Stereoselective conjugate addition of benzyl phenylsulfonyl carbanions to enoates derived from D-mannitol

Article abstract of DOI:10.1021/jo035427d

The conjugate addition of benzylic phenylsulfonyl carbanions (2a′-d′) to enoates derived from D-(+)-mannitol (E- or Z-1a-c) was studied using THF and THF/HMPA as solvent. Under kinetic conditions (-78 °C), enoate E-1a,b led to a mixture of syn-(R,S) and a

Full text of DOI:10.1021/jo035427d

Ster eoselective Con ju ga te Ad d ition of Ben zyl P h en ylsu lfon yl
Ca r ba n ion s to En oa tes Der ived fr om D-Ma n n itol
Andre´ R. G. Ferreira,† Guilherme V. M. de A. Vilela,† Mauro B. Amorim,‡ Ka´tia P. Perry,‡,§
Antoˆnio J . R. da Silva,§ Ayres G. Dias,*,| and Paulo R. R. Costa*,†
Laborato´rio de Qu´ımica Bioorgaˆnica (LQB), Laborato´rio de Qu´ımica Computacional, and
Central Analı´tica, Nu´cleo de Pesquisas de Produtos Naturais, Centro de Cieˆncias da Sau´de, bloco H,
Ilha da Cidade Universita´ria, Universidade Federal do Rio de J aneiro, Brazil, 21941-590, and
Instituto de Quı´mica, Universidade do Estado do Rio de J aneiro, Brazil
lqb@nppn.ufrj.br
Received September 30, 2003
The conjugate addition of benzylic phenylsulfonyl carbanions (2a ′-d ′) to enoates derived from D-(+)-
mannitol (E- or Z-1a -c) was studied using THF and THF/HMPA as solvent. Under kinetic
conditions (-78 °C), enoate E-1a ,b led to a mixture of syn-(R,S) and anti-(S,S) adducts (55/45),
and syn-(R,S) adducts were the main product obtained (∼90/10) from enoate Z-1a . Under
thermodynamic conditions (-78 °C to room temperature) syn-(R,S) adducts were also preferentially
formed (∼90/10), despite the geometry at the double bond in the acceptor. Enoate 1c (E/Z ) 57/
43), bearing an additional benzyl group at the R-position, also reacted with carbanions 2′a ,b, under
thermodynamic conditions, leading to syn-adducts in excellent de (control at the three newly
generated stereogenic centers). The adducts were quantitatively transformed into the corresponding
â-γ-disubstituted γ-butyrolactones and R,â,γ-trisubstituted γ-butyrolactones. 1H NMR studies (NOE
and J -coupling) of these lactones allowed us to determine their configuration at the newly generated
chiral centers. The reduction of the C-S bond in adducts syn-(R,S) with Na/Hg, followed by
treatment of the resulting products in aqueous acid media, led to enantioenriched â-benzyl-γ-
hydroxymethyl-γ-butyrolactones. The conformational equilibrium of enoates E- and Z-1b was
evaluated by theoretical calculations (ab initio, MP2/6-31G*), and a mechanistic rationale was
proposed to explain the observed stereoselectivities.
In tr od u ction
derivatives, in the case of allyl and prenyl phenylsulfonyl
carbanions, anti-adducts predominated under kinetic
conditions (-78°), and syn-adducts were the main prod-
ucts obtained under thermodynamic conditions (rt).
Benzylic organometallics play an important role in
organic synthesis and have been used to prepare com-
Conjugate addition is a versatile reaction that allows
the formation of new carbon-carbon or carbon-hetero-
atom bonds from a variety of acceptors and nucleophiles.1
Enantioenriched adducts can be obtained from prochiral
reagents when chiral auxiliaries,2a-d chiral nucleophiles,2e,f
or chiral catalysts2g-n are used. Enantiopure acceptors
prepared from the chiral pool are also invaluable starting
materials to obtain chiral enantioenriched building blocks
for synthesis.3 Enoates such as 1a ,b (Figure 1), easily
obtained from D-(+)-mannitol, are among the most stud-
ied acceptors of this type.4 The stereochemical outcome
of the conjugate additions to these enoates has been
shown to be dependent on the nature of the nucleophile.5
We previously reported the use of nitromethane deriv-
atives6a-c and phenylsulfone derivatives6d as nucleophiles
in the conjugate addition to 1a -c and 1a ,b, respectively.
Whereas syn-selectivity was observed for nitromethane
(2) For chiral auxiliaries see: (a) d’Angelo, J .; Desmae¨le, D.; Dumas,
F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459. (b) Rossiter,
B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. (c) Palomo, C.
Aizpurua, J . M. Gracenea, J . J . J . Org. Chem. 1999, 64, 1693. (d)
Blaser, H.-U. Chem. Rev. 1992, 92, 935. For chiral nucleophiles see:
(e) Lucet, D.; Toupet, L.; Le Gall, T.; Mioskowski, C. J . Org. Chem.
1997, 62, 2682. (f) Davies, S. G.; Fenwick, D. R.; Ichihara, O.
Tetrahedron: Asymmetry 1997, 8, 3387. For chiral catalysts see: (g)
Myers, J . K.; J acobsen, E. N. J . Am. Chem. Soc. 1999, 121, 8959. (h)
Shibasaki, M. J . Am. Chem. Soc. 2000, 122, 6506. Shibasaki, M.; Sasai,
H.; Arai, T Angew. Chem., Int. Ed. Engl. 1997, 36, 1237. (i) Corey, E.
J .; Zhang, F.-Y. Org. Lett. 2000, 2, 4257. (j) Kanemasa, S., Itoh, K. J .
Am. Chem. Soc. 2002, 124, 13394. (l) Nishikori, H.; Ito, K.; Katsuki,
T. Tetrahedron: Asymmetry 1998, 9, 1165. (m) Evans, D. A.; Rovis,
T.; Kozlowski, M. C.; Tedrow, J . S. J . Am. Chem. Soc. 1999, 121, 1994.
(n) Sibi, M. P.; Shay, J . J .; Liu, M.; J asperse, C. P. J . Am. Chem. Soc.
1998, 120, 6615.
(3) (a) J urczak, J .; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.
(b) Leonard, J . Contemp. Org. Synth. 1994, 387. (c) Takano, S.;
Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis 1986, 403. (d)
Ma, D.; Zou, B.; Zhu, W.; Xu, H. Tetrahedron Lett. 2002, 43, 8511. (e)
Pan, S.; Wang, J .; Zhao, K. J . Org. Chem. 1999, 64, 4.
(4) (a) Leonard, J .; Mohialdin, S.; Swain, P. A. Synth. Commun.
1989, 19, 3529. (b) Mann, J .; Partlett, N.; Thomas, A. J . Chem. Res.,
Synop. 1987, 369. (c) Marshall, J . A.; Trometer, J . D.; Cleary, D. G.
Tetrahedron 1989, 45, 391.
† Laborato´rio de Qu´ımica Bioorgaˆnica.
‡ Laborato´rio de Qu´ımica Computacional.
§ Central Anal´ıtica.
| Instituto de Qu´ımica.
(1) (a) Pelmuter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992. (b) Little, R. D.; Masjedizadeh,
M. R. Org. React. 1995, 47, 315. (c) Parsons, P. J .; Penkett, C. S.; Shell,
A. J . Chem. Rev. 1996, 96, 195. (d) Tietze, L. F. Chem. Rev. 1996, 96,
115. (e) Li, C.-J . Chem. Rev. 1993, 93, 2023.
10.1021/jo035427d CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/12/2004
J . Org. Chem. 2004, 69, 4013-4018
4013

Ferreira et al.
TABLE 1. Ad d ition of 2a -d to En oa tes E- a n d Z-1a a
F IGURE 1. Enoates and benzyl phenylsulfone derivatives
used in this work: (*) o-hydrogen of phenyl ring, (**) more
stable conformer, (#) hydrogen of CH2OAc group.
entry
2
%
1a
conditionb
anti-3
syn-3
pounds of pharmaceutical interest. Benzylic lithium and
magnesium compounds, especially those bearing alkox-
yde groups at the aromatic ring, are difficult to prepare
from the corresponding halides, leading to extensive
formation of Wurtz-coupling side products.7a This prob-
lem can be overcome by the use of lithium powder in the
presence of a catalytic amount of naphthalene,7b lithium-
tellurium exchange,7c magnesium in the presence of
anthracene,7d or through fragmentation of sterically
hindered zinc alcoholates.7a However, the use of these
species as nucleophiles in conjugate addition reactions
is rare. In this paper, we report the use of benzylic
phenylsulfonyl carbanions derived from benzyl phenyl-
sulfones (2a -d ) as synthetic equivalents of benzylic
organometallics in stereoselective conjugate addition
reactions to enoates 1a -c (Figure 1).8
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2a
2a
2a
2b
2b
2c
2c
2d
2a
2a
2b
2b
56
53
59
52
55
57
55
57
52
55
53
65
63
E
E
E
E
E
E
E
E
E
Z
Z
Z
Z
1
2
3
4
1
3
1
3
3
1
3
1
3
55
55
10
10
55
10
55
10
15
<5
<5
13
13
45
45
90
90
45
90
45
90
85
>95
>95
87
87
Product distribution was measured by quantitative 13C NMR
a
or 13H NMR. Condition 1: THF, 1 h at -78 °C, NH4Cl. Condition
b
2: THF/HMPA, 1 h at -78 °C, NH4Cl. Condition 3: THF, -78 °C
to room temperature, NH4Cl. Condition 4: THF/HMPA, -78 °C
to room temperature, NH4Cl.
Resu lts
nucleophile with E-1a as acceptor, the product distribu-
tion at -78 °C did not depend on the nature of the solvent
used (THF or THF/HMPA, entries 1 and 2), and a
mixture of anti-3a and syn-3a (55/45) was obtained.
When the reaction pot was allowed to warm to room
temperature before quenching, however, syn-3a was the
main yield (90/10), regardless of the solvent used (entries
3,4). The reaction of other benzyl phenylsulfonyl carban-
ions (2′b-d ) with E-1a showed similar reactivities and
stereoselectivities. syn-Adducts 3b-d (dr ∼90/10) were
obtained in condition 3 (entries 6, 8, and 9), while in
condition 1 (entries 5 and 7) mixtures of anti-3b-c and
syn-3b-c (55/45) were formed.
We investigated if the stereoselectivity could be in-
creased using enoate Z-1a as acceptor and discovered
that it reacted with carbanion 2′a under conditions 1 and
3, to give exclusively syn-3a (Table 1, entries 10 and 11).
However, the reaction involving 2′b (entries 12 and 13)
was less stereoselective. By chance, the reactions with
Z-1a have similar kinetic and thermodynamic product
distributions (compare entries 10 and 12 with entries 11
and 13). During the course of this study, we eventually
used enoates E- and Z-1b as acceptors and similar
stereoselectivities were obtained.
The product distribution obtained in the conjugate
addition of phenylsulfonyl carbanions 2′a -d 9 to enoate
E-1a is described in Table 1. When 2′a was used as
(5) (a) Ha¨usemann, U. A.; Linden, A.; Song, J .; Hess, M. Helv. Chim.
Acta 1996, 79, 1995. (b) Matsunaga, H.; Sakamaki, T.; Nagaoka, H.;
Yamada, Y. Tetrahedron Lett. 1983, 24, 3009. (c) Yuejun, X.; Gi, H.-
J .; Niu, D.; Schinazi, R. F.; Zhao, K. J . Org. Chem. 1997, 62, 7430. (d)
Mulzer, J .; Kappert, M.; Huttner, G.; J ibrill, J . Angew. Chem., Int. Ed.
Engl. 1984, 23, 4. (e) Leonard, J .; Mohialdin, S.; Reed, D.; J ones, M.
F. Synlett 1992, 741. Raczko, J . Tetrahedron: Asymmetry 1997, 8, 3821.
(f) Smadja, W.; Zahouily, M.; Malacria, M. Tetrhedron Lett. 1992, 33,
5511. (g) Morikawa, T.; Nashio, Y.; Harada, S.; Hanai, R.; Kayashita,
T.; Nemoto, H.; Shiro, M.; Taguchi, T. J . Chem. Soc., Perkin Trans. 1
1995, 271. (h) Nilsson, K.; Ullenius, C. Tetrahedron 1994, 50, 13173.
(i) Normura, M.; Kanemasa, S. Tetrahedron Lett. 1994, 35, 143. (j)
Leonard, J .; Mohialdin, S.; Reed, D.; Ryan, G.; J ones, M. F. J . Chem.
Soc., Chem. Commun 1993, 23. (k) Yamamoto, Y.; Nishii, S.; Ibuka,
T. J . Chem. Soc., Chem. Commun 1987, 464. (l) Takano, S.; Kurotaki,
A.; Takahashi, M.; Ogasawara, K. Synthesis 1986, 403.
(6) (a) Costa, J . S.; Dias, A. G.; Anholeto, A. L.; Monteiro, M. D.;
Patroc´ınio, V. L.; Costa, P. R. R. J . Org. Chem. 1997, 62, 4002. (b)
Patroc´ınio, V. L.; Costa, P. R. R.; Correia, C. R. D. Synthesis 1994,
474. (c) Pinto, A. C.; Freitas, C. B. L.; Dias, A. G.; Patroc´ınio, V. L. P.
P.; Tinant, B.; Declercq, J .-P.; Costa, P. R. R Tetrahedron: Asymmetry
2002, 13, 1025. (d) Ferreira, A. R. G.; Dias, A. G.; Pinto, A. C.; Costa,
P. R. R.; Miguez, E.; da Silva, A. J . R. Tetrahedron Lett. 1998, 39, 5305.
(7) (a) Piazza, C.; Millot, N.; Knochel, P. J . Organomet. Chem. 2001,
624, 88. J ubert, C.; Knochel, P. J . Org. Chem. 1992, 57, 5425. (b) Kim,
S.-H.; Rieke, R. D. J . Org. Chem. 2000, 65, 2322. (c) Kanda, T.; Kato,
S.; Sugino, T.; Kambe, N.; Sonoda, N. J . Organomet. Chem. 1994, 473,
71. (d) Harvey, S.; J unk, P. C.; Raston, C. L.; Salem, G. J . Org. Chem.
1998, 53, 3134.
Enoate 1c (a mixture of geometric isomers, 57/43) was
also used as acceptor in reactions with phenylsulfonyl
carbanions 2′a ,b (Table 2). No reaction was observed at
-78 °C, but when the mixture was allowed to warm to
(8) Phenylnitromethane was previously used by our group as
synthetic equivalent of benzyl carbanions in conjugate addition to
E-1a ,b. However, neither the synthesis of oxygenated phenylnitro-
methane derivatives nor the conjugate addition of these compounds
to E-1a ,b led to satisfactory results.
(9) Benzyl phenylsulphones were prepared as described in Meek,
J . S.; Fowler, J . S. J . Org. Chem. 1968, 33, 3422.
4014 J . Org. Chem., Vol. 69, No. 12, 2004

Conjugate Additions of Carbanions to Enoates
TABLE 2. Con ju ga te Ad d ition of P h en ylsu lfon yl
Ca r ba n ion s 3a ,b to r-Su bstitu ted En oa tea
entry
2
% syn-4
de
1
2
2a
2b
40
74
88
90
a
The assignment of the stereogenic center in C1′ (S) was based
on mechanistic considerations but could not be determined by NOE
experiments. Product distribution was measured by quantitative
13C NMR or 13H NMR.
SCHEME 1. La cton iza tion of Ad d u cts 3a -d in
Acid Med iu m
F IGURE 2. MM2* calculation and NOE effects in lactones
cis-5a and trans-5a .
(∼2%) after irradiation at H4.6 The same trend was
observed for the new lactones, as shown in Scheme 1.
Since the configuration at C4 in these lactones is known,
the measurement of J H3,H4 led to the determination of the
absolute configuration at C3.
room temperature and kept at this temperature for 3 h,
a syn-selective conjugate addition took place leading to
adducts syn-4a ,b as the main yields, along with a very
small amount of a diastereomer whose structure was not
determined, which might be removed by chromatography.
Ster eoch em ica l Assign m en ts. The configurations of
the chiral centers in adducts anti-3a ,b and syn-3a -d (C3
and C1′) were assigned after their transformation into
the corresponding lactones trans-5a ,b and cis-5a -d , by
reaction in aqueous acid medium, followed by acetylation
(Scheme 1). In the course of our studies on â,γ-disubsti-
tuted-γ-butyrolactones derived from D-(+)-mannitol, we
observed that the trans-isomers showed values for J H3,H4
(ca. 4-6 Hz) smaller than those of the cis-isomers (ca.
7-9 Hz). Moreover, in cis-lactones, H3 exhibits an NOE
1
The configuration at C1′ was also determined by H
homonuclear J coupling and NOE measurements. Since
the dihedral angle along C3-C1′ bond affects the NOE
involving H1′ as well as the value of J H3,H1′, we performed
molecular mechanics calculations (MM2*)10 for trans-5a
and cis-5a lactones in order to know more about the
conformational equilibrium in these compounds. Figure
2 shows the most stable conformers for these lactones,
their relative steric energies, and calculated geometries.
(10) Macro Model, v. 6.5: Mohamadi F.; Richards, N. G. J .; Guida,
W. C.; Liskamp, R.; Lipton, M., Caulfield, C., Chang, G., Hendrickson,
T., Still, W. C. J . Comput. Chem. 1990, 11, 440.
J . Org. Chem, Vol. 69, No. 12, 2004 4015

Ferreira et al.
SCHEME 2. La cton iza tion of Ad d u cts Syn 4a ,b in
Acid Med iu m
SCHEME 3. Red u ction of C-S Bon d in Ad d u cts
Syn -3a -d
irradiation of H5 suggests the R configuration for C2. Noe
experiments failed to confirm the stereochemistry at C1′.
Since the S-configuration at C1′ in adducts syn-3a -d did
not depend on the geometry of the double bound in 1a ,b
acceptors or on reaction conditions, we proposed the same
configuration at this stereogenic center for the syn-4a ,b
products, basing ourselves in mechanistic considerations.
Clea va ge of C-S Bon d in Ad d u cts. The C-S bond
in compounds syn-3a -d was cleaved under reductive
conditions (Na/Hg).12 Reactions to these compounds in
aqueous acid led to the corresponding lactones cis-8a -d
(Scheme 3). The measured J H3,H4 for these lactones and
the NOE effects observed between H3 and H4 validated
the proposed configuration at the new stereogenic centers
in C3, generated at the conjugated addition step.
The examination of the structures obtained reveals that,
in all cases, H1′ is over the lactone ring, leaving the
bigger R1 and PhSO2 groups further away from the
lactone ring vicinity. The calculated rotation barriers for
the most stable conformers of lactones trans-5a and cis-
5a ranges between 5 and 7 kcal mol-1, and the sharp
signals observed in the 1H NMR spectra of such com-
pounds suggest that these conformers are in a fast
equilibrium at room temperature.11 In cis-lactone 5a , the
inside position of H1′ was suggested by the observed NOE
between this hydrogen and hydrogens H2R and H5.
Similarly, the strong NOE observed between H1′ and
hydrogens H4 and H2â in the NMR of 5a trans-lactone
was suggestive of the inside position of that hydrogen
in this compound. The calculated dihedral angles
Discu ssion
θH3-C3-C1′-H1′ (ca. 171-176°) for lactones trans-5a and cis-
It seems clear that in conditions 3 and 4 the product
distribution is under thermodynamic control, since the
anti-adducts formed in the reactions of 2′a -d with E-1a
at -78 °C were transformed into syn-adducts by raising
the temperature at which the reaction was quenched
(-78 °C to room temperature), thus suggesting that a
conjugate/retroconjugate addition process is in operation.
The product distribution at room temperature strongly
favors adducts syn-3a -d ; the equilibrium being reached
after 3 h, irrespective of the solvent used (THF or THF-
HMPA).
The reaction of 2′a with E-1a at -78 °C (conditions 1
and 2) was reinvestigated in order to determine if the
stereoselectivity is kinetically controlled or some equili-
bration occurs, even at this temperature. The product
distribution was measured from 10 s to 1 h (the time used
in Table 1), in the presence and absence of HMPA, and
the enoate was completely consumed after 5 min. Since
the syn-3a /anti-3a ratio did not change with time, we
assume that at -78 °C the product distribution is
kinetically controlled, regardless of the presence of
HMPA, disclosing the occurrence of a chelated transition
state.
5a are in accordance with the measured J H3,H1′ values
(10.1 and 11.4 Hz, Figure 2).11 For cis-5a , irradiation of
the hydrogens of CH2OAc group produced a NOE in
aromatic (Ph) hydrogen, placing this ring R-oriented in
the right side of the molecule (S-configuration). The
irradiation of H2â in lactone trans-5a (Figure 2) was the
most elucidative experiment to determine the configu-
ration at C1′, since NOE enhancements were observed
at the aromatic (Ph) group, thus placing this substituent
â-oriented in the left side of the molecule (S-configura-
tion). The NOE measurements on benzyl phenylsulfone
2a and the heteronucler correlation experiments (HET-
COR) on lactone cis-5a permitted the differentiation of
the hydrogen atoms placed at the Ph and the PhSO2
aromatic rings. So did the NOE studies involving lactones
trans-5a and cis-5b,c and benzyl phenylsulfones 2b,c.
The configuration at C2 and C3 in adducts syn-4a ,b
was also determined after their transformation into
lactones trans,cis-6a ,b (Scheme 2). It is worth noting that
the coupling constant between H3 and H4 is smaller (∼4
Hz) than that observed for lactones cis-5a -d (∼7 Hz),
which are not substituted in C2. This change is probably
due to additional conformational constraints imposed by
the presence of the benzyl group at C2. The cis-relation-
ship between the hydrogen H3 and H4 atoms was
confirmed by the strong NOE observed at H3 after
irradiation at H4. The NOE enhancement at H2 after
To propose a mechanistic rationale for the observed
kinetic stereoselectivities, the conformational equilibrium
of enoates Z-1b and E-1b was investigated using ab initio
calculations (MP2/6-31G*).13 These calculations furnished
(11) Oki, M. Applications of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH: New York, 1985.
(12) Anderson, M. B.; Ranasinghe, M. G.; Palmer, J . T.; Fuchs, P.
L. J . Org. Chem. 1988, 53, 3125.
4016 J . Org. Chem., Vol. 69, No. 12, 2004

Conjugate Additions of Carbanions to Enoates
SCHEME 4. Mech a n istic Ra tion a le for th e
Ad d ition of P h en ylsu lfon yl Ca r ba n ion s to En oa te
E-1a
F IGURE 3. Main conformers for enoates E- and Z-1b
calculated by molecular modeling.
two minima of energy for enoate E-1b, CE1 and CE2 (36/
64, Figure 3), whereas only a minimum of energy was
obtained for enoate Z-1b, CZ (Figure 3).14
The chelation between the nucleophile (Li atom) and
the enoate (oxygen atoms of the acetal or ester group)
might affect the conformational equilibrium of the enoate,
but because this possibility had been ruled out (the
product distribution is identical in the presence or
absence of HMPA), we accept that conformer CZ (enoate
Z-1) and conformers CE1 and CE2 (enoate E-1) are
involved in the transition states leading to the conjugate
addition adducts. Taking into account only steric hin-
drance, it is reasonable to expect that the nucleophiles
will attack enoate Z-1 preferentially through the re face
of conformer CZ, yielding syn-adducts. On the other
hand, the two conformers of enoate E-1 have opposite
prochiralities, i.e., whereas the si face of CE2 is the most
available (pro-anti), the re face is the less hindered one
(pro-syn) in CE1.
SCHEME 5. Mech a n istic Ra tion a le for th e
Ad d ition of Ben zyl P h en ylsu lfon yl Ca r ba n ion s to
En oa te Z-1a
A mechanistic rationale to explain the results of the
conjugated addition to E-1 is presented in Scheme 4.
Since the kinetic stereoselection in the additions of 2′a -d
at -78 °C was not affected by the presence of HMPA, it
appears that stereoselectivities are achieved through a
nonchelated approach between the nucleophiles and
conformers CE1 and CE2. The configuration at C1′ in the
anti-adducts (anti-3a -d ) can be explained by the transi-
tion state TS2, where the phenylsulfonyl carbanions
attack the si face of the E-enoate (conformer CE2) in an
anti-periplanar approach. On the other hand, the con-
figuration at C1′ in the syn-adducts (syn-3a -d ) can be
explained by the transition state TS1. In this case, a
synclinal approach was proposed for the attachment of
phenylsulfonyl carbanions to the E-enoate (conformer
CE1), in order to avoid electrostatic interactions between
the oxygen at the stereogenic center and the negatively
charged incoming nucleophile. In both transition states,
the benzylic hydrogen was placed in the more hindered
position.
The stereoselective formation of syn-3a ,b in the con-
jugated addition of 2′a ,b to Z-1a under kinetic conditions
can be explained by the intervention of TS3 (Scheme 5).
As a result of the electrostatic repulsion between the
incoming nucleophile and the oxygen atom at the chiral
center of the acceptor, a synclinal approach of the
(13) Hehre, W. J .; Ditchfield, R.; Pople, J . A. J . Chem. Phys. 1982,
56, 2257.
(14) Because in enoates E-1a and E-1b, as well as in enoates Z-1a
and Z-1b, the J H3,4 are identical and they react with phenylsuphonyl
carbanions with the same stereoselectivity, one can accept that the
conformational equilibrium around C3-C4 bond is little affected by
the nature of the ester moiety.
J . Org. Chem, Vol. 69, No. 12, 2004 4017

Ferreira et al.
phenylsulfonyl carbanions to conformer CZa was pro-
posed. This places the bulky phenyl groups at the least
sterically hindered position available and explains the
configuration at C1′ in the adducts.
Last, the syn-3/anti-3 ratio obtained in the reactions
with E-1 under kinetic conditions was 45/55, whereas the
contribution of conformers CE1 (pro-syn) and CE2 (pro-
anti), calculated by ab initio, was 36/64. To explain these
results, we must accept that in these cases the nucleo-
phile attacks CE1 faster.15
in stereoselective conjugate addition to chiral enoates
derived from D-mannitol. The resulting syn-adducts could
be transformed into the corresponding â,γ- and R,â,γ-
substituted γ-butyrolactones, which are valuable inter-
mediates for organic synthesis.
Ack n ow led gm en t . The authors thank CNPq,
CAPES, FAPERJ , and PRONEX for financial support;
CNPq for fellowships to P.R.R.C., A.R.G.F., and K.P.P.;
CAPES for a fellowship to A.G.D. and G.V.M.deA.V.;
E. Migues and M.C.H.P. Lima for NMR and MS spectra;
and Federal University of Pernambuco for micro-
analysis. The authors also thank Prof. Warner B.
Koover (IQ-UFRJ ) for helpful discussions.
Finally, the reactions involving enoate 1c as acceptor
occurred only at room temperature, and in this case the
product distribution is thermodynamically controlled.
Con clu sion s
Benzylic phenylsulfonyl carbanions were used as syn-
thetic equivalents of oxygenated benzylic organometallics
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods,1H and 13C NMR spectra, materials, theoretical
calculations, and NOE measurements. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(15) The syn/ anti ratio depends of the nucleophile; for example, allyl
and prenyl sulphonyl carbanions attack almost exclusively CE2,6d
leading to anti adducts, while benzylamine and nitronates attack
preferentially CE1, leading to syn adducts.5b The reasons for these
different preferences are being studied in our laboratory.
J O035427D
4018 J . Org. Chem., Vol. 69, No. 12, 2004