Tandem conjugate addition-elimination reaction promoted by chiral pyrrolidinyl sulfonamide (CPS)

Article abstract of DOI:10.1039/b810905m

Chiral pyrrolidinyl sulfonamides have been found to promote the conjugate addition-elimination reaction between activated allylic bromides and 1,3-dicarbonyl compounds with high enantioselectivities and the highly functionalised products can be used to ge

Full text of DOI:10.1039/b810905m

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Tandem conjugate addition–elimination reaction promoted by chiral
pyrrolidinyl sulfonamide (CPS)wz
Junye Xu, Xiao Fu, Ruijuan Low, Yong-Peng Goh, Zhiyong Jiang and
Choon-Hong Tan
Received (in Cambridge, UK) 26th June 2008, Accepted 22nd August 2008
First published as an Advance Article on the web 24th September 2008
DOI: 10.1039/b810905m
Chiral pyrrolidinyl sulfonamides have been found to promote the
conjugate addition–elimination reaction between activated
allylic bromides and 1,3-dicarbonyl compounds with high en-
antioselectivities and the highly functionalised products can be
used to generate a variety of interesting enantiomerically pure
compounds via simple transformations.
MBH adducts can also be transformed to allylic bromides in a
single step using NBS.6 These allylic bromides interact with amines
via SN2 or tandem CA-E reactions depending on the solvent and
The SN20 reaction (1) and the tandem conjugate addition–
elimination reaction (2) which yields SN20 type product are not
reaction conditions.7 It was shown previously by Basavaish that
often distinguished from one another. A possible approach
with 2 equivalents of quinidine, alcohols and phenols can add in a
towards asymmetric tandem conjugate addition–elimination
tandem CA-E mode (3).8 This is a synthetically useful reaction but
(CA-E) is the installation of a chiral auxiliary as the leaving
examples with high enantioselectivities are rare. Thus, we designed
group (LG). Using chiral pyrrolidines as the auxiliary, Tamura
a series of chiral pyrrolidinyl sulfonamides (CPS) (Fig. 1) to
showed that it is possible to achieve high diastereoselectivity
with lithium diorganocuprates, leading to optically active 3-
investigate the asymmetric transformations of activated allylic
bromides via tandem CA-E reactions.
The CPS 1a–d were easily synthesised from commercially
substituted 2-methylene-cycloalkanones.1
available chiral amino alcohols. Formation of aziridines from
the amino alcohols was followed by a regioselective ring opening
reaction using pyrrolidine9 (see ESIz). In 3 steps, the CPS can be
obtained in multigram quantities and high yields. We investigated
the use of CPS 1a in the tandem CA-E reaction of activated allylic
bromide 2 (Table 1), which was previously not investigated as a
substrate for this reaction. We have recently found that S,S0-
dialkyl dithiomalonates are effective donors for chiral bicyclic
The a-methylene-b-hydroxycarbonyl compounds derived
guanidine catalysed Michael reactions10 due to the high a-proton
from Morita–Baylis–Hillman (MBH) reactions, also known
acidity. S,S0-Di-tert-butyl dithiomalonate 3a was employed for the
as MBH adducts, can be modified to acetates or protected
optimization of the reaction. While catalytic amounts of CPS can
with BOC. When such MBH derivatives were used, catalytic
be employed, the reaction rate was too slow to be useful. We
amount of Cinchona alkaloids can be installed as the leaving
increased the amount of CPS to 2 equivalents for subsequent
group (LG) in situ.2,3 Nucleophiles (Nu), such as amines and
investigations. The reaction carried out in toluene (entry 1) proved
phenols, can then be inserted via a tandem CA-E reaction with
to be low-yielding and reactions in polar solvents such as CH2Cl2
moderate enantioselectivity. Allylic amination of MBH acet-
and CH3CN were relatively faster and provided good levels of
ates with a similar strategy using catalytic chiral phosphines
enantioselectivities (entries 2 and 3). Optimization based on mak-
also resulted in moderate enantioselectivity.4 A successful
ing structural changes to CPS revealed that the tert-butyl group
tandem CA-E reaction has been developed by Ramachandran
increases the enantioselectivity of the reaction (entry 4). When the
for the addition of benzophenone imine of glycine tert-butyl
pyrrolidine ring was replaced by a piperidine, there was a slight
ester to MBH acetates using quaternised Cinchona alkaloids
decrease of both yield and ee (entry 5). When the tosyl group was
under phase transfer conditions.5 This is a useful method for
replaced by a bulkier 2,4,6-trimethylphenylsulfonyl group in CPS
the synthesis of glutamic acid derivatives.
1d, we observed the best result (entry 6). The loading of CPS
promoter could be reduced to 1.5 equivalents while the yield and
enantioselectivity were maintained at a satisfactory level (entry 7).
Department of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore. E-mail: chmtanch@nus.edu.sg;
Tel: +65-65162845
w We would like to dedicate this paper to Professor Andrew B. Holmes
on the occasion of his 65th birthday.
z Electronic supplementary information (ESI) available: General
procedures and characterisations. CCDC reference numbers
692929–692932. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b810905m
Fig. 1 Structures of chiral pyrrolidinyl sulfonamides (CPS) 1a–d.
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Table 1 Reaction between 2-(bromomethyl)cyclopent-2-enone and
S,S0-di-tert-butyl dithiomalonate in the presence of CPS 1a–d
Table 3 Reaction between activated allylic bromides 5a–c and
S,S0-di-tert-butyl dithiomalonate in the presence of 1d
Entry
CPS (equiv.) Solvent
Time/h Yield (%)a
ee (%)b
Entry
Substrate Product Time/h Yield (%)a ee (%)b
1
2
3
4
5
6
7
a
1a (2.0)
1a (2.0)
1a (2.0)
1b (2.0)
1c (2.0)
1d (2.0)
1d (1.5)
Toluene
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
48
18
16
14
20
12
12
15
74
88
97
74
97
97
44
54
59
73
70
90
90
1
5a
5b
5c
b
6a
6b
6c
11
20
29
40
37
46
74
88
94
2
3c
a
c
Isolated yield. Chiral HPLC. Reaction at room temperature.
gave slightly lower levels of enantioselectivities than 2. These
reactions were much slower and yields were much lower when
they were conducted at room temperature. Increasing reaction
temperature improved the reaction rate without affecting the
enantioselectivity. Under reflux conditions and with 2 equiva-
lents of 1d, we were able to improve the yield to a moderate
level. The reaction of cycloheptenone 5c was still carried out at
room temperature as product 6c was found to be unstable at
elevated temperature. The double addition product, derived
from the addition of a second 1,3-dicarbonyl donor onto 6a–c,
was found to be a major side product in these reactions.
To demonstrate the usefulness of this reaction, the tandem
CA-E products were further modified to generate a variety of
interesting compounds 7–12 via simple transformations (Scheme
1). Chiral allylic alcohol 7 was obtained with a diastereomeric
ratio 10 : 1 when product 4c was subjected to Luche reduction
conditions.11 A solvent mixture of MeOH/CH2Cl2 1 : 1 was
used, as 4c was only partially soluble in MeOH.
b
Isolated yield. Chiral HPLC.
A series of 1,3-dicarbonyl compounds were explored as
nucleophiles with the optimised conditions (Table 2). Sterically
bulky donors such as S,S0-di-tert-octyl dithiomalonate 3b and
S,S0-di-adamantyl dithiomalonate 3c afforded SN20 type pro-
ducts with high enantioselectivities (entries 1–4). We are con-
cerned about the high amounts of promoter required for this
reaction. Fortunately, the CPS promoter 1d can be recovered
with 90% yield, using a simple acid–base workup. It can also be
reused without further purification, for two further cycles with-
out loss of yield and enantioselectivity of the product 4b (entries
2 and 3). Other 1,3-dicarbonyl compounds such as keto-thio-
esters were proved to be suitable donors for this reaction (entries
5–7). Tandem CA-E products were obtained in high yields and
ees, with diastereomeric ratios of approximately 1 : 1. Interest-
ingly, when 2-acetylcyclopentanone 3g was subjected to this
reaction, high enantioselectivity was also observed (entry 8).
Several allylic bromides of different ring sizes were prepared
and investigated to determine the scope of the reaction
(Table 3). Allylic chloride 5a was much easier to handle than
the corresponding allylic bromide, which was unstable under the
reaction conditions and had led to many side products. The
reactions between 5a–c and 3a were promoted with 1d and
Lewis acid catalysed Diels–Alder reaction between 4c and
cyclopentadiene can lead to chiral spiro-compounds such as 8.12
Such a spiro framework can be found in natural products such
Table 2 Reaction between 2-(bromomethyl)cyclopent-2-enone and
1,3-dicarbonyl compounds in the presence of 1d
Time/ Yield ee
(%)a
Entry 3 [R1, R2]
Product
] 4b
4b
4b
4c
4d
4e
4f
h
(%)b
1
3b [R1 = R2 =
3b
16
21
21
44
26
23
43
29
83
74
87
77
91
89
76
60
94
94
95
2c
3d
4e
5
3b
3c [R1 = R2 =
3d [Ph, StBu]
3e [4-MeOC6H4, StBu]
3f [Me, StBu]
3g
]
97
94, 94
98, 95
94, 94
98, 95
6
7
8
4g
[
]
a
b
Isolated yield. Chiral HPLC. Recovered 1d, 2nd cycle. Recov-
c
d
e
ered 1d, 3rd cycle. Reaction in CH2Cl2.
Scheme 1 Stereoselective synthesis of a diverse range of compounds,
7–12.
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6 H. M. R. Hoffmann and J. Rabe, J. Org. Chem., 1985, 50, 3849.
7 H.-Y. Chen, L. N. Patkar, S.-H. Ueng, C.-C. Lin and A. S.-Y. Lee,
Synlett., 2005, 13, 2035.
8 D. Basavaiah, N. Kumaragurubaran, D. S. Sharada and R. M.
Reddy, Tetrahedron, 2001, 57, 8167.
9 (a) W. Ye, D. Leow, S. L. M. Goh, C.-T. Tan, C.-H. Chian and
C.-H. Tan, Tetrahedron Lett., 2006, 47, 1007; (b) B. M. Kim, S. M.
So and H. J. Choi, Org. Lett., 2002, 4, 949.
Scheme 2 Approach of cyclopentadiene to 4c in the Diels–Alder
reaction.
10 (a) W. Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y.-T. Soh and
C.-H. Tan, Adv. Synth. Catal., 2007, 349, 2454; (b) M. Agostinho
and Shu Kobayashi, J. Am. Chem. Soc., 2008, 130, 2430; (c) G. Lalic
¯
and E. J. Corey, Tetrahedron Lett., 2008, 49, 4894.
11 A. L. Gernal and J.-L. Luche, J. Am. Chem. Soc., 1981, 103, 5454.
12 For Yb(OTf)3 catalysed Diels–Alder reactions, see: S. Kobayashi,
I. Hachiya, T. Takahori, M. Araki and H. Ishitani, Tetrahedron
Lett., 1992, 33, 6815.
13 J. H. Kim, H.-K. Kim, S. B. Jeon, K.-H. Son, E. H. Kim, S. K. Kang,
N.-D. Sung and B.-M. Kwon, Tetrahedron Lett., 2002, 43, 6205.
14 We assigned the exo stereochemistry according to the following report:
R. R. Sauers and T. R. Henderson, J. Org. Chem., 1974, 39, 1850.
15 S. Cabrera, J. Aleman, P. Bolze, S. Bertelsen and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2008, 47, 121.
as artemisolide,13 which is an inhibitor of IkB kinase b. It was
observed that the exo adduct14 8 is preferred, indicating second-
ary orbital interactions between the carbonyls of dithiomalonate
and the developing p bond of cyclopentadiene (Scheme 2).
The a,b-unsaturated moiety of the tandem CA-E product 4a
was suitably set up for conjugate addition reactions. Hetero-
Michael reactions using thiol15 or amine16 as the nucleophile
gave products with high diastereoselectivites (d.r. 4 20 : 1). An
a-methyl ketone 11 was generated with a moderate diastereo-
meric ratio (4 : 1) via a palladium catalysed hydrogenation.17
Conjugate addition reaction with Gilman’s reagent18 provided
adduct 12 with excellent diastereomeric ratio (420 : 1). The
relative and absolute stereochemistry of products 7–12 were
assigned by 1H NMR spectrum19 and comparision with literature
values.20 The assignment was further confirmed by single crystal
X-ray analyses of compounds 8, 11 and 12. (see ref. 23 and ESIz).
We are keenly aware that the key weakness in this methodolgy
is the high amount of CPS required, albeit that they were
recoverable. Studies are on-going to make this reaction even more
synthetically useful. The replacement of Br in the allylic bromides
by CPS to form an ammonium salt21 is a fairly rapid reaction.
However, CPS is a weak base which is not effective in promoting
the conjugate addition of the 1,3-dicarbonyl donors. The use of
stronger organic bases such as TBD22 as additives may promote
the reaction and allow a catalytic amount of CPS to be used. We
have also prepared a polystyrene-supported chiral pyrrolidinyl
sulfonamide (PS-CPS) from chiral diamine and polystyrene-
bonded sulfonyl chloride. We will determine the effectiveness of
this approach to improve the ease of recovery of the CPS.
16 No catalyst is required for the aza-Michael reaction. The reaction
was carried out by mixing 4a and pyrazole in CH2Cl2 at room
temperature (see ESIz).
17 D. A. Evans and C. L. Sims, Tetrahedron Lett., 1973, 47, 4691. Ethyl
acetate was found to provide product with highest diastereoselectivity.
18 E. Nakamura, S. Matsuzawa, Y. Horiguchi and I. Kuwajima,
Tetrahedron Lett., 1986, 27, 4029.
19 The coupling constant of adjacent protons Ha and Hb was determined
to be 3J = 10.1 Hz, which indicates a trans geometry according to the
following report: M. I. Donnoli, P. Scafato, M. Nardiello, D.
Casarini, E. Giorgio and C. Rosini, Tetrahedron, 2004, 60, 4975
20 T. Perrard, J.-C. Plaquevent, J.-R. Desmurs and D. Hebrault, Org.
.
Lett., 2000, 2, 2959.
21 The structure of the ammonium salt was determined by single
crystal X-ray analyses (see ESIz) as follows:
In conclusion, we have developed a tandem conjugate
addition–elimination reaction between activated allylic bro-
mide and various 1,3-dicarbonyl compounds. The reaction
was promoted by CPS which were easily prepared from their
corresponding amino alcohols. Stereoselective synthesis of
several enantiomerically pure compounds were also presented.
We are grateful for financial supports (R-143-000-337-112)
and a scholarship (to J. Xu) from National University of
Singapore. We also thank the Medicinal Chemistry Program
for their financial support. We also thank Ms Tan Geok Kheng
and Dr Koh Lip Lin for their assistance with the X-ray analyses.
.
22 W. Ye, J. Xu, C.-T. Tan and C.-H. Tan, Tetrahedron Lett., 2005,
46, 6875.
23 Crystal data for compounds 8, 11, 12 and ref. 21, CCDC reference
numbers 692929–692932. Crystal data of 8: C34H44O3S2, M =
564.81, monoclinic, a = 18.7796(12), b = 13.0947(8),
c =
11.9738(7) A3, b = 94.651(2)1, T = 296(2) K, space group P2(1)/
c, Z = 4, 19592 refelctions measured, 6730 unique (Rint = 0.0577).
R1 = 0.0666. The final wR(F2) was 0.1418. Crystal data of 11:
C17H28O3S2, M = 344.51, triclinic, a = 9.7296(18), b = 11.309(2),
c = 11.780(2) A3, a = 65.152(4)1, b = 68.166(4)1, g = 64.564(4)1.
T = 295(2) K, space group P1, Z = 2, 11759 refelctions measured,
7994 unique (Rint = 0.0335). R1 = 0.0860. The final wR(F2) was
0.1925. Flack parameter was 0.17(11). Crystal data of 12:
C21H36O3S2, M = 400.62, monoclinic, a = 18.8390(19), b =
12.6378(14), c = 10.2009(10) A3, b = 95.756(3)1. T = 223(2) K,
space group Cc, Z = 4, 8 416 refelctions measured, 4012 unique
(Rint = 0.0523). R1 = 0.0595. The final wR(F2) was 0.1237. Crystal
data of ref. 21: C26H41BrCl2N2O3S, M = 612.48, orthorhombic,
a = 8.1010(7), b = 12.7221(10), c = 28.619(2) A3, T = 223(2) K,
space group P2(1)2(1)2(1), Z = 4, 20732 refelctions measured, 6762
unique (Rint = 0.0662). R1 = 0.0579. The final wR(F2) was 0.1430.
Flack parameter was 0.008(11).
Notes and references
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2 J. N. Kim, H. J. Lee and J. H. Gong, Tetrahedron Lett., 2002, 43, 9141.
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5 P. V. Ramachandran, S. Madhi, L. Bland-Berry, M. V. R. Reddy
and M. J. O’Donnell, J. Am. Chem. Soc., 2005, 127, 13450.
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5528 | Chem. Commun., 2008, 5526–5528