Studies of Diastereoselectivity in Conjugate Addition of Organoaluminum Reagents to (R)-[(p-Tolylsulfinyl)methyl]quinols and Derivatives

Article abstract of DOI:10.1021/jo980084i

(R)-4-Hydroxy-4-[p-tolylsulfinyl)methyl]-2,5-cyclohexadienones 1-3, and 6 reacted with organoaluminum derivatives from the pro-R conjugated position in a highly π-facial diastereoselective manner directed by the C-4 OH. A similar facial diastereoselectivity arose from reactions with 3-alkylsubstituted analogues 4 and 5 and 5-alkyl-4-hydroxy-4-[(p-tolylsuIfinyl)methyl]-2-cyclohexenones 10a,b. Semiempirical calculations (AM1 model) provide data on transition-state energies for additions in full agreement with the experimental results.

Full text of DOI:10.1021/jo980084i

J . Org. Chem. 1998, 63, 3687-3693
3687
Stu d ies of Dia ster eoselectivity in Con ju ga te Ad d ition of
Or ga n oa lu m in u m Rea gen ts to (R)-[(p-Tolylsu lfin yl)m eth yl]qu in ols
a n d Der iva tives
M. Carmen Carren˜o,* Manuel Pe´rez Gonza´lez, and Mar´ıa Ribagorda
Departamento de Quı´mica Orga´nica (C-I), Universidad Auto´noma, Cantoblanco, 28049-Madrid, Spain
K. N. Houk
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569
Received J anuary 16, 1998
(R)-4-Hydroxy-4-[(p-tolylsulfinyl)methyl]-2,5-cyclohexadienones 1-3, and 6 reacted with organoalu-
minum derivatives from the pro-R conjugated position in a highly π-facial diastereoselective manner
directed by the C-4 OH. A similar facial diastereoselectivity arose from reactions with 3-alkyl-
substituted analogues 4 and 5 and 5-alkyl-4-hydroxy-4-[(p-tolylsulfinyl)methyl]-2-cyclohexenones
10a ,b. Semiempirical calculations (AM1 model) provide data on transition-state energies for
additions in full agreement with the experimental results.
In tr od u ction
step. The essential role of the δ hydroxy group in
directing the site and face selectivity of 1,4-conjugate
additions had been pointed out in reactions of similar
p-quinol derivatives7 and acyclic systems8 with Grignard
and organolithium reagents. An analogue-controlling
effect by a δ-NBn2 substituent on a 3-keto acrylate has
recently been reported.9 Nevertheless, the dienone de-
symmetrization of an optically active p-quinol had only
been achieved in an intramolecular conjugate addition.10
The potential usefulness of the resulting 1,4-adducts
as building blocks for chiral targets prompted us to
extend the scope of the reaction to differently mono- and
disubstituted sulfinylmethyl-p-quinols 4-6 as well as to
cyclohexenone derivatives 10a ,b (Table 2). The effects
of varying the double-bond substitution on the reactivity
of the systems as well as the π-facial diastereoselectivity
of the process were evaluated. In the present paper, we
report the results of these studies as well as AM1
calculations showing that transition states arising from
the reagent approach to the pro-R double bond of p-
quinols from the face containing the OH group are the
lowest in energy.
Asymmetric 1,4-conjugate additions have been ef-
ficiently achieved by using chiral electrophiles, nucleo-
philes, and to a lesser extent, chiral catalysts.1 The
sulfinyl group situated on either the acceptor2 or the
nucleophile3 can control the diastereofacial selectivity of
the conjugate addition. In connection with our investiga-
tions devoted to the use of sulfoxides in asymmetric
synthesis,4 we decided to explore the 1,4-conjugate ad-
ditions on p-quinol derivatives 1-6 bearing a sulfoxide
and a OH group in a remote position from the R,â-
unsaturated moiety. The preliminary results we ob-
tained in the reactions of (R)-[(p-tolylsulfinyl)methyl]-
quinols 1 and 2 revealed that only organoaluminum
derivatives5 were able to afford exclusive 1,4-conjugate
addition products in the absence of any other metal
catalysts in good yield and under mild conditions. More-
over, we observed an efficient desymmetrization of the
prochiral dienone moiety: the 1,4-addition occurred in a
highly diastereoselective manner6 from the pro-R double
bond syn to the face containing the C-4 OH, giving rise
to the formation of two stereogenic centers in a single
Resu lts a n d Discu ssion
(1) Reviews: (a) Schmalz, H. G. In Comprehensive Organic Synthe-
sis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4,
Chapter 1.5. (b) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
771. (c) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992. For recent references, see:
(d) Urban, E.; Knu¨hl, G.; Helmchen, G. Tetrahedron 1996, 52, 971-
86. (e) Enders, D.; Kirchhoff, J .; Mannes, D.; Raabe. G. Synthesis 1995,
659-66. (f) Lassaletta, J . M.; Ferna´ndez, R.; Mart´ın Zamora, E.; D´ıez,
E. J . Am. Chem. Soc. 1996, 118, 7002-3.
Enantiomerically pure (R)-4-hydroxy-4-[(p-tolylsulfin-
yl)methyl]-2,5-cyclohexadienones 1-3 (Table 1) were
prepared as previously described.5,6b The synthesis of
(5) Carren˜o, M. C.; Pe´rez Gonza´lez, M.; Ribagorda, M.; Fischer, J .
J . Org. Chem. 1996, 61, 6758-9.
(2) Review: Posner, G. H. In The Chemistry of Sulfones and
Sulfoxide; Patai, S., Rappoport, Z., Stirling, C. J . M., Eds.; J ohn Wiley
& Sons: New York, 1988; Chapter 16.
(6) A high π-facial diastereoselectivity was also observed in Diels-
Alder cycloadditions of 1: (a) Carren˜o, M. C.; Pe´rez Gonza´lez, M.;
Fischer, J . Tetrahedron Lett. 1995, 36, 4893-6. (b) Carren˜o, M. C.;
Pe´rez Gonza´lez, M.; Houk, K. N. J . Org. Chem. 1997, 62, 9128-37.
(7) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J . Am. Chem. Soc.
1990, 112, 9393-4.
(3) (a) Review: Hua, H. D. in Advances in Carbanion Chemistry;
Snieckus, V., Eds.; J AI Press: London, 1992; p 249. (b) Haynes, R. K.;
Katsifis, A. G.; Vowiller, S. C.; Hambley, T. W. J . Am. Chem. Soc. 1988,
110, 5423-33. (c) Marco, J . L.; Ferna´ndez, I.; Khiar, N.; Ferna´ndez,
P.; Romero, A. J . Org. Chem. 1995, 60, 6678-9. (d) Marco, J . L. J .
Org. Chem. 1997, 62, 6575-81.
(4) For an overview of our work see: Carren˜o, M. C. Chem. Rev.
1995, 95, 1717-60. For more recent references see: (a) Bueno, A. B.;
Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Go´mez Arraya´s, R.; Zarzuelo, M.
M. J . Org. Chem. 1997, 62, 2139-43. (b) Carren˜o, M. C.; Garc´ıa Ruano,
J . L.; Urbano, A.; Lo´pez Solera, M. I. J . Org. Chem. 1997, 62, 976-81.
(8) (a) Solomon, M.; J amison, W. C. L.; McCormick, M.; Liotta, D.
C.; Cherry, D. A.; Mills, J . E.; Shah, R. D.; Rodgers, J . D.; Maryanoff,
C. A. J . Am. Chem. Soc. 1988, 110, 3702-4. (b) Swiss, K. A.; Hinkley,
W.; Maryanoff, C. A.; Liotta, D. C. Synthesis 1992, 127-31.
(9) Captain, L. F.; Xia, X.; Liotta, D. C. Tetrahedron Lett. 1996, 37,
4293-6.
(10) Fujioka, H.; Kitagaki, S.; Ohno, N.; Kitagawa, H.; Kita, Y.;
Matsumoto, K. Tetrahedron: Asymmetry 1994, 5, 333-6.
S0022-3263(98)00084-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/08/1998

3688 J . Org. Chem., Vol. 63, No. 11, 1998
Ta ble 1. 1H NMR Da ta for Com p ou n d s 1-6
Carren˜o et al.
δ in ppm (multiplicity, J in Hz)
R3 R4
7.25 (dd, 12.2, 3.2) 6.29 (dd, 10.2, 1.8) 6.18 (dd, 10.2, 1.9) 4.93 3.16 and
2.85 (13.3)
4.23 3.29 and
2.79 (13.4)
4.56 3.13 and
2.82 (13.3)
3.32 and
2.63, (13.3)
5.23 3.33 and
2.62 (13.3)
R1
R2
OH
AB system
AA′BB′ system CH3Ar
1
2
3
4
5
7.00 (dd, 10.2, 3.2)
7.57-7.52 and 2.43 (s)
7.38-7.34
2.03 (d, 1.6, 3H)
6.69 (m)
2.36 (d, 1.6, 3H)
6.98 (m)
6.16 (q, 1.6)
6.02 (q, 1.6)
7.55-7.47 and 2.42 (s)
7.46-7.36
1.94 (d, 1.6, 3H)
1.85 (d, 1.6, 3H)
7.57-7.49 and 2.42 (s)
7.39-7.30
2.02 (d, 1.5, 3H)
7.49 (d, 10.2)
7.51 (d, 10.1)
6.34 (dd, 10.2, 1.5) 6.06 (q, 1.5)
6.33 (dd, 10.1, 1.6) 6.06 (q, 1.6)
7.56-7.53 and 2.42 (s)
7.39-7.32
2.69-2.59 (m,1H);
2.28-2.15, (m, 1H);
1.11 (t, 7.3, 3H)
7.53-7.49 and 2.42 (s)
7.37-7.34
6
2.56-2.47 (m, 1H);
2.20-2.06 (m, 1H);
1.04 (t, 7.3, 3H)
2.24 (s, 3H)
6.09 (s)
5.97 (s)
4.70 3.24 and
2.89 (13.5)
7.42-7.38 and 2.40 (s)
7.31-7.24
Sch em e 1
a rigid structure imposed by the internal hydrogen
bonding existent between the hydroxylic proton and the
sulfinylic oxygen. This association was evidenced by the
chemical shift of the hydroxylic hydrogens which appear
at δ 5.23-4.23. In such spiro-like structures, the most
significant data for the configurational assignment cor-
respond to the different chemical shift observed for the
substituents situated at the olefinic â position (R1 and
R2 in the figure of Table 1). In the prochiral cyclohexa-
dienone moiety of 1 and 3, protons labeled as R1 appear
at δ 7.00 and 6.69, respectively, more shielded than those
labeled as R2, which are observed at δ 7.25 and 6.98.
If we compare the chemical shift of R2 for 1 and 3 with
those of 4 and 5, we observe a high δ value for these
protons (δ 7.49 and 7.51). A similar trend in the chemical
shifts of the methyl substituents is observed for 2, where
R1 (δ 2.03) appears more shielded than R2 (δ 2.36) and
for 4 where the methyl substituent R1 (δ 2.02) is slightly
shielded. In the case of 6, the methyl substituent appears
at δ 2.24, a chemical shift similar to that of the methyl
labeled as R2 (δ 2.36) in 2, whereas the CH2 of the ethyl
group R1 shows a chemical shift (δ 2.56-2.47) very
similar to the corresponding group in 5 (δ 2.69-2.59).
Thus, every group placed in the pro-R double bond
appears more shielded than the same group in the pro-S
double bond. On this basis, and according with the
absolute configuration of the starting sulfoxide, we could
assign the configuration [4R,(S)R] for compounds 4-6.
Or ga n oa lu m in u m Ad d ition s. With the desired p-
quinols in hands, we studied the 1,4-conjugate additions,
choosing the simplest derivative 1 as a model. The
reactions of 1 with organocuprates,11 which typically gave
conjugate additions, yielded complex reaction mixtures.
Only organoaluminum reagents5,12 gave satisfactory re-
asymmetrically substituted compounds 4 and 5 was
achieved from p-quinol 1 in a two-pot, three-step se-
quence based on 1,4-addition of AlMe3 or AlEt3 and
trapping the intermediate aluminum enolate with NBS
followed by HBr elimination upon heating a DMF solu-
tion of bromo derivatives 7 and 8 with Li2CO3/LiBr
(Scheme 1). Inspection of the crude reaction mixture
resulting after NBS treatment revealed that compounds
7 and 8 were stereoselectively formed as 5,6-trans
diastereomers, but after chromatographic purification, a
1:1 mixture of cis and trans isomers was recovered. The
trans diastereomer of 7 could be isolated diastereomeri-
cally pure in a 53% yield. For the preparation of (R)-3-
ethyl-4-hydroxy-5-methyl-4-[(p-tolylsulfinyl)methyl]-2,5-
cyclohexadienone (6), we followed a similar sequence
starting from 5 (Scheme 1): chemoselective 1,4-addition
of AlMe3 and trapping with NBS to give 9 (ca. 56% overall
yield as a cis-trans mixture) and HBr elimination to
afford 6 in a 88% isolated yield.
sults. The reactions of 1 with AlR5R6 were carried out
2
(11) Lipshutz, B. H. In Organometallics in Synthesis: A Manual;
Schlosser, M., Ed.; J ohn Wiley & Sons: Chichester, 1994.
(12) Aluminum derivatives had been successfully used in asym-
metric additions to â-keto sulfoxides: (a) Bueno, A. B.; Carren˜o, M.
C.; Garc´ıa Ruano, J . L.; Pen˜a, B.; Rubio, A.; Hoyos, M. A. Tetrahedron
1994, 50, 9355-64. (b) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Maestro,
M. C.; Pe´rez Gonza´lez, M. Tetrahedron 1993, 49, 11009-18. (c) Bueno,
A. B.; Carren˜o, M. C.; Garc´ıa Ruano, J . L. Tetrahedron Lett. 1995, 36,
3737-40. (d) Escribano, A. M.; Garc´ıa Ruano, J . L.; Mart´ın-Castro, A.
M.; Rodr´ıguez, J . H. Tetrahedron 1994, 50, 7567-78.
The absolute configuration of the stereogenic hydrox-
ylic carbons in 4-6 could be assigned at this stage on
the basis of a comparative analysis of their 1H NMR
parameters with those of 1-3 (Table 1), whose structure
had been already assigned.6b All 1-6 dervatives showed

Conjugate Addition of Organoaluminum Reagents
J . Org. Chem., Vol. 63, No. 11, 1998 3689
Ta ble 2. Con ju ga te Ad d ition s of AlR5R6 to 1, 2, a n d 4-6
2
entry
substrate
R1
R2
R3
R4
R5
R6
solvent (equiv)
T (°C)
t
product
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
4
5
6
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Et
CH2Cl2 (1)
CH2Cl2 (2)
CH2Cl2 (3)
CH2Cl2 (4)
CH2Cl2 (4)
toluene (2)
CH2Cl2 (4)
toluene (2)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
toluene (2)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
-78
24 h
24 h
21 h
4 h
30 m
30 m
3 h
1 h
2 h
3 h
4 h
2 h
24 h
3 h
3 h
3 h
3 h
3 h
3 h
4 h
1
-78
10a a
-78
-78
0
rt
-78
rt
0
0
0
0
rt
0
10a b
10a
71
10a :11a c
10a : 11a c
10b
70d
79d
89
Et
Et
10b:11bc
10c
78d
69e
56e
53e
82
H
H
H
TMS-t-
C4H9-t-
(E)-C4H9-)-
Me
Me
Et
TMS-t-
C4H9-t-
(E)-C4H9-)-
Et
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Et
10d
10e
12a
2
12b
12c
12d
12e
Me
Me
Me
Me
Me
Me
Me
Et
Et
71
67
87
55
48f
45f
76
0
0
0
0
0
0
15
16
17
H
Me
Me
Me
a
d
5% conversion. b 66% conversion. c An 87:13 mixture of 10:11 was formed. Isolated yield of pure 10a ,b. e In the crude reaction mixture,
5-10% of 10a and 10-15% of 1 were present. f Ca. 20% of a 1:1 mixture of 1,2-addition products.
Sch em e 2
with an excess of the reagent (4 equiv) at low tempera-
ture (-78 or 0 °C) in CH2Cl2 to afford only one product
10 (Table 2, entries 4, 7, and 9-11) out of the six possible
isomers that could result from 1,2- or 1,4-addition.
Compounds 10 resulted from the exclusive 1,4-addition
of the organoaluminum reagent to the pro-R conjugate
position syn to the face containing the hydroxy substitu-
ent at C-4.
The use of such a high excess of reagent was necessary
to complete the reaction, because with 1 or 2 equiv of
AlMe3 the reaction of 1 was not complete at -78 °C (Table
2, entries 1 and 2), and 3 equiv gave only a conversion of
66% (Table 2, entry 3). To overcome the drawback of
using such a high excess of reagent, we changed the
solvent and the temperature of the reaction. The reaction
of 1 with AlMe3 was not complete, working in toluene
with 1 or 2 equiv at low temperature (-78 to 0 °C), but
with 2 equiv at room temperature (Table 2, entry 6), a
87:13 mixture of 10a [4S,5S,(S)R] and its [4R,5R,(S)R]
isomer 11a , resulting from 1,4-addition on the pro-S
double bond from the face bearing the OH, was formed.
The major component 10a could be isolated by chroma-
tography in a 79% yield. In a similar fashion, the
reaction between 1 and 2 equiv of AlEt3 in toluene at
room temperature (Table 2, entry 8) gave an 87:13
mixture of diastereomers, from which 10b could be
obtained in a 78% yield. These results indicated that the
increasing temperature decreased the efficiency of the
desymmetrization process but did not affect the π-facial
diastereoselectivity. We further confirmed this temper-
ature effect by treating 1 with 4 equiv of AlMe3 in CH2Cl2
at 0 °C (Table 2, entry 5), observing the formation of a
small amount of diastereomer 11a . After such experi-
ments, we conclude that the use of an excess of reagent
and a low temperature (-78 to 0 °C) should warrant the
overall efficiency of the process. Thus, the reactions of
1 with TMSCtCAlMe2 (Table 2, entry 9), C4H9CtCAlMe2
(Table 2, entry 10), and (E)-C4H9CdCHAlMe2 (Table 2,
entry 11) yielded 10c-e as a single diastereomer in every
case.
p-Quinol derivative 2 (a â,â′-disubstituted enone)
behaved similarly toward trialkyl (Table 2, entries 12 and
14), alkynyl (entries 15 and 16), or vinylalanes (Table 2,
entry 17) when the reactions were run in CH2Cl2, giving
rise to compounds 12 in a highly selective manner.
Nevertheless, in this case, the addition did not occur in
toluene with 2 equiv of AlMe3 at room temperature even
after 24 h (Table 2, entry 13), probably as a consequence
of the diminished electrophilic character of the alkyl-
substituted dienone moiety.
When the substrate was 4-hydroxy-2,6-dimethyl-4-[(p-
tolylsulfinyl)methyl]-p-quinol (3), the treatment with
AlMe3 (4 equiv) led to different results (Scheme 2). Thus,
at 0 °C, the reaction was complete within 4 h, yielding a
mixture of the expected derivative 13 (46% isolated yield)
and two diastereomeric carbinols 14 (a 1:1 mixture, 31%
yield) resulting from 1,2-addition of the reagent to the
carbonyl group of the cyclohexadienone. The difficulties
in getting the 1,4-addition product, in this case, could be
a consequence of their diminished electrophilic character
(see above). The formation of two epimeric carbinols in
the 1,2-addition was surprising since reactions of meth-

3690 J . Org. Chem., Vol. 63, No. 11, 1998
Carren˜o et al.
Ta ble 3. Con ju ga te Ad d ition s of AlR4R5 to 10a ,b a n d 12a ,b
2
entry
substrate
R1
R2
R3
R4
Me
Me
Me
R5
solvent (equiv)
T (°C)
t
product
yield (%)
1
2
3
4
5
6
7
8
9
10a
10a
10a
10a
10a
10a
10b
10b
12a
12b
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Et
Et
Me
Et
Me
Me
Me
Et
Me
Et
Me
Me
Et
CH2Cl2 (4)
CH2Cl2 (2)
toluene (2)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
CH2Cl2 (4)
-78
0
4 h
30 m
30 m
4 h
4 h
4 h
4 h
4 h
4 h
3 h
18a
18a
18a
18b
18ca
18cb
19a
19cc
12a
12b
53
87
82
65
55
25
90
57
0
Et
-78
-78
-78
-78
-78
0
TMS-t-
TMS-t-
Me
TMS-t-
Et
Me
Me
Me
Me
10
Me
Me
30
a
b
In the crude reaction mixture, a 10% of 18a was present. In the crude reaction mixture, a 30% of 18b was present. c In the crude
reaction mixture, a 10% of 19a was present.
ylmagnesium bromide or methyllithium with p-quinol
derivatives13 or [1′-(trifluoromethyl)-4,4-propylenedioxy]-
2,5-cyclohexadien-1-one,14 showing a remote differentia-
tion of both diastereotopic faces similar to that found in
3, evolve diastereoselectively. In our case, the electro-
philic nature of the aluminum reagent could be respon-
sible for such a lack of diastereoselectivity.
With asymmetrically substituted p-quinol 6, the 1,4-
addition of AlMe3 was also highly chemoselective and
π-facial diastereoselective. Thus, compound 17, resulting
from reaction of AlMe3 on the pro-R double bond, bearing
the ethyl substituent, was formed in 76% yield (Table 2,
entry 20). When the reaction was carried out on
monoalkyl-substituted compounds 4 and 5, the system
evolved preferentially from the pro-S unsubstituted
double bond with π-facial diastereoselectivity governed
by the OH (Table 2, entries 18 and 19) to give 15 and
16, respectively. The lower reactivity of the alkyl-
substituted pro-R double bond should be in the origin of
this result.
We further studied the behavior of compounds 10a ,
10b , 12a , and 12b , which contain an R,â-unsaturated
cyclohexenone moiety with the hydroxy and p-tolylsul-
finyl methyl substituent in the δ position, in the presence
of organoaluminum reagents. The results are collected
in Table 3. Starting from 10a , compounds 18a -c, which
resulted from the exclusive 1,4-conjugate addition, were
always formed (Table 3, entries 1-6). Improved yields
were achieved with AlMe3 working at 0 °C, both in
CH2Cl2 (Table 3, entry 2) or toluene (Table 3, entry 3),
and 2 equiv of the organoaluminum derivative. When
the group to be transferred was TMS-CtC- (Table 3,
entries 5 and 6), a small percentage of the product
resulting from the transfer of R5 (Me or Et) was detected.
Derivative 10b behaved similarly. In all cases, a com-
plete π-facial diastereoselective process occurred syn to
the face containing the hydroxy substituent. In contrast,
compounds 12a ,b did not react with an excess of AlEt3
or AlMe3 (Table 3, entries 9 and 10). The presence of
the alkyl substituent at the olefinic â-carbon and/or two
alkyl substituents at C-5 of the cyclohexenone in 12a ,b
precluded both the conjugate and the 1,2-addition. Tak-
ing into account that â,â′-alkyl-substituted p-quinols 2
and 6 lead to the 1,4-addition products at 0 °C (Table 2,
entries 12-17 and 20), the lack of evolution observed in
the case of 12a ,b could be attributed to the substitution
at C-5, which could hinder the approach of any nucleo-
phile either at C-1 or C-3 due to the flexible transition
state that emerges from the equatorial attack.15
A detailed comparative analysis of the 1H NMR pa-
rameters of compounds 10a -e, 12a -e, and 15-17 with
those of 10b, whose structure had been unequivocally
established by X-ray,5 enabled the unambiguous configu-
rational assignments shown in Table 2. In the case of
compounds 18 and 19, a simple chemical transformation
of 18a based on the m-CPBA oxidation of the sulfoxide
to a sulfone led to a meso compound showing a simplified
1H NMR spectrum. The symmetry found in the sulfone
could only result from the sulfoxide precursor 18a bear-
ing both methyl substituents at C-3 and C-5 on the same
face. On this basis, we assumed that the stereochemistry
of compounds 18 and 19 is that indicated in Table 3.
Several aspects of the results presented are notewor-
thy. The high reactivity shown by organoalanes with our
4-hydroxy-4-[(p-tolylsulfinyl)methyl]-substituted enones
is surprising because such an easy 1,4-addition had only
been found in a few cases for simple alanes reacting with
enones that can adopt an s-cis conformation16 or cyclo-
pentenones with a hydroxy group at δ-position17 or in the
presence of some transition metals.18 In the absence of
any other metal, the 1,4-transfer was only possible via a
free-radical process19 or by using dialkylaluminum ha-
lides.20 In our case, we could disregard a free-radical
process based on a control experiment in the presence of
(15) Deslongchamp, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: Oxford, 1983; p 211.
(16) Hooz, J .; Layton, R. B. J . Am. Chem. Soc. 1971, 93, 7320-2.
(17) (a) Pappo, R.; Collins, P. W. Tetrahedron Lett. 1972, 2627-30.
(b) Collins, P. W.; Dajani, E. Z.; Bruhn, M. S.; Brown, C. H.; Palmer,
J . R.; Pappo, R. Tetrahedron Lett. 1975, 4217-20.
(18) For recent references see: (a) Flemming, S.; Kabbara, J .;
Nickisch, K.; Neh, H.; Westermann, J . Synthesis 1995, 317-20. (b)
Kabbara, J .; Flemming, S.; Nickisch, K.; Neh, H.; Westermann, J .
Tetrahedron 1995, 51, 743-54. (c) Westermann, J .; Nickisch, K. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1368-70. (d) Takemoto, Y.; Kuraoka,
S.; Hamaue, N.; Iwata, C. Tetrahedron: Asymmetry 1996, 7, 993-6.
(19) Kabalka, G. W.; Daley, R. F. J . Am. Chem. Soc. 1973, 95, 4428-
9.
(13) Wipf, P.; Kim, Y. J . Am. Chem. Soc. 1994, 116, 11678-88.
(14) Wipf, P. J ung, J . Angew. Chem., Int. Ed. Engl. 1997, 36, 764-
7.

Conjugate Addition of Organoaluminum Reagents
J . Org. Chem., Vol. 63, No. 11, 1998 3691
F igu r e 1. Associated transition state leading to high site and
diastereofacial selectivity.
the radical scavenger galvinoxyl with 1 and AlMe3. The
high π-facial diastereoselectivity directed by the OH could
be expected considering the similar diastereoselective 1,4-
addition found in Grignard reactions on lithium alkoxides
of p-quinols8a in racemic series. Moreover, we could
assume an essential role of the free OH21 in directing the
reaction to the conjugate position since the reaction of
different organometallic species with p-quinol derivatives
having no free OH proceeded through stereoselective 1,2-
addition.13,14,22 Even more remarkable was the effective
diastereotopic CdC bond selection observed when prochiral
cyclohexadienones were present, since to our knowledge,
the dienone desymmetrization of an optically active
p-quinol had only been achieved in an intramolecular
conjugate addition.10
On the basis of a set of experiments previously re-
ported,5 we could rationalize the role of the OH and the
sulfoxide in promoting the 1,4-addition and effecting the
desymmetrization of the dienone moiety. A possible
transition state for the reaction between 1 and AlMe3,
as a model system, is shown in Figure 1.
F igu r e 2. AM1 transition states for conjugate addition of
AlMe3 (relative energies in kJ ‚mol-1).
A stoichiometric addition of AlMe3 to 1 produced the
formation of an unreactive aluminum alkoxide where the
metal is associated with the sulfinylic oxygen. This
species has a frozen chairlike conformation by the
equatorial p-tolyl group. In such an arrangement, the
axial methyl group linked to the aluminum atom is
hindering the pro-S double bond to any nucleophile
approach from the face containing the alkoxide group and
renders only the pro-R conjugate position available. This
could be the origin of the diastereotopic group selection.
A second alane equivalent should begin the addition
assisted by the alkoxide oxygen. The use of an excess of
aluminum reagent warrants the completion due to the
association between the reagent and the sulfinylic oxy-
gen, which could retard the intramolecular transfer
assisted by the alkoxide and the association to the
carbonyl oxygen, which activates the enone moiety.
When pro-R positions have an alkyl substituent, the more
electrophilic pro-S double bond reacts preferentially as
was the case in p-quinols 4 and 5 to yield 15 and 16.
To find further support to our mechanistic proposal,
we undertook a theoretical study of the energy content
of the two possible transition states giving rise to the
attack of the alkylalane syn to the face containing the
OH by using the semiempiric method AM1.23 We as-
sumed that at least 2 equiv of AlMe3 was necessary for
the reaction. We first calculated the geometry of mini-
mum energy content for the transition state of the syn
addition on the pro-R double bond [[(S)R]-TS1 in Figure
2]. The transition state for syn addition on the pro-S
double bond [[(S)S]-TS2 in Figure 2] was modeled by
changing sulfur configuration in (S)R-TS1. Figure 2
presents the geometries24 and energies of these transition
states, which give rise to the [4S,5S,(S)R] isomer 10a
[[(S)R]-TS1] and to the [4S,5S,(S)S] isomer, correspond-
ing to the enantiomer of compound 11a [[(S)S]-TS2]. Both
structures were fully optimized followed by vibrational
frequency calculations, which confirmed that transition
structures have one imaginary frequency.
Data indicated in Figure 2 show that transition state
[(S)S]-TS2 has higher energy than [(S)R]-TS1 (∆E ) 5.9
kJ mol-1). This is consistent with complete pro-R double
bond evolution experimentally observed at -78 °C (de >
95%) and matches well with the formation of a 13% of
the product resulting from the pro-S double bond ap-
proach (74% de of 10a ) observed at 0 °C (theoretically, a
85% de would be observed). A detailed analysis of the
geometry represented in Figure 2 for the most stable
[(S)R]-TS1 revealed that the moiety with the aluminum
alkoxide associated to the sulfinyl oxygen is adopting a
chairlike conformation with the p-tolyl substituent in a
pseudoequatorial position, and a second AlMe3 equivalent
is transferring a methyl group to the pro-R double bond,
through a favorable five-membered ring formed by as-
sociation to the alkoxide oxygen. From this analysis, no
evidence of a blocked pro-S double bond in [(S)R]-TS1
arose. Thus, the efficient desymmetrization observed can
only be a consequence of the different stability [(S)R]-
TS1 and [(S)S]-TS2. The geometry shown in Figure 2
for the latter revealed a boatlike unstable conformation
(20) (a) Ashby, E. C.; Noding, S. A. J . Org. Chem. 1979, 44, 4792.
(b) Ru¨ck, K.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 694-6.
(c) Ru¨ck, K.; Kunz, H. Synlett 1992, 343-4. (d) Ru¨ck, K.; Stamm, A.;
Engel, S.; Kunz, H. J . Org. Chem. 1997, 62, 967-75.
(21) The reaction of methyl-protected p-quinol 1 with AlMe3 (4 equiv)
led to a mixture of 1,2-syn (8%) and 1,2-anti (2%) addition products
and 90% of starting material. See ref 5.
(22) Henes, G.; Rieker, A.; Neumayer, M.; Hiller, W. Z. Naturforsch.
1996, 51b, 381-387.
(23) Dewar, M.; Zoebisch, G.; Healy, E. F. J . Am. Chem. Soc. 1988,
107, 3902-9.
(24) Optimized geometries of both structures are available from the
authors.

3692 J . Org. Chem., Vol. 63, No. 11, 1998
Carren˜o et al.
solid: mp 151 °C dec; [R]20 ) +127 (c 0.99, CHCl3); 1H NMR
for the six-membered ring species resulting from the
association of the aluminum alkoxide and the sulfinylic
oxygen, which can be in the origin of its lower stability.
D
δ 7.59-7.53 (AA′, 2H), 7.45 (d, J ) 10.2 Hz, 1H), 7.44-7.37
(BB′, 2H), 6.25 (d, J ) 10.2 Hz, 1H), 5.06 (s, OH), 4.77 (d, J )
9.8 Hz, 1H), 3.30 (d, J ) 13.3 Hz, 1H), 3.01 (d, J ) 13.3 Hz,
1H), 2.45 (s, 3H), 2.38 (dq, J ) 9.8, 7.2 Hz, 1H), 1.32 (d, J )
7.2 Hz, 3H); 13C NMR δ 190.8, 149.3, 142.5, 139.0, 130.3 (2C),
127.0, 123.8 (2C), 71.2, 64.8, 56.5, 46.2, 21.3, 14.8.
Con clu sion
The 1,4-conjugate addition to p-quinols 1-6 and 4-hy-
droxy-4-[(p-tolylsulfinyl)methyl]-2-cyclohexenones 10a and
10b was achieved with organoaluminum derivatives in
a highly diastereoselective manner directed by the OH
substituent, which acts as an anchimeric assistant in the
transfer of the reagent. The sulfoxide is introducing
optical activity to the enone. Moreover, in the case of
p-quinols 1-3, the sulfinyl group is playing an essential
role in the desymmetrization of the prochiral cyclohexa-
dienone moiety or, in the case of substrate 6, effecting a
chemoselective addition. A mechanistic proposal sup-
ported by semiempirical AM1 calculations, based on the
assisted intramolecular transfer of the organoaluminum
reagent, could justify the easy and controlled formation
of a stereogenic tertiary or quaternary center. At present,
we are applying the good results obtained to the asym-
metric synthesis of complex molecules.
[4R,5R,6S,(S)R]- a n d [4R,5R,6R,(S)R]-6-Br om o-5-et h -
yl-4-h yd r oxy-4-[(p-tolylsu lfin yl)m eth yl]-2-cycloh exen -1-
on e (8). Compound 8 was obtained from 500 mg of 1 following
method B and purified by flash chromatography (CH2Cl2/
acetone from 15:1 to 10:1) in 74% yield as a colorless oil
mixture of epimers in C6. Spectroscopic data for compound 8
as a single epimer were obtained from the crude reaction: 1H
NMR δ 7.56-7.52 (AA′, 2H), 7.38-7.34 (BB′, 2H), 7.30 (dd, J
) 10.5, 1.2 Hz, 1H), 6.16 (d, J ) 10.5 Hz, 1H), 5.36 (s, OH),
4.70 (d, J ) 6.1 Hz, 1H), 3.53 (d, J ) 13.4 Hz, 1H), 3.29 (d, J
) 13.4 Hz, 1H), 2.42 (s, 3H), 2.32-2.26 (m, 1H), 2.20-2.01
(m, 1H), 1.39 (dq, J ) 14.7, 7.5 Hz, 1H), 0.99 (t, J ) 7.5 Hz,
3H); 13C NMR δ 190.8, 150.4, 142.7, 139.4, 130.4 (2C), 126.7,
123.9 (2C), 72.2, 65.5, 53.4, 50.8, 22.2, 21.4, 12.7.
[4R,5R,6S,(S)R]- a n d [4R,5R,6R,(S)R]-6-Br om o-3-eth yl-
4-h yd r oxy-5-m et h yl-4-[(p -t olylsu lfin yl)m et h yl]-2-cyclo-
h exen -1-on e (9). Compound 9 was obtained as a 69:31
mixture of epimers from 230 mg of 5 following method B and
was flash purified by flash chromatography (AcOEt/hexane
1:3): 1H NMR δ 7.61-7.52 (AA′, 2H), 7.40-7.27 (BB′, 2H), 5.93
(s, 1/3H), 5.87 (s, 2/3H), 5.32 (s, 2/3OH), 5.02 (d, J ) 4.3 Hz,
1/3H), 4.99 (s, 1/3OH), 4.53 (d, J ) 2.1 Hz, 2/3H), 3.75 (d, J )
13.4 Hz, 2/3H), 3.62-3.44 (m, 1H), 3.25 (d, J ) 14.0 Hz, 1/3H),
3.16 (d, J ) 13.4 Hz, 2/3H), 2.93 (d, J ) 14.0 Hz, 1/3H), 2.63-
2.47 (m, 1H), 2.44 (s, 1/3 3H), 2.43 (s, 2/3 3H), 2.38-2.16 (m,
1H), 1.33 (d, J ) 7.0 Hz, 2/3 3H), 1.29 (d, J ) 7.0 Hz, 1/3 3H),
1.07 (t, J ) 7.0 Hz, 3H).
Exp er im en ta l Section
All moisture-sensitive reactions were performed in oven- or
flame-dried glassware equipped with rubber septa under a
positive pressure of argon. Solvents were dried according to
literature procedures,25 and commercial reagents were used
without further purification. Melting points were determined
in open capillaries. Proton spectra were recorded at 200.1 or
[4R,(S)R]-4-Hyd r oxy-3-m eth yl-4-[(p-tolylsu lfin yl)m eth -
yl]-2,5-cycloh exa d ien -1-on e (4). Compound 4 was obtained
from 389 mg of 7 following method C and purified by flash
chromatography (AcOEt/hexane 3:1) in 86% yield as a pale
1
300.1 MHz, and H NMR data of compounds 4-6 are collected
in Table 2. Carbon spectra were recorded at 50.3 or 75.4 MHz.
Combustion analyses were performed at the Servicio de
Investigacio´n de la Universidad Auto´noma de Madrid (SIdI).
Meth od A: AlMe3 a n d AlEt3 Ad d ition s. A solution of 1
equiv of p-quinol 1-6 (0.2 M in dried CH2Cl2) was added to a
solution of 4 equiv of trialkylaluminun in hexane (2 M for
AlMe3 and 1 M for AlEt3) diluted in the same volume of
CH2Cl2. The temperature for each reaction is indicated in
Tables 2 and 3. The reaction was monitored by TLC (AcOEt/
hexane 3:1). The excess organoaluminum reagent was de-
stroyed with methanol, and the mixture was poured into an
Erlenmeyer containing ethyl acetate and a saturated solution
of sodium potasium tartrate and stirred vigorously for 30 min.
The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo.
yellow solid: mp 114.5-116 °C; [R]20 ) +69 (c 1.00, CHCl3);
D
13C NMR δ 184.8, 159.0, 149.3, 142.9, 139.7, 130.4 (2C), 128.3,
126.7, 123.8 (2C), 71.5, 65.0, 21.4, 18.2.
[4R,(S)R]-3-E t h yl-4-h yd r oxy-4-[(p -t olylsu lfin yl)m et h -
yl]-2,5-cycloh exa d ien -1-on e (5). Compound 5 was obtained
from 389 mg of 8 following method C and purified by flash
chromatography (CH2Cl2/acetone 10:1) in 74% yield as a pale
yellow solid: mp 122-123 °C; [R]20 ) +49 (c 1.00, CHCl3);
D
13C NMR δ 185.1, 164.4, 149.8, 142.7, 139.8, 130.3 (2C), 128.0,
124.4, 123.8 (2C), 71.5, 65.9, 22.9, 21.4, 11.0. Anal. Calcd for
C
16H18O3S: C, 66.18; H, 6.25; S, 11.04. Found C, 66.22; H,
6.33; S, 11.30.
[4R,(S)R]-3-Eth yl-4-h yd r oxy-5-m eth yl-4-[(p-tolylsu lfin -
yl)m eth yl]-2,5-cycloh exa d ien -1-on e (6). Compound 6 was
obtained from 230 mg of 9 following method C and purified
by flash chromatography (AcOEt/hexane 3:2) in 88% yield as
Meth od B: Syn th esis of r-Br om o Der iva tives. A solu-
tion of 1 equiv of p-quinols 1, 4, and 5 was added to a solution
of 4 equiv of trialkylaluminum in hexane (2 M for AlMe3 and
1 M for AlEt3) diluted in the same volume of CH2Cl2. The
temperature for each reaction is indicated in Tables 2 and 3.
Once the reaction was completed, the mixture was diluted with
the same volume of THF, and a solution (0.5 M) of NBS (3
equiv) in THF was added at -78 °C. After 30 min, the reaction
mixture was treated as in method A.
Meth od C: Hyd r ogen Br om id e Elim in a tion . Lithium
bromide (3 equiv) and lithium carbonate (3.1 equiv) were added
to a solution of 7-9 (ca. 0.15 M) in DMF. After 1 h at 100 °C,
the mixture was cooled at room temperature and poured into
a separatory funnel containing water. The mixture was
extracted three times with ethyl acetate, and the solvent
extracts were washed with brine, dried with Na2SO4, and
evaporated to dryness.
a pale yellow solid: mp 125-126 °C; [R]20 ) +53 (c 1.11,
D
CHCl3); 13C NMR δ 185.2, 165.2, 161.3, 142.5, 140.1, 130.3
(2C), 127.3, 125.1, 123.9 (2C), 73.6, 65.6, 23.0, 21.4, 19.5, 11.4.
Anal. Calcd for C17H20O3S: C, 67.08; H, 6.62; S, 10.53.
Found: C, 67.16; H, 6.72; S, 10.95.
Meth od D: Alk yn yld im eth yla lu m in u m Ad d ition s. To
a solution of (trimethylsilyl)acetylene (5 equiv, 1 M) in hexane
at 0 °C was added n-BuLi (5 equiv, 2.5 M) in hexane, and the
heterogeneous mixture was stirred for 30 min. A commercial
solution of AlMe2Cl (5 equiv, 1 M in hexane) was added at the
same temperature and then stirred for 30 min at room
temperature. The mixture was concentrated in vacuo to obtain
a solution ca. 1 M. After cooling at 0 °C, a solution of 1 equiv
of the indicated compound (1 equiv, 0.2 M in dried CH2Cl2)
was added. From here we followed method A.
[4R,5R,6S,(S)R]-6-Br om o-4-h ydr oxy-5-m eth yl-4-[(p-tolyl-
su lfin yl)m eth yl]-2-cycloh exen -1-on e (7). Compound 7 was
obtained from 1 g of 1 following method B and purified by flash
chromatography (AcOEt/hexane 1:1) in 53% yield as a white
[4R,5S,6R,(S)R]-4-Hyd r oxy-2,5,6-tr im eth yl-4-[(p-tolyl-
su lfin yl)m eth yl]-2-cycloh exen -1-on e (13). Compound 13
was obtained from 166 mg of 3 following method A (AlMe3)
and purified by flash chromatography (AcOEt/hexane 1:2) in
46% yield as a white solid: mp 188 °C dec; [R]20 ) +217 (c
D
(25) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals, 2nd ed.; Pergamon Press: Oxford, 1980.
1.02, CHCl3); 1H NMR δ 7.59-7.53 (AA′, 2H), 7.38-7.32 (BB′,

Conjugate Addition of Organoaluminum Reagents
J . Org. Chem., Vol. 63, No. 11, 1998 3693
2H), 6.72 (dq, J ) 2.2, 1.4 Hz, 1H), 4.94 (s, OH), 3.24 (A, J )
13.1 Hz, 1H), 3.13 (B, J ) 13.1 Hz, 1H), 2.57 (qd, J ) 6.7, 4.0
Hz, 1H), 2.42 (s, 3H), 2.28 (qdd, J ) 6.7, 4.0, 2.3 Hz, 1H), 1.84
(d, J ) 1.4 Hz, 3H), 1.07 (d, J ) 6.7 Hz, 3H), 0.93 (d, J ) 6.9
Hz, 3H); 13C NMR δ 200.4, 143.8, 142.4, 140.3, 135.8, 130.3
(2C), 123.9 (2C), 74.3, 64.9, 46.8, 43.6, 21.4, 15.7, 12.8, 8.1.
Anal. Calcd for C17H22O3S: C, 66.64; H, 7.24; S, 10.46.
Found: C, 66.40; H, 7.33; S, 10.40.
(BB′, 2H), 3.31 (d, J ) 14.0 Hz, 1H), 2.81 (s, OH), 2.78 (d, J )
14.0 Hz, 1H), 2.65-2.41 (m, 3H), 2.43 (s, 3H), 2.34-2.16 (m,
2H), 2.13-1.94 (m, 2H), 1.65-1.39 (m, 1H), 1.06 (d, J ) 6.3
Hz, 3H), 0.97 (t, J ) 7.3 Hz, 3H); 13C NMR δ 210.5, 142.0,
141.0, 130.2 (2C), 123.8 (2C), 74.0, 63.1, 47.1, 44.8, 41.1, 39.9,
22.6, 21.4, 15.5, 11.4. Anal. Calcd for C17H24O3S: C, 66.20;
H, 7.84; S, 10.39. Found: C, 65.88; H, 7.70; S, 10.72.
[3S ,4S ,5S ,(S)R ]-4-H yd r oxy-3-m e t h yl-4-[(p -t olylsu l-
fin yl)m et h yl]-5-[(t r im et h ylsilyl)et h yn yl]cycloh exa n -1-
on e (18c). Compound 18c was obtained from 300 mg of 10a
following method D and purified by flash chromatography
(AcOEt/hexane 1:1) in 55% yield as a white solid: mp 139-
140; [R]20D ) +144 (c 1.03, CHCl3); 1H NMR δ 7.60-7.54 (AA′,
2H), 7.37-7.32 (BB′, 2H), 3.53 (d, J ) 13.5 Hz, 1H), 3.46 (dd,
J ) 12.8, 5.3 Hz, 1H), 2.84-2.17 (m, 6H), 2.78 (d, J ) 13.5
Hz, 1H), 2.43 (s, 3H), 1.18 (d, J ) 6.3 Hz, 3H), 0.18 (s, 9H);
13C NMR δ 207.3, 141.9, 141.3, 130.0 (2C), 123.8 (2C), 104.4,
91.0, 72.3, 63.2, 44.2, 42.4, 41.1, 37.2, 21.3, 15.8, -0.2 (3C).
Anal. Calcd for C20H28O3SSi: C, 63.79; H, 7.49; S, 8.51.
Found: C, 63.83; H, 7.19; S, 8.83.
[4R,5R,(S)R]-5-E t h yl-4-h yd r oxy-3-m et h yl-4-[(p -t olyl-
su lfin yl)m eth yl]-2-cycloh exen -1-on e (15). Compound 15
was obtained from 95 mg of 4 following method A (AlEt3) and
purified by flash chromatography (AcOEt/hexane 1:3) in 48%
yield as a colorless oil: [R]20 ) -75 (c 1.40, CHCl3); 1H NMR
D
δ 7.55-7.52 (AA′, 2H), 7.36-7.33 (BB′, 2H), 5.75 (quint, J )
1.2 Hz, 1H), 4.76 (s, OH), 3.19 (d, J ) 13.7 Hz, 1H), 2.90 (d, J
) 13.7 Hz, 1H), 2.78-2.69 (m, 2H), 2.58-2.50 (m, 1H), 2.41
(s, 3H), 2.12-2.04 (m, 1H), 1.95 (s, 3H), 1.28-1.17 (m, 1H),
0.97 (t, J ) 7.5 Hz, 3H); 13C NMR δ 196.5, 163.3, 124.7, 139.4,
130.4 (2C), 126.6, 123.9 (2C), 76.2, 62.3, 44.9, 38.9, 21.4, 20.3,
19.0, 12.1.
[4S,5R,(S)R]-3-E t h yl-4-h yd r oxy-5-m et h yl-4-[(p -t olyl-
su lfin yl)m eth yl]-2-cycloh exen -1-on e (16). Compound 16
was obtained from 60 mg of 5 following method A (AlMe3) and
purified by flash chromatography (AcOEt/hexane 1:3) in 45%
[3S,4R,5R,(S)R]-3-Eth yl-4-h yd r oxy-5-m eth yl-4-[(p-tolyl-
su lfin yl)m eth yl]cycloh exa n -1-on e (19a ). Compound 19a
was obtained from 266 mg of 10b following method A (AlMe3)
and purified by flash chromatography (AcOEt/hexane 1:2) in
yield as a colorless oil: [R]20 ) -67 (c 1.10, CHCl3); 1H NMR
90% yield as a white solid: mp 125-126 °C; [R]20 ) +200 (c
D
D
δ 7.56-7.51 (AA′, 2H), 7.38-7.34 (BB′, 2H), 5.76 (d, J ) 1.3
Hz, 1H), 4.74 (s, OH), 3.19 (d, J ) 13.7 Hz, 1H), 3.16-2.90
(m, 1H), 2.87 (d, J ) 13.7 Hz, 1H), 2.67 (dd, J ) 18.0, 5.0 Hz,
1H), 2.56-2.45 (m, 2H), 2.42 (s, 3H), 2.22 (dqd, J ) 17.8, 7.3,
1.6 Hz, 1H), 1.19 (d, J ) 6.9 Hz, 3H), 1.04 (t, J ) 7.2 Hz, 3H);
13C NMR (C6D6) δ 195.4, 166.5, 142.0, 140.9, 130.3 (2C), 124.4,
124.1, 76.9, 62.7, 43.0, 38.3, 24.3, 21.1, 15.0, 11.6.
[4S,5R,(S)R]-5-Eth yl-4-h ydr oxy-3,5-dim eth yl-4-[(p-tolyl-
su lfin yl)m eth yl]-2-cycloh exen -1-on e (17). Compound 17
was obtained from 90 mg of 6 following method A (AlMe3) and
purified by flash chromatography (AcOEt/hexane 1:3) in 97%
yield as a colorless oil: [R]20D ) +176 (c 1.15, CHCl3); 1H NMR
δ 7.52-7.48 (AA′, 2H), 7.34-7.30 (BB′, 2H), 6.00 (t, J ) 1.3
Hz, 1H), 4.93 (s, OH), 3.22 (d, J ) 12.9 Hz, 1H), 2.68 (d, J )
12.9 Hz, 1H), 2.39 (s, 3H), 2.36 (d, J ) 1.6 Hz, 3H), 2.33 (d, J
) 18.2 Hz, 1H), 2.04 (d, J ) 18.2 Hz, 1H), 1.77 (dq, J ) 13.3,
7.5 Hz, 1H), 1.26 (dq, J ) 13.3, 7.2 Hz, 1H), 0.99 (s, 3H), 0.82
(t, J ) 7.3 Hz, 3H); 13C NMR δ 196.9, 167.3, 142.6, 139.8, 130.3
(2C), 126.6, 123.8 (2C), 76.6, 63.8, 46.3, 44.7, 28.4, 22.2, 21.3,
17.7, 7.9.
1.00, CHCl3); 1H NMR δ 7.51-7.47 (AA′, 2H), 7.32-7.29 (BB′,
2H), 3.26 (d, J ) 14.1 Hz, 1H), 3.20 (s, OH), 2.29 (d, J ) 14.1
Hz, 1H), 2.54 (dd, J ) 13.7, 13.4 Hz, 1H), 2.46-2.35 (m, 2H),
2.40 (s, 3H), 2.33-2.18 (m, 1H), 2.13 (ddd, J ) 14.1, 4.2, 1.7
Hz, 1H), 2.07-1.88 (m, 1H), 1.73-1.63 (m, 1H), 1.40-1.29 (m,
1H), 1.13 (d, J ) 6.5 Hz, 3H), 0.88 (t, J ) 7.4 Hz, 3H); 13C
NMR δ 210.6, 142.0, 141.0, 130.2 (2C), 123.8 (2C), 73.80, 63.1,
46.1, 45.1, 41.1, 40.8, 22.4, 21.4, 16.0, 11.5.
[3S,4S,5S,(S)R]-3-Eth yl-4-h yd r oxy-4-[(p-tolylsu lfin yl)-
m eth yl]-5-[(tr im eth ylsilyl)eth yn yl]cycloh exan -1-on e (19c).
Compound 19c was obtained from 335 mg of 10b following
method D and purified by flash chromatography (AcOEt/
hexane 1:3) in 57% yield as a white solid: mp 153.5-154.5
1
°C; [R]20 ) +130 (c 0.99, CHCl3); H NMR δ 7.58-7.55 (AA′,
D
2H), 7.35-7.32 (BB′, 2H), 3.59 (d, J ) 13.8 Hz, 1H), 3.46 (dd,
J ) 12.9, 5.3 Hz, 1H), 2.83 (d, J ) 13.8 Hz, 1H), 2.80-2.71
(m, 2H), 2.80-2.41 (m, 3H), 2.42 (s, 3H), 2.16-2.08 (m, 1H),
1.87-1.77 (m, 1H), 1.58-1.47 (m, 1H), 0.93 (t, J ) 7.5 Hz, 3H),
0.16 (s, 9H); 13C NMR δ 207.6, 142.0, 141.5, 130.1 (2C), 123.9
(2C), 104.4, 91.3, 72.8, 63.4, 43.4, 42.4, 41.6, 40.5, 22.8, 21.4,
11.3, -0.1 (3C). Anal. Calcd for C21H30O3SSi: C, 64.57; H,
7.74; S, 8.21. Found: C, 64.48; H, 7.64; S, 7.94.
[3R,4S,5S,(S)R]-4-Hyd r oxy-3,5-d im eth yl-4-[(p-tolylsu l-
fin yl)m eth yl]cycloh exa n -1-on e (18a ). Compound 18a was
obtained from 61 mg of 10a following method A (AlMe3) and
purified by flash chromatography (AcOEt/hexane 1:1) in 87%
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (DGICYT, Grant No.
PB95-174) and Comunidad Auto´noma de Madrid (CAM
Grant No. AE 244/95) for financial support. M.P.G.
thanks CAM and M.R. thanks DGICYT (Ministerio de
Educacio´n y Ciencia) for fellowships.
yield as a white solid: mp 162-163 °C; [R]20 ) +223 (c 1.00,
D
CHCl3); 1H NMR δ 7.55-7.50 (AA′, 2H), 7.35-7.31 (BB′, 2H),
3.25 (d, J ) 13.9 Hz, 1H), 3.03 (s, OH), 2.73 (d, J ) 13.9 Hz,
1H), 2.60-2.50 (m, 2H), 2.42 (s, 3H), 2.34-2.14 (m, 4H), 1.20
(d, J ) 6.4 Hz, 3H), 1.05 (d, J ) 6.4 Hz, 3H); 13C NMR δ 210.0,
142.1, 141.1, 130.2 (2C), 123.8 (2C), 73.6, 63.3, 45.2, 44.9, 40.8,
39.8, 21.4, 16.1, 15.5. Anal. Calcd for C16H22O3S: C, 65.28;
H,7.53; S, 10.89. Found: C, 65.11; H, 7.67; S, 11.20.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra for compounds 4, 15-17, and 19a (10
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
[3R,4S,5S,(S)R]-3-Eth yl-4-h yd r oxy-5-m eth yl-4-[(p-tolyl-
su lfin yl)m eth yl]cycloh exa n -1-on e (18b). Compound 18b
was obtained from 300 mg of 10a following method A (AlEt3)
and purified by flash chromatography (AcOEt/hexane 1:2) in
65% yield as a white solid: mp 151.4-152.0 °C; [R]20D ) +200
(c 1.04, CHCl3); 1H NMR δ 7.57-7.52 (AA′, 2H), 7.37-7.32
J O980084I