Aminothiocarbamate-catalyzed asymmetric bromolactonization of 1,2-disubstituted olefinic acids

Article abstract of DOI:10.1021/ol200840e

An efficient and enantioselective bromolactonization of 1,2-disubstituted olefinic acids using an amino-thiocarbamate catalyst has been developed, resulting in the formation of δ-lactones containing two chiral centers with up to 99% yield, 95% ee.

Full text of DOI:10.1021/ol200840e

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2738–2741
Aminothiocarbamate-Catalyzed
Asymmetric Bromolactonization of
1,2-Disubstituted Olefinic Acids
Chong Kiat Tan, Ling Zhou, and Ying-Yeung Yeung*
3 Science Drive 3, Department of Chemistry, National University of Singapore,
Singapore 117543
chmyyy@nus.edu.sg
Received March 31, 2011
ABSTRACT
An efficient and enantioselective bromolactonization of 1,2-disubstituted olefinic acids using an amino-thiocarbamate catalyst has been
developed, resulting in the formation of δ-lactones containing two chiral centers with up to 99% yield, 95% ee.
Halolactonization is an important class of organic
transformation under the umbrella of halonium-induced
cyclization. The resulting halolactones are of particular
interest to synthetic chemists because of the importance
of the lactone moieties that pervades a wide spectrum of
molecular structures (e.g., the fundamental unit of many
natural products). In addition, the halogen substituents
can be readily modified to other useful functional groups
(e.g., by nucleophilic substitution). The importance of
halolactonization is underscored by the large number
of applications to the synthesis of useful building
blocks and biologically active molecules.1,2 Although
halolactonizations have been studied for decades, their
modifications to the enantioselective versions have been
problematic.3,4 Recently, several elegant reports ap-
peared that provided access to a number of valuable
halolactones with a practical level of enantioselectivities.5
However, the olefinic moieties in the substrates are
limited to 1,1-disubstituted alkenes that result in γ- and
δ-lactones containing quaternary centers. Halolactoniza-
tions that involve substrates with 1,2-disubstituted olefi-
nic moieties6 are attractive targets since the resulting
lactones contain two stereogenic centers with a well-
defined esterÀhalogen antirelationship; asymmetric
halolactonization of this class of substrates remains un-
common, and until now only a substoichiometric cataly-
tic and two stoichiometric chiral auxiliary-controlled
~
ꢀ
(1) (a) Rodrıguez, F.; Fananas, F. J. In Handbook of Cyclization
Reactions; Ma, S., Ed.; Wiley-VCH: New York, 2010; Vol. 4, pp 10À20. (b)
Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N.
Tetrahedron 2004, 60, 5273–5308. (c) Lava, M. S.; Banerjee, A. K.;
Cabrera, E. V. Curr. Org. Chem. 2009, 13, 720–730.
(2) Examples of related halonium-induced cyclizations: (a) Kang,
S. H.; Lee, S. B.; Park, C. M. J. Am. Chem. Soc. 2003, 125, 15748–15749.
(b) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900–903. (c)
Snyder, S. A.; Treitler, D. Angew. Chem., Int. Ed. 2009, 48, 7899–7903.
(d) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc. 2010,
132, 14303–14314. (e) Hennecke, U.; Muller, C. H.; Frohlich, R. Org.
Lett. 2011, 13, 860–863.
(3) Early examples of asymmetric halolactonization reactions: (a)
Haas, J.; Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297–300. (b) Haas, J.;
Bissmire, S.; Wirth, T. Chem.;Eur. J. 2005, 11, 5777–5785.
(4) For a mechanistic discussion on the problems of enantioselective
halocyclization, see:(a) Brown, R. S. Acc. Chem. Res. 1997, 30, 131–137.
(b) Cui, X.-L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653–5658. (c)
Denmark, S. E.; Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132,
1232–1233.
(5) (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J.
Am. Chem. Soc. 2010, 132, 3298–3300. (b) Zhang, W.; Zheng, S.; Liu, N.;
Werness, J. B.; Guzei, I. A.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664–
3665. (c) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2010, 132, 15474–15476. (d) Veitch, G. E.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2010, 49, 7332–7335. (e) Murai, K.; Matsushita,
T.; Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H. Angew.
Chem., Int. Ed. 2010, 49, 9174–9177. (f) Ning, Z.; Jin, R.; Ding, J.; Gao,
L. Synlett 2009, 2291–2294. (g) Chen, G.; Ma, S. Angew. Chem., Int. Ed.
2010, 49, 8306–8308.
(6) During the preparation of this paper, an elegant report appeared
in the literature that is related to the asymmetric co-chlorination of 1,
2-disubstituted olefins: Jaganathan, A.; Garzan, A.; Whitehead, D. C.;
Staples, R. J.; Borhan, B. Angew Chem., Int. Ed. 2011, 50, 2593–2596.
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10.1021/ol200840e
Published on Web 04/26/2011
2011 American Chemical Society

approaches were disclosed that offered low to moderate
enantiomeric purities.7
accommodation of other substrates to the asymmetric
bromolactonization protocol.
Recently, the use of aminothiocarbamate catalyst 3c in
the asymmetric bromolactonization of 1 to 2 was de-
scribed by our research group.5c In the same report, we
also disclosed that aminothiocarbamate 3c was not only
applicable to 1,1-disubstituted olefinic acids but also to
6a, a 1,2-disubstituted alkene substrate (Scheme 1). In this
Scheme 2. Enantioselectivities Obtained with Various Ami-
nothiocarbamates
Scheme 1. Enantioselective Synthesis of γ-Lactones 2 and
δ-Lactone 7a
paper, we disclose our success at attaining practical
enantioselectivities of δ-lactones (up to 95% ee). With
it, we aim to demonstrate that the catalyst is tunable to
match a different alkenoic acid substrate and that the
stereochemistry of the δ-lactone is consistent with our
previously proposed model.
Motivated by the promising results with catalyst 3c
(Scheme 1), we embarked on a round of catalyst screening
in hope of boosting the enantioselectivity. As shown in
Table 1, the best catalyst 3c for the enantioselective
synthesis of γ-lactones 1 (R = Ph, 50% ee in CH2Cl2)5c
was only able to afford the δ-lactone 7a with 39% ee
(Scheme 2). In fact, both 3a and 3b were unable to provide
any enantioenriched δ-lactone 7a in CH2Cl2 despite 3b
being able to furnish the γ-lactone 1 (R = Ph) with 40%
ee.5c Additionally, 3d was only able to afford 4% ee.
Surprisingly, a switch to a quinidine core results in a
dramatic change in the enantioselectivity (Scheme 2, 3b vs
4a, 3c vs 4b), and 4b catalyzed bromolactonization of 6a
afforded 7a with 70% ee. On the other hand, catalyst 5a
could only afford 7a with À47% ee. Since catalysts 3c and
4b differ in only a methoxy group on the quinoline unit,
the dramatic increase in ee suggests yet another site for
potential tuning. This implies that the tuning of steric
and electronic properties of the alkoxy substituent on the
quinoline and N-aryl of the thiocarbamate may allow the
After the identification of the best aminothiocarbamate
catalyst 4b, the reaction solvent was varied to further
boost the enantioselectivity. Gratifyingly, the CHCl3/
toluene (1:2) solvent blend reported previously was found
to boost the enantioselectivity to 91% ee (Table 1,
entry 1).
A series of alkenoic acids 6 was then subjected to this
optimal reaction condition.8À10 For the olefinic acids
with electron-rich aryl substituents, generally excellent
yields and ees were obtained (Table 1, entries 1À12). It is
noteworthy that the electron-rich system (e.g., 4-methox-
yphenyl in 6h) typically has a negative effect on the
enantioselectivity in some reports.5 Nonetheless, this
(8) For details see the Supporting Information.
(9) Representative procedure: to a solution of alkenoic acid 6 (0.05
mmol, 1.0 equiv), catalyst (2.8 mg, 0.005 mmol, 0.1 equiv) in CHCl3 (0.5
mL), and toluene (1.0 mL) at À78 °C in the dark under N2 was added N-
bromosuccinimide (10.6 mg, 0.06 mmol, 1.2 equiv). The resulting
mixture was stirred at the corresponding temperature and monitored
by TLC. The reaction mixture was quenched with satd Na2SO3 (2.0 mL)
at À78 °C and then was warmed to rt. The solution was diluted with
water (3.0 mL) and extracted with CH2Cl2 (3 Â 5 mL). The combined
extracts were washed with brine (5.0 mL), dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography to yield the corresponding product 7.
(7) (a) Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.;
Zhang, S. B. J. Org. Chem. 2004, 69, 2874–2876. (b) Garnier, J. M.;
Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2007, 3281–3291. (c)
Grossman, R. B.; Trupp, R. J. Can. J. Chem. 1998, 76, 1233–1237.
(10) Under the optimized conditions, there was no improvement in ee
when NsNH2 was added as an additive.
Org. Lett., Vol. 13, No. 10, 2011
2739

effect was not apparent in the present studies (Table 1,
entries 3À5, 9, and 10). On the other hand, the 2-sub-
stituted aryl systems returned with lower enantioselectiv-
ities, which may be ascribed to the steric interaction with
the olefinic moiety (Table 1, entries 6 and 8). In some
cases, especially for the electron-deficient substrates, the
reactions were sluggish at À78 °C. Nevertheless, these
reactions could be brought to completion by simply
raising the temperature and high yields, and enantios-
electivities were still achieved (Table 1, entries 4, 8, and
13À17). Heteroaromatic substrates are also amendable to
our protocol (Table 1, entries 11 and 12). The highest
enantioselectivity (95% ee) was obtained with the 2-thio-
phene-substituted 7j. The scalability of the protocol was
tested at 2 mmol with success (Table 1, entry 2). The
absolute stereoconfigurations of 7 were assigned on the
basis of the X-ray crystallographic structure of 7a.8
All of the substrates were found to be selective
toward the generation of the 6-endo lactone 7 as the only
products.11 Such selectivity should not be taken for
granted as demonstrated by a recent study reported by
Denmark and co-workers.12 In the series of Lewis
bases in their study, some of the catalytic systems suffer
from poor 6-endo to 5-exo selectivity. This result fur-
ther demonstrates an additional selectivity (besides
enantioselectivity) that our catalyst confers toward the
bromolactonization of (E)-5-substituted pent-4-enoic
acids.
Examination of the stereoconfiguration of 7a from the
X-ray study appears to indicate a chiral transition-state
model that is consistent with our initial proposal for the
enantioselective formation of γ-lactones, which involves
a dual activation of NBS by the thiocarbamate.5c The key
features of this proposed mechanism are the activation of
the Br by a Lewis basic sulfur13,14 and the activation of the
carbonyl of succinimide by the NÀH hydrogen-bond-
ing interaction. A plausible mechanism is proposed in
Scheme 3, in which alkenoic acid 6 may be captured and
assembled into A,15 where the ensuing nucleophilic attack
by the carboxylate would lead to 7 with the designated
stereoconfiguration. The significant enhancement in ee
when using an ortho-OMe catalyst (e.g., Scheme 1, 4a vs
4b) further suggests that the methoxy substituent may
serve as a steric screening group that can destabilize
transition state B and hence minimize the formation of
ent-7. A lower ee was obtained when the cis-olefinic acid
6q was used (Table 1, entry 18), which could be ascribed to
the less repulsion in transition state B.
Table 1. Enantioselective Bromolactonization of 6
Scheme 3. Plausible Mechanism of the Bromolactonization of 6
entrya acid
R
temp (°C) time (h) yieldb (%), ee (%)
1
6a Ph
6a Ph
À78
À78
À78
À50
À78
À78
À78
À55
À78
À78
À78
À78
À40
À50
À50
À40
À30
À78
32
48
21
56
80
25
40
52
54
25
55
48
48
42
54
48
14
48
99, 91
99, 91
99, 94
92, 80
99, 88
70, 64
95, 61
99, 86
99, 81
80, 94
99, 95
98, 86
90, 90
99, 94
64, 89
85, 88
99, 92
44, 64
2c
3
6b 4-Me-C6H4
6c 4-tBu-C6H4
6d 3-Me-C6H4
6e 2-Me-C6H4
6f 1-naphthyl
6g 2-naphthyl
6h 4-MeO-C6H4
6i 3-MeO-C6H4
6j 2-thienyl
6k 3-thienyl
61 4-CF3O-C6H4
6m 4-Cl-C6H4
6n 3-Cl-C6H4
6o 4-Br-C6H4
6p 4-F-C6H4
6q Ph
4
5
6
7
8
9
10
11
12
13d
14
15
16d
17
18e
In summary, we have developed an efficient and en-
antioselective bromolactonization of 1,2-disubstituted
olefinic acids using a substoichiometric amount of ami-
nothiocarbamate as the catalyst. This report represents the
first asymmetric bromolactonization resulting in the for-
mation of δ-lactones containing two stereogenic centers
a Reactions were conducted with alkenoic acid 6 (0.05 mmol) with
NBS (0.06 mmol). b Isolated yield. c Reaction was conducted on a 2
mmol scale. d A small amount of γ-lactone was detected. For details, see
the Supporting Information. e 6q is a cis-olefinic substrate and the
corresponding 5-exo lactone was obtain as the only product.
(13) (a) Arduengo, A. J.; Burgess, E. M. J. Am. Chem. Soc. 1977, 99,
2376–2378. (b) Boyle, P. D.; Godfrey, S. M. Coord. Chem. Rev. 2001,
223, 265–299.
(11) A small amount of 5-exolactone products was obtained when
substrates 6n and 6o were used. For details, see the Supporting
Information.
(12) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 20655–20660.
(14) An extensive review on Lewis base catalysis: Denmark, S. E.;
Beuter, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638.
(15) No ee was observed when the alcohol substrate corresponding to
acid 6a was used, which indicated that a substrate containing an acidic
proton may be necessary.
2740
Org. Lett., Vol. 13, No. 10, 2011

with synthetically useful yields and enantioselectivities.
The dramatic increase in ee with just the inclusion of a
methoxy subsituent on the quinoline unit indicates a
promising site for tuning the catalyst’s reactivity profile.
Further investigation to clarify the mechanistic picture,
including the role to the MeO group on the quinoline, is
underway.
Acknowledgment. We acknowledge financial support
from the National University of Singapore (Grant No.
143-000-428-112).
Supporting Information Available. Experimental pro-
cedures and additional information. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
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