Stereoselective formation of trisubstituted (Z)-chloroalkenes adjacent to a tertiary carbon stereogenic center by organocuprate-mediated reduction/alkylation

Article abstract of DOI:10.1021/ol301988d

A robust and efficient method for the synthesis of trisubstituted (Z)-chloroalkenes is described. A one-pot reaction of γ,γ-dichloro- α,β-enoyl sultams involving organocuprate-mediated reduction/asymmetric alkylation affords α-chiral (Z)-chloroalkene derivatives in moderate to high yields with excellent diastereoselectivity, and allylic alkylation of internal allylic gem-dichlorides is also demonstrated. This study provides the first examples of the use of allylic gem-dichlorides adjacent to the chiral center for novel 1,4-asymmetric induction.

Full text of DOI:10.1021/ol301988d

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4490–4493
Stereoselective Formation of
Trisubstituted (Z)‑Chloroalkenes Adjacent
to a Tertiary Carbon Stereogenic Center by
Organocuprate-Mediated Reduction/
Alkylation
Tetsuo Narumi, Takuya Kobayakawa, Haruo Aikawa, Shunsuke Seike, and
Hirokazu Tamamura*
Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku,
Tokyo 101-0062, Japan
tamamura.mr@tmd.ac.jp
Received July 17, 2012
ABSTRACT
A robust and efficient method for the synthesis of trisubstituted (Z)-chloroalkenes is described. A one-pot reaction of γ,γ-dichloro-R,β-enoyl
sultams involving organocuprate-mediated reduction/asymmetric alkylation affords R-chiral (Z)-chloroalkene derivatives in moderate to high
yields with excellent diastereoselectivity, and allylic alkylation of internal allylic gem-dichlorides is also demonstrated. This study provides the
first examples of the use of allylic gem-dichlorides adjacent to the chiral center for novel 1,4-asymmetric induction.
Stereoselective formation of functionalized alkenes is a
challenging task in organic synthesis, and construction of
halogenated alkenes while controlling the geometry of double
bonds is of particular interest.1 Among various halogenated
alkenes, chloroalkenes have attracted considerable interest in
recent years,2ꢀ6 not only because of their potential as synthe-
tically valuable intermediates7 but also because of their
importance as structural components of natural products.8
(1) (a) Guinchard, X.; Roulland, E. Synlett 2011, 19, 2779. (b) Shen,
Y. ACC. Chem. Res. 1998, 31, 584.
(4) For examples of terminal (Z)-chloroalkene syntheses, see:
~
ꢀ
(a) Giannerini, M.; Fananas-Mastral, M.; Feringa, B. L. J. Am. Chem.
Soc. 2012, 134, 4108. (b) Sashuk, V.; Samojzowicz, C.; Szadkowska, A.;
Grela, K. Chem. Commun. 2008, 2468. (c) Barluenga, J.; Moriel, P.;
(2) For selected reviews of chloroalkene syntheses, see: (a) Compre-
hensive Organic Functional Group Transformations; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press: Oxford, 1995; Vol. 2,
pp 606ꢀ619. (b) Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Semmelheck, M. F., Eds.; Pergamon Press: Oxford, 1991; Vol. 4,
pp 272ꢀ278. (c) Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Schreiber, S. L., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 807ꢀ809.
(3) For some examples of trisubstituted (E)-chloroalkene syntheses,
see: (a) Kigoshi, H.; Kita, M.; Ogawa, S.; Itoh, M.; Uemura, D. Org.
Lett. 2003, 5, 957. (b) Trost, B. M.; Pinkerton, A. B. J. Am. Chem. Soc.
1999, 121, 1988.
ꢀ
Aznar, F.; Valdes, C. Adv. Synth. Catal. 2006, 348, 347. (d) Baati, R.;
Barma, D. K.; Krishna, U. M.; Mioskowski, C.; Falck, J. R. Tetrahe-
dron Lett. 2002, 43, 959 and references cited therein.
(5) (a) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. J. Am.
Chem. Soc. 2001, 123, 9196. (b) Falck, J. R.; Bandyopadhyay, A.;
Barma, D. K.; Shin, D.-S.; Kundu, A.; Kishore, R. V. K. Tetrahedron
Lett. 2004, 45, 3039. (c) Baati, R.; Barma, D. K.; Falck, J. R.;
Mioskowski, C. Tetrahedron Lett. 2002, 43, 2183. (d) Su, W.; Jin, C.
Org. Lett. 2007, 9, 993.
r
10.1021/ol301988d
Published on Web 08/17/2012
2012 American Chemical Society

Despite the utility and importance of chloroalkenes,
however, reactions leading to the stereoselective formation
of trisubstituted (Z)-chloroalkenes are still limited.5,6
Falck and Mioskowski reported that the reaction of CrCl2
with 1,1,1-trichloroalkanes leads to the formation of (E)-
chlorovinylidene chromium carbenoids, which can react
with aldehydes to afford (Z)-chlorinated allylic alcohols
(Scheme 1a).5a An alternative method is the Pd-catalyzed
cross-coupling of 1,1-dichloro-1-alkenes with organome-
tallic reagents.6 In particular, Pd-catalyzed couplings with
large bite angle bisphosphines such as Xantphos and
DPEphos allow the selective formation of (Z)-chloroalk-
enes while avoiding the formation of bis-substituted pro-
ducts as has been described independently by Negishi6a
and by Roulland6bꢀd (Scheme 1b). While these protocols
have found widespread utility for the synthesis of these
important structures, the development of efficient systems
for stereoselective and divergent synthesis of trisubstituted
(Z)-chloroalkenes bearing various functionalities remains
challenging.
In this paper, we describe the stereoselective formation
of trisubstituted (Z)-chloroalkenes utilizing the organo-
cuprate-mediated reduction/asymmetric alkylation of γ,
γ-dichloro-R,β-enoyl sultam. This is a one-pot reaction
which provides in high yield the synthetically valuable
compounds containing a (Z)-chloroalkene flanking two
stereogenic centers, the R-chiral-β,γ-unsaturated carbonyl
motif, and a chiral allylic alcohol. In addition, we report
the first allylic alkylation of internal allylic gem-dichlorides
that provides an alternative method for the diastereoselec-
tive synthesis via 1,4-asymmetric induction of these im-
portant structural motifs.
We prepared sultam 1 and enoate 2 from chiral
R,R-dichloro-β-hydroxyester,10 reported by Imashiro and
Kuroda, as suitable substrates for reaction development
(Figure 1). At the onset of our studies, it was unclear if the
reaction of those substrates with organocuprates would entail
reduction, generating the dienolate intermediate. In order
to estimate the electron-accepting ability, our investigation
started with measurement of the reduction potentials (ERed).
The reduction potentials of sultam 1 and enoate 2 were ꢀ1.50
and ꢀ1.65 V, respectively. Based on these results and House’s
observation that R,β-unsaturated carbonyl compounds with
reduction potentials between ca. ꢀ2.4 V and ca. ꢀ1.1 V can
react with organocuprates such as Me2CuLi to give the
conjugate addition products,11 these substrates were expected
to promote both the single-electron transfer reduction and
the allylic alkylation.
As part of a program aimed at development of novel
approaches to chloroalkenes, we envisioned that the
organocuprate-mediated reduction9 of γ,γ-dichloro-R,β-
unsaturated carbonyl compounds would permit an effi-
cient access to (Z)-chlorinated dienolate intermediates,
which can be trapped with an appropriate electrophile,
providing trisubstituted (Z)-chloroalkenes (Scheme 1c).
Scheme 1. Synthesis of Trisubstituted (Z)-Chloroalkenes
Figure 1. Substrates for organocuprate-mediated reduction and
their reduction potentials (ERed).
In order to control the reaction products, the reactivity
of sultam 1a with organocuprates was examined (Table 1),
(8) For a recent example of the natural product bearing chloroalkene
motif: Ando, H.; Ueoka, R.; Okada, S.; Fujita, T.; Iwashita, T.; Imai, T.;
Yokoyama, T.; Matsumoto, Y.; van Soest, R. W. M.; Matsunaga, S.
J. Nat. Prod. 2010, 73, 1947 and also ref 1a.
(9) For selected examples of organocuprate-mediated reduction, see:
(a) Narumi, T.; Niida, A.; Tomita, K.; Oishi, S.; Otaka, A.; Ohno, H.;
Fujii, N. Chem. Commun. 2006, 4720. (b) Meyers, A. I.; Snyder, L.
J. Org. Chem. 1992, 57, 3814. (c) Fujii, N.; Habashita, H.; Shigemori, N.;
Otaka, A.; Ibuka, T.; Tanaka, M.; Yamamoto, Y. Tetrahedron lett.
1991, 32, 4969. (d) Takano, S.; Sekiguchi, Y.; Ogasawara, K. J. Chem.
Soc., Chem. Commun. 1988, 449 and references cited therein.
(10) Imashiro, R.; Kuroda, T. J. Org. Chem. 2003, 68, 974. For
details of the preparation of sultam 1 and enoate 2, see the Supporting
Information.
(6) For selected examples of Pd-catalyzed cross-coupling, see: Cross-
coupling with organozincs: (a) Tan, Z.; Negishi, E. Angew. Chem., Int.
Ed. 2006, 45, 762. Cross-coupling with organoborans: (b) Guinchard,
X.; Bugaut, X.; Cook, C.; Roulland, E. Chem.;Eur. J. 2009, 15, 5793.
(c) Roulland, E. Angew Chem. Int. Ed. 2008, 47, 3762. (d) Liron, F.;
Fosse, C.; Pernolet, A.; Roulland, E. J. Org. Chem. 2007, 72, 2220.
Cross-coupling with other organometallics, see ref 1a.
(7) (a) Geary, L. M.; Hultin, P. G. J. Org. Chem. 2010, 75, 6354.
(b) Bell, M.; Poulsen, T. B.; Jørgensen, K. A. J. Org. Chem. 2007, 72,
3053. (c) Jones, G. B.; Wright, J. M.; Plourde, G. W., II; Hynd, G.;
Huber, R. S.; Mathews, J. E. J. Am. Chem. Soc. 2000, 122, 1937.
(d) Alami, M.; Gueugnot, S.; Domingues, E.; Linstrumelle, G. Tetra-
hedron 1995, 51, 1209.
(11) House, H. O.; Umen, M. J. J. Org. Chem. 1973, 38, 2417.
Org. Lett., Vol. 14, No. 17, 2012
4491

Table 1. Reactivity of Sultam 1a with Organocuprates
Table 2. One-Pot Reduction/Asymmetric Alkylation of
(R)-Sultam 1a and (S)-Sultam 1ba
3þ4,
Z/E
of 3c
yield
(%)d
entry
reagents
additivesb
3/4c
1
2
3
4
5
6
7
8
Me2CuLi
ꢀ
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
>97:3
81
93
99
99
83
91
76
99
77:23
>97:3
90:10
61:39f
83:17
31:69
>97:3
>97:3
Me2CuLie
ꢀ
n-Bu2CuLie
MeCu(CN)Li
Me2CuLie
Me2CuLie
Me2CuLie
ꢀ
ꢀ
TMSCl
BF3 OEt2
3
HMPA
4 or 5,
dr
Me2Cu(CN)Li2
ꢀ
entry
substrate
RꢀX
yield (%)b
(%)c
a All reactions were carried out on a 0.1 mmol scale with 4 equiv of
organocuprates in the presence of Li salts. b 4 equiv. c Determined by 1H
NMR. d Yields of isolated products. e Higher order cuprates (ca. 0.4
equiv) were contained. f Diastereomeric ratio (dr) = 97:3.
1
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
MeI
BnBr
4a, 58
4b, 83
4c, 90
4d, 81
4e, 82
5a, 60
5b, 86
5c, 57
5d, 70
5e, 46
97:3
99:1
2d
3
t
BrCH2CO2 Bu
allylBr
97:3
4
97:3
5d
6
propargylBr
MeI
>95:5e
99:1
and as expected, exposure of 1a to Me2CuLi followed by
protic workup afforded a mixture of the reduced com-
pound 3 and the R-alkylated product 4 in high yield
(81%, entry 1). Significantly, excellent Z-selectivity was
7
BnBr
95:5
t
8
BrCH2CO2 Bu
97:3
9
10d
allylBr
97:3
>95:5e
propargylBr
observed.12 The use of a 2.4:1 MeLi LiBr/CuI mixture
3
a All reactions were carried out with 4 equiv of organocuprates,
16 equiv of HMPA, 2 equiv of Ph3SnCl, and 8 equiv of alkyl halide. b Yields
of isolated products. c Determined by HPLC. d At ꢀ30 °C. e Determined by
1H NMR.
enabled selective reduction, providing pure reduced com-
pound 3 in excellent yield (93%, entry 2). Changing the
methyl group of alkyl ligands to an n-butyl group resulted
in decreased selectivity (entry 3). Although the reaction
with lower order cyanocuprate or Me2CuLi with TMSCl
did not furnish better selectivity, addition of BF3 OEt2 led
3
proceeded with excellent diastereoselectivity. The reac-
tions with methyl iodide and bezyl bromide provided the
corresponding R-alkylated products 4a and 4b in 58% and
83% yields, respectively (entries 1 and 2), and the absolute
configuration of 4a was confirmed by single-crystal X-ray
analysis (Figure 2). Importantly, this strategy is amenable
to the introduction of functional groups such as ester, allyl,
and propargyl groups suitable for further transformation.
Treatment of dienolate with tert-butyl bromoacetate and
allyl bromide afforded the desired (Z)-chloroalkenes 4c
and 4d with ester and allyl functionality, in high yields
(entries 3 and 4). Propargyl bromide also gave the corre-
sponding (Z)-chloroalkene 4e in moderate yield (entry 5).
In addition, this one-pot strategy can be applied to (S)-
sultam 1b, providing the corresponding chloroalkenes
5aꢀ5e in moderate to high yields (entries 6ꢀ10).
to the preferable formation of R-alkylated product 4
(entries 4ꢀ6). In contrast, the reaction with HMPA pro-
vided excellent selectivity to the reduction but a decreased
yield (76%, entry 7). The best result was obtained with
higher order cyanocuprate, derived from CuCN 2LiCl
3
and 2 equiv of MeLi LiBr, which gave 3 in excellent yield
3
and selectivity (entry 8). Having identified higher order
cyanocuprate as the preferred reducing agent, we selected
the Gilman reagent (Me2CuLi) as an optimal reducing
agent because of the sufficient reactivity and selectivity to
reduction.
The optimized reduction condition in Table 1 (entry 2)
was applied to the one-pot reduction/asymmetric alkyla-
tion (Table 2). Previous studies have revealed that the
transmetalation from Cu and/or Li dienolate intermedi-
ates to the more reactive Sn dienolate intermediates is
critical for smooth alkylation.9a A variety of alkyl halides
were allowed to react with the (Z)-chlorinated dienolate
intermediate to provide chloroalkenes 4aꢀ4e flanking two
stereogenic centers in moderate to high yield with >97%
Z-selectivity. HPLC analysis showed that all the reactions
Finally, allylic alkylation of allylic gem-dichlorides was
examined. Recently, Feringa reported that terminal allylic
gem-dichlorides undergo Cu-catalyzed asymmetric allylic
alkylation with Grignard reagents affording (Z)-chloro-
alkenes bearing an allylic stereogenic center with excellent
regio- and enantioselectivity.4a Guided by this work, we
attempted Cu-catalyzed SN20-type alkylation with γ,
γ-dichloro-R,β-enoate 2, but these conditions did not work
for enoate 2, possibly due to the lower reactivity of the
(12) A NOESY cross-peak was observed between the olefinic proton
and the allylic stereogenic center, suggesting that the geometry of the
double bond was defined as shown; see the Supporting Information.
4492
Org. Lett., Vol. 14, No. 17, 2012

competes significantly with allylic alkylation of the sultam
1a, and the exclusive formation of 4a was not realized.
During the course of our studies on the allylic alkylation,
we considered that the chiral center at C5 adjacent to the
allylic gem-dichloride might induce the diastereoselectivity
without chiral auxiliaries.
This hypothesis was tested with the enoate 2. As shown
in Table 3, treatment of 2 with MeCu(CN)Li afforded
the R-methylated β,γ-enoate 6a in 98% yield as a 74:26
mixture of diastereomers with excellent Z-selectivity. The
major isomer was the (2S)-isomer, identified by the corre-
lation with the same compound 6a, prepared from the
corresponding (S)-sultam-derived compound 5a.13 Similar
results were obtained using EtCu(CN)MgBr, BnCu(CN)-
MgCl, and iBuCu(CN)MgCl affording the corresponding
R-alkylated chloroalkenes 6bꢀd in high yields with similar
selectivities (entries 2ꢀ4). Although the observed diaste-
reoselectivity has not been rationalized,14 these results
suggest that stereochemistry at C2 can be controlled by
the chiral center at C5 via 1,4-asymmetric induction.
In conclusion, we have described a one-pot organ-
ocuprate-mediated reduction/asymmetric alkylation of
γ,γ-dichloro-R,β-unsaturated carbonyl compounds. This
protocol allows not only the exclusive formation of tri-
substituted (Z)-chloroalkenes in high yields but also the
construction of an R-stereogenic center with excellent
diastereoselectivity. The resulting products are notable
for their high functionality and can perform as a poten-
tially useful intermediate for this important class of mole-
cules. In addition, we have identified a unique reactivity
of substrates containing an allylic gem-dichloride system
with organocuprates. These findings have proven to be
useful for the development of novel reactions based on
these classes of molecules. Efforts to elucidate the origin of
novel 1,4-asymmetric induction and to extend this work to
the diastereoselective synthesis of peptidomimetics with a
chloroalkene moiety are currently in progress.
Figure 2. ORTEP representation of 4a.
Table 3. Diastereoselective Allylic Alkylation of γ,γ-Dichloro-
R,β-enoate 2 by 1,4-Asymmetric Inductiona
entry
RCu(CN)M
Z/Eb
6, yield (%)c
drd
1
2
3
4
MeCu(CN)Li
>97:3
>97:3
>97:3
>97:3
6a, 98
6b, 96
6c, 70
6d, 95
74:26
66:34
77:23
69:31
EtCu(CN)MgBr
BnCu(CN)MgCl
iBuCu(CN)MgCl
a All reactions were carried out on a 0.2 mmol scale with 4 equiv of
organocuprates in the presence of Li salts. b Determined by 1H NMR.
c Yields of isolated products. d Determined by HPLC.
internal allylic system (see Supporting Information). At-
tention was therefore turned to the organocuprate-
mediated allylic alkylation. As presented in Table 1
(entry 4), the lower order cyanocuprate (MeCu(CN)Li)
promotes the allylic alkylation preferably to provide the
R-methylatedproduct4awithexcellent diastereoselectivity
(dr = 97:3). Extensiveexperimentation withMeCu(CN)Li
revealed that the electron transfer from organocuprates
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Young Scientists (B) from the
Ministry of Education, Culture, Sports, Science and a grant
from SENSHIN Medical Research Foundation. We are
grateful to Prof. Shigeru Nishiyama and Dr. Tsuyoshi Saito
(Keio University) for their assistance in the measurement of
the reduction potentials.
Supporting Information Available. Representative pro-
cedures, characterization data, cif file of compound 4a, and
copies of NMR and HPLC spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(13) See the Supporting Information for details.
(14) At the present stage of our understanding, the steric repulsions
between the olefinic proton at C3 and the Ph group at C5 may destabilize
the reactive conformer, which would lead to the (2R)-isomer. DFT
calculations also suggest that the reactive conformer to the (2S)-isomer
is favored by 4.42 kJ/mol over the conformer to the (2R)-isomer. See the
Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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