Synthesis and trimethylaluminum additions on γ-hydroxy-δ- sulfinyl and sulfonyl enoates

Article abstract of DOI:10.1021/ol048577z

(Chemical Equation Presented) The stereoselective synthesis of epimeric (R)- and (S)-γ-hydroxy-δ-p-tolylsulfinyl (or sulfonyl) enoates is reported. Reaction with AIMe₃ occurred exclusively at the ester goup allowing a clean and high-yielding ac

Full text of DOI:10.1021/ol048577z

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3537-3540
Synthesis and Trimethylaluminum
Additions on -Hydroxy- -sulfinyl and
Sulfonyl Enoates
γ
δ
M. Carmen Carren˜o,*,† M. Jesu´s Sanz-Cuesta,†,‡ Franc
¸
oise Colobert,*,‡ and
Guy Solladie´*,‡
Departamento de Qu´ımica Orga´nica (C-I), Facultad de Ciencias, UniVersidad
Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain, Laboratoire de Ste´re´ochimie
associe´ au CNRS, UniVersite´ Louis Pasteur, E.C.P.M., 25 rue Becquerel,
67087 Strasbourg Cedex 2, France
carmen.carrenno@uam.es
Received July 22, 2004
ABSTRACT
The stereoselective synthesis of epimeric (R)- and (S)-γ-hydroxy-δ-p-tolylsulfinyl (or sulfonyl) enoates is reported. Reaction with AlMe3 occurred
exclusively at the ester goup allowing a clean and high-yielding access to enantiopure 1,4-diols bearing a tertiary carbinol.
The ambiphilic character of organoaluminum reagents as well
as their oxyphilicity1 have been successfully utilized in
interesting synthetic applications. Aluminum derivatives react
very efficiently with â-ketosulfoxides,2 giving excellent
asymmetric inductions in DIBALH reductions3 and in
addition reactions,4 which are a consequence of an efficient
association between the sulfinyl oxygen and the organoalu-
minum compounds. Recently, we reported that organoalu-
minum reagents react with (R)-[(p-tolylsulfinyl)methyl]-p-
quinols,5 leading to the 1,4-conjugate addition products in a
highly chemoselective and π-facial diastereoselective manner
with good yields and mild conditions. This high reactivity
was surprising because such an easy conjugate addition had
only been found in a few cases for simple alanes reacting
with enones that can adopt an s-cis conformation6 or
cyclopentenones with a hydroxy group at the δ-position7 or
in the presence of some transition metals.8 The existence of
an OH at C-4 and a sulfoxide in the remote position from
the R,â-unsaturated moiety of the p-quinol seemed to play
an essential role in assisting the transfer of the alkyl group.
The role of the γ-hydroxy group in directing the site and
face selectivity of 1,4-conjugate additions had been pointed
out in reactions of similar p-quinol derivatives9,10 and acyclic
† Universidad Auto´noma de Madrid.
‡ Universite´ Louis Pasteur.
(1) For reviews on organoaluminum reagents, see: (a) Maruoka, K.;
Yamamoto, H. Angew. Chem., Int. Ed. Engl. 1985, 24, 668-682. (b) Ashby,
E. C.; Leemmle, J. T. Chem. ReV. 1975, 75, 521-546.
(2) For a recent review on the use of sulfoxides, see: Khiar, N.;
Fernandez, I. Chem. ReV. 2003, 103 (9), 3651-3705.
(5) (a) Carren˜o, M. C.; Somoza, A. M.; Ribagorda, Urbano, A. Angew.
Chem., Int. Ed. 2002, 41, 2755-2757. (b) Carren˜o, M. C.; Pe´rez Gonza´lez,
M.; Ribagorda, M.; Houk, K. N. J. Org. Chem. 1998, 63, 3687-3693. (c)
Carren˜o, M. C.; Pe´rez Gonza´lez, M.; Ribagorda, M.; Fischer, J. J. Org.
Chem. 1996, 61, 6758-6759.
(6) Hooz, J.; Layton, R. B. J. Am. Chem. Soc. 1971, 93, 7320-7322.
(7) (a) Collins, P. W.; Dajani, E. Z.; Bruhn, M. S.; Brown, C. H.; Palmer,
J. R.; Pappo, R. Tetrahedron Lett. 1975, 16, 4217-4220. (b) Pappo, R.;
Collins, P. W. Tetrahedron Lett. 1972, 13, 2627-2630.
(8) (a) Flemming, S.; Kabbara, J.; Nickisch, K.; Neh, H.; Westermann,
J. Synthesis 1995, 317-320. (b) Kabbara, J.; Flemming, S.; Nickisch, K.;
Neh, H.; Westermann, J. Tetrahedron 1995, 51, 743-754. (c) Westermann,
J.; Nickisch, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1368-1370. (d)
Takemoto, Y.; Kuraoka, S.; Hamaue, N.; Iwata, C. Tetrahedron: Asymmetry
1996, 7, 993-996.
(3) Carren˜o, M. C.; Garc´ıa Ruano, J. L.; Mart´ın, A.; Pedregal, C.;
Rodr´ıguez, J. H.; Rubio, A.; Sanchez, J.; Solladie´ G. J. Org. Chem. 1990,
55, 2120-2128.
(4) (a) Bueno, A. B.; Carren˜o, M. C.; Garc´ıa Ruano, J. L.; Pen˜a, B.;
Rubio, A.; Hoyos, M. A. Tetrahedron 1994, 50, 9355-9364. (b) Carren˜o,
M. C.; Garc´ıa Ruano, J. L.; Maestro, M. C.; Pe´rez Gonza´lez, M. Tetrahedron
1993, 49, 11009-11018. (c) Bueno, A. B.; Carren˜o, M. C.; Garc´ıa Ruano,
J. L. Tetrahedron Lett. 1995, 36, 3737-3740. (d) Escribano, A. M.; Garc´ıa
Ruano, J. L.; Mart´ın-Castro, A. M.; Rodr´ıguez, J. H. Tetrahedron 1994,
50, 7567-7578.
10.1021/ol048577z CCC: $27.50
© 2004 American Chemical Society
Published on Web 08/28/2004

Scheme 1. Synthesis of γ-Hydroxy-δ-sulfinyl and Sulfonyl
Enoates 8a, 9, and 10
Scheme 2. Synthesis of γ-Hydroxy-δ-sulfinyl Enoate 8b
1), in which the sulfur function has a pronounced effect in
promoting the otherwise difficult addition to the ester.
The synthetic sequence leading to enantiomerically pure
ethyl 4-hydroxy-5-(p-tolylsulfinyl)-2-pentenoate [2E,4S,(S)-
R]-8a is outlined in Scheme 1. Methyl p-methoxybenzyloxy
acetate 1 was submitted to reaction with the lithium anion
derived from [(S)R]-methyl p-tolylsulfoxide12 to give the
â-ketosulfoxide 2,13 whose reduction with DIBALH afforded
[2S,(S)R]-3a as a single diastereomer in a 69% yield for the
two steps. After protection of the secondary carbinol as a
TBS (TfOTBS, 2,6-lutidine, 95% yield), the primary group
of 4a was deprotected with DDQ, giving rise to compound
5a (73% yield). The unstable aldehyde 6a resulting from
Moffat oxidation of 5a was immediately submitted to a
Horner-Wadsworth-Emmons reaction to give the (E)-
enoate 7a in an 84% overall yield for two steps from 5a.
Enantiopure hydroxy pentenoate [2E,4S,(S)R]-8a was finally
obtained after deprotection of the TBS group (TBAF, 78%
yield). The respective sulfonyl derivatives 9 and 10 were
furnished, in a quantitative yield, by oxidation of the
sulfoxide moiety to sulfone when compound 7a and free
carbinol 8a were treated with a solution of MCPBA in CH2-
Cl2.
systems10 with Grignard and organolithium reagents. Nev-
ertheless, the behavior of acyclic R,â-unsaturated systems
bearing a γ-hydroxy-δ-sulfinyl moiety, similar to that found
in [(p-tolylsulfinyl)methyl]-p-quinols, had never been inves-
tigated. The accessibility of both diastereomeric hydroxy
sulfinyl moieties by the well-established DIBALH and ZnBr2/
DIBALH reduction of enantiomerically pure â-keto sulfox-
ides precursors3 prompted us to investigate the behavior of
the acyclic enoates 8, bearing both possible relative con-
figurations at the â-hydroxysulfinyl moiety, upon reaction
with AlMe3. The corresponding enantiopure hydroxy sulfone,
easily available from the sulfoxides, was also of interest since
the sulfonyl group11 is very useful for further synthetic
transformations. We now report on a new alkylation process
on chiral epimeric sulfinyl enoates 8 and sulfone 10 (Scheme
The synthesis of epimer [2E,4R,(S)R]-8b was achieved by
a similar reaction sequence from the hydroxy sulfoxide [2R,-
(S)R]-3b (Scheme 2). Surprisingly, the attempts to synthesize
(9) (a) Fleming, F. F.; Wang, Q.; Zhang, Z.; Steward, O. W. J. Org.
Chem. 2002, 67, 5953-5956. Solomon, M.; Jamison, 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, 3702-3704. (b) Swiss, K.
A.; Liotta, D. C.; Maryanoff, C. A. J. Am. Chem. Soc. 1990, 112, 9393-
9394.
(10) (a) Fleming, F. F.; Wang, Q.; Steward, O. W. J. Org. Chem. 2003,
68, 4235-4238. (b) Swiss, K. A.; Hinkley, W.; Maryanoff, C. A.; Liotta,
D. C. Synthesis 1992, 127-128 and references therein.
3538
Org. Lett., Vol. 6, No. 20, 2004

Table 1. Reduction of [(S)R]-â-ketosulfoxide 2 with Hydrides
Table 2. Reactions of 8a, 10, 7a, and 9 with AlMe3
entry
enoate
product
yield (%)
1
2
3
4
8a (X ) : ; R1 ) H)
10 (X ) O; R1 ) H)
7a (X ) : ; R1 ) TBS)
9 (X ) O; R1dTBS)
11
12
13
14
90
98
96
98
entry
hydride
3a :3b
yield (%)
1
2
3
4
5
6
7
ZnCl2/DIBALHa
ZnBr2/DIBALHa
ZnI2/DIBALHa
LiAlH4
NaBH4
Bu4NBH4
Yb(OTf)3/DIBALHa
50:50
67:33
50:50
24:76
36:64
38:72
8:92
62
65
60
41
99
99
96
a A 2 M solution in heptanes (4 equiv) was added to a 0.2 M solution of
enoate 8a, 10, 7a, or 9 in CH2Cl2 at 0 °C.
â-ketosulfoxides reported, a noticeable difference in the
nonequivalence of the methylene hydrogens R to the sul-
foxide for the [R,(S)R]- and [S,(S)R]-epimers has been
observed. For the [R,(S)R]-configuration, the ∆ν value
between these two hydrogens is smaller {∆ν ) 26 Hz in
[R,(S)R]-3b} than in the [S,(S)R]-diastereomer {∆ν ) 81
Hz in [S,(S)R]-3a}.
a DIBALH (1 M in heptane); dr was determined by H NMR from the
crude reaction mixture.
1
[2R,(S)R]-3b by the DIBALH/ZnX2 (X ) Cl, Br, I)3
reduction of â-ketosulfoxide 2 were poorly stereoselective
and led to an almost equimolecular mixture of (2R)- and
(2S)-diastereomers 3a and 3b, respectively (Table 1, entries
1-3).14 The presence of an oxygenated function at C-1 of
the â-keto sulfoxide 2, which could compete with the sulfinyl
oxygen in the chelation with the Zn atom, could be in the
origin of this lack of selectivity.
To improve these results, we checked other hydrides such
as LiAlH4 (Table 1, entry 4), NaBH4 (Table 1, entry 5), and
Bu4NBH4 (Table 1, entry 6). In all cases, the major formation
of [2R,(S)R]-3b was observed, but the diasteromeric ratio
was not in the range of utility. Finally, the treatment of
Compound 3b was transformed into 7b and 8b (Scheme
2) following a reaction sequence similar to that used for the
epimers 7a and 8a shown in Scheme 1. Compound 7b was
obtained diastereomerically pure by chromatographic puri-
fication of the crude resulting from the olefination reaction.
With the desired enoates in hand, we began the study of
their reactions with organometallic reagents in order to
determine the preference of the different reagents for 1,2-
and 1,4-additions. We first tried the reaction of 8a with
BrMgMe (4 equiv in ether) and observed the formation of a
(50:50) mixture of distereomeric 1,4-addition products at 0
°C and a mixture of 1,2- and 1,4-addition products at room
temperature. Surprisingly, when a CH2Cl2 solution of 8a was
added over a 2 M solution of AlMe3 in heptane (4 equiv),
the clean formation of the tertiary carbinol [3E,5S,(S)R]-11
(90% isolated yield) (Table 2, entry 1), resulting from a
double addition on the ester group, was observed. The
hydroxy sulfone 10 behaves similarly under the same
conditions. The tertiary carbinol 12, resulting from the
exclusive addition of the AlMe3 to the ester groups, was
isolated in a 98% yield.
To know if the free OH had an essential role in these
reactions, the TBS-protected sulfoxide 7a and sulfone 9 were
submitted to reaction with AlMe3. Again, the corresponding
tertiary carbinols 13 and 14 were formed in 96 and 98%
yield, respectively. The reactivity shown by the aluminum
reagent with the ester groups was rather surprising due to
the inertness of such a functional group to these organome-
tallic derivatives. The (4R)-epimeric enoate [2E,4R,(S)R]-
8b did not react under the conditions where 8a evolved in
17 h. Previous work had shown that ordinary esters are inert
to AlMe3 and reaction occurred only with AlMe3/DMEDA
complex in refluxing toluene.17 The reactivity of the ester
15
â-ketosulfoxide 2 with Yb(OTf)3 and DIBALH (Table 1,
entry 7) afforded a mixture of [2R,(S)R]-3b and its epimer
in a 3b/3a ratio of 92:8. The epimers could not be separated
at this stage since the mixture was isolated in a 96% yield
by flash column chromatography.
The absolute configuration at the hydroxylic carbons of
epimeric carbinols 3 could be deduced not only from the
mechanism already proposed for the reduction of such
â-ketosulfoxides3,16 but also from the H NMR spectra of
1
the products. From the numerous examples of reduction of
(11) Recent reviews: Na´jera, C.; Sansano, J. M. Rec. Res. DeV. Org.
Chem. 1998, 2, Part 2, 637-683.
(12) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
(13) [(S)S]-Enantiomer had been synthesized from (-)-[(S)S]-methyl-
p-tolylsulfoxide: Solladie´, G.; Adamy, M.; Colobert, F. J. Org. Chem. 1996,
61, 4369-4373.
1
(14) Determined by H NMR from the crude reaction mixture.
(15) (a) Solladie´, G.; Colobert, F.; Samny, F. Tetrahedron Lett. 1999,
40, 1227-1228. (b) Solladie´, G.; Hanquet, G.; Izzo, I.; Crumbie, R.
Tetrahedron Lett. 1999, 40, 3071-3074. (c) Solladie´, G.; Hanquet, G.;
Rolland, C. Tetrahedron Lett. 1997, 38, 5847-5850.
(16) (a) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435-438. (b) Solladie´, G.; Demailly, G.; Greck, C. J. Org. Chem. 1985,
50, 1552-1554. (c) Solladie´, G.; Frechou, C.; Demailly, G.; Greck, C. J.
Org. Chem. 1986, 51, 1912-1914. (d) Solladie´-Cavallo, A.; Suffert, J.;
Adib, A.; Solladie´, G. Tetrahedron Lett. 1990, 31, 6649-6652. (e) Solladie´,
G.; Rubio, A.; Carren˜o, M. C.; Garc´ıa-Ruano, J. L. Tetrahedron: Asymmetry
1990, 1, 187-198.
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7590-7591.
Org. Lett., Vol. 6, No. 20, 2004
3539

Scheme 3. Reactivity of (-)-15 with AlMe3
group is enhanced in glyconolactones18 when the AlMe3 can
be intramolecularly complexed with a donating group prox-
imal to the lactone, which assists the transfer of a methyl
group.
In the case of substrates 8a, 10, 7a, and 9, the addition of
AlMe3 was only completed in the presence of an excess of
the reagent.
Figure 1. SOTol or SO2Tol group assisting the transfer of Me
from AlMe3.
With free OH derivatives 8a and 10, the first equivalent
of AlMe3 added to the reaction mixture must react with the
OH to form an unreactive aluminum alkoxyde, which evolves
into the double-addition product when an excess of the
reactant is added. The presence of different basic centers in
the starting molecules justifies the necessity of an excess of
AlMe3. The existence of the sulfur functions, which could
also assist the transfer of the methyl group from AlMe3,
prompted us to investigate the role of the γ-oxygenated
function in such a process on substrate 15, which lacks the
sulfur moiety. Under the conditions shown in Scheme 3, ethyl
4-hydroxy-2-pentenoate (2E,4S)-1519 remained unchanged
after 3 days at room temperature, even when 8 equiv of
AlMe3 were added. This lack of reaction pointed to an
essential role of the sulfoxide or sulfone in assisting the
aluminum reagent to transfer the methyl groups to the ester.
A species such as A represented in Figure 1, where the
electrophilic aluminum atom, associated to both the sulfinyl
or sulfonyl oxygen and the ester, could be responsible for
the observed results with the (4S)-epimer.
alkoxide substituent should adopt an unfavorable axial
disposition (Figure 1,B).
The enantiopure 1,4-diol moiety present in compounds
11-14 is found in a group of natural products of the
triterpenoid family.20 The transformations reported here,
allowing the synthesis of such fragments in mild conditions
and high yields, open an easy access to the tertiary carbinol
moiety from an R,â-unsaturated ester without competition
with conjugate addition. AlMe3, which fails to alkylate
ordinary esters and γ-hydroxy-R,â-unsaturated analogues, is
easily transferred in the presence of the sulfur function,
whose role in assisting the transfer has been demonstrated.
Acknowledgment. Financial support of this work by the
MCYT (Grant No. BQU2002-03371) and CNRS (Grant Nï.
PICS 537) is gratefully acknowledged.
Supporting Information Available: Complete descrip-
tion of experimental procedures and characterization data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
The inertness of the (4R)-epimer could be due to the
unstability of the analogue species where the aluminum
OL048577Z
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T.; Kasai, R.; Yamasaki, K. Phytochemistry 2002, 59, 215-228.
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(19) Gung, B. W.; Wolf, M. A. J. Org. Chem. 1993, 58, 7038-7044.
3540
Org. Lett., Vol. 6, No. 20, 2004