Selectivity guidelines and a reductive elimination-based model for predicting the stereochemical course of conjugate addition reactions of organocuprates to γ-alkoxy-α,β-enoates

Article abstract of DOI:10.1021/jo052383v

Current models used to predict the stereochemical outcome of organocopper conjugate addition processes focus on the nucleophilic addition step as stereochemistry-determining. Recent kinetic, NMR, kinetic isotope effect, and theoretical density functional

Full text of DOI:10.1021/jo052383v

Selectivity Guidelines and a Reductive Elimination-Based Model for
Predicting the Stereochemical Course of Conjugate Addition
Reactions of Organocuprates to γ-Alkoxy-r,â-enoates
Artem S. Kireev, Madhuri Manpadi, and Alexander Kornienko*
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, New Mexico 87801
akornien@nmt.edu
ReceiVed NoVember 18, 2005
Current models used to predict the stereochemical outcome of organocopper conjugate addition processes
focus on the nucleophilic addition step as stereochemistry-determining. Recent kinetic, NMR, kinetic
isotope effect, and theoretical density functional studies strongly support the proposal that stereochemical
preferences in these processes are dictated by the reductive elimination step, transforming CuIII to CuI
intermediates. A new model that considers various steric and stereoelectronic factors involved in the
transition state of the reductive elimination step is proposed and then used to interpret the results of
systematic studies of arylcuprate conjugate addition reactions with cis and trans γ-alkoxy-R,â-enoates.
The results give rise to the following selectivity guidelines for this process. To achieve high anti-addition
diastereoselectivities the use of trans esters with a bulky nonalkoxy substituent at the γ-position is
recommended. While stereoelectronics disfavor syn-addition, a judicious choice of properly sized
γ-substituents may lead to the predominant formation of syn-products, especially with cis enoates. However,
high syn-selelectivities may be achieved by using γ-amino-R,â-enoates.
Introduction
tionally flexible acyclic substrates are much less predictable
and these processes often produce mixtures of epimeric
products. To make matters worse, the acyclic diastereomers
generated in these reactions are rarely well-resolved chromato-
graphically.
Despite being plagued by these problems, reactions of R,â-
enoates containing γ-stereocenters have found significant utility
in synthesis. Most prominent in this respect are reactions of
organocuprates with trans γ-alkoxy-R,â-enoates, which com-
monly yield products possessing an anti-stereochemical relation-
ship between the γ- and the newly formed â-stereocenters.
Although the magnitude of anti-selectivity varies from moderate
to high, it is consistently observed in reactions of alkyl-, alkenyl-,
and arylcuprates.3,4 The uniformity of this stereochemical
outcome has prompted various investigators to propose transition
state models that can be used to predict the stereoselectivity of
new transformations.
Conjugate addition reactions of organocopper reagents to
R,â-unsaturated carbonyl compounds represent important meth-
ods for carbon-carbon bond construction.1 Control of stereo-
selectivity in these reactions has attracted considerable attention
from both theoretical and synthetic viewpoints.2 Diastereo-
selective addition processes with cyclic enones and enoates are
highly predictable and have proven to be particularly useful. In
contrast, stereochemical outcomes of reactions of conforma-
(1) Krause, N. Modern Organocopper Chemistry; Wiley-VCH: Wein-
heim, Germany, 2002.
(2) (a) Deslongchamps, P. In Stereoelectronic Effects in Organic
Chemistry; Pergamon: Exeter, UK, 1983; pp 221-242. (b) Yamamoto,
K.; Ogura, H.; Jukuta, J.-i.; Inoue, H.; Hamada, K.; Sugiyama, Y.; Yamada,
S. J. Org. Chem. 1998, 63, 4449-4458. (c) Krause, N.; Hoffmann-Ro¨der,
A. Synthesis 2001, 171-196. (d) Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033-8061.
10.1021/jo052383v CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/02/2006
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J. Org. Chem. 2006, 71, 2630-2640

Reactions of Organocuprates to γ-Alkoxy-R,â-enoates
reagent type and enoate double bond geometry. This effort led
to the discovery of a diastereoselectivity reversal from anti to
syn as the enoate geometry is changed from trans to cis.7a,b
A
stereochemical model, involving a transition state in which an
R group is oriented anti to the approaching nucleophile and an
alkoxy group is located at an “inside” position (Figure 1c, D),
was proposed. These investigators argued that this conformation
is stabilized by mixing of the σ-orbital of an electron-rich C-R
bond with the developing σ*-orbital of an electron-deficient
incipient Nu-C bond, a proposal analogous to one serving as
the basis for the Cieplak electronic model.8 While experimental9
and theoretical10 support for the “inside” OR′ preference in
ground state enoates exists, the structure of the reactive
conformer in the conjugate addition process is not necessarily
similar to the ground-state one. Despite having this weakness,
this model explains the syn-selectivity observed in reactions with
cis enoates, since allylic 1,3-strain would force an OR′ group
into an “outside” position as shown in the reactive conformer
E.
Importantly, a chelation model, which is often used success-
fully to predict the stereochemical outcome of organometallic
addition reactions with R-alkoxy carbonyl compounds, is of less
significance due to the lower chelation ability of organocopper
reagents relative to organolithium and organomagnesium coun-
terparts. Yamamoto and co-workers have shown that diastereo-
selectivity trends in organocuprate additions of γ-OTBS and
γ-OBn enoates are similar. Because the TBSO group is
considered nonchelating, this observation supports the view that
chelation is negligible in these reactions.7b
As part of a synthetic program aimed at developing practical
pathways for the synthesis of medicinally promising Amaryl-
lidaceae constituents (Figure 2), we have extensively utilized
conjugate addition reactions of functionalized aromatic copper
reagents with various γ-alkoxy-R,â-enoates.3r,6j The relative cis
orientation of an aromatic group and an adjacent oxygen
(marked with asterisks below) is highly conserved in this series
of natural products. This corresponds to an anti-stereochemical
relationship of these groups in an open-chain precursor.
FIGURE 1. Modified Felkin-Anh and Yamamoto interpretations of
the stereochemical outcome of organocuprate conjugate addition to
γ-alkoxy-R,â-enoates.
The most direct interpretation of anti-selectivity employs the
“modified Felkin-Anh” model, in which the carbonyl group
in the aldehyde of the original model (Figure 1a, A)5 is replaced
by the enoate C-C π-bond (Figure 1b).6 Originally discussed
by Roush more than 20 years ago,6a,b this model suggests that
nucleophilic attack by an organocuprate takes place from the
face opposite to a γ-alkoxy substituent via the preferred reactive
conformation B rather than C owing to allylic 1,3-strain that is
present in C. Yamamoto and co-workers have systematically
studied the dependence of the stereoselectivity on organocopper
(3) For selected synthetic applications, see: (a) Ziegler, F. E.; Gilligan,
P. J. J. Org. Chem. 1981, 46, 3874-3880. (b) Nemoto, H.; Ando, M.;
Fukumoto, K. Tetrahedron Lett. 1990, 31, 6205-6208. (c) Hanessian, S.;
Raghavan, S. Bioorg. Med. Chem. Lett. 1994, 4, 1697-1702. (d) Domin-
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K.; Hachiya, S.; Ogihara, K.; Yoshida, Y.; Nagasawa, M.; Yonemitsu, O.
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Y. J. Org. Chem. 1998, 63, 3, 426-427. (i) Ziegler, F. E.; Wang, Y. J.
Org. Chem. 1998, 63, 7920-7930. (j) Hanessian, S.; Ma, J.; Wang, W.
Tetrahedron Lett. 1999, 40, 4627-4630. (k) Stoncius, A.; Mast, C. A.;
Sewald, N. Tetrahedron: Asymmetry 2000, 11, 3849-3853. (l) Zhu, B.;
Panek, J. S. Eur. J. Org. Chem. 2001, 1701-1714. (m) Hanessian, S.; Ma,
J. Tetrahedron Lett. 2001, 42, 8785-8788. (n) Hanessian, S.; Ma, J.; Wang,
W. J. Am. Chem. Soc. 2001, 123, 10200-10206. (o) Nakamura, S.; Inagaki,
J.; Sugimoto, T.; Ura, Y.; Hashimoto, S. Tetrahedron 2002, 58, 10375-
10386. (p) Powell, S. A.; Tenenbaum, J. M.; Woerpel, K. A. J. Am. Chem.
Soc. 2002, 124, 12648-12649. (q) Hanessian, S.; Yang, Y.; Giroux, S.;
Mascitti, V.; Ma, J. U.; Raeppel, F. J. Am. Chem. Soc. 2003, 125, 13784-
13792. (r) Nadein, O. N.; Kornienko, A. Org. Lett. 2004, 6, 831-834. (s)
Hanessian, S.; Mascitti, V.; Giroux, S. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 11996-12001. (t) Hanessian, S.; Yun, H.; Hou, Y.; Tintelnot-Blomley,
M. J. Org. Chem. 2005, 70, 6746-6756. For further examples of anti-
selective organocuprate additions, see refs 6 and 7.
(6) For selected discussions of the modified Felkin-Anh model, see:
(a) Roush, W. R.; Lesur, B. M. Tetrahedron Lett. 1983, 24, 2231-2234.
(b) Roush, W. R.; Michaelides, M. R.; Tai, D. F.; Lesur, B. M.; Chong, W.
K. M.; Harris, D. J. J. Am. Chem. Soc. 1989, 111, 2984-2995. (c) Bernardi,
A.; Cardani, S.; Poli, G.; Scolastico, C. J. Org. Chem. 1986, 51, 5041-
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R. J. Org. Chem. 1988, 53, 1600-1607. (e) Cardani, S.; Poli, G.; Scolastico,
C.; Villa, R. Tetrahedron 1988, 44, 5929-5938. (f) Hanessian, S.; Sumi,
K. Synthesis 1991, 1083-1089. (g) Nilsson, K.; Ullenius, C. Tetrahedron
1994, 50, 13173-13180. (h) Raczko, J. Tetrahedron: Asymmetry 1997, 8,
3821-3828. (i) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1223.
(j) Manpadi, M.; Kornienko, A. Tetrahedron Lett. 2005, 46, 4433-4437.
See also refs 7a,b,g.
(7) For selected discussions of the Yamamoto model, see: (a) Yamamoto,
Y.; Nishii, S.; Ibuka, T. J. Chem. Soc., Chem. Commun. 1987, 464-466.
(b) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J. Am.
Chem. Soc. 1992, 114, 7652-7660. (c) Dominguez, E.; Carretero, J. C.
Tetrahedron Lett. 1993, 34, 5803-5806. (d) Funaki, I.; Bell, R. P. L.; Thijs,
L.; Zwanenburg, B. Tetrahedron 1996, 52, 12253-12274. (e) Hanessian,
S.; Wang, W.; Gai, Y.; Olivier, E. J. Am. Chem. Soc. 1997, 119, 10034-
10041. (f) Amigoni, S.; Schulz, J.; Martin, L.; LeFloch, Y. Tetrahedron:
Asymmetry 1997, 8, 1515-1518. (g) Chounan, Y.; Ono, Y.; Nishii, S.;
Kitahara, H.; Ito, S.; Yamamoto, Y. Tetrahedron 2000, 56, 2821-2831.
See also refs 6f,g,h,i.
(8) (a) Cieplak, A. S.; Tait, B. D.; Johnson, C. R. J. Am. Chem. Soc.
1989, 111, 8447-8462. (b) Cieplak, A. S. Chem. ReV. 1999, 99, 1265-
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(9) Lessard, J.; Saunders: J. K.; Viet, M. T. P. Tetrahedron Lett. 1982,
23, 2059-2062.
(10) Houk, K. N.; Moses, S. R.; Wu, Y. D.; Rondan, N. G.; Jager, V.;
Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880-3882.
(4) Reactions of allylcopper reagents seem to be an exception to the “anti-
addition” rule, see: Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem.
Soc. 1981, 103, 1224-1226.
(5) For demonstration of the importance of σ*-orbital energies in
determining the “large” group in the Felkin model, see: Lodge, E. P.;
Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353-3361.
J. Org. Chem, Vol. 71, No. 7, 2006 2631

Kireev et al.
FIGURE 3. Highly anti-selective arylcuprate conjugate addition
reactions of carbohydrate-derived γ,δ,ꢀ-trialkoxy-R,â-enoates.
To elucidate the sufficiency of a single γ-alkoxy stereocenter
to attain exclusive anti-selectivities as well as other structural
features that would be necessary for such a highly diastereo-
selective process, we synthesized enoates 1-7 (Figure 4) varying
the identity of the γ-alkoxy group OR′ (1 vs 2), the steric bulk
of the group R (2 vs 3 vs 4 and 5 vs 6 vs 7), and the double
bond geometry (2 vs 5, 3 vs 6, and 4 vs 7). While the synthesis
of enoates 4 and 7 followed previously reported procedures
starting from lactaldehyde,13 compounds 1, 2, 3, 5, and 6 were
prepared through sequences utilizing various known intermedi-
ates derived from D-mannitol.14 Underlying these approaches
is the known (E,Z)-selectivity dependence on the solvent
(CH2Cl2 vs MeOH) in reactions of R-alkoxyaldehydes with
stabilized Wittig reagents.15
We further investigated the reactions of 1-7 with a series of
arylcuprates, derived from various multisubstituted aromatic
Grignard reagents (a-f, Table 1). With enoates 1 and 2 as
substrates, only single (by 1H NMR analysis of crude and
purified product mixtures) diastereomeric addition products were
formed in all reactions. Chemical correlation of the phenyl
adducts 12a and 13a with the known lactones 19 and 2016
confirmed the anti-stereochemical outcome of the cuprate
reactions (Figure 5). The results strongly argue in favor of the
adequacy of a single γ-alkoxy stereocenter for governing
exclusive (within the NMR detection limit) anti-selectivities and
bode well for future synthetic applications of this methodology,
especially in cases where scale-up is anticipated. Combined with
the similar results obtained in experiments with γ,δ,ꢀ-trialkoxy-
enoates these findings lead to the tempting speculation that the
chemical nature of the R group (but not its size) has little
influence on reaction stereoselectivity.
FIGURE 2. Anti-selective arylcuprate conjugate addition to γ-alkoxy-
R,â-enoates as a solution to the stereochemical challenges presented
by selected Amaryllidaceae constituents.
The practicality and scalability of the synthetic sequences
employed in our efforts rely to a large extent on the requirement
that the arylcuprate conjugate addition reactions take place with
anti-diastereoselectivities exclusively. Although we have been
successful with the empirical optimization of reaction conditions
needed for the exclusive formation of anti-products, we have
also searched for a unified, theoretically based stereochemical
model to guide these efforts. While both the modified Felkin-
Anh and Yamamoto models have the virtue of simplicity, it
now appears that they are fundamentally flawed in view of the
recent experimental and theoretical mechanistic investigations
of the organocuprate conjugate addition process.11 Below, the
details of a systematic investigation of arylcuprate reactions with
γ-alkoxy-R,â-enoates are given. In addition, a new stereochem-
ical model, which is consistent with the results of both the
current effort and that previously reported by other investigators
as well as the current mechanistic understanding of this process,
is proposed.
Results
Further, reactions of the trans enoates showed a progressive
erosion of anti-selectivity as the size of the R decreased (2 f
3 f 4). In contrast, the reactions of the cis enoates, while being
moderately anti-selective (enoates 6 and 7), did not display
consistent selectivity dependence on the R group. The chemical
correlation of the epimeric phenyl adduct mixtures 14a and 15a
with the known trans and cis pairs of lactones 19, 2016 and 21,
2217 led to the assignment of stereochemistry for the major and
minor diastereomers (Figure 6).
In the pursuit of practical synthetic approaches to Amaryl-
lidaceae constituents, we recently conducted a study of aryl-
cuprate conjugate addition reactions of a series of γ,δ,ꢀ-
trialkoxyenoates, derived from various carbohydrate precursors
(Figure 3).12 In each one of these processes, a single anti-
addition product was formed regardless of the identity of the
alkoxy groups (OBn or OMOM) or their relative stereochemical
relationship. These observations imply that even in complex
settings 1,2-asymmetric induction by a γ-stereocenter is the
predominant stereochemistry-determining factor in the transition
states of the addition processes.
(13) Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron 1988,
44, 491-502.
(14) (a) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis
1986, 403-406. (b) Peters, U.; Bankova, W.; Welzel, P. Tetrahedron 1987,
43, 3803-3816. (c) Bouzide, A.; Sauve´, G.; Se´vigny, G.; Yelle, J. Bioorg.
Med. Chem. Lett. 2003, 13, 3601-3605.
(11) For a recent review, see: Nakamura, E.; Mori, S. Angew. Chem.,
Int. Ed. 2000, 39, 3750-3771.
(12) A portion of this investigation has been reported, see ref 3r. The
remaining results will be detailed in future publications describing the
synthetic pathways to the target natural products.
(15) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
(16) Ha, H.-J.; Yoon, K.-N.; Lee, S.-Y.; Park, Y.-S.; Lim, M.-S.; Yim,
Y.-G. J. Org. Chem. 1998, 63, 8062-8066.
(17) Reissig, H.-U.; Angert, H. J. Org. Chem. 1993, 58, 6280-6285.
2632 J. Org. Chem., Vol. 71, No. 7, 2006

Reactions of Organocuprates to γ-Alkoxy-R,â-enoates
FIGURE 4. Preparation of trans and cis R,â-enoates with a single γ-alkoxy stereocenter.
TABLE 1. Stereoselectivities of Reactions of Arylcuprates with Trans and Cis r,â-Enoates with a Single γ-Alkoxy Stereocenter
trans enoates
% yield
cis enoates
enoate
adduct
anti:syn
enoate
adduct
% yield
anti:syn
1
1
1
1
1
1
2
2
2
3
3
3
4
4
4
12a
12b
12c
12d
12e
12f
13a
13d
13f
14a
14d
14f
15a
15d
15f
80
78
79
75
76
75
88
93
82
94
76
88
89
80
82
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
14.6:1
11.3:1
9.9:1
5
5
5
6
6
6
7
7
7
16a
16d
16f
17a
17d
17f
18a
18d
18f
87
69
53
72
68
63
65
56
54
1.6:1
1:1.3
1:1.3
2.8:1
2.7:1
2.9:1
3.4:1
1.9:1
2.2:1
5.4:1
6.1:1
5.9:1
Discussion
oriented anti to the incoming nucleophile. In agreement with
this prediction, no difference was seen between reactions of the
γ-OMOM and γ-OBn enoates 1 and 2. Moreover, others have
reported high anti-addition selectivities in reactions with
γ-OMe,6a,b,f γ-OBOM,3j,m,n,q,s γ-O-CR2-δ-O (part of a ketal with
a vicinal oxygen),3a,b,k,p,6g γ-OMTM,6f and γ-OMPM3f enoates.
In principle, the observations made in studies with trans
enoates can be adequately interpreted on the basis of the
modified Felkin-Anh model (Figure 1b). According to this
model, the stereochemistry of the addition process should not
depend on the identity of the alkoxy substituent, which is
J. Org. Chem, Vol. 71, No. 7, 2006 2633

Kireev et al.
FIGURE 5. Confirmation of anti-stereochemistry for the phenyl
addition products 12a and 13a.
FIGURE 7. Summary of experimental and theoretical mechanistic
studies of the organocopper conjugate addition reaction as adapted for
the case of γ-alkoxy-R,â-enoates.
understanding of these reactions. As a result, the recent,
insightful experimental and theoretical investigations of the
mechanism of organocopper reactions11 had not been included
in developing models for predicting the stereochemical course
of these processes. The fundamental assumption made in
developing the modified Felkin-Ahn and Yamamoto models is
that diastereofacial selection takes place during the first step
involving either copper-olefin π-complex formation or simple
nucleophilic addition of the cuprate.6f,7b Yet, detailed studies
by several research groups18 clearly indicate that the carbon-
carbon bond forming reductive elimination step, converting
CuIII to CuI intermediates, is both rate- and stereochemistry-
determining. Recent theoretical studies by Nakamura and co-
workers19 have provided a more detailed mechanistic description
that has been adapted in developing a new model (Figure 7)
for predicting the stereochemical course of organocuprate
γ-alkoxy-R,â-enoate conjugate addition reactions.
FIGURE 6. Confirmation of stereochemistry for the major and minor
phenyl addition products 14a and 15a.
The Felkin-Anh model also suggests that large γ-R groups
further destabilize the transition state conformer C leading to
syn-products. The results of experiments with enoates 2, 3, and
4 match this expectation. Interestingly, application of the
Yamamoto model for organocuprate conjugate additions leads
to an opposite prediction: specifically that the stereochemical
outcome of these processes should be strongly dependent on
the identity of the alkoxy group and that a change in the size of
the anti oriented R group should result in only a small
perturbation.
Importantly, the low stereochemical selectivities observed for
conjugate addition reactions of cis enoates cannot be explained
by using either of these models or even by invoking a more
complex four-conformer equilibrium process that mixes both
models. For example, the modified Felkin-Anh interpretation
predicts improved anti-selectivities, since 1,3-strain, the main
factor causing energetic difference between conformers B and
C, significantly increases in transition states for reactions of
the cis enoates. In contrast, a preponderance of syn-products
would be expected on the basis of the Yamamoto model due to
allylic strain-promoted destabilization of the conformer D.
It is clear that synthetic applications of organocuprate
conjugate additions to enoates have outpaced the mechanistic
In the route for organocuprate conjugate additions, π-com-
plexation of a cuprate reagent with the enoate double bond is
followed by reversible formation of the â-cuprio(III) enolate,
(18) (a) Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103, 141-
148. (b) Horiguchi, Y.; Komatsu, M.; Kuwajima, I. Tetrahedron Lett. 1989,
30, 7087-7090. (c) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwa-
jima, I. Tetrahedron 1989, 45, 349-362. (d) Lipshutz, B. H.; Dimock, S.
H.; James, B. J. Am. Chem. Soc. 1993, 115, 9283-9284. (e) Vellekoop, A.
S.; Smith, R. J. J. Am. Chem. Soc. 1994, 116, 2902-2913. (f) Krause, N.;
Wagner, R.; Gerold, A. J. Am. Chem. Soc. 1994, 116, 381-382. (g) Dorigo,
A. E.; Wanner, J.; Schleyer, P. v. R. Angew. Chem., Int. Ed. Engl. 1995,
34, 476-478. (h) Bertz, S. H.; Miao, G.; Rossiter, B. E.; Snyder, J. P. J.
Am. Chem. Soc. 1995, 117, 11023-11024. (i) Frantz, D. E.; Singleton, D.
A.; Snyder, J. P. J. Am. Chem. Soc. 1997, 119, 3383-3384. (j) Canisius,
J.; Gerold, A.; Krause, N. Angew. Chem., Int. Ed. 1999, 38, 1644-1646.
(k) Frantz, D. F.; Singleton, D. A. J. Am. Chem. Soc. 2000, 122, 3288-
3295. (l) Pfretzschner, T.; Kleemann, L.; Janza, B.; Harms, K.; Schrader,
T. Chem. Eur. J. 2004, 10, 6048-6057. (m) Mori, S.; Uerdingen, M.;
Krause, N.; Morokuma, K. Angew. Chem., Int. Ed. 2005, 44, 4715-4719.
(19) (a) Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1997,
119, 4900-4910. (b) Mori, S.; Nakamura, E. Chem. Eur. J. 1999, 5, 1534-
1543. (c) Nakamura, E.; Yamanaka M. J. Am. Chem. Soc. 1999, 121, 8941-
8942. (d) Reference 11. (e) Yamanaka, M.; Inagaki, A.; Nakamura, E. J.
Comput. Chem. 2003, 24, 1401-1409. (f) Nakanishi, W.; Yamanaka, M.;
Nakamura, E. J. Am. Chem. Soc. 2005, 127, 1446-1453. (g) Yoshikai, N.;
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4723.
2634 J. Org. Chem., Vol. 71, No. 7, 2006

Reactions of Organocuprates to γ-Alkoxy-R,â-enoates
FIGURE 8. Inadequacy of the Felkin-Anh and Yamamoto models
(F and G) and the proposed reductive elimination-based transition state
conformations (H and I).
FIGURE 9. The “flat” approach model proposed by Reetz and co-
workers21c and the aerofoil long-range steric congestion invoked by
Barrett and co-workers.21a
in which the high oxidation state of copper is stabilized by the
donation from the electron-rich enolate double bond. A cor-
relation of the results of density functional studies with those
arising from experimental 13C NMR19b and kinetic isotope effect
investigations18i demonstrates that â-cuprio(III) enolates are
direct precursors of addition products with enals and enones,
formed through rate- and stereochemistry-determining reductive
elimination.20 With less reactive esters a Lewis acidic or
electrophilic additive, such as BF3 or Me3SiCl, is required to
reduce the electron-rich enolate double bond character, thus
destabilizing the CuIII intermediate and promoting reductive
elimination to generate CuI species. Clearly, a model aimed at
understanding and predicting the stereochemical course of
organocopper conjugate addition processes should center on
the reductiVe elimination step in this general pathway. Both
the modified Felkin-Anh and Yamamoto models are incon-
sistent with this new mechanistic information. Furthermore,
processes involving these models in the first mechanistic step
evolve into highly energetic reductive elimination transition state
conformations that are highly destabilized by eclipsing interac-
tions (Figure 8, F and G).
We propose a mechanistically more relevant approach to
evaluating the stereochemistry of organocuprate enoate conju-
gate additions. The “Reductive Elimination” model focuses on
competitive transition states (H and I) for the C-C bond
formation step. In these transition states, the γ-H atom is oriented
toward the cuprate cluster, thus minimizing steric strain associ-
ated with interactions of the large R and OR′ substituents with
the nearly planar copper complex. Reactive conformation H,
leading to the anti-product, is energetically more favorable than
I from both stereoelectronic and steric perspectives. In the
reductive elimination transition state the Câ-Ar bond is forming,
while the Câ-Cu bond is being broken. Both of these processes
are facilitated in conformer H by the relative positioning of R
and OR′, which allows favorable mixing of the σ-orbital of the
forming Câ-Ar bond with the low-lying σ*-orbital of the Cγ-
ÃR′ bond. In addition, donation from the electron-rich Cγ-R
bond into the σ* Câ-Cu orbital weakens the Câ-Cu bond and
assists departure of copper. Importantly, both of these interac-
tions increase during the course of reductive elimination due to
the increasingly better overlap of the component orbitals: the
dihedral angles Ar-Câ-Cγ-H and Cu-Câ-Cγ-H become
larger as the Ar-Cu bond elongates. Furthermore, as the size
of the group R increases, conformer I becomes increasingly
disfavored due to allylic 1,3-strain. The results of the current
study (Table 1) fully comply with this new stereochemical
model.
Similar transition state models have been proposed by other
investigators for reactions involving “flat” or “aerofoil” nu-
cleophiles.21 An instructive example comes from a study by
Reetz and co-workers of the stereochemistry of the cycloaddition
reactions of ester 23 with diazomethane (Figure 9a).21c The
authors noted that the “flat” nature of the approaching π-system
results in a consensus transition state conformation, in which
the hydrogen atom points toward the incoming reagent and the
bulky NBn2 group occupies an “outside” position, leading to
the major cycloaddition product 24. As the size of the R group
increased the ratio of the diastereomeric products 24:25
decreases, a consequence presumably of allylic 1,3-strain in the
transition state to 24. Barrett and co-workers reported an
(21) (a) Barrett, A. G. M.; Weipert, P. D.; Dhanak, D.; Husa, R. K.;
Lebold, S. A. J. Am. Chem. Soc. 1991, 113, 9820-9824. (b) Burgess, L.
E.; Meyers, A. I. J. Am. Chem. Soc. 1991, 113, 9858-9859. (c) Reetz, M.
T.; Kayser, F.; Harms, K. Tetrahedron Lett. 1992, 33, 3453-3456.
(20) The first evidence for this pathway and its role in the stereochemistry
of organocopper addition reactions was disclosed by Corey and Boaz:
Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 26, 6015-6018.
J. Org. Chem, Vol. 71, No. 7, 2006 2635

Kireev et al.
FIGURE 10. Possible additional transition states that may result from
reactions of cis enoates.
interesting divergent stereochemical outcome in Michael addi-
tion reactions of nucleophiles to nitroolefin 26 (Figure 9b).
“Small” nucleophiles (NaOMe, NaOBn, TsNHK) led to highly
selective formation of S-configured products 27, while reactions
with “aerofoil” shaped nucleophiles, such as phthalimide K or
succinamide K, give mainly R-adducts 28.21a Barrett noted that
the modified Felkin-Anh transition state, leading to the
S-configured phthalimide adduct, suffers from a steric interaction
between the phthalimide carbonyl and the C-3 oxygen substitu-
ent. This steric congestion would be minimized in the transition
state leading to 28 even though it is not favored stereoelec-
tronically.
FIGURE 11. Alternative mechanism for cis f trans isomerization of
γ-akoxy-R,â-enoates with the assistance of Me3SiCl.
The “Reductive Elimination” model accounts for the signifi-
cant decrease in anti-selectivity observed in conjugate addition
reactions of cis enoates 5-7. The severe 1,3-strain that arises
when cis double bond geometry is present leads to rotation about
the Câ-Cγ to produce an energetic minimum (Figure 10).
Reactive conformations J and K may become more competitive
and, conceivably, the absence of a clearly defined transition
state preference leads to small selectivity values. Although
Yamamoto and co-workers reported selectivity reversal from
anti to syn when the enoate geometry is changed from trans to
cis, their results show that anti-selectivities in reactions with
trans enoates are high, while syn-stereochemical preference with
cis enoates was at best marginal (on the order of 2:1 to 3:1).7a,b
The “Reductive Elimination” model can also be used to
understand the significant decrease in reaction yields and an
increase in reaction times from 6 h at -30 °C for trans enoates
1-4 to 24-48 h at 25 °C for cis enoates 5-7 found in this
study. Other investigators have reported similar observations,
including the complete failure of cis enoates to undergo
conjugate additions compared to facile reactions of their trans
counterparts.2b,7a,b In this connection it is noteworthy that several
research groups have reported that identical stereoselectivitites
accompany reactions of trans and cis enoates.2b,3f,t,6a,b,g While
cis f trans enoate isomerization in organocuprate reactions is
a logical interpretation, an electron transfer mechanism for this
process has been substantially refuted.11 The density functional
investigation by Nakamura and co-workers suggests that the
3-cuprio(III) enolate may be viewed as a copper(III) species
with the enolate double bond serving as a ligand.19a In addition,
the early experiments by Corey and Boaz indicate that this
species may undergo silylation with Me3SiCl changing the
stereochemical course of the addition process.20 This conclusion
FIGURE 12. Stereochemistry reversal as the enoate double bond
geometry is changed from trans to cis observed by Yamamoto and co-
workers.7g
is further supported by the results of kinetic isotope studies (with
17O replacement at the carbonyl oxygen) by Frantz and
Singleton18k which show that silylation with Me3SiCl could be
rate-limiting. Thus, it is not inconceivable that the slow reactivity
of cis enoates enables silylation of the 3-cuprio(III) enolate to
take place, a process that weakens the donor ability of the
enolate double bond (Figure 11). Ligand exchange (with HMPA
or THF) may allow rotation about the CR-Câ bond leading to
a 3-cuprio(III) enolate that would be derived directly from the
trans enoate starting material. It is not unlikely that the marginal
excesses of anti-addition products formed in reactions of enoates
5-7 are a consequence of competing double bond isomerization
of the reactants. It should be noted that Yamamoto and co-
workers performed their addition reactions in the presence of
BF3 as an activating agent compared with Me3SiCl used in our
experiments.
The “Reductive Elimination” model can be effectively applied
to predicting the stereochemistry of conjugate addition reactions
of other types of γ-stereocenter-containing enoates. If an alkoxy
substituent is not present at the γ-position, the stereochemical
outcome will depend on the relative sizes of the two non-
hydrogen substituents. For example, ethyl E-4-phenyl-2-pen-
tenoate (Figure 12) is known to react with Bu2CuLi‚BF3 to yield
mainly the anti-product (anti:syn ) 7:3).7g When the Z-enoate
is reacted with the copper reagent, stereochemistry reversal (anti:
2636 J. Org. Chem., Vol. 71, No. 7, 2006

Reactions of Organocuprates to γ-Alkoxy-R,â-enoates
FIGURE 13. Correct prediction of the stereochemical outcome of
reactions of γ-amino-R,â-enoates with the reductive elimination model
and prediction of the opposite result with the modified Felkin-Anh
interpretation.22a
FIGURE 14. Application of the reductive elimination model and the
modified Felkin-Anh interpretation to SN2′ processes indicating their
mechanistic kinship to conjugate addition reactions.26
syn ) 3:7) is observed. It is possible that in the Z-enoate case
the 1,3-strain is minimized in a transition state conformation in
which the smaller Me group is close to the copper complex
(bottom transition state in Figure 12). This would result in
preferential formation of the syn-product. Thus, in reactions of
trans enoates that lack γ-substituents capable of exerting strong
stereoelectronic effects, a transition state conformation that
places the smaller of the two non-hydrogen groups into the 1,3-
strain position would lead to an accurate prediction of the
stereochemical outcome. Similar selelectivity patterns have also
been reported by Yamada and co-workers in their systematic
studies with enoates and enones containing a methyl group and
a large steroidal substituent at the γ-position.2b
Reactions of trans γ-amino-R,â-enoates with organocopper
reagents generally take place with syn-stereoselectivities.22
While these processes have been extensively employed in
synthesis, no logical reason for why their stereochemistry is
opposite to that observed with γ-akoxy-R,â-enoates has been
offered. Interestingly, application of the new model to reactions
of the trans γ-amino-R,â-enoate substrates nicely explains this
stereochemical divergence. Accordingly, a lower energy reduc-
tive elimination transition state conformation that has the bulky
amino group23 in the “outside” position (Figure 13) would result
in formation of the observed syn-products.22a Importantly, when
the other non-hydrogen subsituent is large, this transition state
would be of exceptionally high energy and, as a result, the
enoate would be unreactive toward conjugate addition.6f It is
noteworthy that the application of the Felkin-Anh model is
equally successful with R-amino-aldehydes as it is with
R-alkoxy-aldehydes. Yet, the modified Felkin-Anh hypothesis
predicts anti-selelectivity for γ-amino-R,â-enoates, which is not
what is observed experimentally.
A last point worth making stems from the proposal that if
the transition state model works well for predicting two
synthetically distinct organocopper-promoted processes then
there is a high probability that the two processes follow similar
mechanistic pathways. The case in point is the SN2′ reaction of
allylic substrates with organocopper reagents where little is
known about the mechanism. Experimental studies by Ba¨ckvall
and co-workers24 and density functional investigation by Na-
kamura and co-workers25 suggest that these reactions proceed
through the intermediacy of π-allylcopper(III) intermediates.
Furthermore, the conclusion of theoretical study is that C-C
bond formation occurs not from σ-allylcopper(III) species, as
had been thought previously, but rather via enyl[σ+π]-type
transition states that are mechanistically similar to those involved
in the enoate conjugate addition process. Since the selectivities
of reactions of γ-substituted allylic halides follow a pattern26,6i
that is similar to that for enoate conjugate additions, we believe
that the reductive elimination step is rate- and stereochemistry-
determining for organocuprate SN2′ reactions as well (Figure
14). Importantly, the application of the modified Felkin-Anh
model to these processes leads to the expectation that syn-
stereochemistry would predominate, a prediction that opposes
the experimental observations. We believe that this stereochem-
ical analogy provides an important clue about the mechanism
of SN2′ reactions of organocuprates with allylic substrates, which
matches the conclusions drawn from theoretical studies.25
Conclusions
The reductive elimination-based stereochemical model de-
scribed above explains the high anti-selectivities observed in
organocopper conjugate addition reactions with trans γ-alkoxy-
R,â-enoates. Both steric and stereoelectronic factors favor the
transition state conformer that leads to the anti-adduct. However,
it is possible to direct preferential formation of syn-products
by judiciously choosing properly sized γ-substituents, especially
in cis enoate reactants. In this event, steric factors outweigh
stereoelectronic control. Analysis of previous observations
demonstrates that the proposed model is fully consistent with
the stereochemical outcomes of conjugate additions of other
γ-stereocenter-containing enoates, such as those containing
(22) For selected examples, see: (a) Reetz, M. T.; Rohrig, D. Angew.
Chem., Int. Ed. Engl. 1989, 28, 1706-1709. (b) Jako, I.; Uiber, P.; Mann,
A.; Taddei, M.; Wermuth, C. G. Tetrahedron Lett. 1990, 31, 1011-1014.
(c) Reference 6f. (d) Hanessian, S.; Wang, W.; Gai, Y. Tetrahedron Lett.
1996, 37, 7477-7480. (e) Hanessian, S.; Demont, E.; van Otterlo, W. A.
L. Tetrahedron Lett. 2000, 41, 4999-5003. (f) Liang, X.; Andersch, J.;
Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136-2157. (g) Flamant-
Robin, C.; Wang, Q.; Sasaki, N. A. Tetrahedron Lett. 2001, 42, 8483-
8484. (h) Flamant-Robin, C.; Wang, Q.; Chiaroni, A.; Sasaki, N. A.
Tetrahedron 2002, 58, 10475-10484. (i) Kumar, S.; Flamant-Robin, C.;
Wang, Q.; Chiaroni, A.; Sasaki, A. J. Org. Chem. 2005, 70, 5946-5953.
(23) Amino groups are considerably more bulky than ethers, presumably
due to the fact that the ether alkyl group can turn so as to point away from
the steric congestion site. For example, various reported “A values” for
-OMe and -NMe2 groups are 2.13-3.14 and 6.4-10.0 kJ/mol, respec-
tively. See in: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994.
(24) Karlstrom, A.; Sofia, E.; Ba¨ckvall, J.-E. Chem. Eur. J. 2001, 7,
1981-1989.
(25) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004,
126, 6287-6293.
(26) Arai, M.; Kawasuji, T.; Nakamura, E. J. Org. Chem. 1993, 58,
5121-5129.
J. Org. Chem, Vol. 71, No. 7, 2006 2637

Kireev et al.
in ether (50 mL) and the formed precipitate was filtered. The ether
fraction was evaporated under reduced pressure to give viscous oil.
The residue was dissolved in dry CH2Cl2 (100 mL). To this solution
at -78 °C was added methyl (triphenylphosphoranylidene)acetate
(2.6 g, 8.0 mmol) in one portion. The resulting mixture was stirred
for 28 h while it was allowed to warm to room temperature. Water
(100 mL) was added to the reaction mixture, the two layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 ×
50 mL). The combined organic layers were washed with brine, dried
(MgSO4), and evaporated under reduced pressure. The crude olefin
(E:Z ) 7:1) was presorbed on silica gel and purified by column
chromatography (2-5% EtOAc/hexanes) to afford enoate 2 (3.08
γ-C,C,H and γ-C,H,N substituents. Significantly, the model can
be used to design highly diastereoselective conjugate addition
processes. For example, by using trans γ-alkoxy-R,â-enoates
containing a larger γ-R group high anti-selective transformation
should take place. In contrast, trans γ-amino-R,â-enoates with
smaller γ-R groups should be employed if syn-selective
processes are desired. Also, the proposed stereochemical/
mechanistic analogy with organocopper-mediated SN2′ processes
is expected to facilitate mechanistic investigations of this
important synthetic method. Further work is underway to study
the proposed transition states computationally and to validate
the results of the theoretical analysis by designing more narrowly
targeted experimental systems.
g, 88%) as a colorless oil. Rf 0.4 (12% EtOAc/hexanes); [R]21
D
16.4 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.76-7.65 (m, 5H), 7.47-
7.30 (m, 10H), 6.93 (dd, J ) 15.7, 5.8 Hz, 1H), 6.12 (dd, J )
15.7, 1.4 Hz, 1H), 4.64 (d, J ) 11.8 Hz, 1H), 4.51 (d, J ) 11.8
Hz, 1H), 4.14 (q, J ) 5.0 Hz, 1H), 3.82 (dd, J ) 10.7, 6.3 Hz,
1H), 3.76 (s, 3H), 3.71 (dd, J ) 10.7, 5.0 Hz, 1H), 1.07 (s, 9H);
13C NMR (CDCl3) δ 166.6, 145.9, 138.1, 135.7, 134.9, 133.2, 129.9,
129.7, 128.5, 127.8, 127.7, 122.7, 78.9, 71.7, 66.1, 51.7, 26.9, 19.3;
HRMS m/z (ESI) calcd for C29H34O4SiNa (M + Na)+ 497.2118,
found 497.2123.
Experimental Section
A. Preparation of Enoates: Ethyl (2E,4S)-5-(tert-Butyldi-
phenylsilanyloxy)-4-hydroxy-2-pentenoate (9). Compound 814a
(4.8 g, 24 mmol) was stirred in a mixture of water and acetic acid
(100 mL, 1:3) for 20 h at room temperature. The mixture was
evaporated under reduced pressure and the traces of acetic acid
were removed by coevaporating with toluene (5 × 10 mL). The
oily residue was dissolved in DMF (26 mL) and cooled to 0 °C.
To the mixture were added DMAP (0.3 g, 2.4 mmol), imidazole
(1.94 g, 24.8 mmol), and tert-butyl(chloro)diphenylsilane (7.8 g,
28.4 mmol). The resulting mixture was stirred overnight at room
temperature. The reaction mixture was quenched with water (20
mL). The aqueous phase was extracted with CH2Cl2 (3 × 30 mL).
The combined organic layers were washed with brine, dried
(MgSO4), and evaporated under reduced pressure. The residual oil
was presorbed on silica gel and purified by column chromatography
(5-20% EtOAc/hexanes) to afford enoate 9 (7.0 g, 73%) as a
colorless oil. Rf 0.59 (20% EtOAc/hexanes); [R]22D -16.4 (c 0.17,
Methyl (2E,4S)-4,5-Dibenzyloxy-2-pentenoate (3). To a solu-
tion of diol 1114c (2.01 g, 3.7 mmol) in dry methanol (150 mL) at
0 °C was added NaIO4 (0.94 g, 4.4 mmol). The resulting suspension
was vigorously stirred for 24 h at room temperature. The precipitate
was filtered and the solution was concentrated under reduced
pressure. The residue was dissolved in ether (50 mL) and the formed
precipitate was filtered. The ether fraction was evaporated under
reduced pressure to give viscous oil. The residue was dissolved in
dry CH2Cl2 (100 mL). To this solution at -78 °C was added methyl
(triphenylphosphoranylidene)acetate (2.7 g, 8.1 mmol) in one
portion. The resulting mixture was stirred for 10 h while it was
allowed to warm to room temperature. Water (100 mL) was added,
the two layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with brine, dried (MgSO4), and evaporated under reduced
pressure. The crude olefin (E:Z ) 8:1) was presorbed on silica gel
and purified by column chromatography (5-10% EtOAc/hexanes)
1
CHCl3); H NMR (CDCl3) δ 7.39-7.65 (m, 10H), 6.83 (dd, J )
15.7, 4.1 Hz, 1H), 6.11 (dd, J ) 15.7, 1.9, Hz, 1H), 4.41 (m, 1H),
4.18 (q, J ) 7.2 Hz, 2H), 3.75 (dd, J ) 10.2, 4.0 Hz, 1H), 3.54
(dd, J ) 10.2, 7.2, Hz, 1H), 2.73 (d, J ) 4.1 Hz, 1H), 1.27 (t, J )
7.2 Hz, 3H), 1.06 (s, 9H); 13C NMR (CDCl3) δ 166.3, 145.8, 135.6,
132.8, 130.1, 127.9, 127.8, 122.0, 71.5, 67.0, 60.5, 26.9, 19.3, 14.3;
HRMS m/z (ESI) calcd for C23H30O4SiNa (M + Na)+ 421.1805,
found 421.1805.
to afford enoate 3 (1.92 g, 80%) as a colorless oil. Rf 0.3 (35%
1
EtOAc/hexanes); [R]28 22.6 (c 1, CHCl3); H NMR (CDCl3) δ
D
7.45-7.20 (m, 10H), 6.94 (dd, J ) 15.7, 5.5 Hz, 1H), 6.16 (dd, J
) 16.0, 1.4 Hz, 1H), 4.68 (d, J ) 12.1 Hz, 1H), 4.58 (s, 2H), 4.54
(d, J ) 12.1 Hz, 1H), 4.25 (q, J ) 5.0 Hz, 1H), 3.77 (s, 3H), 3.61
(t, J ) 6.3 Hz, 2H); 13C NMR (CDCl3) δ 166.6, 145.6, 138.0, 137.9,
128.5, 127.9, 127.8, 127.7, 122.8, 73.6, 72.2, 71.7, 51.8; HRMS
m/z (ESI) calcd for C20H22O4Na (M + Na)+ 349.1410, found
349.1419.
Ethyl (2E,4S)-5-(tert-Butyldiphenylsilanyloxy)-4-methoxy-
methoxy-2-pentenoate (1). To a solution of 9 (1.36 g, 3.42 mmol)
in CH2Cl2 (80 mL) at 0 °C was added i-Pr2NEt (4.3 g, 33.3 mmol)
followed by the dropwise addition of chloro(methoxy)methane (1.34
g, 16.6 mmol). The resulting solution was stirred for 20 h while it
was allowed to warm to room temperature. The reaction mixture
was quenched with saturated NH4Cl (30 mL). The aqueous phase
was extracted with ether (3 × 50 mL). The combined organic layers
were washed with brine, dried (MgSO4), and evaporated to afford
dark yellow oil. The crude material was presorbed on silica gel
and purified by column chromatography (5-20% EtOAc/hexanes)
Methyl (2Z,4S)-4-Benzyloxy-5-(tert-butyldiphenylsilanyloxy)-
2-pentenoate (5). To a solution of diol 1014b (3.15 g, 3.7 mmol) in
dry methanol (150 mL) at 0 °C was added NaIO4 (0.96 g, 4.5
mmol). The resulting suspension was vigorously stirred for 24 h at
room temperature. The precipitate was filtered and solution was
concentrated under reduced pressure. The residue was dissolved
in ether (50 mL) and the formed precipitate was filtered. The ether
fraction was evaporated under reduced pressure to give viscous oil.
The residue was dissolved in dry methanol (100 mL). To this
solution at 0 °C was added methyl (triphenylphosphoranylidene)-
acetate (2.6 g, 8 mmol) in one portion. The resulting mixture was
stirred for 10 h while it was allowed to warm to room temperature.
The solvent was evaporated under reduced pressure. The residue
was dissolved in CH2Cl2 (100 mL), washed with water (3 × 50
mL) and brine, dried (MgSO4), and evaporated under reduced
pressure. The crude olefin (E:Z ) 1:2) was presorbed on silica gel
and purified by column chromatography (2-5% EtOAc/hexanes)
to afford enoate 1 (1.2 g, 85%) as a colorless oil. Rf 0.64 (20%
1
EtOAc/hexanes); [R]21 12.3 (c 1.7, CHCl3); H NMR (CDCl3) δ
D
7.38-7.69 (m, 10H), 6.85 (dd, J ) 15.7, 5.5 Hz, 1H), 6.06 (dd, J
) 15.7, 1.4 Hz, 1H), 4.72 (d, J ) 6.6 Hz, 1H), 4.65 (d, J ) 6.6
Hz, 1H), 4.32 (m, 1H), 4.16 (q, J ) 7.1 Hz, 2H), 3.71 (dd, J )
10.5, 6.6 Hz, 1H), 3.63 (dd, J ) 10.7, 5.2 Hz, 1H), 3.35 (s, 3H),
1.26 (t, J ) 7.1 Hz, 3H), 1.05 (s, 9H); 13C NMR (CDCl3) δ 166.2,
145.2, 135.7, 133.2, 129.9, 127.8, 122.9, 95.3, 76.0, 66.1, 60.5,
55.7, 26.8, 19.3, 14.3; HRMS m/z (ESI) calcd for C25H34O5SiNa
(M + Na)+ 465.2067, found 465.2063.
Methyl (2E,4S)-4-Benzyloxy-5-(tert-butyldiphenylsilanyloxy)-
2-pentenoate (2). To a solution of diol 1014b (3.15 g, 3.7 mmol) in
dry methanol (150 mL) at 0 °C was added NaIO4 (0.96 g, 4.5
mmol). The resulting suspension was vigorously stirred for 24 h at
room temperature. The precipitate was filtered and solution was
concentrated under reduced pressure. The residue was dissolved
to afford enoate 5 (2.08 g, 61%) as a colorless oil. Rf 0.47 (12%
1
EtOAc/hexanes); [R]21 16.4 (c 1, CHCl3); H NMR (CDCl3) δ
D
7.73-7.68 (m, 5H), 7.45-7.28 (m, 10H), 6.25 (dd, J ) 11.8, 8.5
Hz, 1H), 5.95 (dd, J ) 11.8, 1.1 Hz, 1H), 5.32-5.25 (m, 1H),
2638 J. Org. Chem., Vol. 71, No. 7, 2006

Reactions of Organocuprates to γ-Alkoxy-R,â-enoates
4.63 (d, J ) 11.8 Hz, 1H), 4.57 (d, J ) 11.8 Hz, 1H), 3.85 (dd, J
) 10.5, 5.8 Hz, 1H), 3.8 (dd, J ) 10.5, 4.4 Hz, 1H), 3.69(s, 3H),
1.06 (s, 9H); 13C NMR (CDCl3) δ 166.2, 148.1, 138.7, 135.8, 135.7,
133.6, 133.5, 129.7, 128.4, 127.8, 127.7, 127.6, 122.1, 76.2, 71.7,
66.2, 51.4, 26.9, 19.4; HRMS m/z (ESI) calcd for C29H34O4SiNa
(M + Na)+ 497.2118, found 497.2127.
19.3, 14.2; HRMS m/z (ESI) calcd for C32H42O6SiNa (M + Na+)
573.2642, found 573.2630.
Compound 12c: 79%, Rf 0.48 (20% EtOAc/hexanes); [R]21
D
1
-37.8 (c 0.6, CHCl3); H NMR (CDCl3) δ 7.63-6.92 (m, 14H),
4.67 (d, J ) 6.9 Hz, 1H), 4.50 (d, J ) 6.9 Hz, 1H), 3.99 (q, J )
7.1 Hz, 2H), 3.71 (m, 1H), 3.52 (m, 3H), 3.27 (s, 3H), 2.97 (dd, J
) 15.7, 4.9 Hz, 1H), 2.60 (dd, J ) 15.7, 10.5 Hz, 1H), 1.07 (t, J
) 7.1 Hz, 3H), 1.03 (s, 3H); 13C NMR (CDCl3) δ 172.4, 136.9,
135.7, 135.5, 133.3, 133.1, 129.9, 129.8, 127.7, 115.4, 115.1, 96.4,
80.8, 63.6, 60.3, 56.1, 42.6, 37.1, 31.0, 26.9, 19.2, 14.2; HRMS
m/z (ESI) calcd for C31H39FO5SiNa (M + Na)+ 561.2443, found
561.2422.
Methyl (2Z,4S)-4,5-Dibenzyloxy-2-pentenoate (6).2727 To a
solution of diol 1114c (2.01 g, 3.7 mmol) in dry methanol (150 mL)
at 0 °C was added NaIO4 (0.94 g, 4.4 mmol). The resulting
suspension was vigorously stirred for 24 h at room temperature.
The precipitate was filtered and solution was concentrated under
reduced pressure. The residue was dissolved in ether (50 mL) and
the formed precipitate was filtered. The ether fraction was
evaporated under reduced pressure to give viscous oil. The residue
was dissolved in dry methanol (100 mL). To this solution at 0 °C
was added methyl (triphenylphosphoranylidene)acetate (2.7 g, 8.1
mmol) in one portion. The resulting mixture was stirred for 10 h
while it was allowed to warm to room temperature. The solvent
was evaporated under reduced pressure. The residue was dissolved
in CH2Cl2 (100 mL), washed with water (3 × 50 mL) and brine,
dried (MgSO4), and evaporated under reduced pressure. The crude
olefin (E:Z ) 1:8) was presorbed on silica gel and purified by
column chromatography (5-10% EtOAc/hexanes) to afford enoate
6 (1.56 g, 65%) as a colorless oil.
Compound 12d: 75%, Rf 0.46 (20% EtOAc/hexanes); [R]21
D
1
-35.6 (c 0.2, CHCl3); H NMR (CDCl3) δ 7.59-7.30 (m, 10H),
6.66 (m, 3H), 5.91 (s, 2H), 4.70 (d, J ) 6.9 Hz, 1H), 4.53 (d, J )
6.9 Hz, 1H), 4.0 (q, J ) 7.2 Hz, 2H), 3.69 (m, 1H), 3.51 (m, 3H),
2.94 (dd, J ) 15.4, 4.95 Hz, 1H), 2.56 (dd, J ) 15.4, 10.2, Hz,
1H), 1.12 (t, J ) 7.2 Hz, 3H), 1.03 (s, 9H); 13C NMR (CDCl3) δ
172.5, 147.8, 146.3, 135.6, 133.7, 129.7, 127.7, 121.8, 108.3, 108.0,
100.9, 96.5, 81.7, 64.0, 60.3, 56.0, 35.8, 34.7, 31.7, 26.9, 25.3, 22.7,
14.2; HRMS m/z (ESI) calcd for C32H40O7SiNa (M + Na)+
587.2435, found 587.2421.
Compound 12e: 76%, Rf 0.38 (20% EtOAc/hexanes); [R]21
D
1
-26.8 (c 0.4, CHCl3); H NMR (CDCl3) δ 7.63-7.28 (m, 10H),
B. Arylcuprate Reactions: General Procedure for Aryl-
cuprate Addition. A few drops of a required aryl bromide were
added to crushed Mg turnings (0.17 g, 7.03 mmol) in THF (10
mL) under nitrogen atmosphere. Once the reaction started the
solution warmed and slightly darkened. The rest of the aryl bromide
(7.03 mmol total) was added dropwise to allow a gentle reaction.
The reaction mixture was allowed to cool to room temperature and
then cannulated to a slurry of CuI (0.67 g, 3.52 mmol) in THF (10
mL) at -78 °C. The mixture was stirred at -78 °C for 40 min (in
the synthesis of 12e the mixture was stirred at 0 °C for 2 h, as no
trans-metalation occurred at -78 °C). Me3SiCl (0.38 g, 7.03 mmol)
and a corresponding enoate (0.703 mmol in 10 mL of THF) were
added sequentially dropwise at -78 °C. The yellow-brown suspen-
sion was stirred overnight while slowly being warmed up to room
temperature. At this time reactions of trans enoates 1, 2, 3, and 4
were finished. In the addition reactions of cis enoates 5, 6, and 7
the reaction mixtures were stirred for an additional 24-48 h until
the starting material disappeared. The reaction mixture was
quenched with a mixture of concentrated NH4OH and saturated
NH4Cl (1:9, 30 mL) and extracted with ether (3 × 30 mL). The
combined organic layers were washed with brine, dried with
MgSO4, and concentrated under reduced pressure. The residue was
absorbed on silica gel and purified by column chromatography (5-
30% EtOAc/hexanes) to yield corresponding addition product as
an oil.
6.73 (m, 3H), 4.69 (d, J ) 6.9 Hz, 1H), 4.52 (d, J ) 6.9 Hz, 1H),
3.99 (q, J ) 7.7 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.73 (m, 1H),
3.52 (m, 3H), 3.30 (s, 3H), 2.97 (dd, J ) 15.4, 4.9 Hz, 1H), 2.61
(dd, J ) 15.4, 10.5 Hz, 1H), 1.11 (t, J ) 7.7 Hz, 3H), 1.03 (s, 9H);
13C NMR (CDCl3) δ 172.7, 148.7, 147.7, 135.6, 133.7, 133.4, 133.1,
129.8, 27.7, 120.3, 111.5, 111.0, 96.4, 81.0, 63.7, 60.2, 56.1, 55.9,
43.0, 37.6, 26.9, 19.3, 14.2; HRMS m/z (ESI) calcd for C33H44O7-
SiNa (M + Na)+ 603.2748, found 603.2764.
Compound 12f: 75%, Rf 0.56 (40% EtOAc/hexanes); [R]21
D
1
-27.2 (c 0.2, CHCl3); H NMR (CDCl3) δ 7.61-7.30 (m, 10H),
6.38 (m, 2H), 5.92 (s, 2H), 4.69 (d, J ) 6.7 Hz, 1H), 4.52 (d, J )
6.7 Hz, 1H), 4.02 (q, J ) 6.9 Hz, 2H), 3.79 (s, 3H), 3.68 (m, 1H),
3.50 (m, 3H), 3.29 (s, 3H), 2.94 (dd, J ) 15.4, 4.9 Hz, 1H), 2.56
(dd, J ) 15.4, 10.2 Hz, 1H), 1.13 (t, J ) 6.9 Hz, 3H), 1.04 (s, 9H);
13C NMR (CDCl3) δ 172.5, 148.7, 143.3, 135.8, 135.7, 135.5, 133.9,
133.3, 133.1, 129.7, 127.7, 107.7, 102.1, 101.4, 96.4, 80.9, 63.7,
60.3, 56.4, 56.1, 43.4, 37.4, 26.8, 19.2, 14.2; HRMS m/z (ESI) calcd
for C33H42O8SiNa (M + Na)+ 617.2541, found 617.2551.
Compound 13a: 88%, Rf 0.35 (15% EtOAc/hexanes); [R]25
D
-49.2 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.66-7.57 (m, 5H), 7.47-
7.22 (m, 15H), 4.72 (d, J ) 11.6 Hz, 1H), 4.44 (d, J ) 11.6 Hz,
1H), 3.73-3.52 (m, 4H), 3.49 (s, 3H), 3.02 (dd, J ) 16.0, 4.9 Hz,
1H), 2.71 (dd, J ) 16.0, 8.8 Hz, 1H), 1.09 (s, 9H); 13C NMR
(CDCl3) δ 173.2, 141.7, 138.6, 135.7, 135.6, 135.4, 134.9, 133.5,
133.3, 129.7, 128.6, 128.4, 127.9, 127.8, 127.6, 126.9, 83.4, 72.7,
63.5, 51.5, 43.6, 37.4, 26.9, 19.3; HRMS m/z (ESI) calcd for
C35H40O4SiNa (M + Na)+ 575.2588, found 575.2598.
Compound 12a: 80%, Rf 0.58 (20% EtOAc/hexanes); [R]21
D
1
-43.9 (c 0.5, CHCl3); H NMR (CDCl3) δ 7.19-7.60 (m, 15H),
Compound 13d: 93%, Rf 0.4 (15% EtOAc/hexanes); [R]26
4.68 (d, J ) 6.9 Hz, 1H), 4.51 (d, J ) 6.9 Hz, 1H), 3.97 (q, J )
7.2 Hz, 2H), 3.75 (m, 1H), 3.46 (m, 3H), 3.27 (s, 3H), 2.97 (dd, J
) 15.6, 5.2 Hz, 1H), 2.64 (dd, J ) 15.6, 10.2 Hz, 1H), 1.08 (t, J
) 7.2 Hz, 3H), 1.03 (s, 9H); 13C NMR (CDCl3) δ 172.8, 141.3,
135.5, 133.2, 129.8, 128.5, 127.8, 126.9, 96.4, 81.0, 63.9, 60.0,
56.0, 43.1, 37.2, 26.8, 19.2, 14.0; HRMS m/z (ESI) calcd for
C31H40O5SiNa (M + Na)+ 543.2537, found 543.2530.
D
-49.4 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.61-7.55 (m, 5H), 7.42-
7.26 (m, 10H), 6.67 (d, J ) 8.0 Hz, 3H), 5.92 (s, 2H), 4.67 (d, J
) 11.6 Hz, 1H), 4.39 (d, J ) 11.6 Hz, 1H), 3.67-3.43 (m, 4H),
3.48 (s, 3H), 2.92 (dd, J ) 16.0, 4.9 Hz, 1H), 2.60 (dd, J ) 16.0,
9.4 Hz, 1H), 1.04 (s, 9H); 13C NMR (CDCl3) δ 173.0, 147.6, 146.3,
138.5, 135.7, 135.6, 135.4, 133.4, 133.2, 129.7, 128.3, 127.8, 127.7,
127.5, 121.5, 108.5, 108.2, 100.9, 83.4, 72.7, 63.6, 51.4, 43.3, 37.5,
26.9, 19.2; HRMS m/z (ESI) calcd for C36H40O6SiNa (M + Na)+
619.2486, found 619.2495.
Compound 12b: 78%, Rf 0.45 (20% EtOAc/hexanes); [R]21
D
1
-45.7 (c 0.2, CHCl3); H NMR (CDCl3) δ 6.76-7.60 (m, 14H),
4.52 (d, J ) 6.9 Hz, 1H), 4.69 (d, J ) 6.9 Hz, 1H), 3.98 (q, J )
7.0 Hz, 2H), 3.77 (s, 3H), 3.75 (m, 1H), 3.42 (m, 3H), 3.29 (s,
3H), 2.96 (dd, J ) 15.4, 5.2 Hz, 1H), 2.59 (dd, J ) 15.4, 10.5 Hz,
1H), 1.07 (t, J ) 7.0 Hz, 3H), 1.03 (s, 3H); 13C NMR (CDCl3) δ
172.7, 158.4, 135.7, 135.6, 133.4, 133.2, 129.7, 129.3, 127.7, 116.1,
114.8, 113.8, 96.4, 81.1, 63.7, 60.2, 56.1, 55.3, 42.6, 37.4, 26.9,
Compound 13f: 82%, Rf 0.6 (30% EtOAc/hexanes); [R]25
D
-47.9 (c 1, CHCl3); 1H NMR (CDCl3) δ 7.62-7.56 (m, 5H), 7.43-
7.26 (m, 10H), 6.39 (s, 2H), 5.95 (s, 2H), 4.68 (d, J ) 11.6 Hz,
1H), 4.39 (d, J ) 11.6 Hz, 1H), 3.77 (s, 3H), 3.74-3.44 (m, 4H),
3.50 (s, 3H), 2.92 (dd, J ) 16.0, 4.9 Hz, 1H), 2.60 (dd, J ) 16.0,
9.4 Hz, 1H), 1.05 (s, 9H); 13C NMR (CDCl3) δ 173.0, 148.8, 143.4,
138.5, 136.3, 135.7, 135.6, 134.0, 133.5, 133.1, 129.7, 128.5, 128.3,
127.8, 127.7, 127.7, 127.6, 107.8, 101.9, 101.4, 83.4, 72.6, 63.5,
(27) Annunziata, R.; Cinquini, M.; Cozzi, F. Tetrahedron 1987, 43,
2369-2380.
J. Org. Chem, Vol. 71, No. 7, 2006 2639

Kireev et al.
56.5, 51.5, 43.6, 37.3, 26.9, 19.3; HRMS m/z (ESI) calcd for
C37H42O7SiNa (M + Na)+ 649.2592, found 649.2569.
evaporated. The residue was presorbed on silica gel and purified
by column chromatography (5-10% EtOAc/hexanes) to afford
lactone 1916 (12 mg, 66%).
Epimeric mixture 14a:28 94% (anti:syn ) 14.6:1), Rf 0.45 (30%
EtOAc/hexanes); selected 1H NMR (CDCl3) data for the anti-isomer
δ 7.55-7.15 (m, 15H), 4.80 (d, J ) 11.6 Hz, 1H), 4.55 (d, J )
11.6 Hz, 1H), 4.44 (s, 2H), 3.81-3.73 (m, 1H), 3.58-3.47 (m,
1H), 3.50 (s, 3H), 3.36 (dd, J ) 10.5, 5.2 Hz, 1H), 3.04 (dd, J )
16.0, 5.8 Hz, 1H), 2.64 (dd, J ) 16.0, 9.1 Hz, 1H); HRMS m/z
(ESI) calcd for C26H28O4Na (M + Na)+ 427.1879, found 427.1891.
Method 2: To a stirred solution of phenyl addition product 13a
(54.6 mg, 0.1 mmol) in a mixture of dioxane-water (1:1, 5 mL)
was added 10% Pd/C (5 mg, 0.004 mmol). The suspension was
stirred for 3 days under H2 atmosphere at atmospheric pressure.
The catalyst was filtered off with a Celite pad and solution was
concentrated under reduced pressure. The residue was dissolved
in ether (30 mL), washed with water (3 × 20 mL) and brine, dried
(MgSO4), and evaporated under reduced pressure. The crude residue
was presorbed on silica gel and purified by column chromatography
(10-20% EtOAc/hexane) to give pure lactone 29 (35 mg, 67%),
which was treated as in method 1 to provide 19.
Method 3: To a stirred solution of the epimeric mixture 14a
(14:1, 0.48 g, 1.2 mmol) in dioxane-water (1:1, 25 mL) was added
10% Pd/C (25 mg, 0.02 mmol). The suspension was stirred for 3
days under H2 atmosphere at atmospheric pressure. The catalyst
was filtered off with a Celite pad and solution was concentrated
under reduced pressure. The residue was dissolved in ether (50 mL),
washed with water (3 × 20 mL) and brine, dried (MgSO4), and
evaporated under reduced pressure to give trans lactone 30 (0.24
g, 90%) with traces of the corresponding cis lactone. This mixture
was further treated as in method 1 to obtain 19 with only traces of
20.
(4R,5R)-5-Methyl-4-phenyl-4,5-dihydro-2(3H)-furanone (21)
and (4S,5R)-5-Methyl-4-phenyl-4,5-dihydro-2(3H)-furanone (22).17
To a stirred solution of the epimeric mixture (6:1) of 15a (0.4 g,
1.2 mmol) in dioxane-water (1:1, 25 mL) was added 10% Pd/C
(25 mg, 0.02 mmol). The suspension was stirred for 3 days under
H2 atmosphere at atmospheric pressure. The catalyst was filtered
off with a Celite pad and solution was concentrated under reduced
pressure. The residue was dissolved in ether (50 mL), washed with
water (3 × 20 mL) and brine, dried (MgSO4), and evaporated under
reduced pressure to give lactones 2117 (0.174 g, 76%) and 2216
(0.029 g, 13%).
C. Stereochemistry Confirmation: (4R,5S)-5-Acetoxymethyl-
4-phenyl-4,5-dihydro-2(3H)-furanone (19).16 Method 1: To a
solution of 12a (136 mg, 0.26 mmol) in CH2Cl2 (15 mL) was added
Me2BBr (0.8 mL of 1.6 M solution in CH2Cl2) at -78 °C. The
resulting mixture was stirred for 3 h at -78 °C. THF (3 mL) and
saturated aqueous NaHCO3 (1.5 mL) was added to reaction mixture
at -78 °C and the temperature was raised to room temperature.
Ether (50 mL) was added to the mixture. The two layers were
separated and the organic layer was washed with saturated NH4Cl
and brine, dried with Na2SO4, and evaporated. The crude residue
was presorbed on silica gel and purified by column chromatography
(10-20% EtOAc/hexane) to give pure intermediate 5-tert-butyl-
diphenylsilyloxymethyl lactone 29 (65 mg, 63%) as a colorless oil.
1
Rf 0.4 (12% EtOAc/hexanes); [R]21 23.8 (c 1, CHCl3); H NMR
D
(CDCl3) δ 7.25-7.66 (m, 15H), 4.51 (m, 1H), 3.94 (dd, J ) 2.8,
11.6 Hz, 1H), 3.73 (m, 2H), 3.09 (dd, J ) 9.4, 17.8 Hz, 1H), 2.69
(dd, J ) 8.0, 17.8 Hz, 1H), 1.06 (s, 9H); 13C NMR (CDCl3) δ
176.2, 140.7, 135.7, 135.6, 130.0, 129.2, 127.9, 127.7, 127.0, 86.8,
63.7, 42.4, 37.4, 26.9, 19.3; HRMS m/z (ESI) calcd for C27H30O3-
SiNa (M + Na+) 453.1856, found 453.1851.
To a solution of the lactone 29 (25 mg, 0.058 mmol) in THF (1
mL) at 0 °C was added TBAF (0.29 mL of 1 M solution in THF,
0.29 mmol). The resulting mixture was stirred for 1 h at 0 °C and
then aqueous saturated NH4Cl (1 mL) was added. The aqueous
phase was extracted with ether (3 × 5 mL). The combined organic
layers were dried with Na2SO4 and evaporated to give pure
intermediate 5-hydroxymethyl lactone 30 (10.8 mg, 96%). Rf 0.4
(35% EtOAc/hexanes); [R]22 28.3 (c 0.68, CHCl3); 1H NMR
D
(CDCl3) δ 7.39-7.16 (m, 5H), 4.56-4.51 (m, 1H), 4.10-3.85 (m,
1H), 3.81-3.56 (m, 2H), 3.03 (dd, J ) 18.0, 9.1 Hz, 1H), 2.78
(dd, J ) 18.0, 9.6 Hz, 1H), 2.44 (t, J ) 6.3 Hz, 1H); 13C NMR
(CDCl3) δ 176.0, 139.2, 129.3, 127.9, 127.3, 87.0, 62.0, 42.1, 37.3;
HRMS m/z (ESI) calcd for C11H12O3Na (M + Na)+ 215.0678, found
215.0679.
Acknowledgment. We thank Professor Patrick S. Mariano
for his advice and help with the preparation of the manuscript.
This work is supported by the National Institutes of Health (CA-
99957 and RR-16480) under the AREA and BRIN/INBRE
programs.
Lactone 30 (15 mg, 0.078 mmol) was dried by coevaporating
with toluene (5 × 1 mL) and dissolved in anhydrous pyridine (1
mL). To this solution at 0 °C was added acetic anhydride (80 mg,
0.78 mmol). The resulting mixture was allowed to warm to room
temperature and the reaction mixture was stirred for 5 h. The
mixture was extracted with ether (3 × 5 mL). The combined organic
layers were washed with water (5 mL), dried (MgSO4), and
Supporting Information Available: Description of the general
methods, copies of 1H and 13C NMR of all new compounds,
1
complete characterization data, and copies of H NMR showing
the epimeric ratios of cuprate addition product mixtures 14a, 14d,
14f, 15a, 15d, 15f, 16a, 16d, 16f, 17a, 17d, 17f, 18a, 18d, and
18f. This material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Characterization data of all epimeric mixtures obtained in this work
can be found in the Supporting Information.
JO052383V
2640 J. Org. Chem., Vol. 71, No. 7, 2006