Enantioselective bromolactonization of cis-1,2-disubstituted olefinic acids using an amino-thiocarbamate catalyst

Article abstract of DOI:10.1039/c2cc31148h

A facile, highly regio- and enantioselective amino-thiocarbamate-catalyzed bromolactonization of cis-1,2-disubstituted olefinic acids has been developed. The use of the enantio-enriched lactones in the synthesis of chiral synthetic intermediates is also demonstrated. 2012

Full text of DOI:10.1039/c2cc31148h

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COMMUNICATION
Enantioselective bromolactonization of cis-1,2-disubstituted olefinic acids
using an amino-thiocarbamate catalystwz
Chong Kiat Tan, Chencheng Le and Ying-Yeung Yeung*
Received 15th February 2012, Accepted 19th March 2012
DOI: 10.1039/c2cc31148h
A facile, highly regio- and enantioselective amino-thiocarbamate-
catalyzed bromolactonization of cis-1,2-disubstituted olefinic acids
has been developed. The use of the enantio-enriched lactones in the
synthesis of chiral synthetic intermediates is also demonstrated.
3 and 5a in the synthesis of highly useful chiral building blocks
are shown.
To tackle the lack of enantioselectivity of 5a, acid 4a was
subjected to optimization using various catalysts (Table 1).
After a round of screening of the quinidine-derived catalysts 1,
it was found that 1a was still superior (Table 1, entry 1).
The asymmetric halocyclization of olefins is a class of reactions that
remains under-investigated despite the usefulness of the products1
and the promising breakthroughs in the recent years.2,3 Most of the
catalytic systems reported till date4,5 are only applicable to a
narrow spectrum of olefins. And this severely limits the application
of enantioselective halocyclization to the synthesis of enantio-
enriched biologically active molecules or natural products.
Table 1 Catalyst screening of the bromolactonization of 4a
A case in point is our recent report on the enantioselective
bromolactonization of the olefinic acid 2 to 6-endo lactone 3
using catalyst 1a (Scheme 1).5b While lactone 3 was formed with
91% ee, the bromolactonization of the isomeric cis-olefinic acid
4a resulted in the formation of the 5-exo lactone 5a with only
64% ee. It is important to note that both lactones 3 and 5,
which are not readily interchangeable, are valuable synthetic
building blocks (vide infra). Although 2 and 4a have a similar
structure, a catalytic and highly enantioselective cyclization of
4a remains absent. In addition, controlling the regioselectivity,
i.e. the 5-exo/6-endo ratio, seems not a trivial task as shown
by Denmark and Burk.6 In this report we will describe
the structural modifications of the catalyst needed to resolve
the problem. In addition, the applications of both lactones
Entrya
Cat.
R
Time/h
Yieldb, ee(%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
6a
6b
7
2,4-(MeO)2-C6H3
C6H5
4-MeO-C6H4
2,5-(MeO)2-C6H3
4-(NMe2)-C6H4
4-Br-C6H4
2,4-(CF3)2-C6H3
2,4-(MeO)2-C6H3
2,6-(EtO)2-C6H3
2,6-(EtO)2-C6H3
2,6-(EtO)2-C6H3
2,6-(EtO)2-C6H3
2,6-(EtO)2-C6H3
43
19
21
21
23
19
18
24
18
18
30
21
48
76, 60
94, 11
83, 38
62, 38
88, 0
98, 17
52, 19
82, ꢀ33
51, ꢀ71
50, 83
80, ꢀ82
77, 93
84, 93
Scheme 1 Asymmetric bromolactonization of acids 2 and 4a.
9
10
11c
12c
13c,d
6b
7
7
Department of Chemistry, NUS, 3 Science Drive 3, Singapore, 11754,
Singapore. E-mail: chmyyy@nus.edu.sg; Fax: +65-6779-1691;
Tel: +65-6516-7760
w This article is part of the joint ChemComm-Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
a
Reactions were conducted with acid 4a (0.05 mmol) and NBS
b
(0.06 mmol) in CH2Cl2 (1.5 ml). Isolated yield. Reactions were
c
z Electronic supplementary information (ESI) available. CCDC
864876. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc31148h
conducted in a blend of CHCl3 (0.5 ml) and n-hexane (1.0 ml).
d
Reaction was conducted on a 1 mmol scale.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5793–5795 5793

Next, we drew lessons from our previous studies which
confirmed the 6-alkoxy position as another tunable site. Thus,
catalyst 6a, which contains a 2,4-dimethoxyphenyl thiocarbamate
and a 6-O-isoamylquinoline unit, was used. However, only ꢀ33%
ee of the desired product was obtained (Table 1, entry 8). Next,
substituting 2,4-dimethoxyphenyl with 2,6-diethoxyphenyl
(catalyst 6b) gave a much improved ꢀ71% ee (Table 1, entry 9).
A switch to the pseudo-enantiomeric core (catalyst 7) returned
with 83% ee in CH2Cl2 (Table 1, entry 10). With further solvent
screening, we determined the blend of CHCl3/n-hexane (1: 2) to
be the optimal system (Table 1, entries 11 and 12). Lastly, the
reaction was also scalable to at least 1 mmol (Table 1, entry 13).
Having determined the optimal conditions, the substrate scope
of the catalytic protocol was probed. As shown in Table 2, good
yields and excellent ees (up to 98% ee) were generally obtained.
The highest enantioselectivity obtained in our study is for
lactone 5b (98% ee) which carries a 4-methylphenyl substituent
(Table 2, entry 2).
Scheme 2 Regioselectivity of the bromolactonization of 4d.
it was found that substantial amounts of 6-endo lactones were
obtained for some substrates. As shown in Scheme 2, the prepara-
tion of racemic 5d with triphenylphosphine sulfide came with a
substantial amount of the 6-endo lactone 8d. Alternatively, the use
of a 1 : 1 blend of the pseudo-enantiomeric 6b and 7 led to a highly
regioselective bromolactonization favouring the formation of 5d,
indicating that the amino-thiocarbamate catalyst could somewhat
control the regioselectivity.9
In addition, we rescreened the reaction with various bromine
sources. It emerged from the study that there was virtually no
difference in the enantioselectivity and regioselectivity when NBP
was used (Table 3, entry 1 vs. 2). However, the ee deteriorated to
84% when DBH was used (Table 3, entry 3). Interestingly, 89% ee
was obtained when TABCO10 was used together with a negligible
deterioration in the regioselectivity (Table 3, entry 4). In addition,
the bromolactonization of 2 with TABCO resulted in a slightly
diminished 85% ee (Table 3, entry 5 vs. Scheme 1).
Surprisingly, acid 4e bearing the 4-methoxyphenyl substituent
reacted sluggishly even at ꢀ30 1C (Table 2, entry 5). In addition
the corresponding 6-endo lactone 8e was isolated exclusively with
only 30% ee. This lack of enantioselectivity is consistent with the
observations from various reports on the halolactonization of
substrates bearing the 4-methoxyphenyl substituent.7
Another interesting observation is the surprisingly good 86% ee
obtained for lactone 5d bearing a 2-methylphenyl substituent
(Table 2, entry 4). While previous observations have found ortho-
substituents to be detrimental to the enantioselectivity, this example
appears to be an exception.5 The bromolactonization of substrates
bearing alkyl substituents resulted in moderate ees (Table 2, entries
14 and 15). The absolute configuration of lactones 5 was assigned
unambiguously by an X-ray crystallographic study on 5a.8
It is noteworthy that the regioselectivity of the bromolactoniza-
tion favoured the 5-exo lactones 5 almost exclusively. However,
during the preparation of racemic samples for the HPLC analysis,
The synthetic applications of both the 6-endo lactone 3 from the
previous study as well as the 5-exo lactone 5a are demonstrated by
the various transformations shown in Scheme 3. Displacement of
the bromide in 3 with sodium azide followed by hydrogenation led
to the formation of g-lactam 11 with preservation of the enantio-
selectivity (Scheme 3, eqn (1)). g-Lactam 11 is an important
building block of several biologically active molecules11 as
well as a chiral backbone as the oxazaborolidine catalyst.12 In
addition, treatment of 3 with DBU in refluxing THF affected the
cyclopropanation that yielded the bicyclic system 12 (Scheme 3,
eqn (2)); this represents a useful metal-free asymmetric cyclopro-
panation protocol.13 Indeed, hydrolysis of 12 affords a cyclopropyl
entity that is found in several peptidomimetics14 and other
natural products synthesis.15
Table 2 Substrate scope of the bromolactonization of 4
Next, in a similar scheme to eqn (1), 5a - 13 - 14 transfor-
mation could be achieved. d-Lactam 14 has been used as a
Entrya Acid
R
Temp/1C Time/h Yieldb, ee (%)
Table 3 Effect of various halogen sources on bromolactonization
1
2
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
C6H5
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ30
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ60
ꢀ78
21
43
42
48
72
42
95
96
96
70
108
94
108
60
60
77, 93
94, 98
95, 97
90, 86
49, 30
65, 95
83, 93
80, 92
78, 93
75, 94
70, 91
85, 87
83, 95
89, 53
80, 75
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
4-F-C6H4
4c
5d
6
7c
8
3-F-C6H4
Entry Acid Catalyst X+
Time/h Yielda (%) ee (%)
9
4-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
10c
11
12
13
14
15
1
2
4a
4a
4a
4a
2
7
7
7
7
1a
NBS
NBP
DBH
TABCO 94
TABCO 48
21
40
40
77
49
60
66
61
93
93
84
89
85
4-CF3O-C6H4 ꢀ60
2-Napthyl
Isopropyl
Cyclohexyl
ꢀ78
ꢀ78
ꢀ78
3
4b
5
a
Reactions were conducted with acid 4a (0.05 mmol) and NBS
NBP = N-bromophthalimide, DBH = 1,3-dibromo-5,5-dimethyl-
hydantoin, TABCO 2,4,4,6-tetrabromo-2,5-cyclohexadienone.
Isolated yield. Trace amount of the 6-endo product was obtained
(5-exo/6-endo 17 : 1).
(0.06 mmol) in a blend of CHCl3 (0.5 ml) and n-hexane (1.0 ml).
b
d
=
c
Isolated yield. Trace amount of 6-endo lactone was obtained.
a
b
The 6-endo d-lactone was isolated exclusively.
c
This journal is The Royal Society of Chemistry 2012
5794 Chem. Commun., 2012, 48, 5793–5795

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substituent. For examples, please refer to ref. 4 and 5.
8 CCDC no: 864876.
9 The sole origin of the regioselective bromolactonization with the
amino-thiocarbamate catalyst is still under further investigation.
10 TABCO is a bromine source without an N-haloamide system
unlike the other bromine sources used. The exact mechanistic
picture, in particular the halogenation activation mode, remains
unclear and is subjected to further studies.
Scheme 3 Synthetic applications of bromolactones 3 and 5.
synthetic precursor to several alkaloids (Scheme 3, eqn (3)).16
For example, reduction of d-lactam 14 with BH3ꢁSMe2 gave
3-hydroxypiperidine 15, which is found in the skeleton of several
biologically active molecules such as CP-99994 and L-733060.17
In summary, we disclosed a facile and highly enantio-
selective amino-thiocarbamate-catalyzed bromolactonization
of cis-1,2-disubstituted olefinic acids. The reaction is also
highly regioselective, forming 5-exo lactones in most cases.
The lactones from both the trans and the cis-1,2-disubstituted
olefinic acid could readily be modified into useful advanced
intermediates.
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We are grateful for the financial support from National
University of Singapore (grant no. 143-000-428-112).
Notes and references
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5793–5795 5795