Formal [4 + 1]- and [5 + 1]-annulation by an SN2-conjugate addition sequence: Stereoselective synthesis of highly substituted carbocycles

Article abstract of DOI:10.1021/ol301044e

K₂CO₃-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted cyclopentane and cyclohexane derivatives, respectively via a sequence of S _N2-conjugate a

Full text of DOI:10.1021/ol301044e

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2826–2829
Formal [4 þ 1]- and [5 þ 1]-Annulation by
an SN2ꢀConjugate Addition Sequence:
Stereoselective Synthesis of Highly
Substituted Carbocycles
Benny Meng Kiat Tong, Hui Chen, Sin Yee Chong, Yi Li Heng, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received April 20, 2012
ABSTRACT
K2CO3-mediated reactions of 6-bromo-2-hexenoates and 7-bromo-2-heptenoate with active methylene compounds deliver highly substituted
cyclopentane and cyclohexane derivatives, respectively via a sequence of SN2ꢀconjugate addition reactions (formal [4 þ 1]- and [5 þ 1]-
annulation) in a diastereoselective manner.
Stereo- and regioselective construction of five- and six-
membered carbocycles (cyclopentane and cyclohexane
derivatives) is one of the most fundamental and important
issues in synthetic organic chemistry because of the im-
portance and prevalence of these motifs in many biologi-
cally active natural products and drug molecules.1 Inter-
molecular annulation reactions allow for the rapid and
selective construction of complex cyclic structures in a one-
pot manner from relatively simplebuildingblocks, whichis
one of the most ideal processes in organic synthesis
from atom-2 and step-economical3 points of view. While
the annulation approaches to construct cyclopentane
and cyclohexane derivatives have typically relied on the
[3 þ 2]-4 and [4 þ 2]-modes5 (cycloaddition),6 respectively,
the corresponding [4 þ 1]-7 and [5 þ 1]-processes8 are
scarce. Guided by these views as well as our current interest
in conjugate addition reactions9 of carbon nucleophiles
ꢀ
ꢀ
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2002, 35, 867. (g) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
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Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
J. S.; Gree, R. Chem. Rev. 2007, 107, 3286. (b) Pihko, A. J.; Koskinen,
(6) For recent selected reviews on construction of carbocycles by the
other approaches, see: (a) Moyano, A.; Rios, R. Chem. Rev. 2011, 111,
4703. (b) Leemans, E.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2011,
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r
10.1021/ol301044e
Published on Web 05/14/2012
2012 American Chemical Society

toward acrylate derivatives,10 we became interested in
the base-mediated reaction of 6-halo-2-hexenoates and
7-halo-2-heptenoates with active methylene compounds
that would provide cyclopentane and cyclohexane deriva-
tives, respectively, via a sequence of SN2ꢀconjugate addi-
tion (a formal [4 þ 1]- and [5 þ 1]-annulation).11ꢀ13
Herein, we report a study of this strategy on the carbocycle
synthesis in terms of the reaction efficiency as well as the
diastereoselectivity with various substituents.
with low selectivity while the cyclization proceeded
smoothly (93% yield for 24 h, dr = 39:36:25; see Supporting
Information).
Chart 1. Synthesis of carbocycles by K2CO3-mediated reactions
of 1 with active methylene compounds 2a,b
We began our investigation by studying the K2CO3-
mediated reactions of (E)-ethyl 4-benzyl-6-bromo-2-hex-
enoate (1a)14 with a series of active methylene compounds
2 (Chart 1).15 Malononitrile (2a), dimethylmalonate (2b)
underwent smooth reactions in DMF at room temperature
to afford trisubsituted-cyclopentanes 3aa and 3ab in good
yields with high 2,3-trans-diastereoselectivity. The reaction
of bis(phenylsulfonyl)methane (2c) was sluggish, giving
cyclopentane 3ac only in 13% yield (in spite of excellent
diastereoselectivity) even at a higher temperature of 60 °C.
Three successive stereogenic centers were constructed on
cyclopentane frameworks 3 using (phenylsulfonyl)aceto-
nitrile (2d) and tert-butyl cyanoacetate (2e). The reaction
with 2d provided a nearly single isomer of 3ad, while that
of 2e dropped the diastereoselectivity of 3ae, where the
stereochemistry of the major compound was 1,2-trans-
2,3-trans. Interestingly, construction of a cyclohexane
ring from (E)-ethyl 4-benzyl-7-bromo-2-heptenoate (1b)
with malononitrile (2a) resulted in a reversal of diaster-
eoselectivity that gave 2,3-cis-cyclohexane 3ba as a
major product in good yield. However, the reaction of
1b with dimethyl malonate (2b) was very sluggish (70%
yield, dr = 2.3:1 for 5 days), and that with (phenylsulfonyl)-
acetonitrile (2d) gave three inseparable diastereomers
a Unless otherwise noted, the reactions were carried out on the scale
of 0.3 mmol of 1 and 2 (1.5 equiv) with K2CO3 (1.1 equiv) in DMF (3 mL)
at rt under a N2 atmosphere. b Isolated yields were recorded above.
Diastereomer ratio determined by 1H NMR, and the structure of the
major isomer shown. c The reaction was carried out at 60 °C. The acyclic
product obtained only via the SN2 reaction was isolated in 60% yield (see
Supporting Information).
(7) For recent reports, see: (a) Coscia, R. W.; Lambert, T. H. J. Am.
Chem. Soc. 2009, 131, 2496. (b) Park, S.; Shintani, R.; Hayashi, T. Chem.
Lett. 2009, 38, 204. (c) Davie, C. P.; Danheiser, R. L. Angew. Chem., Int.
Ed. 2005, 117, 6017. (d) Spino, C.; Rezaei, H.; Dupont-Gaudet, K.;
Belanger, F. J. Am. Chem. Soc. 2004, 126, 9926. (e) Rigby, J. H.; Wang,
Z. Org. Lett. 2003, 5, 263. (f) Murakami, M.; Itami, K.; Ito, Y. J. Am.
Chem. Soc. 1997, 119, 2950.
(8) For recent reports, see: (a) Pan, L.; Liu, Q. Synlett 2011, 1073. (b)
Silvanus, A. C.; Groombridge, B. J.; Andrews, B. I.; Kociok-Kohn, G.;
Carbery, D. R. J. Org. Chem. 2010, 75, 7491.
(9) (1) For reviews, see: (a) Little, R. D.; Masjedizadeh, M. R.;
Wallquist, O.; McLoughlin, J. I. Org. React. 1995, 47, 315–552. (b) Jung,
M. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, U.K., 1991; Vol. 4, p 1. (c) Perlmutter, P. Conjugate
Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992.
(10) Tong, B. M. K.; Chiba, S. Org. Lett. 2011, 13, 2948.
Encouraged by the diastereoselective [4 þ 1]-annulation
toconstructcyclopentane, we nextset out toinvestigate the
reaction of malononitrile (2a) with various 4-substituted
6-bromo-2-hexenoates (Table 1). Methyl (1c), methoxy-
methyl (1d), allylic (1e), propargylic (1f), isopropyl (1g),
and phenyl (1h) moieties could be installed to afford the
corresponding cyclopentanes in good to excellent chemical
yields with high trans-diastereoselectivity.
The construction of cyclopentanes bearing three succes-
sive stereogenic centers was also examined using (phenyl-
sulfonyl)acetonitrile (2d) with various (E)-ethyl 4-benzyl-
6-bromo-2-hexenoates 1 (Table 2). The cyclopentanes 3
were obtained in good yields as a nearly single isomer
except for the reactions of 1c and 1d (entries 1 and 2).
We next examined the effect of the substituents on the
other positions of 6-bromo-2-hexenoates 1 for the diaster-
eoselectivity (Schemes 1 and 2). Installation of a phenyl
group on the C(5) position of 1i rendered the diastereos-
electivity to be lower, giving trisubsituted cyclopentanes
3ia and 3ia0 in a 1.7:1 ratio (Scheme 1a). It was found that
thereactionsoftrans-4,5-disubstituted6-bromo-2-hexeno-
ate 1j with 2a and 2d provided tetrasubstituted cyclopen-
tanes 3ja and 3jd, respectively, in high diastereoselectivity
(11) For prior reports on an SN2ꢀconjugate addition sequence, see:
(a) Gharpure, S. J.; Reddy, S. R. B. Tetrahedron Lett. 2010, 51, 6093. (b)
Gharpure, S. J.; Reddy, S. R. B. Org. Lett. 2009, 11, 2519. (c) Gharpure,
€
S. J.; Reddy, S. R. B.; Sanyal, U. Synlett 2007, 1889. (d) Desmael, D.;
Louvet, J.-M. Tetrahedron Lett. 1994, 35, 2549. (e) Bunce, R. A.;
Peeples, C. J.; Jones, P. B. J. Org. Chem. 1992, 57, 1727.
(12) For reports on synthesis of carbocycles by double conjugate
addition, see: Kamenecka, T. M.; Overman, L. E.; Ly Sakata, S. K. Org.
Lett. 2002, 4, 79 and references therein.
(13) For reports on the synthesis of carbocycles by a conjugate
additionꢀSN2 sequence, see: Atta, A. K.; Pathak, T. Eur. J. Org. Chem.
2010, 6810 and references therein.
(14) All the starting materials 1 used in this manuscript were prepared
from the corresponding lactones as a racemic form; see Supporting
Information for more details.
(15) Optimization of the reaction conditions for the present annula-
tion was examined using (E)-ethyl 6-bromohex-2-enoate and
(phenylsulfonyl)acetonitrile (2d), see Supporting Information.
Org. Lett., Vol. 14, No. 11, 2012
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Table 1. Reactions with Malononitrile (2a)a
Scheme 1. Effects of the Position of Substituents
a Unless otherwise noted, the reactions were carried out on the scale
of 0.3 mmol of 1 and 1.5 equiv of 2 in DMF (3 mL) at rt under a N2
atmosphere. b Isolated yields were recorded above. c The diastereomer
ratio was determined by 1H NMR.
was selective,17 (E)-ethyl 6-bromo-2-methylhex-2-enoate (1l)
was subjected to the present reaction conditions with
malononitrile (2a). The reaction afforded cyclopentane
3la with good diastereoselectivity (7.7:1), where the (R*,
R*)-isomer was formed as a major product probably via a
concerted process of CꢀC bond formation and protona-
tion (Scheme 2b; see Supporting Information for more
details).18
Table 2. Reactions with (Phenylsulfonyl)acetonitrile (2d)a
Finally, further derivatization of the dicyanocyclopen-
tanes and cyanophenylsulfonylcyclopentanes 3 was ex-
plored (Schemes 3 and 4). Dicyanocyclopentane 3aa was
treated with n-Bu3SnH in the presence of a catalytic
Scheme 2. Reactions of 1k and 1l
a Unless otherwise noted, the reactions were carried out on the scale
of 0.3 mmol of 1 and 1.5 equiv of 2 in DMF (3 mL) at rt under a N2
atmosphere. b Isolated yields were recorded above. c The diastereomer
ratio was determined by 1H NMR.
(Scheme 1b, c). These results implied that the diastereos-
electivity of the present cyclization could be controlled
mostly by the C(4) substituent.16
amount of AIBN, affording monodecyanated product
4aa.19 Chemoselective reduction of the ethoxycarbonyl
The reaction of (E)-ethyl 6-bromo-3-methylhex-2-enoate
(1k) with 2a delivered cyclopentane 3ka bearing two succes-
sive quaternary carbon centers (Scheme 2a). Intrigued by
whether the protonation process after the conjugate addition
(17) For discussion of diastereoselective (enantioselective) protona-
tion in conjugate addition of nucleophiles to acrylate derivatives, see:
(a) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1, 359. (b)
Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron: Asymmetry
2004, 15, 3653. (c) Niu, D.; Zhao, K. J. Am. Chem. Soc. 1999, 121, 2456.
(18) The stereochemistry of 3la was determined by the NOE analysis
of the corresponding lactone derivative 6la prepared from 3la via the
procedures in Scheme 3.
(16) The diastereoselectivity of the cyclized product 3 was confirmed
by the X-ray crystallographic analysis of several compounds as well as
the NOE analysis of the corresponding lactone derivatives in Schemes 3
and 4. See Supporting Information for more details.
(19) Curran, D. P.; Seong, C. M. Synlett 1991, 107.
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Org. Lett., Vol. 14, No. 11, 2012

group of 4aa by Kim’s procedure20 using the ate complex
of DIBAL-H and n-BuLi gave alcohol 5aa, which with
aqueous acid treatment underwent lactonization, deliver-
ing cis-bicyclic lactone 6aa in good yield (Scheme 3).
The conversion of 3la to lactone 6la could lead to the
confirmation of the stereochemical outcome by NOE
measurement.
Scheme 4. Chemoselective ReductionꢀLactonization of Cya-
nophenylsulfonylcyclopentanes 3ad and 3hd
Scheme 3. Chemoselective ReductionꢀLactonization of
Dicyanocyclopentanes 3aa and 3la
In summary, a concise and stereoselective methodology
for the synthesis of highly substituted carbocycles has been
developed.22 Further investigation on the application of
the present strategy to construct complex organic mole-
cules is currently underway.
Acknowledgment. This work was supported by funding
from Nanyang Technological University and Singapore
Ministry of Education (Academic Research Fund Tier 2:
MOE2010-T2-1-009). We thank Dr. Yongxin Li and Dr.
Rakesh Ganguly (Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University) for assistance in
X-ray crystallographic analysis.
Kim’s chemoselective reduction of the ethoxycarbonyl
group of 3ad and 3hd followed by aqueous acid treatment
gave R-sulfonyl bicyclic lactones 8ad and 8hd, respectively,
in good yields. Reductive cleavage of the phenylsulfonyl
group of 8 with lithium naphthalenide followed by proto-
nation could afford cis-bicyclic lactone 6 smoothly with
retention of the configuration. Similarly, the resulting
lithium enolate generated from 8 could be trapped with
carbon electrophiles such as methyl iodide and allyl bro-
mide, giving 9ad and 10ad bearing a new quaternary
carbon center with retention of the configuration.21
Supporting Information Available. Experimental pro-
cedures, characterization of new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org. The authors declare no competing financial
interest.
(20) Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1217.
(21) The stereochemistry of 9ad and 10ad was determined by the
NOE analysis, see Supporting Information.
(22) The preliminary discussion about the orign of the diastereo-
selectivity in the cyclization was described in Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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