N-Carbamate-Assisted Stereoselective Synthesis of Chiral Vicinal Amino Sulfides

Article abstract of DOI:10.1021/ol025743z

matrix presented Simply mixing amino alcohol A and thiol in toluene and TFA provided the corresponding amino sulfide B in excellent chemical yield and diastereoselectivity. A double S_N2 process initiated by O-5 participation of the neighboring

Full text of DOI:10.1021/ol025743z

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1235-1238
N-Carbamate-Assisted Stereoselective
Synthesis of Chiral Vicinal Amino
Sulfides
Michae1l De Paolis, Jo1rg Blankenstein, Miche`le Bois-Choussy, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received February 19, 2002
ABSTRACT
Simply mixing amino alcohol A and thiol in toluene and TFA provided the corresponding amino sulfide B in excellent chemical yield and
diastereoselectivity. A double SN2 process initiated by O-5 participation of the neighboring N-carbamate group was advanced to explain the
overall retention of configuration at the chiral benzylic center.
Chiral benzyl sulfides have been found in a number of
medicinally important compounds, such as diltiazem1 (Figure
1) and SKF 104353, etc.2 The chiral vicinal amino sulfide,
in an ecteinascidine family marine alkaloid, an important
class of anticancer agents isolated from the Caribbean
tunicate Ecteinascidia turbinata.4
The nucleophilic substitution at the benzylic position by
a thiol is difficult to control stereoselectively due to the
possible concurrent occurrence of both SN1 and SN2 pro-
cesses.5 Excellent diastereoselectivity was observed only in
cases wherein the access of the nucleophile was anchimeri-
cally assisted6 or conformationally biased, as, for example,
in a polycyclic7 or in a bridged ring system.8 Alternatively,
(1) Schwartz, A.; Madan, P. B.; Mohacsi, E.; O’Brien, J. P.; Todaro, L.
J.; Coffen, D. L. J. Org. Chem. 1992, 57, 851-856 and references therein.
(2) (a) Ku, T. W.; Kondrad, K. H.; Gleason, J. G. J. Org. Chem. 1989,
54, 3487-3491. (b) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,
10515-10530.
(3) (a) Kang, J.; Lee, J. W.; Kim, J. I. J. Chem. Soc., Chem. Commun.
1994, 2009-2010. (b) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.;
Kellogg, R. M. Tetrahedron: Asymmetry 1994, 5, 31-34. (c) Jin, M. J.;
Ahn, S. J.; Lee K. S. Tetrahedron Lett. 1996, 37, 8767-8770. (d)
Christoffers, J. Liebigs Ann. 1997, 1353-1358. (e) Fulton, D. A.; Gibson,
C. L. Tetrahedron Lett. 1997, 38, 2019-2022. (f) Kossenjans, M.; Soeberdt,
M.; Wallbaum, S.; Harms, K.; Martens, J.; Aurich, H. G. J. Chem. Soc.,
Perkin Trans. I 1999, 2353-2365. (g) Jimeno, C.; Moyano, A.; Pe´rica`s,
M. A.; Riera, A. Synlett 2001, 1155-1157.
(4) For a recent review, see: Rinehart, K. L. Med. Res. ReV. 2000, 20,
1-27.
Figure 1.
(5) (a) Hashiyama, T.; Inoue, H.; Takeda, M.; Aoe, K.; Kotera, K. J.
Chem. Soc., Pekin Trans. I 1985, 421-427. (b) Showalter, H. D. H.;
Winters, R. T.; Sercel, A. D.; Michel, A. Tetrahedron Lett. 1991, 32, 2849-
2852. (c) Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A. L.; Tillequin,
F.; Koch, M.; Pierre, A.; Guilbaud, N.; Le´once, S.; Kraus-Berthier, L.;
Rolland, Y.; Atassi, G. J. Med. Chem. 1996, 39, 4762-4766.
on the other hand, has been used as chiral ligand in
enantioselective synthesis3 and is a key structural unit found
10.1021/ol025743z CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/15/2002

Michael addition of arenethiols to R,â-unsaturated carbonyl
compounds has been reported to give excellent diastereo-
and enantioselectivity.9 An elegant enantioselective conden-
sation of configurationally labile R-thiobenzyllithium with
electrophile has recently been developed.10
A neighboring group participation could bypass the
trigonal planar carbenium ion intermediate and give rise to
stereocontrolled substitution products via a double SN2
process.11 In the case of â-amino alcohols, stereoselective
transformation via aziridinium and aziridine intermediates
is well documented.12 We report herein a diastereoselective
synthesis of amino sulfide and provide evidences for the
formation of an iminocarbonate intermediate by way of the
O-5 participation of the vicinal N-carbamate.13
While working on the hydrolysis of compound 3,14 we
found that treatment of its methanol solution with aqueous
HCl led to the stereoselective incorporation of the methoxy
function at the benzylic position (yield ) 40%, de ) 10/1).
Although the transformation itself can be understood on the
solvolysis basis, a process involving N-3 and/or O-5 par-
ticipation of the vicinal N-carbamate can also be advanced,
leading to a stereoselective process. This assumption together
with our interests in the synthesis of chiral amino sulfides
prompted us to examine the thiolation of amino diol 3 using
6-acetoxyhexanethiol (4) as a sterically nonbiased nucleo-
phile (Scheme 1). After a brief survey of reaction conditions,
of 3 and 4 (1.1 equiv relative to 3) at 0 °C for 10 min
provided the sulfide 5 in 95% yield after the reintroduction
of the N-Boc function. The concentration was found to be
an important factor that governs the diastereoseletivity of
this reaction. While a de of 6/1 in favor of the syn-
stereoisomer (vide infra) was obtained at 0.03 M, it decreased
to 3/1 when the reaction was performed at 0.3 M. These
results are indicative of the interplay between a simple
nucleophilic substitution and a double SN2 process via the
participation of the N-carbamate function. Even better
diastereoselectivity (10/1) was observed when the thiolation
was performed on diol 6 under otherwise identical conditions.
The reaction conditions developed were found to be quite
general, and various thiols including cysteine derivatives are
effective reaction partners (Figure 2). The relative stereo-
Scheme 1
Figure 2.
chemistry of 5 was determined to be syn by comparing the
coupling constant (J ) 8-10 Hz) with that of the starting
material as well as the related sulfide derived from pseudo-
ephedrine.15 This stereochemical assignment was further
corroborated by NMR analysis of thiomorpholinone (7)
obtained from 5c under classic conditions (i. TFA; ii. toluene,
2-hydroxypyridine). The benzylic proton resonanced at δ )
4.53 ppm with a coupling constant of 9.1 Hz clearly indicated
the trans-diequatorial orientation of the 1-aryl and the
2-hydroxymethyl groups and hence the syn-stereochemistry
of 5c. Thus, thiolation occurred with overall retention of
configuration at the benzylic position. The high diastereo-
selectivity observed made the SN1 process unlikely and is
in line with a double SN2 process via neighboring group
participation.
a i) toluene-TFA (v/v ) 1/1), 4, c ) 0.03 M 0 °C; ii) Boc2O,
NaHCO3, THF.
trifluoroacetic acid (TFA) was found to be the acid of choice.
Thus, simply stirring a toluene-TFA (v/v ) 1/1) solution
(6) Lohray, B. B.; Jayachandran, B.; Bhushan, V.; Nandanan, E.;
Ravindranathan, T. J. Org. Chem. 1995, 60, 5983-5985.
(7) (a) Allevi, P.; Anastasia, M.; Ciuffreda, P. Tetrahedron Lett. 1991,
32, 6927-6930. (b) Yin, S. F.; Ma, W. Y.; Wang, T. D.; Chen, X. H.;
Zhang, C. N. Acta Pharm. Sin. 1993, 28, 668-672.
(8) (a) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996,
118, 9202-9203. (b) Zhou, B.; Guo, J.; Danishefsky, S. Org. Lett. 2002,
4, 43-46.
(9) (a) Nishimura, K.; Tomioka, K. J. Org. Chem. 2002, 67, 431-434
and references therein. (b) Diastereoselective intramolecular sulfur transfer,
see: Palomo, C.; Oiarbide, M.; Dias, F.; Ortiz, A.; Linden, A. J. Am. Chem.
Soc. 2001, 123, 5602-5603.
(10) Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. J. Am. Chem.
Soc. 2000, 122, 11340-11347.
(11) Capon, B. Q. ReV. 1964, 8, 45-111.
(12) For recent reviews, see: (a) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599-619. (b) Osborn, H. M. I.; Sweeney, J. Tetrahedron:
Asymmetry 1997, 8, 1693-1715. (c) Atkinson, R. A. Tetrahedron 1999,
55, 1519-1559. (d) McCoull, W.; David, F. Synthesis 2000, 1347-1365.
(13) For nomenclature, see Winstein, S.; Allred, E.; Heck, R.; Glick, R.
Tetrahedron 1958, 3, 1-13. (b) Reference 10, p 45.
(14) Compound 3 was synthesized by a phenolic aldol condensation
between sesamol and Garner’s aldehyde followed by selective O-methy-
lation, see: Casiraghi, G.; Cornia, M.; Rassu, G. J. Org. Chem. 1988, 53,
4919-4922.
(15) Poelert, M. A.; Hof, R. P.; Peper, N. C. M. W.; Kellog, R. M.
Heterocycles 1994, 37, 461-475.
1236
Org. Lett., Vol. 4, No. 7, 2002

The 2,4-dimethoxyphenyl-substituted amino diol (8) par-
ticipates as well in this process. It is interesting to note that
even with sterically hindered tert-butylthiol, the correspond-
ing sulfide 9b (Figure 3) can still be isolated in reasonably
Scheme 3
Figure 3.
N-carbamate leading to aziridine 14 and iminocarbonate salt
15, respectively, can be envisaged. Ring opening of 14 or
15 by thiol via a second SN2 process then accounts for the
overall retention of configuration at the benzylic position.
We favored the pathway b based on the following arguments.
First of all, the formation of the five-membered ring is
kinetically and thermodynamically favored over the three-
membered counterpart for both the entropy and the enthalpy
factors. Indeed, ring closure of N-2-bromoethylbenzamide
with methoxide gave exclusively the 2-oxazolines,20 even
though it is known that N-attack leading to the aziridine
should be favored with an ionized (basic conditions) amide
group.21 Second, control experiments showed that formation
of the 2-oxazolidinone from 16 is extremely facile. Thus,
treatment of a dichloromethane solution of 16 with triflic
anhydride (Tf2O) in the presence of 2,6-lutidine provided
directly the 2-oxazolidinone 17 whose stereochemistry was
determined to be 4R,5S from detailed NMR studies (Scheme
4).22 Even more relevant, treatment of a dichloromethane
good yield. On the other hand, compound 10 lacking the
o-methoxy substituent did not react with the thiol and only
deprotection of the N-Boc function was observed under
identical conditions. The requirement of an O-methoxy group
for thiolation is tentatively attributed to its inductive effect
arising from the close proximity of the electronegative
oxygen to the reaction center and is also in accord with the
double SN2 rather than SN1 process.16 Taft and co-workers
have demonstrated that the inductive effect dominates over
the resonance effect for ortho substituents by a factor of
nearly two to one, while for para substituents the reverse is
true.17
It is reasonable to hypothesize the neighboring group
participation in view of the excellent diastereoselectivity
obtained in such an acyclic system. Nevertheless, it is unclear
whether the N-Boc was removed before or after the introduc-
tion of the thiol unit.18 Indeed, the ring opening of N-
unprotected aziridine by thiol in the presence of Lewis acid
is known.19 To clarify this point, the N-Cbz derivative 11
was synthesized. Reaction of 11 with methyl thioglycolate
(12) under the standard conditions provided the sulfide 13
again in excellent diastereoselectivity (Scheme 2).
Scheme 4
Scheme 2
solution of 18 with pTsOH provided 19 in about 75% yield
after acylation of the primary alcohol.23 No trace amount of
N-Boc aziridine was isolable from the reaction mixture under
these conditions. Although these considerations did not
Starting from 11, two reaction manifolds via either N-3
(path a, Scheme 3) or O-5 participation (path b) of the vicinal
(16) Smith, M. B.; March, J. AdVances in Organic Chemistry, 5th ed.;
John Wiley & Sons: New York, 2001; pp 436-437.
(17) Ehrenson, S.; Brownlee, R. T. C.; Taft, R. W. Prog. Phys. Org.
Chem. 1973, 10, 1-80.
(18) Neighboring group participation of N-tert-butyloxycarbamate can
be a very fast process that is able to override the reduction of epoxide with
a strong reductant such as LAH and Red-Al, see note 7 of: Urabe, H.;
Aoyama, Y.; Sato, F. Tetrahedron 1992, 48, 5639-5646.
Org. Lett., Vol. 4, No. 7, 2002
1237

preclude the possibility of aziridine intermediate 14, they
are supportive of the iminocarbonate intermediate 15 in the
present thiolation reaction. The preferential attack of thiol
at the benzylic position rather than the C-2 position of 15
can be explained on the basis of the HSAB principle.24
In conclusion, we developed a stereoselective thiolation
process of a vicinal amino alcohol via an iminocarbonate
intermediate. To the best of our knowledge, it is the first
example wherein the iminocarbonate was used as a transient
aziridine equivalent for the introduction of thio unit with
retention of configuration.26
The potential application of the present synthesis of chiral
aminosulfide is illustrated in Scheme 5. Thus, condensation
Acknowledgment. We thank the CNRS for financial
support. M. De Paolis thanks the Ministe`re de l’Enseignement
Supe´rieur et de la Recherche for a doctoral fellowship and
J. Blankenstein thanks the Swiss National Science Founda-
tion for a postdoctoral grant.
Scheme 5
Supporting Information Available: Full experimental
details and characterization data for compounds 5a-5d, 7,
9a, 9b, 13, 17, 19, and 21. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL025743Z
of 6 with N-Cbz-cysteine methyl ester (20) followed by
saponification of the ester and lactamization provided the
thiazepinone 21. Compound 21 can also be considered as a
reduced form of the ring-constrained dipeptide mimetic of
â-aryl Ser-Cys whose potential as a dual ACE/NEP inhibitor
has been demonstrated.25
(22) The (4R,5R) diastereoisomer of 17 was synthesized by reaction of
16 with NaH followed by acidic hydrolysis.
(23) While sulfide 5 was stable in TFA, the amino diols 3 and 6
decompose rapidly in TFA at 0 °C.
(24) (a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533-3539. (b)
Pearson, R. G. J. Chem. Educ. 1987, 64, 561-567.
(25) Crescenza, A.; Botta, M.; Corelli, F.; Santini, A.; Tafi, A. J. Org.
Chem. 1999, 64, 3019-3025.
(19) Shao, H.; Zhu, Q.; Goodman, M. J. Org. Chem. 1995, 60, 790-
791.
(26) (a) For bromide-mediated rearrangement of cyclic iminocarbonate
to cyclic carbamate, see: Cho, G. Y.; Ko, S. Y. J. Org. Chem. 1999, 64,
8745-8747. (b) For ring opening of oxazolidinone by thiolate, see:
Ishibashi, H.; Uegaki, M.; Sakai, M.; Takeda, Y. Tetrahedron 2001, 57,
2115-2120. (c) Imide carbonyl assisted thiolation of benzylic alcohol has
also been postulated; see ref 2a.
(20) (a) Winstein, S.; Goodman, L.; Boschan, R. J. Am. Chem. Soc. 1950,
72, 2311. (b) Heine, H. W. J. Am. Chem. Soc. 1956, 78, 3708-3710.
(21) For a recent example of N-Cbz aziridine formation under specific
conditions, see: Han, H.; Yoon, J.; Janda, K. D. J. Org. Chem. 1998, 63,
2045-2048.
1238
Org. Lett., Vol. 4, No. 7, 2002