantioselectivity of the reaction; an
N-allyl substitutent was found to be suitable (Table 4,
entry 8). After systematic variation of the solvent, a tolu-
ene/chlorobenzene (9:1) solvent mixture together with NBP
was found to be optimal (see the Supporting Information,
Table S5).[16] By using these reaction conditions in the
bromolactonization of 6a, lactone 7a could be obtained
The selection of proline-derived catalysts allowed lac-
tones of either configuration to be obtained, a characteristic,
which is important for applications. For example, treatment of
7k with nBu3SnH and AIBN gave (R)-(+)-boivinianin A (8)
in 90% yield (Scheme 2). One could use the ent-3 f catalyst if
one wanted to synthesize (S)-(À)-boivinianin A.[20]
After achieving a number of successes with the O-alkyl
thiocarbamates, the ability of the S-alkyl thiocarbamates to
catalyze asymmetric bromolactionization came as a surprise.
Scheme 2. Synthesis of (R)-(+)-boivinianin A (8). AIBN=2,2’-azoiso-
butyronitrile.
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2
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2 f
2i
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S
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S
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90
83
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12
In summary, we have prepared a novel l-proline-derived
S-alkyl thiocarbarmate and used it for catalyzing bromolac-
tonization reactions that lead to the formation of d-lactones
with high enantioselectivity. The corresponding O-alkyl
thiocarbamate analogue was found to be a useful catalyst
for the enantioselective synthesis of g-lactones. The simplicity
of the prolinol synthesis facilitates the synthesis of catalyst
analogues with different steric and electronic environments.
The tunable handles, which include: a) the amine substituent,
b) the substituent on the oxygen- or sulfur-bearing methine
carbon, c) the thiocarbamate, which can be S type or O type,
and d) the N-aryl substituent of the thiocarbamate allow us to
modify the catalyst to adapt to different substrates. Further
investigation of the mechanism of the S-alkyl thiocarbamate
catalyzed halolactonization, as well as further expansion of
the substrate scope, are currently in progress.
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Received: March 15, 2012
Revised: June 4, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · cyclization · lactones ·
.
Lewis bases · natural products
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Chemie
[12] a) C. E. Song in Cinchona Alkaloids in Synthesis & Catalysis,
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formation of catalyst 2, see the Supporting Information,
Scheme S1.
[15] CCDC 870474 (2a) and 870475 (5 f) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[16] For more details, see the Supporting Information.
[17] Reactivity and enantioselectivity were not satisfactory in these
studies; see Refs. [8b] and [11].
[18] Despite the fact that 4 and 6 are homologs, it has been observed
that their behaviour in asymmetric halocyclization can be very
different; see Ref. [2j].
[19] We have examined the ability of 3 to catalyse the transformation
of olefinic acid 4a. Although the corresponding product was
obtained in good yields, the ee value was low; for more details,
see the Supporting Information, Table S4.
[14] Typically, elevated temperature is required to effect a Newman–
Kwart rearrangement. For representative reviews of Newman–
Kwart rearrangement, see: a) E. Schaumann, in Sulfur-Mediated
Rearrangement II, Springer, New York, 2007; b) G. C. Lloyd-
Jones, J. D. Moseley, J. S. Renny, Synthesis 2008, 661 – 689; the
Newman – Kwart rearrangement, which presumably forms part
of the conversion of 1 into 2, proceeded smoothly at room
temperature,
a facility, which could be attributed to the
neighboring-group effect. Products derived from a Newman –
Kwart rearrangement were not observed in the synthesis of 3, an
observation, which could be due to geometrical restriction. For
examples of the Newman – Kwart rearrangement that occur at
relatively low temperature, see: c) R. E. Hackler, T. W. Balko, J.
Org. Chem. 1973, 38, 2106 – 2109; d) M. Alajarin, M. Marin-
Luna, M. Ortin, P. Sanchez-Andrada, A. Vidal, Tetrahedron
[20] a) D. A. Mulholland, K. McFarland, M. Randrianarivelojosia,
ˇ
´
Biochem. Syst. Ecol. 2006, 34, 365 – 369; b) I. Coric, S. Mꢂller, B.
List, J. Am. Chem. Soc. 2010, 132, 17370 – 17373.
[21] We performed a series of NMR experiments with the carbamate
analogues. Preliminary results indicated that both S- and O-alkyl
thiocarbamates can interact with NBS but not with acetic acid.
For details, see the Supporting Information, Figure S1.
2009, 65, 2579 – 2590. For
a proposed mechanism of the
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5
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.
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Communications
Communications
Asymmetric Catalysis
X. Jiang, C. K. Tan, L. Zhou,
Y.-Y. Yeung*
&&&& — &&&&
Enantioselective Bromolactonization
Using an S-Alkyl Thiocarbamate Catalyst
The apple never falls far from the tree: S-
alkyl thiocarbamate 1 (see scheme,
NBP=N-bromophthalimide) was pre-
pared in high yield through a synthetic
sequence involving a Newman–Kwart
rearrangement of the corresponding O-
alkyl thiocarbamates. Compound 1 was
used to catalyze bromolactonization,
thus providing enantioenriched d-lac-
tones in excellent yield and enantioselec-
tivity.
6
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!