Novel approach to the synthesis of enantioenriched sulfoxides. Highly diastereoselective alkylation of sulfenate anions with 1,4-asymmetric induction

Article abstract of DOI:10.1021/ol026563s

(equation presented) Efficient 1,4-asymmetric induction with an enantiopure aminoalkyl group as the chiral auxiliary has been achieved in the first example of diastereoselective alkylation (up to 98:2) of a sulfenate anion, readily prepared by oxidation of the corresponding thiolate. The stereochemistry of the sulfoxide produced is the opposite of that obtained by the conventional route based on oxidation of the sulfide precursor.

Full text of DOI:10.1021/ol026563s

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3619-3622
Novel Approach to the Synthesis of
Enantioenriched Sulfoxides. Highly
Diastereoselective Alkylation of
Sulfenate Anions with 1,4-Asymmetric
Induction
,†
Franck Sandrinelli,† Ste´phane Perrio,* and Marie-The´re`se Averbuch-Pouchot‡
Laboratoire de Chimie Mole´culaire et Thio-organique (UMR CNRS 6507),
ISMRA-UniVersite´ de Caen, 6 BouleVard du Mare´chal Juin,
F-14050 Caen, France, and LEDSS (UMR CNRS 5616), UniVersite´ Joseph Fourier,
BP 53, F-38041 Grenoble 9, France
stephane.perrio@ismra.fr
Received July 19, 2002
ABSTRACT
Efficient 1,4-asymmetric induction with an enantiopure aminoalkyl group as the chiral auxiliary has been achieved in the first example of
diastereoselective alkylation (up to 98:2) of a sulfenate anion, readily prepared by oxidation of the corresponding thiolate. The stereochemistry
of the sulfoxide produced is the opposite of that obtained by the conventional route based on oxidation of the sulfide precursor.
Sulfenate anions (RSO-) have been postulated as intermedi-
ates in various reactions involving sulfenate derivatives,1
sulfoxides,2 or sulfines3 as substrates. However, no general
procedures for their preparation have so far been reported.
In some recent studies of the oxidation of thiolates (RS-)
with N-sulfonyloxaziridines,4 we showed that aromatic
lithium sulfenates could be obtained very efficiently using
the unusual5 (()-trans-3-(1,1-dimethylethyl)-3-methyl-2-
(phenylsulfonyl)oxaziridine 1 derived from pinacolone
(Scheme 1). In situ S-alkylation of sulfenate anions with
aliphatic halides afforded the corresponding sulfoxides in
good to excellent yield. The overall sequence (deprotona-
tion, oxidation, and alkylation) constitutes an original and
effective approach to the synthesis of sulfoxides from thiols
and has the considerable advantage of being carried out in
one pot.
† Laboratoire de Chimie Mole´culaire et Thio-organique.
‡ LEDSS.
(1) (a) The Chemistry of Sulfenic Acids and their DeriVatiVes-The
Chemistry of Functional Groups; Patai, S., Ed.; Wiley: Chichester, 1990.
(b) Oida, T.; Nakamura, M.; Takashima, Y.; Hayashi, Y. Bull. Inst. Chem.
Res., Kyoto UniV. 1992, 70, 295-301.
(2) (a) O’Connor, D. E.; Lyness, W. I. J. Org. Chem. 1965, 30, 1620-
1623. (b) Jones, D. N.; Kogan, T. P.; Newton, R. F.; Smith, S. J. Chem.
Soc., Chem. Commun. 1982, 589-591. (c) Dodson, R. M.; Hammen, P.
D.; Fan, J. Y. J. Org. Chem. 1971, 36, 2703-2708. (d) Bonini, B. F.;
Maccagnani, G.; Mazzanti, G.; Zani, P. Gazz. Chim. Ital. 1990, 120, 115-
121. (e) Refvik, M. D.; Froese, R. D. J.; Goddard, J. D.; Pham, H. H.;
Pippert, M. F.; Schwan, A. L. J. Am. Chem. Soc. 1995, 117, 184-192. (f)
Blake, A. J.; Westaway, S. M.; Simpkins, N. S. Synlett 1997, 919-920.
(g) Schank, K.; Wilmes, R.; Ferdinand, G. Int. J. Sulfur Chem. 1973, 8,
397-400. (h) Furukawa, N.; Konno, Y.; Tsuruoka, M.; Ogawa, S. Heteroat.
Chem. 1992, 3, 495-503.
(4) (a) Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997, 62,
8626-8627. (b) Sandrinelli, F.; Perrio, S.; Beslin, P. Org. Lett. 1999, 1,
1177-1180.
(5) With the exception of our work, there is only one reported example
of the use of oxaziridine 1 (hydroxylation of a â-lactam). Shimizu, M.;
Ishida, T.; Fujisawa, T. Chem. Lett. 1994, 1403-1406.
(3) (a) Veenstra, G. E.; Zwanenburg, B. Recl. TraV. Chim. Pays-Bas 1976,
95, 37-39. (b) van der Leij, M.; Zwanenburg, B. Recl. TraV. Chim. Pays-
Bas 1980, 99, 49-52.
10.1021/ol026563s CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002

The influence of various parameters (temperature, addition
of salts or crown ethers, nature of the electrophile) was
examined. In addition, the stereochemistry was compared
with that obtained using the more traditional route to
sulfoxides through the oxidation of the sulfide precursors.7b
Scheme 1
Enantiopure thiophenol 2 was prepared from 1-(R)-
phenylethylamine. The first step, synthesis of tertiary amine,
was achieved in 73% yield by Eschweiler-Clark methyla-
tion.12 The subsequent conversion into the thiol using the
methodology of van Koten et al.13 comprises ortho-lithiation
in pentane and isolation of the resulting carbanion by
centrifugation, followed by trapping with elemental sulfur
in THF, acidic workup, and purification by sublimation under
reduced pressure. In our hands, however, this sequence gave
only poor yields (<19%) under the literature conditions. The
protonation of the intermediate thiolate was found to be
particularly critical and highly dependent on the nature of
the proton source. Optimum results were ultimately obtained
using a stoichiometric amount of glacial acetic acid in THF,
which afforded the dimethylamino thiol 2 in 65% yield.14
This reaction was carried out on a 17 mmol scale, allowing
the preparation of 2 g of product in one batch. Moreover,
isolation of the ortho-metalated species was found to be
unnecessary; the solution of the carbanion in pentane was
added directly to the suspension of sulfur in THF.
In this Letter we wish to describe an asymmetric version
of this methodology, starting from enantiopure thiophenol 2
(Scheme 2). Since the substrate in this case possesses a
Scheme 2
stereogenic center, we anticipated a transfer of chirality
during alkylation of the prochiral sulfenate and hence the
preferential formation of one of the possible sulfoxide
diastereoisomers. No examples of such diastereoselectivity
have been reported up to now,6 this being largely due to the
previously mentioned lack of efficient methods for the
generation of sulfenates. In contrast, diastereocontrolled
syntheses of sulfoxides by oxidation of the corresponding
chiral thioethers are well-documented.7
Our decision to pursue these investigations was for the
following reasons: (i) The starting thiol 2 is reported to be
readily available8 from enantiopure (R)-phenylethylamine,
which is an inexpensive chiral amine sold as either enanti-
omer. (ii) Dialkylaminoethyl groups are known9 to be
efficient chiral auxiliaries. (iii) The products formed, which
contain both amino and sulfoxide functions, are potentially
useful chiral starting materials10 for asymmetric synthesis
or ligands11 for catalysis.
The sequence (deprotonation, oxidation, and alkylation)
was then applied to thiophenol 2, using methyl iodide (1
equiv) as an initial electrophile, and the influence of various
parameters (temperature, auxiliary reagents) was examined.
Because of the low solubility of compound 2 at low
temperature in THF, the deprotonation with methyllithium
was carried out with warming from -78 to -10 °C, at which
temperature complete solubilization was observed. After
recooling to -78 °C, oxidation of the thiolate was carried
out15 by addition of 1.05 equiv of N-sulfonyloxaziridine 1.
The alkylation was likewise performed at low temperature
(9) (a) Gong, Y.; Kato, K. Tetrahedron: Asymmetry 2001, 12, 2121-
2127. (b) Alajar´ın, M.; Vidal, A.; Tovar, F.; Ram´ırez de Arellano, M. C.;
Coss´ıo, F. P.; Arrieta, A.; Lecea, B. J. Org. Chem. 2000, 65, 7512-7515.
(c) Juaristi, E.; Escalante, J.; Leo´n-Romo, J. L.; Reyes, A. Tetrahedron:
Asymmetry 1998, 9, 715-740. (d) Juaristi, E.; Leo´n-Romo, J. L.; Reyes,
A.; Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441-2495. (e)
Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377-
2407. (f) Fukuzawa, S.-i.; Kato, H.; Ohtaguchi, M.; Hayashi, Y.; Yamazaki,
H. J. Chem. Soc., Perkin Trans. 1 1997, 3059-3063.
(6) The sole example involving sulfenate salts in asymmetric synthesis
concerns enantioselective alkylation with enantiopure sulfonium salts.
Kobayashi, M.; Manabe, K.; Umemura, K.; Matsuyama, H. Sulfur Lett.
1987, 6, 19-24.
(7) (a) Kagan, H. B.; Diter P. Asymmetric Sulfoxidation-Chemical and
Enzymatic. In Organosulfur Chemistry-Synthetic and Stereochemical
Aspects; Page, P. C. B., Ed.; Academic Press: London, 1998; Vol. 2, Chapter
1. (b) Shimazaki, M.; Takahashi, M.; Komatsu, H.; Ohta, A.; Kajii, K.;
Kodama, Y. Synthesis 1992, 555-557. (c) Bower, J. F.; Martin, C. J.;
Rawson, D. J.; Slawin, A. M. Z.; Williams J. M. J. J. Chem. Soc., Perkin
Trans. 1 1996, 333-342. (d) Cardellicchio, C.; Fracchiolla, G.; Naso, F.;
Tortorella P. Tetrahedron 1999, 55, 525-532. (e) Sato, T.; Otera, J. Synlett
1995, 365-366. (f) Siedlecka, R.; Skarzewski, J. Synlett 1996, 757-758.
(8) These thiols and related structures have been sucessfully used as chiral
ligands for the catalytic asymmetric addition of dialkylzinc to aldehydes
and in the substitution reaction of Grignard reagents with allylic acetates.
(a) Kleijn, H.; Jastrzebski, J. T. B. H.; Boersma, J.; van Koten, G.
Tetrahedron Lett. 2001, 42, 3933-3937. (b) Kleijn, H.; Rijnberg, E.;
Jastrzebski, J. T. B. H.; van Koten, G. Org. Lett. 1999, 1, 853-855. (c)
Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454-6455. (d) Karlstro¨m, A.
S. E.; Huerta, F. F.; Meuzelaar, G. J.; Ba¨ckvall, J.-E. Synlett 2001, SI, 923-
926. (e) Meuzelaar, G. J.; Karlstro¨m, A. S. E.; van Klaveren, M.; Persson,
E. S. M.; del Villar, A.; van Koten, G.; Ba¨ckvall, J.-E. Tetrahedron 2000,
56, 2895-2903.
(10) Use of these substrates has previously been reported in the synthesis
of two naturally occurring compounds. (a) Shimazaki, M.; Ohta, A. Synthesis
1992, 957-958. (b) Shimazaki, M.; Ichihara, N.; Goto, M.; Ohta, A. Chem.
Pharm. Bull. 1992, 40, 3072-3075.
(11) (a) Buezo, N. D.; de la Rosa, J. C.; Priego, J.; Alonso, I.; Carretero,
J. C. Chem. Eur. J. 2001, 7, 3890-3900. (b) Hiroi, K.; Suzuki, Y.; Abe, I.;
Hasegawa, Y.; Suzuki, K. Tetrahedron: Asymmetry 1998, 9, 3797-3817.
(c) Hiroi, K.; Watanabe, K.; Abe, I.; Koseki, M. Tetrahedron Lett. 2001,
42, 7617-7619. (d) Hiroi, K.; Suzuki, Y.; Kaneko, Y.; Kato, F.; Abe, I.;
Kawagishi, R. Polyhedron 2000, 19, 525-528. (e) Petra, D. G. I.; Kamer,
P. C. J.; Spek, A. L.; Schoemaker, H. E.; van Leeuwen, P. W. N. M. J.
Org. Chem. 2000, 65, 3010-3017.
(12) Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc., Perkin Trans.
1 1983, 1009-1027.
(13) Knotter, D. M.; van Maanen, H. L.; Grove, D. M.; Spek, A. L.;
van Koten, G. Inorg. Chem. 1991, 30, 3309-3317.
(14) Disulfide can be easily removed by washing with diethyl ether.
Compound 2 was obtained in 33% yield through addition of a stoichimetric
amount of p-TsOH, whereas no thiol at all was isolated with methanolic
HCl.
3620
Org. Lett., Vol. 4, No. 21, 2002

Table 1. Sulfenate Alkylation with Methyl Iodide According
Table 2. Sulfenate Alkylation with Various Alkyl Halides
to Scheme 2
According to Scheme 2
entry T °C time (h) additives (equiv) 3a :4a
yield (%)
entry RX time (h) products (ratio) yield (%) oxidation ratioa
1
2
3
4
5
-40
-78
-40
-40
-40
24
48
36
36
36
none
none
LiBr (1)
LiBr (5)
12-crown-4 (1)
84:16a
85:15
83:17
83:17
80:20
70
82
89
83
80
1
2
3
4
MeI
EtI
AllBr
BnBr
24
48
48
36
3a :4a (84:16)
3b:4b (84:16)
3c:4c (81:19)
3d :4d (98:2)
70
86
70b
43c
11:89
17:83
40:60
a Oxidation with sodium perborate in glacial acetic acid (see ref 7b).
b Crude yield. c The lower yield in this case is a consequence of substancial
N-alkylation during workup owing to the presence of unreacted benzyl
bromide, which is nonvolatile.
a These conditions were also employed in the corresponding reaction
with the piperidinyl analogue [2-(CH2)4NCH(Me)C6H4SH], affording the
methyl sulfoxides in 83% isolated yield and with a diastereomeric ratio of
84:16 (see ref 17).
The same reaction was then investigated with various other
electrophiles, including ethyl iodide and allyl and benzyl
bromides. Once again, good to excellent diastereoselectivities
were observed (Table 2). When quenching with ethyl iodide
or allyl bromide, the diastereomeric distribution is similar
to that obtained with methyl iodide (entries 1-3), though
an excess of halide (3-5 equiv) is necessary to efficiently
trap the sulfenate. The major products 3a and 3b were shown
to have a (Rc,Rs) configuration by comparison with literature
data.7b Interestingly, a single diastereoisomer was produced
using benzyl bromide as the electrophile (entry 4), the X-ray
structure of which confirmed the same (Rc,Rs) configuration
(see Supporting Information). Separation of diastereoisomers
3 and 4 was straightforward, with the exception of the allyl
sulfoxides, which decomposed upon attempted purification.
to minimize the competitive N-alkylation and consequent
formation of a water-soluble quaternary ammonium salt.16
A lengthy reaction time of one or more days was allowed to
efficiently trap the intermediate sulfenate.
Good diastereoselectivities were observed under all condi-
tions tested (Table 1).18 The alkylation of the lithium
sulfenate proceeded with the predominant formation of the
(Rc,Rs)-diastereoisomer 3a.7b A diastereoisomeric ratio of 84:
16 was obtained when the alkylation was performed at -40
°C (entry 1), with no increase in diastereoselectivity at lower
temperature (-78 °C; entry 2). Addition of varying amounts
of lithium bromide19 to break up possible intermediate
aggregate species had no significant effect (entries 3 and 4).
The addition of 12-crown-4-ether to trap the lithium coun-
terion and prevent internal chelations was also examined20
but had negligible effect on the diastereomeric ratio observed
(80:20; entry 5). Isolated yields were thus fairly consistent
across a range of conditions, varying from 70% to 89%.
Diastereomeric sulfoxides 3a and 4a were easily separated
by column chromatography on silica gel, and their enantio-
meric purity was checked by HPLC (see Supporting Infor-
mation). This was greater than 99%, indicating that no
epimerization had taken place in respect to the commercial
1-(R)-phenylethylamine.
Remarkable differences in NMR data are observed for the
pair of diastereoisomeric sulfoxides, the benzylic methine
proton in 3 occurring some 0.7 ppm downfield of the
corresponding proton in 4, as has previously been reported
by Ohta.7b An unambiguous configuration dependence was
likewise observed in the 13C NMR spectra for the benzylic
methine and methyl signals. The methyl substituent occurs
below 10 ppm in compound 3 but is substantially deshielded
at δ 20 ppm in 4, and the tertiary carbon has a chemical
shift of 58 ppm in diastereoisomer 3, compared with a value
of 63 ppm in 4.
(15) The oxidation is completely chemoselective at sulfur. No N-oxidation
byproducts were detected in the final reaction mixture.
This novel approach to the synthesis of chiral sulfoxides
was compared with the alternative strategy based on oxida-
tion of the corresponding aryl thioethers. This reaction,
previously examined by Ohta7b with substrates containing
methyl, ethyl, and benzylic substituents at sulfur, was found
to show a dramatic dependence on the reaction conditions
employed. The highest diastereoselectivities were achieved
using sodium perborate in glacial AcOH as oxidant (Table
2), with the (Rc,Ss) configuration products predominantly
obtained. This stereochemistry is the opposite to that
observed using our sulfenate-based approach. With the
methyl and ethyl sulfides, ratios of 11:89 and 17:83,
respectively, in favor of diastereoisomers 4a and 4b were
obtained, whereas the alkylation of the sulfenate gave a
reversed diastereoselectivity of 84:16 (entries 1-2). A
moderate diastereoselectivity of 40:60 was reported for the
benzyl derivative (entry 4). In contrast, our methodology gave
exclusively diastereoisomer 4d. Since N-sulfonyloxaziridines
(16) On stirring (1R)-N,N-dimethyl-1-phenylethylamine with methyl
iodide at room temperature in THF, precipitation occurred rapidly. The solid
product was identified as the ammonium salt and was isolated in quantitative
yield after a reaction time of 2 h.
(17) For the preparation of the piperidinyl thiol, see: (a) Tsuge, H.;
Okano, T.; Eguchi, S.; Kimoto, H. J. Chem. Soc., Perkin Trans. 1 1997,
1581-1586. (b) Rijnberg, E.; Hovestad, N. J.; Kleij, A. W.; Jastrzebski, J.
T. B. H.; Boersma, J.; Janssen, M. D.; Spek, A. L.; van Koten, G.
Organometallics 1997, 16, 2847-2857.
(18) The diastereomeric ratio was evaluated from the 1H NMR of the
crude mixture and was consistent with that of the purified product ((2%).
The most diagnostically useful signals are those of the methine and methyl
protons of the dimethylaminoethyl side chain.
(19) For examples in enolate chemistry, see: (a) Seebach, D. Angew.
Chem., Int. Ed. Engl. 1988, 27, 1624-1654. (b) Henderson, K. W.; Dorigo,
A. E.; Liu, Q.-Y.; Williard, P. G.; Schleyer, P. v. R.; Bernstein, P. R. J.
Am. Chem. Soc. 1996, 118, 1339-1347. (c) Asensio, G.; Aleman, P. A.;
Domingo, L. R.; Medio-Simo´n, M. Tetrahedron Lett. 1998, 39, 3277-
3280. (d) Yanagisawa, A.; Kikuchi, T.; Yamamoto, H. Synlett 1998, 174-
176. (e) Murakata, M.; Yasukata, T.; Aoki, T.; Nakajima, M.; Koga, K.
Tetrahedron 1998, 54, 2449-2458. (f) Matsuo, J.-i; Kobayashi, S.; Koga,
K. Tetrahedron Lett. 1998, 39, 9723-9726.
(20) Chini, M.; Crotti, P.; Flippin, L. A.; Macchia, F. J. Org. Chem.
1990, 55, 4265-4272.
Org. Lett., Vol. 4, No. 21, 2002
3621

have not been tested21 by Ohta, we decided to perform in
this series the oxidation of the methyl sulfide22 with
compound 1. This reaction, carried out in THF, led to the
formation in 84% yield of sulfoxides 3a and 4a respectively
in a 31:69 ratio.23 Similar results were also obtained with
dichloromethane or toluene as solvent. The diastereoselec-
tivity is slightly lower than that reported with sodium
perborate but is still in favor of compound 4a.
Figure 1. Proposed model.
To rationalize the asymmetric induction observed in the
alkylation of the prochiral sulfenate, we suggest a model24
combining steric factors and restricted conformation of the
benzylic dimethylamino group through chelation of the
nitrogen atom with the lithium counterion, as depicted in
Figure 1. In such a conformation, the methyl group of the
stereogenic center hinders the approach of the electrophile
toward the upper sulfur lone pair. The other diastereotopic
lone pair is more accessible and can thus react preferentially
to give the (Rc,Ss)-diastereoisomer. Evidence pointing to a
strong interaction between lithium and nitrogen is the very
modest difference in diastereoselectivity observed in the
presence of crown ether and the Li-N distance value25 of
1.45 Å calculated using Spartan software.
In conclusion, we have described the very first diastereo-
selective alkylation of sulfenate ions to give sulfoxides. An
efficient 1,4-asymmetric induction, with diastereomeric ratios
of up to 98:2, was accomplished using an enantiopure
dimethylaminoethyl group as the chiral auxiliary. One
interesting feature of this method is that the major diaste-
reoisomer formed is the opposite of that available via the
sulfide oxidation route, thus affording two complementary
approaches to sulfoxides from thiols. Further investigations
into the use of sulfenates in asymmetric synthesis are
underway.
(21) The oxidizing agents tested were peracids, hydrogen peroxide,
potassium persulfate, and sodium perborate.
(22) The methyl sulfide was prepared in 86% yield from (1R)-N,N-
dimethyl-1-phenylethylamine by ortho-lithiation and trapping with dimethyl
disulfide (see ref 7b).
(23) In contrast, oxidation with the more classical benzaldehyde-derived
oxaziridine, namely, (()-trans-2-(phenylsulfonyl)-3-phenyloxaziridine, gave
a complex mixture in which sulfoxides 3a and 4a could be detected (yield
< 40%). Among the side products, 1-methylsulfanyl-2-vinylbenzene was
produced in 28% yield, with spectral data in agreement with those
reported: Bianchini, C.; Frediani, P.; Herrera, V.; Jime´nez, M. V.; Meli,
A.; Rinco´n, L.; Sa´nchez-Delgado, R.; Vizza, F. J. Am. Chem. Soc. 1995,
117, 4333-4346. The formation of this styrene derivative can be interpreted
in terms of a competitive oxidation on nitrogen followed by Cope
elimination and illustrates the difference of oxidizing power of the two
oxaziridines. For precedents, see: Christian, P. W. N.; Gibson (ne´e Thomas),
S. E.; Gil, R.; Jones, C. V.; Marcos, C. F.; Prechtl, F.; Wierzchleyski, A.
T. Recl. TraV. Chim. Pays-Bas 1995, 114, 195-202. For a review of the
use of this oxaziridine, see: Davis, F. A.; Sheppard, A. C. Tetrahedron
1989, 45, 5703-5742.
Acknowledgment. We gratefully acknowledge financial
support from the Ministe`re de l’Education Nationale de
l’Enseignement Supe´rieur et de la Recherche (F.S.). We also
thank Prof. Pierre Beslin for discussions.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for thiophenol 2 and
sulfoxides 3 and 4. Details of the X-ray crystallographic
analysis of benzyl sulfoxide 3d. HPLC chromatogram for
methyl sulfoxides 3a and 4a. This material is available free
of charge via the Internet at http://pubs.acs.org.
(24) No X-ray crystallographic structural data for sulfenate salts has been
reported in the literature. However, we believe that lithium is coordinated
to oxygen rather than to sulfur, on the basis of the accepted concepts of
hard and soft acids and bases: Pearson, R. G. Hard and Soft Acids and
Bases; Sisler, H. H., Ed.; Dowden, Hutchinson and Ross: Stroudsburg,
1973.
OL026563S
(25) Bond lengths of around 2 Å have previously been reported in
sparteine-mediated reactions of lithium reagents: Hoppe, D.; Hense, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2282-2316.
3622
Org. Lett., Vol. 4, No. 21, 2002