Tandem regio- And stereoselective organocuprate-mediated bis-allylic substitutions

Article abstract of DOI:10.1021/ol800727f

anti-5-Acetoxy-4-halo-α,β-enoates undergo sequential or tandem reactions with two different magnesium cuprate reagents to afford anti-2,3-dialkyl-4,5-enoates in high chemical yield and with excellent diastereoselectivity. The one-pot tandem procedure can be achieved with 30 mol % of CuCN and affords a rapid stereoselective combinatorial approach to vicinal disubstituted γ,λ-enoates containing functionality a either end of the carbon chain for subsequent functional group elaboration. The methodology should provide a powerful practical strategy for acyclic stereoselection.

Full text of DOI:10.1021/ol800727f

ORGANIC
LETTERS
2
008
Vol. 10, No. 10
087-2090
Tandem Regio- and Stereoselective
Organocuprate-Mediated Bis-Allylic
Substitutions
2
R. Karl Dieter* and Fenghai Guo
Hunter Laboratory, Department of Chemistry, Clemson UniVersity,
Clemson, South Carolina 29634-0973
dieterr@clemson.edu
Received March 31, 2008
ABSTRACT
anti-5-Acetoxy-4-halo-r,ꢀ-enoates undergo sequential or tandem reactions with two different magnesium cuprate reagents to afford anti-2,3-
dialkyl-4,5-enoates in high chemical yield and with excellent diastereoselectivity. The one-pot tandem procedure can be achieved with 30 mol
%
of CuCN and affords a rapid stereoselective combinatorial approach to vicinal disubstituted γ,δ-enoates containing functionality at either
end of the carbon chain for subsequent functional group elaboration. The methodology should provide a powerful practical strategy for
acyclic stereoselection.
1
Allylic substitution reactions mediated by organocopper,
amines, alcohols) and/or malonate nucleophiles and generally
encompass either two S 2 reactions or one S 2′ reaction
followed by an S 2 reaction where the latter is not an allylic
substitution. To our knowledge, there are no reports of two
sequential or tandem S 2′-allylic substitution reactions
mediated by palladium or copper, although copper-mediated
multipot sequential S 2 reactions on vicinal epoxymesylates
2
1c
palladium, and less frequently nickel reagents constitute
a powerful synthetic strategy for functional group transfor-
mations, substituent introduction, and chirality transfer.
N
N
N
Although inherent problems of regio- (e.g., S
N
2 vs S
N
2′) and
N
stereocontrol (e.g., anti vs syn-S 2′) abound, regio- and
N
stereoselectivity can be mediated by choice of metal reagent,
leaving group, solvent, and other reaction conditions. While
palladium-mediated tandem allylic substitutions have been
N
4
have been reported. Although no precedent existed for these
chemoselective bis-S 2′-allylic substitutions, the synthetic
utility of monoallylic substitutions suggested that tandem
or sequential copper mediated S 2′-allylic substitution reac-
N
3
1,2
described, the reported reactions involve heteroatom (e.g.,
N
tions on vinyl oxiranes or 3,4-diheteroatom-substituted
alkenes could provide a powerful methodology for asym-
metric acyclic stereoselection if solutions to the problems
of chemo-, regio-, and stereocontrol could be found. We now
(
1) For reviews see: (a) Breit, B.; Demel, P. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; Chapter 6, pp
88-223. (b) Karlstrom, A. S. E.; Backvall, J.-E. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; Chapter 8, pp
59-288. (c) Kar, A.; Argade, N. P. Synthesis 2005, 2995–3022. (d)
Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2005, 44, 4435–4439.
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1
2
(
2
(3) (a) Bredenkamp, M. W.; Holzapfel, C. W.; Toerien, F. Synth.
Commun. 1992, 22, 2447–57. (b) Uozumi, Y.; Tanahashi, A.; Hayashi, T.
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Martens, J.; Mehler, T.; Muzart, J. Tetrahedron Lett. 1995, 36, 5527–30.
(d) Ito, K.; Imahayashi, Y.; Kuroda, T.; Eno, S.; Saito, B.; Katsuki, T.
Tetrahedron Lett. 2004, 45, 7277–7281.
(
T. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol. 2, Chapter
V.2.2.1 pp 1845-1885. (c) Kazmaier, U.; Pohlman, M. In Metal-Catalyzed
Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004; Vol. 2, Chapter 9, pp 531-583. (d) Trost, B. M. Chem.
ReV. 1996, 96, 395–422.
(4) Girard, C.; Mandville, G.; Bloch, R. Tetrahedron: Asymmetry 1993,
4, 613–616.
10.1021/ol800727f CCC: $40.75
Published on Web 04/19/2008
 2008 American Chemical Society

report solutions to these problems that afford a practical and
versatile methodology for vicinal acyclic stereoselection.
Although enantioenriched vinyl oxiranes are readily avail-
Table 1. Reaction of Organometallic Reagents with
δ-Acetoxy-γ-halo-R,ꢀ-enoates
5
able, they undergo copper-mediated allylic substitution
reactions with variable regioselectivity (i.e., S
N
2′ vs S
N
2)
1
e,f
depending upon the substitution pattern. The reactions of
6
7
epoxide 1 (or the methyl ester) and its aziridine analogue
with cuprate reagents have been studied by several groups,
and similar transformations have been reported for nonep-
8
oxide γ,δ-dioxygenated R,ꢀ-enoates and γ-bromo-R,ꢀ-
a
b
c
d
entry RX R (RM)
equiv
product % yield
dr
9
enoates. Although reaction of 1 with Me
2
Zn/CuCN in DMF
2′-regioselectivity (94:6), the
reaction was only examined for the methylzinc cuprate
n
e
1
2
3
4
5
6
7
8
9
1
1
1
1
4a
4a
4b
4a
4b
4b
4a
4b
4a
4a
4b
4b
4b
Bu (A)
1.1
1.1
1.1
1.0
1.0
1.1
1.1
2.0
2.0
2.2
2.0
1.0
1.0
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5c
5d
25
85
89
86
77
83
86
90
88
89
83
87
43
84:16
83.5:16.5
85:15
93:7
90:10
88:12
87:13
92:8
85:15
89:11
88:12
85:15
>95:5
reportedly affords excellent S
N
n
n
n
n
n
n
e
e
Bu (B)
Bu (B)
Bu (B)
Bu (B)
Bu (C)
Bu (C)
6
a
reagent. We quickly ascertained that the reaction was not
general, affording a comparable regioselectivity for Et Zn/
2
n
CuCN, but lower regioselectivity (87:13) for the Bu
transferable ligand (eq 1) under comparable conditions. The
major anti-diastereomer was formed in all three cases with
excellent diastereoselectivity (dr ) 97:3).
e
Et (C)
Et (C)
Et (C)
f
h
f
0
1
2
3
a
Et (C)
s
Bu (B)
Bu (B)
t
e,g
A ) R2CuLi, -78 °C. B ) RCuCNLi, -78 °C. C ) R2Zn/CuCN,
23 °C. Equivalents of RCuCNLi and R2Zn and CuCN unless otherwise
noted. Yieldsbaseduponisolatedproductspurifiedbycolumnchromatography.
Diastereomeric ratio determined from H NMR integration values for the
b
-
c
d
1
1
3
e
vinyl protons or alkene C absorption peak heights. Ethyl 2-n-butyl-2,4-
hexadienoate (entry, % yield: 1, 60%; 2, 4%; 3, 2%; 7, 2%) or ethyl sorbate
f
We turned our attention to δ-acetoxy-γ-halo-R,ꢀ-enoates
(entry 13, 24%) was formed. Catalytic amounts of CuCN (0.1 equiv) were
g
1
0
employed. Ethyl 4-chloro-2,4-hexadienoate was also formed in 20% yield.
4
a,b (Table 1), which can be prepared from epoxide 1.
h
Catalytic amounts of CuCN (0.2 equiv) were employed. Reaction was
n
2
Initially, treatment of 4a with Bu CuLi in THF gave low
run at -40 °C.
N
chemical yields of the S 2′ syn-diastereomer with modest
diastereoselectivity (entry 1). Utilization of the less reactive
alkylcyanocuprate reagent (i.e., RCuCNLi) gave good chemi-
cal yields with 4a-b (entries 2 and 3), but with the same
modest diastereoselectivity. Using exact and precise stoichi-
ometries, the diastereoselectivity could be significantly
improved (entries 4 and 5), suggesting stereochemical
point to the facility with which allylic acetates 5a-d can
undergo elimination and perhaps isomerization as the cause
of low diastereoselectivity. Formation of ethyl 4-chloro-2,4-
t
hexadienoate (20%) upon reaction of 4b with BuCuCNLi
presumably arises via a reductive elimination pathway.
Despite these sensitivities to side reactions, high chemical
yields and diastereoselectivities could be achieved under the
optimized reaction conditions.
We next examined the possibility of effecting a stereospe-
cific allylic substitution on allylic acetate 5a formed from
sensitivity to excess cuprate reagent. Utilization of the
n
Bu Zn/CuCN reagent afforded comparable yields of 5a but
2
diminished diastereoselectivities (entries 6 and 7). With
stoichiometric quantities of CuCN, Et Zn gave good chemical
2
yields and dr’s of 5b (entry 8), and the latter was significantly
diminished when catalytic quantities of CuCN were em-
ployed (entries 9-11). Branched alkylcyanocuprates gave
high to modest chemical yields and modest to high dr’s
4
a or 4b via the first allylic substitution. Treatment of 5a
with the lithium alkyl(cyano)cuprate reagent afforded only
diene via elimination of the acetate substituent (eq 2). A
trialkylzincate reagent in the presence of CuCN gave clean
S 2′-substitution but with poor diastereoselectivity, while
N
utilization of a magnesium dialkylcuprate reagent gave good
chemical yield and modest diastereoselectivity (eq 2).
(
entries 12 and 13).
In several instances, formation of ethyl 2-alkyl-2,4-
hexadienoates (entry 1: 60%) or ethyl sorbate (entry 13: 24%)
(
5) Olofsson, B.; Somfai, P. In Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Darmstadt, 2006; Chapter 9, pp
15-347.
6) (a) Hirai, A.; Matsui, A.; Komatsu, K.; Tanino, K.; Miyashita, M.
3
(
Chem. Commun. 2002, 1970–1971. (b) Ibuka, T.; Tanaka, M.; Nemoto,
H.; Yamamoto, Y. Tetrahedron 1989, 45, 435–442.
(
(
7) Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875–4886.
8) (a) Ibuka, T.; Nako, T.; Nishii, S.; Yamamoto, Y. J. Am. Chem.
Soc. 1986, 108, 7420–7422. (b) Yamamoto, Y.; Asao, N. J. Org. Chem.
1
990, 55, 5303–5304.
9) Girard, C.; Mandville, G.; Bloch, R. Tetrahedron: Asymmetry 1993,
, 613–616.
10) Ha, D. J.; Kim, Y.; Lee, S. J.; Kang, S. K.; Ahn, J. H.; Kim, S. S.
Choi, J.-K. Tetrahedron Lett. 2004, 45, 5969–5972.
(
4
Having determined that magnesium dialkylcuprates were
the reagents of choice, we examined a series of solvents in
(
2088
Org. Lett., Vol. 10, No. 10, 2008

6
-8 in good chemical yields and with excellent diastereo-
selectivity (Table 3). The initial protocol utilized 2 equiv of
Table 2. Reaction of 5-Acetoxy-2-alkyl-3,4-enoates with
Cuprate Reagents
Table 3. Tandem Reactions of 4b with Two Different
Magnesium Cuprate Reagents
a
b
c
entry
ROAc
solvent
product
% yield
dr
d
1
2
3
4
5
6
7
8
9
5b
5b
5a
5a
5a
5b
5b
5b
5a
5a
5a
5b
5b
5a
5a
5a
5a
5b
Et2O
6b
6b
6b
6a
6a
7b
7b
7b
7a
7a
7a
8b
8b
8a
8a
8a
9a
9b
89
84
82
85
86
85
92
89
87
83
90
84
77
81
82
90
73
71
90:10
92:8
86:14
93:7
t-BuOMe
d
Et2O
d
CH2Cl2
CH2Cl2
a
b
c
entry
CuCN quiv
product
% yield
dr
d
92:8
Et2O
Et2O
85:15
85:15
88:12
87:13
85:15
93:7
79:21
94:6
83:17
92:8
1
2
3
4
5
6
7
8
9
2.0
1.0
2.0
1.0
2.0
1.0
1.0
2.0
1.0
0.3
2.0
6a
6a
6b
6b
7a
7a
7b
8a
8a
8a
8b
85
70
76
74
73
70
71
71
69
68
82
1
95:5
92:8
95:5
95:5
96:4
94:6
92:8
97:3
94:6
93:7
98:2
e
g
CH2Cl2
Et2O
PhCH3
CH2Cl2
t-BuOMe
CH2Cl2
Et2O
CH2Cl2
t-BuOMe
10
11
12
13
14
15
16
17
18
d,f
g
g
10
11
a
g
91:9
90:10
86:14
h
CH2Cl2
CH2Cl2
Reactions conditions: (1) CuCN (2.0 equiv): (i) R CuCNMgX (1.0
h
equiv, X ) Cl, Br), CH2Cl2, -78 °C, 4 h, warm to -40 °C, stir 2 h; (ii)
a
CuCN (1.0 equiv), -78 °C, 10 min; (iii) RMgX (2.0 equiv, X ) Cl, Br),
Reactions were run at -78 °C for approximately 8 h and then allowed
1
-
78 to 25 °C. (2) CuCN (0.3-1.0 equiv): (i) R MgX (1.0 equiv, X ) Cl,
to warm to room temperature before quenching, unless otherwise noted.
Yields are based upon isolated products purified by column chromatography.
Diastereomeric ratios were determined from integration of the H NMR
vinyl absorptions or via peak heights of C NMR absorptions. Consists
b
Br), CuCN (0.3-1.0 equiv), CH2Cl2, -78 °C, 4 h, warm to -40 °C, stir
b
c
1
2 h; (ii) RMgX (2.0 equiv, X ) Cl, Br), -78 to +25 °C. Yields are based
c
1
3
d
upon isolated products purified by column chromatography. Diastereomeric
1
ratios were determined from integration of the H NMR vinyl absorptions
of solvent/t-BuOMe (11-12:1) from the t-BuOMe solution of RMgBr.
13
e
or via peak heights of C NMR absorptions.
Reaction was run at - 78 °C for 12 h, warmed to room temperature and
f
g
quenched. Quenched at -30 °C. Consists of solvent:Et2O (11-12:1) from
h
the Et2O solution of n-BuMgBr or i-PrMgCl. Consists of solvent:THF
(
22:1) from the THF solution of PhMgCl.
CuCN (entries 1, 3, 5, 8, and 11) with the second equivalent
of CuCN being added after completion of the first allylic
substitution. Seeking to minimize the amount of CuCN
employed, the tandem reaction was then carried out with
one equivalent of CuCN and the chemical yields and
diastereoselectivities were only slightly lower (entries 2 vs
an effort to optimize the diastereoselectivity (Table 2). While
Et O uniformly gave modest to good dr’s ranging between
3:17 to 90:10 (entries 1, 3, 6-7, 9, and 14), BuOMe gave
2
t
8
slightly better dr’s (entry 2 vs 1, 16 vs 14). Toluene did not
improve the stereoselectivity (entry 10 vs 9). Consistently
better dr’s were obtained when CH
1
, 4 vs 3, 6 vs 5, and 9 vs 8). Utilization of 0.3 equiv of
CuCN gave the same chemical yields and diastereoselectivity
as 1.0 equiv of CuCN for 8a (entry 10). When catalytic
amounts of CuCN (5 mol %) were employed under otherwise
identical reaction conditions for the reaction of 4b with
n-BuMgCl, 5a, 8a, and the elimination product ethyl
2 2
Cl was used as solvent
(
entries 4-5, 11, 13, 15), except when a sterically bulky
transferable ligand was employed (entries 8, 17-18). Utiliza-
tion of Pr or Ph transferable ligands generally resulted in a
diminuation of the diastereoselectivity (entries 8, 17, and 18),
although in one case good diastereoselectivity could be
achieved in CH
i
4-chloro-2,4-hexadienoate were formed in a 3:3:1 ratio. Thus,
under these reaction conditions, 0.3 equiv of CuCN repre-
sents the minimum amount of Cu(I) salt that may be
employed. This one-pot tandem protocol affords the anti-
2
Cl
2
(entry 11). These results indicate that
2′ substitution is
the stereochemical preference for anti-S
N
the dominant control element and that steric factors in either
the cuprate reagent or allylic substrate have minor effects
on the stereoselectivity of the reaction.
1
1
diastereomers complementing formation of the syn-dias-
tereomer obtained via epoxide 1.
In summary, we have developed a versatile method for
vicinal acyclic stereoselection that offers significant advan-
tages over existing methods for the stereoselective prepara-
tion of anti-2,3-dialkyl-4-alkenoates. The existing procedures
With optimization of the magnesium dialkylcuprate reac-
tion with allylic acetate 5 in hand (Table 2), we turned our
attention to the development of a one-pot tandem bis S
allylic substitution protocol. Sequential treatment of 4b with
R CuCNMgX (X ) Cl, Br) and then with R CuMgX (X )
N
2′-
1
2
(
11) The stereochemistry of 7a was confirmed by conversion of 7a to
Cl, Br) under the reaction conditions developed for 5 afforded
the iodo lactone and X-ray analysis of the iodo lactone.
Org. Lett., Vol. 10, No. 10, 2008
2089

afford poor to good diastereoselectivity (e.g., Claisen rear-
offers the potential to introduce a variety of alkyl and aryl
ligands onto an acyclic backbone in a highly stereoselective
fashion. Extension of the methodology to enantioenriched
epoxides and vicinal halo acetates will provide a versatile
route to enantioenriched synthons containing functionality
at both ends of the chain for further elaboration.
12
rangements depending upon substitution patterns), require
the construction of unique substrate structures (e.g., Claisen
1
2
13
rearrangements or lithium amide alkylations of 3-alkyl
enoates) or are limited in choice of nucleophile (e.g., Pd-
14
mediated allylic substitutions) in contrast to the introduction
of substituents via variation of the cuprate ligands. The
utilization of lithium, zinc, and magnesium cuprate reagents
Acknowledgment. This work was generously supported
by the ACS-Petroleum Research Fund (42853-AC1). The
NSF Chemical Instrumentation Program supported purchase
of a JEOL 500 MHz NMR instrument (CHE-9700278).
(
12) (a) Meza-Avi n˜ a, M. E.; Ordo n˜ ez, M.; Fern a´ ndez-Zertuche, M.;
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Supporting Information Available: General experimental
1
13
information, materials, data reduction, and H and C NMR
spectra for 5a-d and 6(a-b)-9(a-b). This material is
available free of charge via the Internet at http://pubs.acs.org.
(
13) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2006, 128, 9705–9710.
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(
OL800727F
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Org. Lett., Vol. 10, No. 10, 2008