C O M M U N I C A T I O N S
Table 1. Diastereoselective Formation of endo-8
Scheme 3
entry
7
R
base(solvent)
TEA(THF)
TEA(CH2Cl2)
TEA(EtOAc)
imidazole(THF)
py(THF)
2,6-lutidine(THF)
3,5-lutidine (THF)
4-picoline (THF)
2,4,6-collidine(THF)
2,4,6-collidine(THF)
3,5-lutidine (THF)
2,4,6-collidine(THF)
endo-8:exo-8a
7
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7c
4-tolyl
4-tolyl
4-tolyl
4-tolyl
4-tolyl
4-tolyl
4-tolyl
4-tolyl
4-tolyl
75:25
19:81
73:27
70:30
80:20
85:15
87:13
78:22
91:9
10
11
12
2,4,6-mesityl
2,4,6-mesityl
2,4,6-isopropyl-Ph
93:7
97:3
95:5
ee of (R)-10d. However, upon treatment of 9d with NaN(TMS)2
in THF at -78 °C, it provided 99% ee with an 85% yield of (R)-
10d.12,10b To the best of our knowledge, this is the first modular
synthesis for production of this valuable family of enantiopure
sulfinamides.
In conclusion, we have developed a general and practical
technology to prepare enantiopure endo-1,2,3-oxathiazolidine-2-
oxide 8 using chiral N-sulfonyl amino alcohol derivatives and
thionyl chloride. The importance of this new chiral reagent was
exemplified by the expedient production of unique sulfinamide
ligands in excellent yields and enantiopurities. The behavior of
structurally diverse sulfinimines derived from these sulfinamides
on the organometallic delivery processes are under active investiga-
tion. Further applications of actiVated 1,2,3-oxathiazolidine 2-oxide
reagents as the central chiral building block for many asymmetric
processes are under evaluation.13
1
a endo/exo ratio is determined by H NMR analysis.
Our attention was next focused on the optimization of the steric
effect of the arylsulfonyl group on the diastereoselectivity. As
illustrated in Table 1, in the THF collidine mixture, a substitution
of the 2- and 6-positions of the phenyl ring of R7 with methyl groups
increased the endo/exo selectivity to 93:7. Furthermore, increasing
the bulk at the 2,4,6-position of the phenyl ring with triisopropyl
groups gave the highest endo/exo selectivity (95:5). Due to the
higher selectivity, and the readily available and inexpensive nature
of 2,4,6-mesitylenesulfonyl chloride and (1R,2S)-aminoindanol,
further optimization work centered on the preparation of endo-8b.
Surprisingly, when 3,5-lutidine was used as the base in THF, the
endo/exo selectivity jumped to 97:3. It is extremely gratifying to
mention that the preparation of kilogram quantities of this syntheti-
cally important enantiopure, endo-8b, is not difficult and that the
procedure is amenable to scale-up.10
Supporting Information Available: Experimental details and X-ray
structures for endo-8b, exo-8b, and (1R,2S,R)-9a (PDF). This material
Having generated large quantities of (2S,4R,5S)-8b (endo-8b),
our immediate attention was then focused on the production of (R)-
TBSA, utilizing a chemoselective ring-opening (CRO) with inver-
sion of configuration at the sulfur atom, using tert-butyl organo-
metallic reagent followed by a lithium amide addition. We first
evaluated the addition of tert-butyl Grignard to endo-8b in THF at
low temperature (-78 to -10 °C). It is important to note that tert-
butyl Grignard only cleaves the S-N bond in the presence of the
S-O bond of 8b to produce stable, and crystalline (1R,2S,R)-9a
sulfinate ester in >95% yield with diastereopure form.11 The
exposure of 9a to lithium amide in liquid ammonia at -78 °C in
THF led to S-O bond breakage with inversion of configuration at
the S atom, giving quantitative conversions of enantiopure (R)-
10a and 7b. This overall process is highly reproducible for the
production of (R)-10a (>90%) with regeneration of auxiliary 7b,
with an excellent recovery (>96%). It is worth noting that (S)-
TBSA can also be generated with the same procedure utilizing
antipode (2R,4S,5R)-8b.
Viability of this stereospecific double inversion nucleophilic
displacement process was extended to the production of other
structurally diverse tertiary alkyl and aryl sulfinamides. As il-
lustrated in Scheme 3, (R)-2-methylbutyl-((R)-10b), (R)-3-ethyl-
pentyl-((R)-10c), (R)-2,4,6-mesityl-((R)-10e), and (R)-1-adamantyl
((R)-10f) sulfinamides were produced in >99% ee with excellent
yields, without any complications.10b In the case of diastereopure
9d, when exposed to LiNH2/NH3 at -78 °C, it provided only 90%
References
(1) (a) Hett, R.; Fang, Q. K.; Gao, Y. Wald, S. A.; Senanayake, C. H. Org.
Process Res. DeV. 1998, 2, 96. (b) Fang, Q. K.; Senanayake, C. H.; Han,
Z.; Morency, C.; Grover, P.; Malone, R. E.; Butler. H.; Wald, S. A.;
Cameron, T. S. Tetrahedron: Asymmetry 1999, 10, 4477.
(2) Davis, F. A.; Zhang. Y.; Andemichael.; Fang, T.; Fanelli, D. L.; Zhang,
H. J. Org. Chem. 1999, 64, 1403 and references therein.
(3) (a) Fanelli, D. L.; Szewczyk, J. M.; Zhang, G.; Reddy, V.; Burns, D. M.;
Davis, F. A. Org. Synth. 1999, 77, 50. (b) Davis, F. A.; Zhou, P.; Chen,
B.-C. Chem. Soc. ReV. 1998, 27, 13. (c) Zhou, P.; Chen, B.-C.; Davis, F.
A. In AdVances in Sulfur Chemistry; Rayner, C. M., Ed.; JAL Press:
Greenwich, CT, 2000; Vol. 2, p 249.
(4) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913. (b) Owens, D, T.; Hollander, J. F.; Oliver, A, G.; Ellman, J. A. J.
Am. Chem. Soc. 2001, 123, 1539.
(5) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J. Am. Chem.
Soc. 1998, 120, 8011.
(6) Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.; Senanayake, C.
H. Tetrahedron Lett. 2002, 43, 923.
(7) (S)-TBSA is available from Aldrich Chemical Co. for $130 g-1
.
(8) (a) Wudl, F.; Lee, T. B. K. J. Chem. Soc., Chem. Commun. 1972, 61. (b)
Wudl, F.; Lee, T. B. K. J. Am. Chem. Soc. 1973, 95, 6349.
(9) Kagan, H. B.; Rebiere, F. Synlett 1990, 643.
(10) (a) The absolute stereochemistry of endo-8b was unambiguously estab-
lished by single-crystal X-ray analysis to be S-configuration at the sulfur
atom. (b) For the detailed experimental procedure, see Supporting
Information.
(11) The reaction proceeds with clean SN2 at the S atom to produce a single
diastereomer (1R,2S,R)-9a, which was established by single-crystal X-ray
analysis.
(12) This NaN(TMS)2 addition method can be applied to the synthesis of (R)-
10e.10b
(13) Preparation of functionally diverse sulfoxides using endo-8 will be reported
soon.
JA0200692
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J. AM. CHEM. SOC. VOL. 124, NO. 27, 2002 7881