Reductive cyclizations of hydroxysulfinyl ketones: Enantioselective access to tetrahydropyran and tetrahydrofuran derivatives

Article abstract of DOI:10.1021/jo034817x

The stereocontrolled formation of cis-2,5-disubstituted tetrahydrofurans and cis-2,6-disubstituted tetrahydropyrans is achieved from enantiopure ketosulfinyl esters by reduction, Weinreb's amide, and ketone formation, followed by the reductive cyclization (Et₃SiH/TMSOTf) of the resulting hydroxysulfinyl ketones. The sulfoxide-bearing heterocycles were transformed into two natural products, (-)-centrolobine (1) and both enantiomers of cis-(6-methyltetrahydropyran-2-yl)acetic acid (2).

Full text of DOI:10.1021/jo034817x

Red u ctive Cycliza tion s of Hyd r oxysu lfin yl Keton es:
En a n tioselective Access to Tetr a h yd r op yr a n a n d Tetr a h yd r ofu r a n
Der iva tives
M. Carmen Carren˜o,*,† Renaud Des Mazery,†,‡ Antonio Urbano,† Franc¸oise Colobert,*,‡ and
Guy Solladie´*,‡
Departamento de Qu´ımica Orga´nica (C-I), Universidad Auto´noma, Cantoblanco, 28049-Madrid, Spain,
and Laboratoire de Ste´re´ochimie associe´ au CNRS, Universite´ Louis Pasteur, ECPM,
25 rue Becquerel, 67087 Strasbourg Cedex 2, France
carmen.carrenno@uam.es
Received J une 12, 2003
The stereocontrolled formation of cis-2,5-disubstituted tetrahydrofurans and cis-2,6-disubstituted
tetrahydropyrans is achieved from enantiopure ketosulfinyl esters by reduction, Weinreb’s amide,
and ketone formation, followed by the reductive cyclization (Et3SiH/TMSOTf) of the resulting
hydroxysulfinyl ketones. The sulfoxide-bearing heterocycles were transformed into two natural
products, (-)-centrolobine (1) and both enantiomers of cis-(6-methyltetrahydropyran-2-yl)acetic acid
(2).
In tr od u ction
tetrahydrofuran and tetrahydropyran derivatives,5 de-
spite the accessibility of γ- or δ-hydroxyketones necessary
as starting materials.
2,5-Disubstituted tetrahydrofuran and 2,6-disubstitut-
ed tetrahydropyran systems occur in many natural
products exhibiting important biological activities.1 These
units can be found in monocyclic and polycyclic struc-
tures, fused with carbocyclic or other cyclic ethers, or as
spiroketals. The syntheses of such moieties have been
achieved through a wide range of methods that have been
recently reviewed.1,2 One of them, the trimethylsilyl
triflate catalyzed synthesis of ethers by reductive con-
densation of carbonyl compounds and alkoxysilanes
originally reported by Olah,3 was later modified by
Nicolaou4 and applied to the intramolecular preparation
of cis-2,7-disubstituted oxepane rings from ꢀ-hydroxy
ketones (Scheme 1, eq 1). Although this approach to cyclic
ethers is a stereoselective and high-yielding method, it
has been scarcely used in the asymmetric synthesis of
In connection with a program devoted to asymmetric
synthesis mediated by sulfoxides,6 we were interested in
the preparation of enantiomerically pure 2,5-disubsti-
tuted tetrahydrofuran and 2,6-disubstituted tetrahydro-
pyran derivatives. The key reaction in our synthesis
would be the reductive cyclization of the corresponding
enantiopure γ-hydroxy-δ-sulfinyl ketones (n ) 1 in
Scheme 1, eq 2) or δ-hydroxy-ꢀ-sulfinyl ketones (n ) 2 in
Scheme 1, eq 2), easily accessible through the well-
established stereocontrolled reduction of enantiopure
â-ketosulfoxides.7 To know the generality of the stereo-
selective ring-forming step, we decided to study the
reaction not only on aryl ketones which could facilitate
the cyclization step but also on alkyl ketones giving rise
to dialkyl-substituted derivatives.
In this paper, we present our results showing that the
reductive cyclization of hydroxysulfinyl ketones is a short
and efficient protocol to enantiopure tetrahydrofuran and
tetrahydropyran derivatives. We have previously com-
† Universidad Auto´noma de Madrid.
‡ Universite´ Louis Pasteur.
(1) For reviews, see: (a) AÄ lvarez, E.; Candenas, M. L.; Pe´rez, R.;
Ravelo, J . L.; Mart´ın, J . D. Chem. Rev. 1995, 95, 1953-1980. (b)
Shimizu, Y. M. Chem. Rev. 1993, 93, 1685-1698. (c) Yasumoto, T.;
Murata, M. Chem. Rev. 1993, 93, 1897-1909. (d) Perron, F.; Albizati,
K. M. Chem. Rev. 1989, 89, 1617-1661.
(5) Gonza´lez, I.; Forsyth, C. J . J . Am. Chem. Soc. 2000, 122, 9099-
9108.
(2) For a series of review articles on synthesis of saturated oxygen
heterocycles, see: (a) Elliott, M. C. J . Chem. Soc., Perkin Trans. 1 2002,
2301-2323. (b) Elliott, M. C.; Williams, E. J . Chem. Soc., Perkin Trans.
1 2001, 2303-2340. (c) Elliott, M. C. J . Chem. Soc., Perkin Trans. 1
2000, 1291-1318. (d) Elliott, M. C. J . Chem. Soc., Perkin Trans. 1 1998,
4175-4200. (e) Elliott, M. C. Contemp. Org. Synth. 1997, 4, 238-259.
(f) Burns, C. J .; Middleton, D. S. Contemp. Org. Synth. 1996, 3, 229-
242. (g) Elliott, M. C. Contemp. Org. Synth. 1994, 1, 457-474.
(3) (a) Sassaman, M. B.; Prakash, G. K. S.; Olah, G. A. Tetrahedron
1988, 44, 3371-3380. (b) Sassaman, M. B.; Kotian, K. D.; Prakash, G.
K. S.; Olah, G. A. J . Org. Chem. 1987, 52, 4314-4319.
(4) (a) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel, D.
A.; Abe, Y.; Reddy, K. Bal; DeFrees, S. A.; Reddy, D. R.; Awartani, R.
A.; Conley, S. R.; Rutjes, F. P. J . T.; Theodorakis, E. A. J . Am. Chem.
Soc. 1995, 117, 10227-10238. (b) Nicolaou, K. C.; Hwang, C.-K.;
Nugiel, D. A. J . Am. Chem. Soc. 1989, 111, 4136-4137.
(6) For an overview of our work, see: (a) Carren˜o, M. C. Chem.
Rev. 1995, 95, 1717-1760. (b) Solladie´, G.; Carren˜o, M. C. In Orga-
nosulphur Chemistry: Synthetic Aspects; Page, P. C. B., Ed.; Academic
Press: New York, 1995; pp 1-47. For recent references, see: (c)
Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Urbano, A. Chem. Eur. J . 2003,
9, 4118-4131. (d) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Sanz-Cuesta,
M. J .; Urbano, A. J . Org. Chem. 2003, 68, 4315-4321. (e) Carren˜o, M.
C.; Ribagorda, M.; Somoza, A.; Urbano, A. Angew. Chem., Int. Ed. 2002,
41, 2755-2757. (f) Carren˜o, M. C.; Ribagorda, M.; Posner, G. H. Angew.
Chem., Int. Ed. 2002, 41, 2753-2755. (g) Obringer, M.; Colobert, F.;
Neugnot, B.; Solladie´, G. Org. Lett. 2003, 5, 629-632. (h) Hanquet,
G.; Salom-Roig, X. J .; Lemeitour, S.; Solladie´, G. Eur. J . Org. Chem.
2002, 2112.
(7) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Mart´ın, A.; Pedregal, C.;
Rodr´ıguez, J . H.; Rubio, A.; Sa´nchez, J .; Solladie´, G. J . Org. Chem.
1990, 55, 2120-2128.
10.1021/jo034817x CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/06/2003
J . Org. Chem. 2003, 68, 7779-7787
7779

Carren˜o et al.
SCHEME 2. Ster eoselective Syn th esis of
SCHEME 1. Syn th esis of Oxygen a ted
Heter ocycles fr om Hyd r oxy Keton es
Hyd r oxysu lfin yl k eton es 14-18
municated the first application of this methodology for
the enantioselective synthesis of (-)-centrolobine (1),8 a
natural product bearing a cis-2-aryl-6-alkyl-substituted
tetrahydropyran skeleton (Scheme 1). We report now a
full account of our results as well as a new and diaste-
reodivergent synthesis of (2S,6S)-cis-6-(methyltetrahy-
dropyran-2-yl)acetic acid ((+)-2) (Scheme 1),9 a natural
compound isolated from glandular secretions of the civet
cat (Viverra civetta),9a and its unnatural enantiomer (-)-
2.
Resu lts a n d Discu ssion
The synthesis of enantiomerically pure hydroxysulfinyl
ketones 14-18, necessary to prepare the oxygenated
heterocycles, is shown in Scheme 2. Two important points
in our strategy are the use of easily accessible enantio-
merically pure â-ketosulfoxides10 5 and 6, with an ester
function at the terminal position, as starting materials,
and the synthesis of Weinreb amides11 11-13 as versatile
intermediates which give easy access to a variety of
ketones through the simple and well-established reaction
with organometallic reagents.
modifying the esterification procedure (see the Experi-
mental Section).
The synthesis of sulfinyl ketoesters 5 and 6 was
achieved by condensation of the lithium anion derived
from [(S)R]-methyl-p-tolylsulfoxide12 and succinic anhy-
dride (3) or glutaric anhydride (4) (Scheme 2). Esterifi-
cation of the resulting acid with dimethyl sulfate in the
presence of potassium carbonate gave esters [(S)R]-5 and
[(S)R]-6 in 69% and 93% yield, respectively, for the two
steps. Although this sequence had been already reported
for the reaction with glutaric anhydride,13 we have
improved the overall yield of 6 by working at -78 °C and
Reduction of â-ketosulfoxides 5 and 6 with DIBALH
in the presence of ZnBr2 afforded â-hydroxysulfoxides [R,-
(S)R]-7 (67% yield) and [R,(S)R]-913 (87% yield) with an
excellent diastereoselectivity (de >98%). In the reaction
of compound 5, a byproduct characterized as 3-[(p-
tolylsulfinyl)methyl]cyclopentanone (8)14 was isolated in
13% yield. When DIBALH alone was used to reduce the
ketosulfinyl ester 6, compound [S,(S)R]-10 was exclu-
sively formed.15 The R absolute configuration at the
hydroxylic carbon of 7 and 9, as well as the S absolute
configuration of the stereogenic carbon at C-5 of 10, could
be deduced not only from the mechanism already pub-
lished for the reduction of such â-ketosulfoxides7,16 but
(8) Colobert, F.; Des Mazery, R.; Solladie´, G.; Carren˜o M. C. Org.
Lett. 2002, 4, 1723-1725.
(9) (a) Maurer, B.; Grieder, A.; Thommen, W. Helv. Chim. Acta
1979, 62, 44-47. (b) Maurer, B.; Thommen, W. Helv. Chim. Acta 1979,
62, 1096-1097. (c) Van Dorp, D. A.; Ward, J . P. Experientia 1981, 37,
917-921.
1
also from the H NMR spectra of the products. From the
numerous examples of reduction of â-ketosulfoxides
(10) For recent synthetic applications of â-ketosulfoxides, see: (a)
Colobert, F.; Tito, A.; Khiar, N.; Denni, D.; Medina, M. A.; Martin-
Lomas, M.; Garcia Ruano, J . L.; Solladie´, G. J . Org. Chem. 1998, 63,
8918-8920. (b) Solladie´, G.; Gressot, L.; Colobert, F. Eur. J . Org. Chem.
2000, 2, 357-364.
(11) (a) Mentzel, M.; Hoffmann, H. M. R. J . Prakt. Chem. 1997, 6,
517-524. (b) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun.
1982, 12, 989-993. (c) Basha, A.; Lipton, M.; Weinreb, S. M. Tetra-
hedron Lett. 1977, 4171-4174.
(12) Solladie´, G.; Hutt, J .; Girardin, A. Synthesis 1987, 173-175.
(13) Solladie´, G.; Maestro, M. C.; Rubio, A.; Pedregal, C.; Carren˜o,
M. C.; Garc´ıa-Ruano, J . L. J . Org. Chem. 1991, 56, 2317-2322.
(14) Garc´ıa Ruano, J . L.; Fuerte, A.; Maestro, M. C. Tetrahedron:
Asymmetry 1994, 5, 1443-1446.
(15) Solladie´, G.; Huser, N.; Garcia Ruano, J . L.; Adrio, J .; Carren˜o,
M. C.; Tito, A. Tetrahedron Lett. 1994, 35, 5297-5300.
(16) (a) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435-438. (b) Solladie´, G.; Demailly, 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.
7780 J . Org. Chem., Vol. 68, No. 20, 2003

Reductive Cyclizations of Hydroxysulfinyl Ketones
SCHEME 3. Dih yd r op yr a n F or m a tion by
Acid -Ca ta lyzed Cycliza tion of Hyd r oxysu lfin yl
Keton e 16
SCHEME 4. Red u ctive Cycliza tion of
Hyd r oxysu lfin yl Keton es 16-18
reported, a noticeable difference in the nonequivalence
of the methylene hydrogens R to the sulfoxide for the
[R,(S)R] and the [S,(S)R] epimers has been observed. For
the [R,(S)R] configuration, the ∆ν value between these
two hydrogens is smaller (∆ν ) 49 Hz in 7 and 38 Hz in
9) than in the [S,(S)R] diastereomer (∆ν ) 96 Hz in 10).
This configurational assignment was essential to revise
the absolute configuration of the natural product cen-
trolobine 18 and was confirmed in the case of compounds
9 and 10 by correlation with both known enantiomers of
Under the same conditions, cyclization of methyl
ketone [5R,(S)R]-17 was slower, and after 1 h, the
reaction was quenched giving rise to a 60:40 mixture of
tetrahydropyran diasteromer 22 and starting material
17. After flash chromatography, compound [2R,6R,(S)-
R]-22 was isolated pure in 43% yield. The behavior of
the diastereoisomeric hydroxysulfinyl ketone [5S,(S)R]-
18 was similar when it was treated with the mixture
TMSOTf/Et3SiH. After 1 h at 0 °C, the reaction was not
completed but a clean mixture of [2S,6S,(S)R]-23 and
starting material 18 was detected from which compound
23 could be isolated as a pure diastereomer in 45% yield.
We tried to improve these moderate yields by changing
the order of addition of the reactants. Indeed, the
treatment of methyl ketone [5R,(S)R]-17 first with an
excess of Et3SiH (2-5 equiv), followed by the addition of
TMSOTf (1 equiv) in CH2Cl2 at 0 °C, yielded pure
[2R,6R,(S)R]-22 in an excellent 97% yield. Under the
same conditions, the diastereoisomeric hydroxysulfinyl
ketone [5S,(S)R]-18 gave rise to tetrahydropyran deriva-
tive [2S,6S,(S)R]-23 as a pure diastereomer in 96% yield
(Scheme 4). The competitive enolization of the starting
hydroxy ketones 17 and 18 under the former conditions
could be the origin of the low yield achieved.
The efficiency of this methodology was then checked
on hydroxysulfinyl ketones 14 and 15 en route to tet-
rahydrofuran ring systems. The treatment of aryl ketone
[4R,(S)R]-14 with an excess of Et3SiH (2-5 equiv) fol-
lowed by addition of TMSOTf afforded, after 15 min, a
mixture of two isomers, the trans-2,5-disubstituted tet-
rahydrofuran [2R,5R,(S)R]-24 and the cis derivative
[2S,5R,(S)R]-25 in a 14:86 ratio from which the cis
diastereomer was isolated pure in 71% yield (Scheme 5).
The cis substitution of compound 25 was confirmed by
NOESY experiments and the relative configuration of the
stereogenic carbons of 24 and 25 was determined by
m-CPBA oxidation of a 50:50 mixture which yielded a
50:50 mixture of sulfones 26 and 27. A chemical correla-
tion of compound [2S,5R,(S)R]-25 with tetrahydrofuran
derivative (2S,5R)-29, whose (2R,5S) enantiomer have
been recently described,20allowed confirmation of its
absolute configuration. Thus, compound [2S,5R,(S)R]-25
was submitted to the Pummerer reaction conditions21
(TFAA, 2,4,6-collidine) followed by treatment with satu-
cis-6-(methyltetrahydropyran-2-yl)acetic acid
2 (see
below).
The synthesis of N-methoxy-N-methylamides (Wein-
reb’s amides) 11-13 was achieved in good to excellent
yields (74-97%) by treatment of hydroxysulfinyl esters
7, 9, and 10 with N-methyl methylhydroxylamine in the
presence of an excess of AlMe3 to avoid alcohol protec-
tion.17 Enantiomerically pure hydroxysulfinyl ketones
14-18 were finally obtained by reaction of 11-13 with
an excess of Grignard reagents. Both aryl (R ) Ph,
p-MeOC6H4) and alkyl (R ) Me) magnesium bromides
reacted in THF or mixtures of THF/Et2O to give the
corresponding ketones in excellent yields.
The cyclization to the tetrahydropyran ring was first
tried by acid-catalyzed acetalization of compound 16
(Scheme 3). The use of p-toluenesulfonic acid18 and
camphorsulfonic acid19 allowed the formation of the cyclic
system 19 resulting from the intramolecular acetalization
followed by dehydration of the intermediate hemiacetal
20 which could not be detected. In these reactions, 50%
of the starting hydroxysulfinyl ketone 16 was recovered
unchanged and the 50% isolated yield of dihydropyran
19 could not be improved.
We then turned our attention to the method described
by Nicolaou4 for the reductive cyclization of hydroxy
ketones. Thus, treatment of the aryl ketone [5R,(S)R]-
16 with TMSOTf (1 equiv), followed by an excess of
Et3SiH (2-5 equiv) in CH2Cl2 at 0 °C, led to the rapid
formation (15 min) of the tetrahydropyran derivative
[2S,6R,(S)R]-21 as a sole diastereomer (Scheme 4).
(17) Boukouvalas, J .; Fortier, G.; Radu, I. I. J . Org. Chem. 1998,
63, 916-917.
(18) (a) Pothier, N.; Goldstein, S.; Deslongchamps, P. Helv. Chim.
Acta 1992, 604-620. (b) Chen, J .; Fletcher, M. T.; Kitching, W.
Tetrahedron: Asymmetry 1995, 6, 967-972. (c) White, J . D.; Bolton,
G. L.; Dantanarayana, A. P.; Fox, C. M. J .; Hiner, R. N.; J ackson, R.
W.; Sakuma, K.; Warrier, U. S. J . Am. Chem. Soc. 1995, 117, 1908-
1939.
(19) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J . A.;
Charrette, A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998, 37, 2354-
2359.
(20) Pilli, R. A.; Rialto, V. B. Tetrahedron Asymmetry 2000, 11,
3675-3686.
(21) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881.
J . Org. Chem, Vol. 68, No. 20, 2003 7781

Carren˜o et al.
SCHEME 7. Mech a n istic a n d Ster eoch em ica l
SCHEME 5. Ster eoselective Syn th esis a n d
Con figu r a tion a l Assign m en t of Tetr a h yd r ofu r a n s
24 a n d 25
P a th w a y for th e Red u ctive Cycliza tion P r ocess
that when aliphatic ketone 15 was first submitted to the
addition of TMSOTf followed by Et3SiH, no cyclization
occurred.
A possible mechanistic pathway explaining the major
formation of the cis diastereomers in the cyclization step
is shown in Scheme 7 for the tetrahydropyran system.
Activation of the carbonyl group of the hydroxysulfinyl
ketone by the TMSOTf, favors the intramolecular nu-
cleophilic addition of the OH to give an intermediate
mixed acetal precursor of the carboxonium intermediate
A. The axial approach of Et3SiH4,23to A, affording the cis
diastereomer, is certainly favored because of the higher
stability of the resulting chairlike transition state. Simi-
lar reasons could explain the major formation of the cis
isomer in the case of tetrahydrofurans 25 and 30.
SCHEME 6. Ster eoselective Syn th esis a n d
Con figu r a tion a l Assign m en t of Tetr a h yd r ofu r a n
30
The application of this efficient methodology to the
asymmetric total synthesis of tetrahydropyran natural
products from compounds 21-23 is illustrated in Schemes
8 and 9, the sulfoxide present in these molecules facili-
tating further transformations on the side chain to
quickly end up the syntheses.
(-)-Centrolobine, 6-[â(p-hydroxyphenyl)ethyl]-2-(p-
methoxyphenyl)tetrahydropyran (1) (Scheme 8), is a
natural product isolated from the heartwood of Centrolo-
bium robustum24 and from the stem of Brosinum pota-
bile25 in the Amazon forest. Although its basic structure
was elucidated in 1964 from the total synthesis of the
racemic methyl ether,23a,b its absolute configuration had
not been unequivocally established until 2002, when we
reported the first enantioselective total synthesis.8 Mean-
while, a new asymmetric synthesis of the natural enan-
tiomer based on Prins cyclizations was published by
Rychnovsky.26 Tetrahydropyranylsulfinyl derivative 21
was easily transformed into centrolobine by the synthetic
sequence shown in Scheme 8.
rated aqueous sodium hydrogen carbonate and sodium
borohydride. The resulting alcohol (2S,5R)-28 (87% yield
from 25) was protected as the TBDPS ether to give
tetrahydrofuran (2S,5R)-29 in 96% yield. 1H and 13C
spectroscopic data of (2S,5R)-29 were identical to those
previously reported for the (2R,5S) enantiomer,20 and the
optical rotation [[R]20 ) -35 (c 0.85, CH2Cl2)] was
D
identical but of opposite sign [lit.20 [R]20D ) +34.9 (c 0.85,
CH2Cl2)].
When the aliphatic hydroxysulfinyl ketone 15 was
submitted to the same Et3SiH/TMSOTf treatment, we
obtained only the cis diastereomer 30 in 85% yield
(Scheme 6). The configuration of [2R,5R,(S)R]-30 was
again confirmed by chemical correlation with the known22
(2S,5S) enantiomer of carbinol 31. Thus, the reductive
Pummerer reaction on derivative 30 gave alcohol (2R,5R)-
(23) Homma, K.; Mukaiyama, T. Chem. Lett. 1989, 259-262.
(24) (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.; Marini-
Bettolo, G. B. Gazz. Chim. Ital. 1964, 287-295. (b) Galeffi, C.; Casinovi,
C. G.; Marini-Betto`lo, G. B. Gazz. Chim. Ital. 1965, 95-100. (c) Aragao
Craveiro, A.; da Costa Prado, A.; Gottlieb, O. R.; Welerson de
Albuquerque, P. C. Phytochemistry 1970, 9, 1869-1875.
(25) Alcantara, A. F. de C.; Souza, M. R.; Pilo´-Veloso, D. Fitoterapia
2000, 71, 613-615
31 [[R]20 ) -11 (c 2, EtOH)], whose spectroscopic
D
parameters were identical to those of its enantiomer but
showing the opposite sign of the optical rotation [lit.22
[R]20 ) +11.1 (c 9.3, EtOH)]. It is interesting to note
D
(22) Cook, M. M.; Djerassi, C. J . Am. Chem. Soc. 1973, 95, 3678-
3686.
(26) Marumoto, S.; J aber, J . J .; Vitale, J . P.; Rychnovsky, S. D. Org.
Lett. 2002, 4, 3919-3922.
7782 J . Org. Chem., Vol. 68, No. 20, 2003

Reductive Cyclizations of Hydroxysulfinyl Ketones
SCHEME 8. En a n tioselective Syn th esis of
(-)-Cen tr olobin e
treatment with saturated aqueous sodium hydrogen
carbonate also gave rise to aldehyde 34 (82% yield from
21). This aldehyde was then submitted to a Wittig
reaction with the 4-benzyloxybenzyltriphenylphosphonium
salt 36 prepared in 95% overall yield from commercially
available 4-benzyloxybenzyl alcohol (35), after substitu-
tion of the OH by Br27and further reaction with PPh3.
The Wittig reaction between 2 equiv of the salt 36 and
the aldehyde 34 was carried out in the presence of 2 equiv
of BuLi to give the olefin 37 in excellent yield (96%) as a
mixture of E/Z isomers.28 Finally, simultaneous reduction
of the double bond and deprotection of the benzyl ether
by catalytic hydrogenation afforded (-)-centrolobine (1)
in 93% yield.
1H and 13C NMR and IR spectroscopic data, melting
point (95 °C), and optical rotation ([R]20 ) -93, c 1,
D
CHCl3) of 1 were identical to those described for the
natural product.24,25 De Albuquerque and co-workers24c
had proposed a (2R,6S) absolute configuration for (-)-
centrolobine (1) on the basis of Brewster’s empirical
rules29 on the correlation between molecular rotation and
absolute configuration. Our synthesis showed that the
absolute configuration of (-)-centrolobine (1) must be
corrected to (2S,6R), taking into account the [5R,(S)R]
absolute configuration of the precursor â-hydroxysulfox-
ide 16 established considering the well-known behavior
of â-ketosulfoxide [(S)R]-6 in the reduction with DIBALH/
ZnBr2.
Another synthetic application to test the efficiency of
this methodology was the asymmetric synthesis of both
enantiomers of (cis-6-methyltetrahydropyran-2-yl)acetic
acid 2 (Scheme 9). The natural enantiomer (+)-(S,S)-2,
first isolated by Maurer9a from a glandular secretion of
the civet cat (V. civetta), is highly appreciated as a
component of civet, an expensive animal-derived per-
fume. Several successful synthetic strategies have been
reported to access to such simple structure both in the
racemic9a,23,30 and optically enriched forms.31 Our highly
stereoselective synthetic strategy combining reduction of
a â-ketosulfoxide with the reductive cyclization of a
hydroxysulfinyl ketone afforded compounds 22 and 23
which were transformed in two steps into both enanti-
omers of 2 (Scheme 9).
SCHEME 9. En a n tioselective Syn th esis of (-)-2
a n d (+)-2
First, reaction of the R-sulfinyl carbanion resulting in
the treatment of 22 or 23 with MeLi and CO2 gave
carboxylic acids 38 (83% yield) or 39 (82% yield), which
(27) Whalley, J . L.; Oldfield, M. F.; Botting, N. P. Tetrahedron 2000,
56, 455-460.
(28) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 863-927.
(29) Brewster, J . H. J . Am. Chem. Soc. 1959, 81, 5481-5493.
(30) (a) Banwell, M. G.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W.
J . Chem. Soc., Perkin Trans. 1 1996, 967-969. (b) Muraoka, O.;
Okumura, M.; Maeda, T.; Wang, L.; Tanabe, G. Chem. Pharm. Bull.
1995, 43, 517-519. (c) Varelis, P.; Graham, A. J .; J ohnson, B. L.;
Skelton, B. W.; White, A. H. Aust. J . Chem. 1994, 47, 1735-1739. (d)
Lee, E., J in, S., Lee, C. Tetrahedron Lett. 1993, 34, 4831-4834. (e)
Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990, 46, 4595-
4612. (f) Homma, K.; Mukaiyama, T. Chem. Lett. 1989, 893-896. (g)
Kobayashi, K.; Suginome, H. Bull. Chem. Soc. J pn. 1989, 62, 951-
952. (h) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron Lett. 1987,
28, 6613-6616. (i) Coppi, L.; Ricci, A.; Taddei, M. J . Org. Chem. 1988,
53, 911-913. (j) Nussbaumer, C.; Frater, G. Helv. Chim. Acta 1987,
70, 396-401. (k) Gallagher, T. J . Chem. Soc., Chem. Commun. 1984,
1554-1555. (l) Ley, S.; Lygo, B.; Molines, H. J . Chem. Soc., Perkin
Trans. 1 1984, 2403-2405. (m) Bates, H. A.; Deng, P. J . Org. Chem.
1983, 48, 4479-4481. (n) Ley, S.; Lygo, B.; Molines, H.; Morton, J . A.
J . Chem. Soc., Chem. Commun. 1982, 1521-1522. (o) Kim, Y.; Mundy,
B. P. J . Org. Chem. 1982, 47, 3556-3557.
First, compound 21 was transformed into derivative
32 under the classical TFAA/2,4,6-collidine Pummerer
conditions. The reaction of 32 with NaBH4 allowed the
preparation of the corresponding alcohol 33 (91% yield
from 21), which, after oxidation in the presence of PCC,
yielded aldehyde 34 in 81% yield. A shorter sequence
based on the Pummerer rearrangement followed by
J . Org. Chem, Vol. 68, No. 20, 2003 7783

Carren˜o et al.
was added. The aqueous phase was extracted with EtOAc to
eliminate the remaining methyl-p-tolylsulfoxide and acidified
with 1 M HCl. After extraction with ethyl acetate and workup,
the crude ketosulfinyl carboxylic acid was obtained. The acid
was dissolved in acetone (0.9 M) and added to a solution of
anhydrous K2CO3 (1.1 equiv) in acetone (1.6 M) at rt. The
reaction mixture was stirred for 5 min, and dimethyl sulfate
(1.1 equiv) was added. The solution was refluxed for 2 h, cooled,
filtered, and concentrated under reduced pressure. Purification
was effected as indicated in each case.
Meth yl [(S)R]-4-Oxo-5-(p-tolylsu lfin yl)p en ta n oa te (5).
Compound 5 was obtained from succinic anhydride (3) follow-
ing method A, after purification by flash chromatography
(eluent EtOAc), as a white solid, in 69% yield: mp 91-92 °C;
[R]20D +185 (c 1, CHCl3); 1H NMR δ 7.52 and 7.32 (4H, AA′BB′
system), 3.88 and 3.80 (2H, AB system, J ) 13.4 Hz), 3.65 (3H,
s), 2.80 (2H, m), 2.56 (2H, t, J ) 6.2 Hz), 2.41 (3H, s); 13C NMR
δ 199.8, 172.7, 142.2, 139.6, 130.2, 124.0, 68.0, 51.9, 39.5, 27.5,
21.7.
were characterized as a 1:1 mixture of two epimers at
the carbon R to the carboxylic acid (Scheme 8). Each
diastereoisomeric mixture was submitted to desulfuriza-
tion with Ra/Ni to obtain each enantiomer of cis-(6-
methyltetrahydropyran-2-yl)acetic acid ((-)-(2R,6R)-2
(71%) and (+)-(2S,6S)-2 (75%)). The final comparison of
the [R]20 value of (+)-(2S,6S)-2 with that of the natural
D
enantiomer confirmed again the configurational assign-
ment previously established for the precursor 23 on the
basis of the mechanism of the â-ketosulfoxides reductions
and the spectroscopic parameters of the â-hydroxy-
sulfoxides 9 and 10.
Con clu sion s
We have reported a highly enantioselective approach
to cis-2,5-disubstituted tetrahydrofuran and 2,6-disub-
stituted tetrahydropyran systems combining two efficient
processes: the stereocontrolled reduction of enantiopure
â-ketosulfoxides and the reductive cyclization of hydrox-
ysulfinyl ketones easily accessible from the former. The
yield of the cyclization step strongly depends on the sense
of addition of the reactants. The best yields were obtained
by adding first the Et3SiH on the solution containing the
hydroxysulfynilketone, followed by TMSOTf. The meth-
odology is highly versatile due to the intermediate
formation of a heterocyclic system bearing a sulfoxide
which facilitates further functionalization. Application to
the enantioselective synthesis of natural products has
given rise to the efficient asymmetric synthesis of (-)-
centrolobine (1) (nine steps and 32% overall yield from
glutaric anhydride) and both enantiomers of cis-(6-
methyltetrahydropyran-2-yl)acetic acid 2 [eight steps,
41% overall yield for (-)-(2R,6R)-2 and 24% overall yield
for (+)-(2S,6S)-2 from glutaric anhydride].
Meth yl [(S)R]-5-Oxo-6-(p-tolylsu lfin yl)h exa n oa te (6).
Compound 6 was obtained from glutaric anhydride (4) follow-
ing method A as a white solid, in 93% yield: mp 45 °C (lit.13
mp 45-47 °C); [R]20 +192 (c 1, acetone) [(lit.13 [R]20 +195 (c
D
D
1, acetone)]; 1H NMR δ 7.50 and 7.31 (4H, AA′BB′ system),
3.82 and 3.72 (2H, AB system, J ) 13.2 Hz), 3.63 (3H, s), 2.59
(2H, m), 2.42 (3H, s), 2.30 (2H, t, J ) 7.2 Hz), 1.85 (2H, m);
13C NMR δ 200.6, 173.1, 141.9, 139.3, 129.8, 123.8, 67.5, 51.3,
43.5, 32.3, 21.6, 17.9.
Gen er a l P r oced u r e for th e Zn Br 2-Med ia ted Red u c-
tion s of Ketosu lfin yl Ester s. Meth od B. A solution of the
corresponding â-ketosulfoxide 5 or 6 (7.7 mmol) and dry zinc
bromide (11.6 mmol) in THF (100 mL) was stirred at rt for 90
min and cooled to -78 °C. DIBALH (9.5 mL of a 0.9 M solution
in heptane, 8.5 mmol) was added dropwise for 2 h, and the
resulting mixture was stirred at -78 °C for 30 min and
quenched by addition of a saturated solution of sodium
tartrate. After extraction with EtOAc and workup, the crude
mixture was purified by flash chromatography.
Meth yl [4R,(S)R]-4-Hyd r oxy-5-(p-tolylsu lfin yl)p en ta -
n oa te (7). Reduction of compound 5 following method B
afforded a crude mixture which after flash chromatography
(eluent EtOAc) gave starting material 5 in 16% yield, 3-[(p-
tolylsulfinyl)methyl]cyclopentanone (8)14 in 13% yield, and
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of Ketosu lfin yl
Ester s. Meth od A. The synthesis of compounds 5 and 6 was
carried out by following our previously reported procedure13
modified as follows: To a solution of LDA (2.1 equiv) in THF
was added a solution of [(S)R]-methyl-p-tolylsulfoxide12 (2
equiv for 5; 1 equiv for 6) in THF (0.75 M) dropwise at -78
°C, under argon. After the mixture was stirred for 90 min, a
solution of the corresponding anhydride 3 or 4 (1 equiv) in THF
(0.9 M) was slowly added. The resulting mixture was stirred
at -78 °C for 2 h, and a saturated NH4Cl aqueous solution
alcohol 7 as a white solid, in 67% yield: mp 68-69 °C; [R]20
D
+212 (c 1, CHCl3); 1H NMR δ 7.56 and 7.32 (4H, AA′BB′
system), 3.63 (3H, s), 4.07, 3.12 and 2.84 (3H, ABX system, J
) 13.4, 8.1, 3.8 Hz), 2.48 (2H, m), 2.40 (3H, s), 1.89 (2H, m);
13C NMR δ 173.5, 141.5, 139.8, 129.8, 123.7, 66.5, 63.0, 51.3,
31.4, 29.3, 21.1; MS (EI) m/z 270 (M+, 0.1), 238 (11), 222 (5),
139 (100), 115 (8), 99 (36), 77 (12), 65 (20); HRMS (EI) calcd
for C13H18O4S (M+) 270.0926, found 270.0924.
Met h yl [5R,(S)R]-5-H yd r oxy-6-(p -t olylsu lfin yl)h exa -
n oa te (9). Compound 9 was obtained from 6 following method
B, after flash chromatography (eluent EtOAc) as a white solid,
(31) (+)-Enantiomer: (a) Dixon, D. J .; Ley, S. V.; Tate, E. W. J .
Chem. Soc., Perkin Trans. 1 2000, 2385-2394. (b) Banwell, M. G.;
Bissett, B. D.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W. Aust. J . Chem.
1998, 51, 9-18. (c) Edmunds, A. J . F.; Trueb, W. Tetrahedron Lett.
1997, 38, 1009-1012. (d) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita,
Y. J . Org. Chem. 1996, 61, 7309-7315. (e) Ragoussis, V.; Theodorou,
V. Synthesis 1993, 84-86. (f) Mandai, T.; Ueda, M.; Kashiwagi, K.;
Kawada, M.; Tsuji, J . Tetrahedron Lett. 1993, 34, 111-114. (g)
Bredenkamp, M. W.; Holzapfel, C. W.; Toerien, F. Synth. Commun.
1992, 22, 2447-2457. (h) Hansson, S.; Miller, J . F.; Liebeskind, L. S.
J . Am. Chem. Soc. 1990, 112, 9660-9661. (i) Greenspoon, N.; Keinan,
E. J . Org. Chem. 1988, 53, 3723-3731. (j) J ones, J . B.; Hinks, R. S.
Can. J . Chem. 1987, 65, 704-707. (k) Keinan, E.; Seth, K. K.; Lamed,
R. J . Am. Chem. Soc. 1986, 108, 3474-3480. (l) Semmelhack, M. F.;
Bodurow, C. J . Am. Chem. Soc. 1984, 106, 1496-1498. (m) Masaki,
Y.; Serizawa, Y.; Nagata, K.; Kaji, K. Chem. Lett. 1983, 1601-1602.
(n) Seebach, D.; Pohmakotr, M.; Schregenberger, C.; Weidmann, B.;
Mali, R. S.; Pohmakotr, S. Helv. Chim. Acta 1982, 65, 419-450. (-)-
Enantiomer: see ref 31c,f,g,h and the following: (o) Wei, Z. Y.; Wang,
D.; Li, J . S.; Chan, T. H. J . Org. Chem. 1989, 54, 5768-5774. (p)
Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. Chem. Lett. 1988, 927-
930.
in 87% yield: mp 46 °C (lit.13 mp 46-47 °C); [R]20 +180 (c 1,
D
CHCl3) [lit.13 [R]20 +178 (c 1, CHCl3)]; 1H NMR δ 7.54 and
D
7.33 (4H, AA′BB′ system), 3.91 (1H, br s), 3.66 (3H, s), 4.30,
2.99 and 2.78 (3H, ABX system, J ) 12.9, 9.1, 2.6 Hz), 2.42
(3H, s), 2.35 (2H, t, J ) 7 Hz), 1.8-1.5 (4H, m); 13C NMR δ
174.3, 142.5, 140.9, 130.6, 124.3, 68.7, 62.8, 52.0, 36.8, 33.9,
20.8, 21.8.
Meth yl [5S,(S)R]-5-Hydr oxy-6-(p-tolylsu lfin yl)h exan oate
(10). DIBALH (4.0 mL of a 1 M solution in toluene, 4.0 mmol)
was added dropwise to a solution of the â-ketosulfoxide 6 (0.9
g, 3.2 mmol) in THF (30 mL) at -78 °C. The solution was
stirred at -78 °C for 90 min, quenched with methanol (10 mL),
and concentrated under reduced pressure. The residue was
diluted with EtOAc and acidified with 1 M HCl. After extrac-
tion with EtOAc, workup, and flash chromatography (eluent
EtOAc), compound 10 was obtained as a white solid, in 60%
yield: mp 80 °C (lit.15 mp 80-82 °C); [R]20D +231 (c 0.9, CHCl3)
[lit.15 [R]20D +232 (c 0.9, CHCl3)]; 1H NMR δ 7.50 and 7.36 (4H,
7784 J . Org. Chem., Vol. 68, No. 20, 2003

Reductive Cyclizations of Hydroxysulfinyl Ketones
AA′BB′ system, J ) 8.1 Hz), 3.65 (3H, s), 4.20, 2.93 and 2.75
(3H, ABX system, J ) 13.4, 9.9, 2.1 Hz), 2.42 (3H, s), 2.30 (2H,
t, J ) 7 Hz), 1.8-1.4 (4H, m); 13C NMR δ 174.1, 141.7, 139.4,
130.2, 124.1, 66.3, 61.2, 51.7, 36.4, 33.6, 21.5, 20.5.
Gen er a l P r oced u r e for th e Syn th esis of Wein r eb’s
Am id es. Meth od C. A solution of AlMe3 (3.6 mL of a 2 M
solution in toluene, 7.2 mmol) was added dropwise at rt to a
solution of N,O-dimethylhydroxylamine hydrochloride (718 mg,
7.2 mmol) in CH2Cl2 (20 mL). After the mixture was stirred
for 30 min, a solution of the corresponding ketosulfinyl ester
(2.4 mmol) in CH2Cl2 (10 mL) was added. The mixture was
refluxed for 4 h, cooled, and quenched with 0.5 M HCl. After
workup, the pure amide was obtained.
(EI) m/z 236 (M+ - 18, 6), 220 (16), 154 (16), 137 (100), 124
(29), 97 (68), 84 (92), 65 (34).
[5R,(S)R]-5-H yd r oxy-1-(p -m et h oxyp h en yl)-6-(p -t olyl-
su lfin yl)h exa n on e (16). Compound 16 was obtained from
amide 12 and p-methoxyphenylmagnesium bromide in ether
following method D, stirring the mixture at 50 °C (eluent
EtOAc followed by EtOAc/MeOH 10:1), as an oil, in 71%
yield: [R]20 +127 (c 1, CHCl3); 1H NMR δ 7.92 and 6.91 (4H,
D
AA′BB′ system), 7.53 and 7.31 (4H, AA′BB′ system), 3.98 (1H,
br s), 3.86 (3H, s), 2.97 (2H, t, J ) 7 Hz), 4.29, 2.97 and 2.86
(3H, ABX system, J ) 13.2, 8.9, 2.7 Hz), 2.41 (3H, s), 2.0-1.6
(4H, m); 13C NMR δ 199.1, 163.9, 142.4, 140.9, 130.5, 130.7,
130.3, 124.4, 114.1, 68.7, 62.9, 55.9, 38.0, 37.0, 21.8, 20.1. Anal.
Calcd for C20H24O4S: C, 66.32; H, 6.71. Found: C, 66.07; H,
6.63.
[4R,(S)R]-N-Met h oxy-N-m et h yl-4-h yd r oxy-5-(p -t olyl-
su lfin yl)p en ta n a m id e (11). Compound 11 was obtained from
7 following method C as a yellowish oil, in 97% yield: [R]20
[6R,(S)R]-6-Hydr oxy-7-(p-tolylsu lfin yl)h eptan -2-on e (17).
Compound 17 was obtained from amide 12 and MeMgBr
following method D as a white solid, in 95% yield: mp 58-59
D
+156 (c 1, CHCl3); 1H NMR δ 7.54 and 7.32 (4H, AA′BB′
system), 4.37 (1H, br s), 3.69 (3H, s), 3.18 (3H, s), 4.26, 2.97
and 2.85 (3H, ABX system, J ) 13.2, 8.8, 2.9 Hz), 2.60 (2H,
m), 2.41 (3H, s), 1.88 (2H, m); 13C NMR δ 174.7, 141.8, 140.9,
130.0, 124.0, 67.9, 63.0, 61.2, 32.1, 31.4, 27.6, 21.4; MS (EI)
m/z 299 (M+, 0.2), 238 (8), 160 (17), 139 (100), 123 (9), 99 (32),
77 (11), 65 (17); HRMS (EI) calcd for C14H21O4S (M+) 299.1191,
found 299.1178.
°C; [R]20 +157 (c 1, CHCl3); 1H NMR δ 7.50 and 7.29 (4H,
D
AA′BB′ system), 4.16, 2.94 and 2.73 (3H, ABX system, J )
12.9, 9.1, 2.7 Hz), 2.43 (2H, t, J ) 6.9 Hz), 2.38 (3H, s), 2.09
(3H, s), 1.7-1.1 (4H, m); 13C NMR δ 208.8, 142.0, 140.6, 130.2,
129.8, 124.5, 123.9, 68.4, 62.2, 43.1, 36.4, 29.9, 21.4, 19.0; MS
(EI) m/z 268 (M+, 0.3), 251 (4), 233 (11), 140 (100), 129 (28),
111 (49), 92 (71), 77 (14), 71 (64); HRMS (EI) calcd for
[5R,(S)R]-N-Met h oxy-N-m et h yl-5-h yd r oxy-6-(p -t olyl-
su lfin yl)h exa n a m id e (12). Compound 12 was obtained from
9 following method C as a yellow oil, in 93% yield: [R]20D +139
C
14H20O3S (M+) 268.1133, found 268.1126.
[6S,(S)R]-6-Hydr oxy-7-(p-tolylsu lfin yl)h eptan -2-on e (18).
1
(c 1, CHCl3); H NMR δ 7.53 and 7.32 (4H, AA′BB′ system),
Compound 18 was obtained from amide 13 and MeMgBr
following method D as a colorless oil, in 96% yield: [R]20D +220
(c 1.16, CHCl3); 1H NMR δ 7.48 and 7.29 (4H, AA′BB′ system),
4.69 (1H, br s), 4.14, 2.92 and 2.67 (3H, ABX system, J ) 13.4,
9.9, 2.1 Hz), 2.41 (2H, t, J ) 6.9 Hz), 2.38 (3H, s), 2.07 (3H, s),
1.8-1.1 (4H, m); 13C NMR δ 208.8, 141.5, 139.4, 130.0, 123.9,
4.07 (1H, br s), 3.66 (3H, s), 3.16 (3H, s), 4.24, 2.97 and 2.78
(3H, ABX system, J ) 13.1, 9.2, 2.7 Hz), 2.41 (3H, s), 2.46 (2H,
m), 1.9-1.5 (4H, m); 13C NMR δ 174.7, 142.3, 140.9, 130.5,
124.4, 68.3, 63.4, 61.6, 32.4, 36.9, 31.6, 30.2, 21.8; MS (EI) m/z
313 (M+, 0.7), 253 (16), 174 (16), 139 (100), 113 (42), 85 (27),
67 (18); HRMS (EI) calcd for C15H23NO4S (M+) 313.1348, found
313.1335. Anal. Calcd for C15H23NO4S: C, 57.19; H, 7.36.
Found: C, 57.24; H, 7.36.
66.1, 61.4, 43.0, 36.3, 29.9, 21.4, 19.0; MS (EI) m/z 250 (M+
18, 5), 247 (10), 233 (17), 163 (7), 139 (100), 124 (52), 91 (99),
77 (34).
-
N-Met h oxy-N-m et h yl-[5S,(S)R]-5-h yd r oxy-6-(p -t olyl-
su lfin yl)h exa n a m id e (13). Compound 13 was obtained from
10 following method C as a yellow oil, in 74% yield: [R]20D +178
Gen er a l P r oced u r e for th e Red u ctive Cycliza tion s of
Hyd r oxysu lfin yl Keton es. Meth od E. To a solution of the
corresponding hydroxysulfinyl ketone (1.12 mmol) in CH2Cl2
(30 mL) was added dropwise Et3SiH (360 µL, 2.24 mmol) at 0
°C, followed by TMSOTf (264 µL, 1.45 mmol). The mixture was
stirred for 15 min at 0 °C and quenched with water. After
workup and flash chromatography, pure tetrahydropyran or
tetrahydrofuran derivatives were obtained.
1
(c 1, CHCl3); H NMR δ 7.52 and 7.32 (4H, AA′BB′ system),
4.85 (1H, br s), 3.66 (3H, s), 3.16 (3H, s), 4.21, 2.94 and 2.75
(3H, ABX system, J ) 13.4, 9.9, 2.1 Hz), 2.45 (2H, t, J ) 7
Hz), 2.41 (3H, s), 1.8-1.4 (4H, m); 13C NMR δ 174.0, 141.1,
139.9, 129.7, 123.7, 65.1, 63.6, 60.9, 36.4, 31.8, 31.0, 29.7, 21.1;
MS (EI) m/z 313 (M+, 0.2), 253 (9), 156 (13), 139 (100), 126
[2S,6R,(S)R]-2-(p-Meth oxyp h en yl)-6-[(p-tolylsu lfin yl)-
m eth yl]tetr a h yd r op yr a n (21). Compound 21 was obtained
(25), 113 (31), 91 (54), 69 (17); HRMS (EI) calcd for C15H23
-
NO4S (M+) 313.1348, found 313.1346.
from 16 following method E (eluent EtOAc) as a white solid,
1
Gen er a l P r oced u r e for th e Syn th esis of Hyd r oxysu l-
fin yl Keton es. Meth od D. A solution of the corresponding
Grignard reagent in ether or THF (1.0 mmol) was added to a
solution of Weinreb’s amide (1.0 mmol) in THF (10 mL) at rt,
under argon. The reaction mixture was stirred for 1-2 h at rt
and quenched with saturated NH4Cl. After workup and flash
chromatography, pure keto hydroxy sulfoxides were obtained.
[4R,(S)R]-4-H yd r oxy-1-p h en yl-5-(p -t olylsu lfin yl)p en -
ta n on e (14). Compound 14 was obtained from amide 11 and
PhMgBr in ether following method D (eluent EtOAc) as a white
in 92% yield: mp 127 °C; [R]20 -71 (c 1, CHCl3); H NMR δ
D
7.55 and 7.30 (4H, AA′BB′ system), 7.23 and 6.88 (4H, AA′BB′
system), 4.20 (1H, m), 3.79 (3H, s), 3.63, 3.33 and 2.86 (3H,
ABX system, J ) 13.2, 7.1, 5.2 Hz), 2.38 (3H, s), 2.0-1.4 (6H,
m); 13C NMR δ 159.3, 141.9, 140.8, 135.2, 130.2, 127.3, 124.8,
114.0, 79.8, 73.3, 63.8, 55.7, 33.3, 31.0, 24.0, 21.8. Anal. Calcd
for C20H24O3S: C, 69.15; H, 7.02. Found: C, 68.80; H, 6.95.
[2R,6R,(S)R]-2-Met h yl-6-[(p -t olylsu lfin yl)m et h yl]t et -
r a h yd r op yr a n (22). Compound 22 was obtained from 17
following method E (eluent EtOAc) as a colorless oil, in 97%
solid, in 90% yield: mp 98-99 °C; [R]20 +187 (c 1, CHCl3);
yield: [R]20 +47 (c 1, CHCl3); H NMR δ 7.53 and 7.29 (4H,
1
D
D
1H NMR δ 8.0-7.3 (9H, m), 4.13 (1H, br s), 3.20 (2H, t, J ) 7
Hz), 4.43, 2.99 and 2.84 (3H, ABX system, J ) 12.9, 9.1, 2.2
Hz), 2.42 (3H, s), 1.99 (2H, m); 13C NMR δ 199.99, 142.09,
140.28, 136.68, 133.17, 130.19, 128.57, 128.07, 123.94, 68.05,
62.55, 33.99, 31.15, 21.42; MS (EI) m/z 298 (M+ - 18, 0.5),
282 (24), 158 (53), 137 (43), 124 (26), 105 (70), 84 (100).
[5R,(S)R]-5-Hydr oxy-6-(p-tolylsu lfin yl)h exan -2-on e (15).
Compound 15 was obtained from amide 11 and MeMgBr in
ether following method D as a colorless oil, in 98% yield, and
AA′BB′ system), 3.25 (1H, m), 3.41, 3.23 and 2.71 (3H, ABX
system, J ) 12.9, 7.5, 4.8 Hz), 2.40 (3H, s), 1.8-1.2 (6H, m),
1.08 (3H, d, J ) 6.1 Hz); 13C NMR δ 141.4, 140.4, 129.7, 124.3,
74.0, 72.3, 63.3, 32.6, 30.5, 23.1, 21.8, 21.4; MS (EI) m/z 252
(M+, 7), 140 (57), 113 (100), 95 (53), 69 (40); HRMS (EI) calcd
for C14H20O2S (M+) 252.1184, found 252.1174.
[2S,6S,(S)R]-2-Met h yl-6-[(p -t olylsu lfin yl)m et h yl]t et -
r a h yd r op yr a n (23). Compound 23 was obtained from 18
following method E (eluent EtOAc) as a colorless oil, in 96%
used without further purification: [R]20 +177 (c 1, CHCl3);
yield: [R]20 +232 (c 1, CHCl3); 1H NMR δ 7.54 and 7.30 (4H,
D
D
1H NMR δ 7.51 and 7.30 (4H, AA′BB′ system), 4.23, 2.94 and
2.82 (3H, ABX system, J ) 13.4, 9.1, 2.7 Hz), 2.62 (2H, t, J )
7 Hz), 2.39 (3H, s), 2.13 (3H, s), 1.80 (2H, m); 13C NMR δ 208.7,
142.0, 140.3, 130.1, 123.8, 67.8, 62.5, 38.9, 30.6, 29.6, 21.4; MS
AA′BB′ system), 3.96 (1H, m), 3.59 (1H, m), 2.77 (2H, m), 2.40
(3H, s), 1.9-1.4 (6H, m), 1.22 (3H, d, J ) 6.3 Hz); 13C NMR δ
141.6, 141.1, 129.8, 123.7, 74.0, 71.1, 65.1, 32.7, 30.9, 23.3, 21.8,
21.2; MS (EI) m/z 252 (M+, 8), 140 (61), 127 (7), 113 (100), 95
J . Org. Chem, Vol. 68, No. 20, 2003 7785

Carren˜o et al.
(56), 81 (26), 69 (44); HRMS (EI) calcd for C14H20O2S (M+)
252.1184, found 252.1176.
After being stirred at 0 °C for 10 min, the mixture was
neutralized with a 20% K2CO3 solution (3 mL). Then, an excess
of NaBH4 (103 mg, 2.75 mmol) was added at 0 °C, and the
mixture was stirred for 30 min at rt and quenched with
saturated NH4Cl. The mixture was neutralized with a 20%
K2CO3 solution and extracted with CH2Cl2, dried over MgSO4,
and concentrated under reduced pressure. Excess collidine was
removed by treatment of a solution of the crude mixture in
CH2Cl2 with excess zinc chloride. After being stirred for 1 h
at rt, the mixture was filtered. After workup and flash
chromatography (eluent ethyl ether), compound 31 was ob-
[2S,5R,(S)R]-2-P h en yl-5-[(p -t olylsu lfin yl)m et h yl]t et -
r a h yd r ofu r a n (25). Compound 25 was obtained from 14
following method E, as a 1:6 mixture of diastereoisomers 24
and 25 from which 25 was isolated pure by flash chromatog-
raphy (eluent EtOAc/hexane 3:1) as a white solid, in 71%
yield: mp 93-94 °C; [R]20 -27 (c 1, CHCl3); 1H NMR δ 7.6-
D
7.2 (9H, m), 4.87 (1H, t, J ) 7 Hz), 4.14 (1H, m), 3.26 and 2.97
(2H, ABX system, part AB, J ) 12.9, 6.5, 5.9 Hz), 2.41 (3H, s),
2.3-1.8 (4H, m); 13C NMR δ 142.2, 141.8, 140.3, 130.0, 128.1,
127.5, 125.7, 124.3, 81.5, 74.0, 62.84, 34.2, 31.1, 21.6; MS (EI)
m/z 300 (M+, 0.6), 284 (9), 161 (95), 140 (31), 117 (69), 105
(30), 91 (100), 77 (29); HRMS (EI) calcd for C18H20O2S (M+)
300.1184, found 300.1172.
tained as a colorless oil, in 63% yield: [R]20 -11 (c 2, C2H5-
D
OH); 1H NMR δ 3.99 (1H, m), 3.68 and 3.48 (3H, ABX system,
J ) 11.5, 3.2 and 5.7 Hz), 2.27 (1H, br s), 2.1-1.3 (4H, m),
1.23 (3H, d, J ) 6 Hz); 13C NMR δ 79.5, 76.0, 65.3, 33.2, 27.3,
21.1.
2-P h en yl-5-[(p-t olylsu lfon yl)m et h yl]t et r a h yd r ofu r a n
(26 a n d 27). A solution of compounds 24 and 25 (50:50
mixture, 18 mg, 0.06 mmol) in CH2Cl2 (2 mL) was treated with
m-CPBA (0.12 mmol) at rt. The mixture was stirred for 30
min and washed with saturated NaHCO3. After workup, a
50:50 mixture of sulfones 26 and 27 was obtained as a white
solid, in 95% yield: 1H NMR δ 7.6-7.2 (9H, m), 4.9-4.7 (1H,
m), 4.4-4.6 (1H, m), 3.53 and 3.27 (1H, part AB of ABX
system, J ) 14.0, 5.9, 6.5 Hz), 3.55 and 3.28 (1H, part AB of
ABX system, J ) 14.0, 5.9, 6.5 Hz), 2.41 (3H, s), 2.3-1.8 (4H,
m); 13C NMR δ 145.1, 143.0, 137.5 (3C), 130.6, 130.2, 128.7,
127.7, 125.8 (9C), 81.5, 74.1, 62.2, 34.9, 32.9, 22.1, 145.1, 142.4,
137.3 (3C), 130.5, 130.2, 128.6, 127.7, 125.8 (9C), 80.9, 74.0,
61.9, 34.0, 31.9, 22.0.
(2S,6R)-2-(p -Met h oxyp h en yl)-6-(h yd r oxym et h yl)t et -
r a h yd r op yr a n (33). To a solution of compound 21 (100 mg,
0.29 mmol) and 2,4,6-collidine (115 µL, 0.87 mmol) in CH3CN
(3 mL) was added trifluoroacetic anhydride (205 µL, 1.45
mmol) at 0 °C. After the solution was stirred at 0 °C for 10
min, water (1 mL) was added and the resulting solution was
neutralized with solid K2CO3. After an additional 30 min of
stirring, an excess of NaBH4 was added. The mixture was
stirred for 1 h at rt and quenched at 0 °C with saturated NH4-
Cl. The solution was extracted with ethyl acetate and washed
with 1 M HCl, saturated NaHCO3, and brine. After workup
and flash chromatography (eluent EtOAc/hexane 1:1), com-
pound 33 was obtained as a colorless oil, in 91% yield: [R]20
D
1
-53 (c 0.806, CHCl3); H NMR δ 7.29 and 6.88 (4H, AA′BB′
(2S ,5R )-2-P h e n y l-5-(h y d r o x y m e t h y l)t e t r a h y d r o -
fu r a n (28). To a solution of 24 (651 mg, 2.2 mmol) and 2,4,6-
collidine (868 µL, 6.6 mmol) in CH3CN (25 mL) was added
trifluoroacetic anhydride (1.54 mL, 10.8 mmol) at 0 °C. After
the mixture was stirred at 0 °C for 10 min, water (3 mL) was
added, and the resulting solution was neutralized with solid
K2CO3. After the solution was stirred for 30 min, an excess of
NaBH4 (410 mg, 10.8 mmol) was added. The mixture was
stirred for 1 h at rt and quenched at 0 °C with saturated NH4-
Cl. The solution was extracted with EtOAc and washed with
1 M HCl, saturated NaHCO3, and brine. After workup and
flash chromatography (eluent EtOAc/hexane 1:1), compound
system), 4.36 (1H, m), 3.61 (1H, m), 3.80 (3H, s), 2.24 (1H, br
s), 2.0-1.2 (6H, m); 13C NMR δ 159.4, 135.7, 127.7, 114.1, 79.9,
79.1, 66.7, 55.7, 33.9, 27.3, 23.9; MS (EI) m/z 222 (M+, 49),
191 (97), 147 (100), 135 (68), 121 (57), 109 (20); HRMS (EI)
calcd for C13H18O3 (M+) 222.1256, found 222.1246.
(2S,6R)-2-(p-Meth oxyp h en yl)-6-for m yltetr a h yd r op yr -
a n (34). Meth od A. To a mixture of PCC (400 mg, 1.44 mmol),
4A molecular sieves (1 g/mmol alcohol), and Celite (400 mg)
previously dried under vacuum, in CH2Cl2 (5 mL), was added
a solution of 33 (80 mg, 0.36 mmol) in CH2Cl2 (3 mL) at rt.
After the mixture was stirred for 3 h at rt, ethyl ether was
added, and the resulting mixture was filtered through silica
gel, washed with ethyl ether, and concentrated under reduced
pressure to give aldehyde 34 as a colorless oil, in 81% yield.
28 was obtained as a colorless oil, in 87% yield: [R]20 -52 (c
D
1, CHCl3); 1H NMR δ 7.34 (5H, m), 4.92 (1H, t, J ) 7 Hz),
4.20, 3.80 and 3.65 (3H, ABX system, J ) 11.5, 2.8, 6.0 Hz),
2.4-1.8 (4H, m); 13C NMR δ 142.4, 128.4, 127.5, 125.9, 81.5,
80.00, 65.4, 34.5, 27.6.
Meth od B. To a solution of compound 21 (380 mg, 1.10
mmol) and 2,4,6-collidine (440 µL, 3.31 mmol) in CH3CN (11
mL) was added trifluoroacetic anhydride (780 µL, 5.52 mmol)
at 0 °C. The mixture was stirred at 0 °C for 10 min and
quenched with saturated NaHCO3. After an additonal 3 h of
stirring at rt, extraction with EtOAc, workup, and flash
chromatography (eluent EtOAc/hexane 2:3), compound 34 was
(2S,5R)-2-P h en yl-5-[(ter t-bu tyld ip h en ylsilyloxy)m eth -
yl]tetr a h yd r ofu r a n (29). To a solution of 28 (200 mg, 1,12
mmol) in dry DMF (5 mL) at rt, imidazole (170 mg, 2.47 mmol)
and TBDPSCl (328 µL, 1.23 mmol) were slowly added. The
mixture was stirred for 1 h at rt and concentrated under
reduced pressure. The residue was diluted with CH2Cl2 and
washed with water and brine. After workup and flash chro-
matography (eluent EtOAc/hexane 1:16), compound 29 was
obtained as a colorless oil, in 82% yield: [R]20 -6 (c 0.874,
D
CHCl3); 1H NMR δ 9.71 (1H, s), 7.33 and 6.90 (4H, AA′BB′
system), 4.43 (1H, m), 3.98 (1H, m), 3.81 (3H, s), 2.1-1.3 (6H,
m); 13C NMR (CDCl3) 202.7, 159.6,134.8, 127.6, 114.2, 82.6,
80.1, 55.7, 33.5, 26.4, 23.7. Anal. Calcd for C13H16O3: C, 70.22;
H, 7.32. Found: C, 69.79; H, 7.35.
obtained as a colorless oil, in 96% yield: [R]20 -35 (c 0.86,
D
CH2Cl2); 1H NMR δ 7.72 (4H, m), 7.4-7.2 (11H, m), 4.91 (1H,
dd, J ) 6.4 and 8.3 Hz), 4.22 (1H, m), 3.81 (2H, d, J ) 4.6 Hz),
2.3-1.7 (4H, m), 1.08 (9H, s); 13C NMR δ 143.1, 133.7, 133.6,
135.7, 135.7, 129.66, 129.63, 128.2, 127.7, 127.2, 125.6, 81.4,
80.0, 66.3, 34.5, 28.1, 26.9, 19.3.
(p-Ben zyloxyben zyl)tr ip h en ylp h osp h on iu m br om id e
(36). Commercially available p-benzyloxy benzyl alcohol (35)
was transformed into p-benzyloxybenzyl bromide following the
method previously reported.27 To a solution of the resulting
bromide (1.88 g, 6.8 mmol) in toluene (50 mL) was added PPh3
(5.34 g, 20.3 mmol) at rt. The reaction mixture was refluxed
for 20 h and concentrated under reduced pressure. The residue
was dissolved in ethyl ether, and the precipitate was filtered,
washed with ethyl ether, and concentrated under reduced
pressure to give the phosphonium salt 36 as a white solid, in
quantitative yield: mp 235 °C; 1H NMR δ 7.8-7.3 (2H, m),
7.01 and 6.70 (4H, AA′BB′ system), 5.30 (2H, d, J ) 13.7 Hz),
4.96 (2H, s); 13C NMR (CDCl3) 158.7, 134.9, 134.4, 134.3, 132.7,
132.7, 130.2, 130.0, 128.5, 128.0, 127.4, 118.5, 117.3, 115.1,
69.9, 44.5; MS (EI) m/z 459 (M+ - Br, 100), 262 (10), 183 (8),
[2R,5R,(S)R]-2-Met h yl-5-[(p -t olylsu lfin yl)m et h yl]t et -
r a h yd r ofu r a n (30). Compound 30 was obtained from 15
following Method E (eluent EtOAc) as a colorless oil, in 85%
yield: [R]20D +68 (c 1.2, CHCl3); 1H NMR δ 7.56 and 7.31 (4H,
AA′BB′ system), 3.93 (1H, m), 3.93, 3.19 and 2.86 (3H, ABX
system, J ) 12.8, 6.2, 5.9 Hz), 2.40 (3H, s), 2.03 (2H, m), 1.85
(1H, m), 1.54 (1H, m), 1.25 (3H, d, J ) 6 Hz); 13C NMR δ 141.6,
140.6, 129.9, 124.4, 76.1, 73.8, 63.4, 32.7, 31.1, 21.4, 21.3.
(2R ,5R )-2-Me t h y l-5-(h y d r o x y m e t h y l)t e t r a h y d r o -
fu r a n (31). To a solution of compound 30 (130 mg, 0.55 mmol)
and 2,4,6-collidine (219 µL, 1.65 mmol) in CH3CN (4 mL) was
added trifluoroacetic anhydride (389 µL, 2.75 mmol) at 0 °C.
7786 J . Org. Chem., Vol. 68, No. 20, 2003

Reductive Cyclizations of Hydroxysulfinyl Ketones
91 (65); HRMS (EI) calcd for C32H28OP (M+ - Br) 459.1878,
found 459.1875.
br s), 3.77 (2H, m), 3.54 (2H, m), 3.24 (2H, m), 2.41 (3H, s),
2.36 (3H, s), 2.0-1.2 (12H, br m), 1.13 (3H, d, J ) 6.4 Hz),
1.03 (3H, d, J ) 6.4 Hz).
(2S,6R)-6-[(p -Ben zyloxyp h en yl)vin yl]-2-(p -m et h oxy-
p h en yl)tetr a h yd r op yr a n (37). To a solution of phosphonium
salt 36 (245 mg, 0.45 mmol) in THF (5 mL) at 0 °C was added
n-BuLi (284 µL of a 1.6 M solution in hexanes, 0.45 mmol).
The solution turned orange and was stirred for 15 min at 0
°C. Then, a solution of aldehyde 34 (50 mg, 0.23 mmol) in THF
(1 mL) was added. The mixture was stirred at 0 °C for 30 min
before addition of silica gel. After being stirred for 15 min at
rt, the solution was filtered and concentrated under reduced
pressure. After flash chromatography (eluent EtOAc/hexane
1:5), compound 37 was obtained as a white solid, in 96% yield
as a 3:2 mixture of Z/E isomers: 1H NMR δ 7.5-6.8 (13H, m),
6.96 (1H, d, J ) 15.9 Hz), 6.51 (1H, d, J ) 11.8 Hz), 6.17 (1H,
dd, J ) 15.9, 5.9 Hz), 5.68 (1H, dd, J ) 11.8, 8.6 Hz), 5.09
(2H, s), 5.07 (2H, s), 4.42 (1H, m), 4.41 (1H, m), 4.18 (1H, m),
3.81 (3H, s), 2.1-1.5 (6H, m); 13C NMR δ 159.3, 158.7, 158.4,
137.4, 137.4, 136.0, 135.9, 132.0, 131.2, 130.6, 130.4, 129.6,
129.4, 129.0, 129.0, 128.4, 128.4, 128.0, 127.9, 127.8, 127.7,
115.3, 115.0, 114.1, 80.0, 79.4, 79.3, 75.3, 70.4, 55.7, 33.8, 33.2,
32.2, 32.0, 24.5, 24.3. Anal. Calcd for C27H28O3: C, 80.96; H,
7.05. Found: C, 80.61; H, 7.04.
(2R,6R)-(6-Met h ylt et r a h yd r op yr a n -2-yl)a cet ic Acid
((-)-2). To a stirred solution of 38 (50 mg, 0.17 mmol) in
absolute ethanol was added a large excess of activated Raney
Ni, and the mixture was vigorously stirred for 1 h at rt. Raney
Ni was removed by filtration through a Celite pad and washing
with ethanol. Ethanol was removed under reduced pressure,
and a K2CO3-saturated solution was added. The aqueous layer
was extracted with CH2Cl2 and then acidified with 1 M HCl
to obtain the crude carboxylic which was dissolved in CH2Cl2.
After workup, compound (-)-2 was obtained as a colorless oil,
in 71% yield: [R]20 -22 (c 1.3, CHCl3) [lit.31p [R]20 -24.8 (c
D
D
1
1, CHCl3)]; H NMR δ 3.77 (1H, m), 3.54 (1H, m), 2.57 (1H,
dd, J ) 7.5, 16.1 Hz), 2.50 (1H, dd, J ) 16.1, 5.0 Hz), 1.9-1.2
(6H, m), 1.19 (3H, d, J ) 6.2 Hz); 13C NMR δ 174.4, 74.6, 73.9,
41.1, 32.7, 30.7, 23.1, 22.0.
[2S,6S,(S)R]-(6-Met h ylt et r a h yd r op yr a n -2-yl)(p -t olyl-
su lfin yl)a cetic Acid (39). Compound 39 was obtained fol-
lowing the procedure reported for 38 as a colorless oil, in 82%
yield as a mixture of epimers: 1H NMR δ 8.92 (1H, br s), 7.6-
7.2 (4H, br m), 3.99 (1H, m), 3.69 (1H, m), 3.50 (1H, m), 2.39
(3H, s), 2.0-1.3 (6H, m), 1.27 (3H, d, J ) 6.3 Hz); 13C NMR δ
166.9, 166.2, 142.8, 142.3, 138.1, 136.1, 130.1, 130.0, 125.5,
124.3, 75.4, 74.8, 73.1, 72.5, 67.8, 32.6, 32.5, 29.4, 28.5, 23.1,
23.0, 21.4, 21.5, 21.7; MS (EI) m/z 296 (M+, 4), 236 (11), 157
(19), 139 (64), 124 (60), 99 (40), 84 (100), 69 (42); HRMS (EI)
calcd for C15H20O4S (M+) 296,1082, found 296,1073.
(2S,6R)-2-(p-Meth oxyp h en yl)-6-[â-(p-h yd r oxyp h en yl)-
eth yl]tetr a h yd r op yr a n (1) [(-)-Cen tr olobin e]. A mixture
of 37 (150 mg, 0.37 mmol) and Pd/Al2O3 (150 mg) in THF was
stirred under hydrogen pressure of 50 bar at rt for 4 h. The
resulting mixture was filtered, washed with THF, and con-
centrated under reduced pressure to give pure (-)-centrolobine
(1) as a white solid, in 93% yield: mp 85 °C (lit.24 mp 84-86
°C); [R]20 -93 (c 1, CHCl3) [lit.24 [R]20 -92.1 (c 1, CHCl3)];
(2S,6S)-(6-Meth yltetr ah ydr opyr an -2-yl)acetic Acid ((+)-
2). Compound (+)-2 was obtained from 39 following the
procedure reported for (-)-2 as a colorless oil, in 75% yield:
[R]20 +26 (c 0.18, CHCl3) [lit.31d [R]20 +26 (c 0.18, CHCl3)];
D
D
1H NMR δ 7.34 and 6.90 (4H, AA′BB′ system), 7.04 and 6.71
(4H, AA′BB′ system), 5.43 (1H, br s), 4.33 (1H, m), 3.47 (2H,
m), 3.81 (3H, s), 2.70 (2H, s), 2.0-1.2 (8H, m); 13C NMR δ
159.1, 154.0, 136.2, 134.8, 129.9, 127.6, 115.6, 114.1, 79.6, 77.7,
66.7, 55.7, 38.7, 33.6, 31.7, 31.2, 24.5. Anal. Calcd for
D
D
1H NMR δ 6.6 (1H, br s), 3.77 (1H, m), 3.54 (1H, m), 2.56 (1H,
m), 2.52 (1H, m), 1.8-1.2 (6H, m), 1.19 (3H, d, J ) 6.2 Hz);
13C NMR (CDCl3) 174.4, 74.6, 73.9, 41.1, 32.7, 30.7, 23.1, 22.0.
C
20H24O3: C, 76.78; H, 7.74. Found: C, 76.50; H, 7.82.
[2R,6R,(S)R]-(6-Met h ylt et r a h yd r op yr a n -2-yl)(p -t olyl-
Ack n ow led gm en t. We thank CNRS (PICS 537),
Comunidad Auto´noma de Madrid, and MCYT (Grant
BQU2002-03371) for financial support. R.D.M. thanks
the Ministe`re Franc¸ais de l’Enseignement et de la
Recherche for a fellowship.
su lfin yl)a cetic Acid (38). To a solution of 22 (76 mg, 0.30
mmol) in THF (10 mL) was added dropwise MeLi (282 µL of a
1.6 M solution in ether, 0.45 mmol) at -78 °C. After the
mixture was stirred for 30 min at -78 °C, a stream of CO2
was passed through it for 45 min at 0 °C. The reaction was
quenched with water, and THF was removed under reduced
pressure. The aqueous layer was extracted with CH2Cl2 and
then acidified with 1 M HCl to obtain the carboxylic acid which
was dissolved in CH2Cl2. After workup, compound 38 was
obtained as a colorless oil, in 83% yield as a mixture of
epimers: 1H NMR δ 7.6-7.1 (8H, m), 6.24 (1H, br s), 6.09 (1H,
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal paragraph; H and 13C NMR spectra for compounds 14-
18, 21-23, 25, 29-31, 1, and 2. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034817X
J . Org. Chem, Vol. 68, No. 20, 2003 7787