New strategy for the synthesis of iminoglycitols from amino acids

Article abstract of DOI:10.1021/jo010665z

A novel strategy for the enantioselective synthesis of polyhydroxypiperidines, which can be considered as iminoglycitols or 2,6-dideoxyazasugars, was developed. α-Benzolsulfonylamino esters served as a C₂N building block while 2-bromo-3-(bromomethyl)oxazoles and -thiazoles contributed a C3-unit to the final piperidine ring. At first a dihydropyridine ring was established via alkylation and bromine-lithium exchange. The keto group of the resulting 5,6-dihydro[1,3]oxazolo- and 5,6-dihydro[1,3]thiazolo[4,5-c]pyridin-7(4H)-ones was reduced and, after alkylation reactions, the azole ring was cleaved, thus providing heteroatom substituents for the target piperdines. Protected 5-amino-3,4-dihydroxy and 5-amino-3-hydroxy-4-thiohydroxypiperdines were obtained in the talose series while Mitsunobu reaction of the intermiediates provided access to the altrose series.

Full text of DOI:10.1021/jo010665z

3184
J . Org. Chem. 2002, 67, 3184-3193
New Str a tegy for th e Syn th esis of Im in oglycitols fr om Am in o
Acid s†
Sauda Swaleh and J u¨rgen Liebscher*
Institut fu¨r Chemie, Humboldt-Universita¨t Berlin, Brook-Taylor-Strasse 2, D-12489 Berlin, Germany
liebscher@chemie.hu-berlin.de
Received J uly 2, 2001
A novel strategy for the enantioselective synthesis of polyhydroxypiperidines, which can be
considered as iminoglycitols or 2,6-dideoxyazasugars, was developed. R-Benzolsulfonylamino esters
served as a C2N building block while 2-bromo-3-(bromomethyl)oxazoles and -thiazoles contributed
a C3-unit to the final piperidine ring. At first a dihydropyridine ring was established via alkylation
and bromine-lithium exchange. The keto group of the resulting 5,6-dihydro[1,3]oxazolo- and 5,6-
dihydro[1,3]thiazolo[4,5-c]pyridin-7(4H)-ones was reduced and, after alkylation reactions, the azole
ring was cleaved, thus providing heteroatom substituents for the target piperdines. Protected
5-amino-3,4-dihydroxy and 5-amino-3-hydroxy-4-thiohydroxypiperdines were obtained in the talose
series while Mitsunobu reaction of the intermiediates provided access to the altrose series.
Sch em e 1
Polyhydroxylated chiral piperidines widely occur as
azasugars and alkaloids. Deoxynojirimycin, swainsonine,
and castanospermine derivatives are prominent examples
in this area.1 Since a number of these products exhibit
interesting pharmaceutical properties such as glycidase
2,3
inhibition,
many syntheses have been developed in
order to get access to new analogues of this type of
structure. A number of these approaches start with chiral
pool precursors, which incorporate the requisite chirality
centers;4 others establish new stereogenic centers by
asymmetric synthesis, e.g., starting with amino acids.5,6
We recently published a first example where a member
of the hitherto unknown (L)-2,5-diamino-1,6-dideoxyta-
lose series could be synthesized from (L)-alanine following
a novel strategy,7 exploiting a synthesis of annulated
dihydropyridin-3-ones developed in our laboratories.8
According to the retrosynthetic scheme (Scheme 1), the
† Dedicated to Professor Dr. Horst Hartmann on the occasion of his
65th birthday.
(1) (a) Gallengher, T.; Giles, M.; Subramanian, R. S.; Hadley, M, S.
J . Chem. Soc., Chem. Commun. 1992, 166. (b) Fleet, G. W. J .; Ramsden,
N. G.; Molyneux, R. J .; J acob, G. S. Tetrahedron Lett. 1988, 29, 3603.
(c) Margolin, A. L.; Delinck, D. L.; Whalon, M. R. J . Am. Chem. Soc.
1990, 112, 2849. (d) Miller, S. A.; Chamberlin, A. R.. J Am. Chem.
Soc. 1990, 112, 8100.
(2) (a) Herdeis, C.; Schiffer, T. Tetrahedron 1996, 52, 14745. (b)
Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994, 11, 135. (c) Van den
Broek, L.; Vermaas, D. J .; Heskamp, B. M.; Van Boeckel, C. A.; Tan,
M. C.; Bolscher, J . G.; Ploegh, H. L.; Van Kemenade, F. J .; de Goede
R. E.; Miedema, F. Rec. Trav. Chim. Pays-Bas 1993, 112, 82. (d)
Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199. (e) Tyms, A.
S.; Taylor, D. L.; Sunkara, P. S.; Kang, M. S. Glycoprotein Synthesis
and Human Immunodeficiency Viruses. In Design of Anti-Aids Drugs;
Declerg, E., Ed.; Elsevier: New York, 1990; p 257.
(3) (a) J adhavi, P. K.; Wo¨rner, F.; Tetrahedron Lett. 1994, 35, 8973.
(b) Kim, N.-S.; Kang, C. H.; Cha, J . K. Tetrahedron Lett. 1994, 35,
3489. (c) Ina, H.; Kibayashi, C. J . Org. Chem. 1993, 58, 52.
(4) (a) Fleet, G. W.J .; Ramsden, N. G.; Witty, D. R. Tetrahedron
1989, 45, 327. (b) Furneaux, R. H.; Tyler, P. C.; Whitehouse, L. A.
Tetrahedron Lett. 1993, 34, 3613. (c) Baxter, E. W.; Reitz, A. B. J . Org.
Chem. 1994, 59, 3175. (d) Poitout, L.; Le Merrer, Y.; Depezay, J . C.
Tetrahedron Lett. 1994, 35, 3293.
piperidine ring was established from 5-bromo-4-(bromo-
methyl)-2-phenyl-1,3-oxazole 1 (see C) as the C3 building
block and an amino acid, contributing two carbons and
one ring nitrogen atom via N-alkylation and a Barbier-
type cyclization. The oxazole ring of the resulting B
served as a precursor for the substituents at positions 4
and 5 of the piperidine ring. In this synthetic sequence
three new stereogenic centers were established in a
highly stereoselective manner. Here, we give full report
on this synthesis including new examples as well as the
extension of this approach to the altrose series and to
5-amino-4-thiohydroxypiperidine derivatives A (X ) S),
revealing this method as a versatile way to iminoglycitols.
N-Benzosulfonated amino esters 2 (R1 ) SO2Ph) turned
out to be appropriate for the establishment of the 5,6-
(5) Altenbach, H.-J .; Himmeldirk, K. Tetrahedron Asymmetry 1995,
6, 1077.
(6) Kiciak, K.; J acobson, U.; Golebiowski, A.; J urczak, J . Polish. J .
Chem. 1994, 68, 199 and references therein.
(7) Swaleh, S.:, Liebscher, J . Tetrahedron Lett. 1999, 40, 2099.
(8) Faltz, H.; Radspieler, A.; Liebscher, J . Synlett 1997, 1071.
10.1021/jo010665z CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

Synthesis of Iminoglycitols from Amino Acids
J . Org. Chem., Vol. 67, No. 10, 2002 3185
Sch em e 2
dihydro[1,3]oxazolo[4,5-c]pyridin-7(4H)-ones 4, while other
protective groups such as Cbz or allyl or unprotected
amino esters gave low yields or failed to give the desired
products. While N-alkylation to 3 was routine, the sub-
sequent cyclization via bromine-lithium exchange needed
careful control of the reaction temperature (-100 °C).
Otherwise, side reactions or racemization occurred. Re-
duction of the 5,6-dihydro[1,3]oxazolo[4,5-c]pyridin-7(4H)-
ones 4 with sodium borohydride was completely stereo-
selective. Since several methods were reported in the
literature for the reductive cleavage of oxazole rings,9,10
the resulting cis-7-hydroxy-4,5,6,7-tetrahydro[1,3]oxazolo-
(9) (a) Turchi, I. J .; Dewar, M. J . S. Chem. Rev. 1975, 75, 389. (b)
Cornforth, J . W. In Heterocyclic Compounds; Elderfield, C., Ed.;
Wiley: New York, 1957; Vol. 5, p 298. (c) Boyd, G. V. In Comprehensive
Heterocyclic Chemistry; Potts, K. T., Ed., Pergamon Press: New York,
1984; Vol. 6, p 177.
(10) (a) Dornow, A.; Eichholtz, H. Chem Ber. 1953, 86, 384. (b)
Yamaki, N.; Kibayashi, C. J . Am. Chem. Soc. 1989, 111, 1396. (c) Lown,
W.; Yadagiri, B. Synth. Commun. 1990, 20. (d) Gaylord, N. G.; Kay, J .
D. J . Am. Chem. Soc. 1956, 2167.

3186 J . Org. Chem., Vol. 67, No. 10, 2002
Swaleh and Liebscher
F igu r e 2. Stereochemical mode of reduction of 15.
F igu r e 1. Stereochemical mode of reduction of 9.
Sch em e 3
[4,5-c]pyridines 5 were submitted to more forcing reduc-
tion conditions in order to get access to ring-opened
piperidines similar to 10 (R3 ) H). However, the oxazo-
lopyridine ring turned out to be resisitant to all these
approaches including treatment with sodium in boiling
ethanol, with lithium alanate in THF, or ether and
sodium borohydride in acetic acid. Thus, activation of the
oxazole ring by N-alkylation was envisaged. As far as the
yields are concerned, a two-step procedure turned out to
be advantageous, alkylating first the hydroxy group in
the presence of sodium hydride (formation of 6) followed
by quaternization of the ring nitrogen atom under forcing
conditions (neat methyl triflate or dimethyl sulfate) to
afford the oxazolium salts 8. As in nonalkylated 4,5,6,7-
tetrahydro[1,3]oxazolo[4,5-c]pyridines 5, all attempts to
cleave the oxazole ring of the 4,5,6,7-tetrahydro[1,3]-
oxazolo[4,5-c]pyridin-3-ium salts 8 by reduction failed too.
Hydrolytic cleavage was thus attempted. Treatment with
1 M aqueous potassium hydroxide afforded 5-(benzoyl-
amino)-3-alkoxypiperidin-4-ones 9, which could further
be reduced to the desired talo-5-amino-3,4-dihydroxypi-
peridine derivatives 10 by sodium borohydride. The
whole sequence comprised eight synthetic steps with an
overall maximum yield of 21%. All reactions occurred
with high levels of diastereoselectivity. No diastereomers
of 5-10 could be deduced by NMR (de > 90%). HPLC
analysis of final product 10a revealed an ee > 99%. The
configuration of the products could be proved by the X-ray
analysis of 10a (see ref 7 and Supporting Information)
which revealed an all-cis relationship consistent with the
1H NMR spectra in the series of 10. As far as the
stereochemical course of the synthesis is concerned, the
reduction of the 5,6-dihydro[1,3]oxazolo[4,5-c]pyridin-
7(4H)-ones 4 occurred anti with respect to the substituent
R2, thus affording cis products 5. The stereoselective ring
opening of 8 to the piperidinones 9 is likely to be caused
by the formation of the thermodynamically more stable
stereoisomer after protonation of an intermediate enolate.
The final reduction of the piperidones 9 might be
governed by 1,3-shielding by the substituent R2 during
the attack of sodium borohydride at the most stable chair
conformation (see Figure 1). Remarkably, the reduction
of the tricyclic proline derivate 4f showed the opposite
facial selectivity, i.e., the trans-product epi-5f was formed
as major product (Scheme 2) as proved by NOE experi-
ments of epi-5f and X-ray crystal analysis of the minor
isomer 5f (see Supporting Information). Similar selectivi-
ties were observed in the reduction of benzoanelated
benzoindolizidinones.11 The epimers 5f and epi-5f could
be separated. O-Alkylation to epi-6 was achieved in the
presence of sodium hydride but subsequent N-alkylation
affected the piperidine nitrogen atom rather than the
oxazole N-atom, thus leading to a 56:44 mixture of
epimeric indolizidinium salts epi-11. All attempts to
achieve a further N-alkylation of the oxazole N-atom
failed. Thus, the envisaged opening of the oxazole ring
of epi-11 in order to get access to aminohydroxyindol-
izidines analogous to swainsonine or castanospermine
could not be followed up.
An exchange of the benzosulfonyl protective group with
other protective groups, which are easier to remove, was
feasible at the stage of the 7-alkoxy-4,5,6,7-tetrahydro-
[1,3]oxazolo[4,5-c]pyridine 6 (Scheme 2). Thus 6a was
treated with samarium(II) iodide in THF/1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU).12 Since
the resulting N-unprotected compound 6 (H instead of
SO2Ph) could not be separated from the DMPU, it was
further converted to the Cbz derivative 7a . Further
transformations into the end product 10e occurred in a
similar fashion as with the benzosulfonyl-protected com-
pounds, affording the talo compound 10e.
To extend the scope of the synthesis of azasugars
according to the retrosynthetic Scheme 1, further at-
tempts were made to obtain analogues with other con-
figurations or other substituents. Mitsunobu reaction13,14
(11) (a) Buckley, T. F., III; Rapoport, H. J . Org. Chem. 1983, 48,
4222. (b) Kubo, A.; Nakai, T.; Koizumi, Y.; Kitahara, Y.; Saito, N.;
Mikami, Y.; Yazawa, K.; Uno, J . Heterocycles 1996, 42, 195. (c) Szemes,
F.; Marchalin, S.; Bar, N.; Decroix, B. J . Heterocycl. Chem. 1998, 35,
1371.
(12) (a) Vedejs, E.; Lin, S. J . Org. Chem. 1994, 59, 1602. (b)
Hasegawa, E.; Curran, D. P. J . Org. Chem. 1993, 58, 5008.
(13) Mitsunobu, O. Synthesis 1981, 1

Synthesis of Iminoglycitols from Amino Acids
J . Org. Chem., Vol. 67, No. 10, 2002 3187
Sch em e 4
of the 7-hydroxy-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]py-
ridine 5a turned out to be a useful tool to invert the
configuration at position 7. Benzoate or phthalimide was
introduced in this manner (Scheme 3). The substitution
products 12 were submitted to the same protocol as the
7-alkoxyproducts 6, i.e., N-methylation and hydrolytic
opening of the oxazole ring. As could be clearly deduced
in the literature,15 all efforts to reduce the hydroxythi-
azolopyridines 19 failed. Thus, O-alkylation and quater-
nization was employed to activate the thiazole ring.
Unlike the corresponding oxazolium salts 8, the 4,5,6,7-
tetrahydro-1,3-thiazolo[4,5-c]pyridin-3-ium salts 21 could
be reduced by sodium borohydride in methanol. The
resulting perhydro-1,3-thiazolo[4,5-c]pyridines 24 repre-
sent novel, suitably protected talo-5-amino-3-hydroxy-4-
thiohydroxypiperidines. It is worth mentioning that the
morpholino group was lost during the reduction of 20c
or 20d . Obviously the corresponding morpholino products
24 (R3 ) morpholino) originally formed suffered the
elimination of morpholine, and further reduction afforded
the 2-unsubstituted final products 24 (R3 ) H). The
structure of the aminothiohydroxypiperidine derivatives
24 was deduced from the NMR spectra. The all-cis
relationship of substituents in the piperidine ring is in
agreement with the small coupling constants. The con-
figuration at position 2, i.e., the orientation of substituent
R3 could be proved by NOE. In addition, an X-ray crystal
analysis could be provided for the thiazolopyridinium salt
1
by the vicinal coupling constants in the H NMR spectra,
the resulting aminohydroxypiperidines 15 differed in the
configurations at positions 3 and 4 (trans-cis-trans
relation) and thus belong to the altro series. Obviously,
protonation after basic hydrolysis of 13 occurred in the
same stereochemical manner as with 8 while the final
reduction of the keto group of 14 gave the opposite
stereochemical outcome. A likely transition state of the
latter reaction is shown in Figure 2. Presumably, the
axial 3-hydroxy group, after deprotonation, directs the
attack of the hydride toward the opposite side.
As a further extension of the azasugar strategy ac-
cording to Scheme 1, 5-bromo-4-(bromomethyl)-1,3-thia-
zoles 16 were used as starting materials, and the
corresponding 5,6-dihydro-1,3-thiazolo[4,5-c]pyridin-7(4H)-
ones 18 could be obtained in excellent yields and were
reduced to corresponding alcohols 19 (Scheme 4). In
contrast to reductive cleavages of 1,3-thiazoles reported
(15) a) Metzger, J . V. In Comprehensive Heterocyclic Chemistry;
Potts, K. T., Ed. Pergamon Press: Oxford, 1984; Vol. 6, p 234. (b)
Dondoni, A.; Merino, P. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford,
U.K., 1996; Vol. 3, p 375. (c) Liebscher, J . In Methoden der Organischen
Chemie (Houben Weyl); Georg Thieme Verlag: Stuttgart, 1994; Vol.
E8b, Part 2, p 1.
(14) Merrer, Y. L.; Poitout, L.; Depezay, J .-C.; Dosbaa, I.; Geoffrey,
S.; Foglietti, M. G. Bioorg. Med. Chem. 1997, 5, 519.

3188 J . Org. Chem., Vol. 67, No. 10, 2002
Swaleh and Liebscher
Supporting Information) had the following data; Rf ) 0.5
21c. An alternative manipulation of the thiazole ring of
4,5,6,7-tetrahydro-1,3-thiazolo[4,5-c]pyridin-3-ium salts
21 by hydrolytic ring opening gave disulfides 23 rather
than the expected piperidinethiones 22 due to oxidation
of the alkaline solution by air. This reaction was not
further followed up since the transformation of 21 into
the 24 turned out to be a more feasible way to orthogonal-
protected thioiminoglycitols derivatives.
(pentane:EtOAc:CH2Cl2 ) 10.5:1.5:3.5); light yellow oil; [R]20
D
) +1.0 (c 1, CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): -0.37,
0.00 (s, 6H), 0.7 (s, 9H), 3.55 (s, 3H), 4.2, 4.41 (d, J ) 5.21 Hz,
2H), 4.5, 4.7 (d, J ) 17.0 Hz, 2H), 4.8 (m, 1H), 7.37 (m, 2H),
7.38 (m, 1H), 7.40 (m, 2H), 7.80 (m, 2H), 7.82 (m, 1H), 7.84
(m, 2H); 13C NMR (δ/ppm, CDCl3): -5.8, -5.7, 18.0, 25.6, 41.2,
52.0, 61.3, 63.1, 119.3, 126.0, 126.6, 127.4, 128.6, 128.7,130.6,
132.5, 136.4, 140.0, 161.9, 169.8.
Meth yl (2S)-2-[[(5-Br om o-2-ph en yl-1,3-oxazol-4-yl)m eth -
yl](ph en ylsu lfon yl)am in o]-3-h ydr oxypr opan oate (3d). The
product 3d (3.1 g, 63% yield) had the following data: Rf ) 0.32
In summary a novel straightforward strategy for
amino- and aminothiohydroxy-1,6-dideoxyazasugars was
developed based on 5-bromo-4-(bromomethyl)azoles and
N-protected R-amino esters. The starting azole ring
served as the source for three carbon ring atoms and two
heteroatom substituents as well as for a suitable protec-
tive group, i.e., an economic conservation of atoms was
achieved. Three new stereogenic centers were established
in a highly stereoselective way. By inclusion of an
additional Mitsunobu step in the synthetic sequence,
additional heteroatom substituents could be introduced,
and the configurations were manipulated. The method
allows synthesis of new compounds, whose configuration
can be governed by the configuration of the starting
amino acid and the eventual involvement of Mitsunobu
steps. Biological activities of the new products need to
be investigated.
(CH2Cl2:acetone ) 97:3); pale yellow wax; [R]20 ) -2.36 (c 1,
D
CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): 3.48 (s, 3H), 3.83 (m,
1H), 3.95, 4.6 (d, J ) 17.10, 2H), 4.8, 5.8 (d, J ) 5.14 Hz, 2H),
7.08 (m, 2H), 7.12 (m, 1H), 7.22 (m, 2H), 7.27 (m, 2H), 7.5 (m,
1H), 7.56 (m, 2H); 13C NMR (δ/ppm, CDCl3): 39.5, 52.4, 60.4,
63.5, 119.7, 126.0, 127.1, 129.0, 131.5, 132.5, 135.9, 139.7,
162.7, 169; HRMS calcd for
Found: 494.0148.
C20H19BrN2O6S: 494.0148.
Meth yl (2S)-1-[(5-Br om o-2-ph en yl-1,3-oxazol-4-yl)m eth -
yl]-2-p yr r olid in eca r boxyla te (3f). The product 3f (2.99 g,
82% yield) had the following data: Rf ) 0.23 (CHCl3:MeOH )
95:5); pale yellow oil; [R]20D ) -51.4 (c ) 1.35, CHCl3); 1H NMR
(δ/ppm, J /Hz, CDCl3): 1.86 (m, 2H), 2.0 (m, 2), 2.57 (m, 2H),
3.35 (m, 1H), 3.60 (s, 3H), 3.71 (d, J ) 5.4 Hz, 2H), 7.33 (m,
3H), 7.91 (m, 2H); 13C NMR (δ/ppm, CDCl3): 23.0, 29.4, 47.4,
51.7, 53.1, 64.0, 120.1, 126.1, 126.6, 128.6, 130.5, 136.7, 162.2,
174.1; HRMS Calcd for C16H17BrN2O3: 364.0423. Found:
364.0425.
Met h yl (2S)-2-[[(5-Br om o-2-p h en yl-1,3-t h ia zol-4-yl)-
m eth yl](p h en ylsu lfon yl)a m in o] p r op a n oa te (17a ). The
product 17a (4.5 g, 92% yield) had the following data: Rf )
Exp er im en ta l Section
All reactions were carried out under argon in oven-dried
glassware. Solvents were dried and deoxygenated by standard
procedures. Starting materials were purchased from Aldrich
and Merck. Compounds 1,16 16a , and 16c17 were synthesized
according to literature procedures. TLC analysis was per-
formed on Merck silica gel 60F254 plates and visualized with
UV illumination and charring with phosphomolybdic acid in
EtOH (5%, v/v) or 0.3% ninhydrin in EtOH. Column chroma-
tography was conducted with Merck silica gel 60 (400-639
mesh). Melting points were determined on a Boetius hot-stage
apparatus and are reported uncorrected. 1H NMR and 13C
NMR spectra were recorded at 300 and 75.5 MHz, respectively,
on a Bruker AC-300 in CDCl3 with TMS as internal standard.
Mass spectra were measured at 70 eV. Optical rotations were
determined with a Perkin-Elmer polarimeter 241 (d ) 2 mm).
Enantiomeric purity was proved by analytical HPLC on
cellulose carbamate (Chiral PAK AD).
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
3 a n d 17. A mixture of 1 (10 mmol), or 16 (10 mmmol), K2-
CO3 (2.07 g, 15.0 mmol), and 2 (20 mmol) in MeCN (30 mL)
was stirred under reflux for 2 h. The resulting suspensions
were cooled and filtered, and the filtrates were concentrated.
The crude materials were chromatographed on silica gel,
affording the pure products.
0.42 (hexane:EtOAc ) 2:1); brown oil; [R]20 ) -31.0 (c 1,-
D
1
CHCl3); H NMR (δ/ppm, J /Hz, CDCl3): 1.42 (d, J ) 7.3 Hz,
3H), 3.36 (s, 3H), 4.4, 4.6 (d, J ) 16.18 Hz, 2H), 4.65 (m, 1H),
7.18 (m, 2H), 7.20 (m, 2H), 7.23 (m, 1H), 7.48 (m, 1H), 7.5 (m,
2H), 7.7 (m, 2H); 13C NMR (δ/ppm, CDCl3): 16.9, 43.1, 52.7,
55.8, 107.0, 126.5, 126.6, 127.0, 129.0, 129.4, 130.9, 132.8,
133.2, 140.7, 151.1, 167.8, 172.3; HRMS Calcd for C20H19
BrN2O4S2: 493.9971. Found: 493.9973.
-
Meth yl (2S)-2-[{[5-Br om o-2-(4-m or p h olin o)-1,3-th ia zol-
4-yl]m eth yl}(ph en ylsu lfon yl)am in o]pr opan oate (17c). The
product 17c (3.3 g, 66% yield, starting from 16 with R )
morpholino) had the following data: Rf ) 0.36 (pentane:EtOAc:
CH2Cl2 ) 10:1.5:3.5); pale yellow oil; [R]20 ) -13.6 (c 5.35,
D
CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): 1. 24 (d, J ) 7.31 Hz,
3H), 2.94 (t, J ) 5.31 Hz, 4H), 3.32 (s, 3H), 3.44(t, J ) 4.88
Hz, 4H), 4.0, 4.27 (d, J ) 15.93 Hz, 2H), 4.43 (q, J ) 7.31 Hz,
1H), 7.2 (m, 2H), 7.24 (m, 1H), 7.54 (m, 2H); 13C NMR (δ/ppm,
CDCl3): 16.4, 42.9, 47.8, 52.2, 55.5, 65.8, 93.5, 127.0, 129.0,
132.7, 140.7, 146.1, 169.3, 171.9; HRMS Calcd for C18H22
BrN3O5S2: 503.0186. Found: 503.0188.
-
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
4 a n d 18. To a solution of 3 or 17 (1.80 mmol) in THF (30
mL) under argon atmosphere n-BuLi (1.25 mL, 2.00 mmol,
1.60 M solution in hexane) was added dropwise at -100 °C.
The solution was quenched by saturated aqueous NH4Cl
solution after stirring for 4-5 h at -100 °C (-115 °C in the
case of 4f). The organic layer was separated and the aqueous
layer extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were dried with Na2SO4 and concentrated. The
crude materials were chromatographed on silica gel affording
pure products.
Meth yl (2S)-2-[[(5-Br om o-2-ph en yl-1,3-oxazol-4-yl)m eth -
yl](p h en ylsu lfon yl)a m in o]p r op a n oa te (3a ). The product
3a (4.3 g, 90% yield) had the following data: Rf ) 0.50 (CH2-
Cl2:acetone ) 97:3); light yellow oil; [R]20 ) -19.7 (c 1.3
D
CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): 1.60 (d, J ) 7.29 Hz,
3H), 3.56 (s, 3H), 4.37, 4.56 (d, J ) 16.31 Hz, 2H), 4.77 (q, J
) 7.29 Hz, 1H), 7.43 (m, 2H), 7.45 (m, 2H), 7.46 (m, 2H), 7.86
(m, 2H), 7.87 (m, 1H), 7.90 (m, 1H); 13C NMR (δ/ppm, CDCl3):
17.0, 40.5, 52.6, 55.7, 120.4, 126.5, 126.8, 127.8, 129.1, 129.2,
(6S)-6-Meth yl-2-p h en yl-5-(p h en ylsu lfon yl)-5,6-d ih yd r o-
[1,3]oxa zolo[4,5-c]p yr id in -7(4H)-on e (4a ). The product 4a
(490 mg, 74% yield) had the following data: Rf ) 0.35 (pentane:
131.2, 132.9, 136.2, 140.5, 162.6, 172.3. Anal. Calcd for C20H19
BrN2O5S: C 50.20, H 4.01, N 5.86, S 6.69, Br 16.50. Found:
C 49.96, H 3.89, N 6.01, S 6.84, Br 16.76.
Meth yl (2S)-2-[[(5-Br om o-2-ph en yl-1,3-oxazol-4-yl)m eth -
yl](p h en ylsu lfon yl)a m in o]-3-{[ter t-bu tyl(d im eth yl)silyl]-
oxy}p r op a n oa te (3c). The product 3c (84.4% yield, see also
-
EtOAc ) 2:1); colorless crystals; mp 160-162 °C (EtOH), [R]20
D
1
) +31.0 (c 0.3, EtOH); H NMR (δ/ppm, J /Hz, CDCl3): 1.51
(d, J ) 7.3 Hz, 3H), 4.63, 5.18 (d, J ) 18.72 Hz, 2H), 4.82 (q,
J ) 7.3 Hz, 1H), 7.42 (m, 1H), 7.46 (m, 1H), 7.55 (m, 2H), 7.62
(m, 1H) 8.1 (m, 2H), 7.8 (m, 2H); 13C NMR (δ/ppm, CDCl3),
16.6, 40.7, 59.6, 125.7, 127.2, 129.1, 130.7, 133.1, 133.6, 139.2,
141.3, 152.3, 166.4, 183.3; MS, m/z (%), 368.05 (M, 4.5), 227.06
(M - PhSO2, 40.7), 157.1 (23), 129 (100), 104.1 (66), 51 (28).
(16) Gompper, R.; Ru¨hle, H. Liebigs Ann. Chem. 1959, 626, 83.
(17) Asinger, F.; Thiel, M.; Gewald, K. Liebigs Ann. Chem. 1961,
639, 133.

Synthesis of Iminoglycitols from Amino Acids
J . Org. Chem., Vol. 67, No. 10, 2002 3189
Anal. Calcd for C19H16N2O4S: C 62.0, H 4.38, N 7.61, S, 8.68.
Found: C 61.98, H 4.42, N 7.77, S 8.93.
(6S)-6-({[ter t-Bu tyl(d im eth yl)silyl]oxy}m eth yl)-2-ph en -
yl-5-(p h en ylsu lfon yl)-5,6-d ih yd r o[1,3]oxa zolo[4,5-c]p yr i-
d in -7(4H)-on e (4c). The product 4c (804 mg, 60% yield) had
(6S,7R)-6-Meth yl-2-p h en yl-5-(p h en ylsu lfon yl)oxa zolo-
[4,5-c]p yr id in -7-ol (5a ). The product 5a (467 mg, 93% yield)
had the following data: Rf ) 0.42 (CH2Cl2:acetone ) 94:6);
white crystals; mp 155-156 °C (EtOH), [R]20 ) -64.3 (c 1,
D
acetone); 1H NMR (δ/ppm, J /Hz, CD3COCD3): 0.77 (d, J ) 6.87
Hz, 3H), 3.92, 4.46 (d, J ) 14.11, 2H), 4.34 (q, J ) 6.81, 1H),
4.78 (m, 1H), 4.93 (d, J ) 5.91 Hz, 1H), 7.28 (2Hr), 7.30 (1H),
7.34 (2H), 7.40 (2H), 7.48 (1H), 7.76 (2H); 13C NMR (δ/ppm,
CD3COCD3): 11.5, 41.5, 55.1, 66.2, 128.2, 129.2, 129.4, 131.2,
131.6, 132.7, 135.1, 135.2, 143.2, 149.0, 167.1; MS, m/z (%),
370.1 (M, 0.97), 229.05(4.6), 187 (100), 158 (20), 141 (27), 104
the following data: Rf ) 0.26 (pentane:EtOAc:CH2Cl2 ) 11:
1
1:3); yellow oil; [R]20 ) -10.1 (c 1, CHCl3); H NMR (δ/ppm,
D
J /Hz, CDCl3): -0.94, 0.00 (s, 6H), 0.70 (s, 9H), 4.19 (m, 2H),
4.75 (m, 1H), 4.9, 5.2 (d, J ) 16.0, 2H), 7.47 (m, 2H), 7.51 (m,
2H), 7.55 (m, 1H), 7.59 (m, 2H) 8.1 (m, 2H); 13C NMR (δ/ppm,
CDCl3), -6.1, -5.9, 17.7, 25.7, 44.1, 64.7, 66.7, 125.7, 126.7,
127.9, 129.1, 129.4, 132.7, 139.1, 142.6, 153.6, 165.7 180.9; MS,
m/z (%): 441.1 (M - 57, 3.1), 299 (12), 148.95 (7), 105 (20), 89
(54), 77 (83), 57 (37), 41 (29). Anal. Calcd for C25H30N2O5SSi:
C 59.97, H 6.44, N 5.66, S 6.38. Found: C 59.61, H 6.52, N
5.72, S 6.18.
(69), 76.95 (71), 55 (24), 43 (13.91); HRMS Calcd for C19H18
N2O4S: 370.0984. Found: 370.0990.
-
(6S,7R)-6-({[ter t-Bu t yl(d im et h yl)silyl]oxy}m et h yl)-2-
ph en yl-5-(ph en ylsu lfon yl)-4,5,6,7-tetr ah ydr o[1,3]oxazolo-
[4,5-c]p yr id in -7-ol (5c). The product 5c (489 mg, 72% yield)
had the following data: Rf ) 0.30 (CH2Cl2:acetone); white wax;
mp 166-167 °C (EtOH), [R]20D ) -14.55 (c 1, CHCl3); 1H NMR
(δ/ppm, J /Hz, CDCl3): -0.31, 0.00 (s, 6H), 0.77 (s, 9H), 3.93-
4.1 (dd, 2H), 3.96 (br, 1H), 4.2, 4.7 (d, J ) 14.0, 2H), 4.6 (m,
1H), 5.0 (m, 1H), 7.42 (m, 2H), 7.47 (m, 2H), 7.52 (m, 1H), 7.81
(m, 1H) 7.99 (m, 2H); 13C NMR (δ/ppm, CDCl3): -5.78, 17.9,
25.6, 41.1, 55.5, 61.8, 64.2, 126.3, 126.9, 127.1, 128.8, 129.3,
130.6, 132.4, 133.2, 140.1, 145.6, 161.9; MS, m/z (%): C25H32N2-
O5SSi (500), 443.25 (M - 57, 3.50), 301.0 (3), 256 (14), 197
(69), 187 (30), 173 (30), 158 (15), 116 (30), 103 (58), 76 (100),
56.9 (78).
Ben zyl (6S)-6-Meth yl-7-oxo-2-p h en yl-6,7-d ih yd r o[1,3]-
oxa zolo[4,5-c]p yr id in e-5(4H)-ca r boxyla te (4e). The prod-
uct 4e (155 mg, 33% yield) had the following data: Rf ) 0.53
(CH2Cl2:acetone ) 95:5); pale yellow oil; [R]20 ) -1.4 (c 1,
D
1
CHCl3); H NMR (δ/ppm, J /Hz, CDCl3): 1.31(d, J ) 7.21 Hz,
3H), 4.38 (m, 1H), 5.05-5.14 (d, J ) 15.52, 2H), 5.01, 5.20 (d,
J ) 12.26, 2H), 7.21 (m, 2H), 7.24 (m, 2H), 7.33 (m, 1H), 7.35
(m, 2H), 7.41 (m, 1H), 8.0 (m, 2H); 13C NMR (δ/ppm, CDCl3):
16.0, 39.9, 58.2, 68.4, 129.0, 26.4, 126.5, 128.5, 128.8, 129.0,
129.5, 133.0, 136.3, 142.0, 155.0, 166.6, 184.0; MS, m/z (%),
363.2 (M + 1, 2), 227 (M - Cbz, 4.2), 129 (12), 91.1 (100), 76.9
(11), 65 (17), 56 (12), 42 (5); HRMS Calcd for C21H18N2O4:
262.1267. Found: 262.1269.
(8a S,9S)-2-P h en yl-4,6,7,8,8a ,9-h exa h yd r o[1,3]oxa zolo-
[4,5-f]in d olizin -9-ol (epi-5f). The product epi-5f (265 mg, 76%
yield) had the following data: Rf ) 0.33 (CHCl3:MeOH ) 9:1);
(8a S)-2-P h en yl-6,7,8,8a -t et r a h yd r o[1,3]oxa zolo[4,5-f]-
in d olizin -9(4H)-on e (4f). The product 4f (347 mg, 76% yield)
had the following data: Rf ) 0.41 (CHCl3:MeOH ) 9:1); light
20
white crystals; mp 190-191 °C (EtOH), [R]D ) +120.4 (c 1,
CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): 1.67 (m, 2H), 1.85 (m,
1H), 2.38 (br, 1H), 2.40 (m, 2H), 3.12 (q, J ) 16.0 Hz, 1H),
3.20, 3.88 (d, J ) 14.0 Hz, 2H), 4.58 (d, J ) 7.25 Hz, 1H), 7.34
(m, 2H), 7.91 (m, 1H), 7.93 (m, 2H); 13C NMR (δ/ppm, CDCl3):
22.8, 28.6, 49.6, 54.0, 68.8, 69.3, 126.5, 127.6, 128.9, 130.5,
133.1, 147.5, 162.0; MS, m/z (%): 256.1 (M, 20), 187.1 (30),
104.0 (40), 70 (100), 55 (15); HRMS calcd for C15H14N2O4:
256.1213. Found: 256.1215.
yellow crystals; mp 89-90 °C (EtOH), [R]20 ) -10.0 (c 1.1,
D
EtOH); 1H NMR (δ/ppm, J /Hz, CDCl3): 1.83 (m, 2H), 2.58 (m,
1H), 3.04-3.2 (d, J ) 18.59 Hz, 2H), 3.67-4.15 (d, J ) 16.49,
2H), 7.41 (m, 2H), 7.47 (m, 1H); 13C NMR (δ/ppm, CDCl3), 21.8,
24.5, 48.8, 52.9, 125.9, 127.6, 128.9, 132.1, 155.5, 165.1, 185.1;
MS, m/z (%), 254.1 (M, 70), 226.1 (20), 183 (10), 145 (10), 123.1
(100), 70.1 (100); HRMS Calcd for C15H14N2O4: 254.1056.
Found, 254.1053.
(8a S,9R)-2-P h en yl-4,6,7,8,8a ,9-h exa h yd r o[1,3]oxa zolo-
[4,5-f]in d olizin -9-ol (5f). The product 5f (69.7 mg, 20% yield)
had the following data: Rf ) 0.46 (CHCl3:MeOH ) 9:1); white
(6S)-6-Meth yl-2-p h en yl-5-(p h en ylsu lfon yl)-5,6-dih yd r o-
[1,3]t h ia zolo[4,5-c]p yr id in -7(4H )-on e (18a ). The product
18a (580 mg, 84% yield) had the following data: Rf ) 0.46
(CH2Cl2:acetone ) 98:2); pale yellow crystals; mp 163-165 °C
crystals; mp 181-182 °C, (EtOH), [R]20 ) -17.3 (c 1.1, CH3-
D
Cl); 1H NMR (δ/ppm, J /Hz, CDCl3): 1.76 (m, 2H), 1.79 (m, 1H),
2.1 (m, 2H), 2.6 (br, 1H), 3.12, 3.85 (d, J ) 14.5 Hz, 2H), 3.14
(q, J ) 16.0 Hz, 1H), 4.50 (d, J ) 1.89 Hz, 1H), 7.34 (m, 2H,),
7.90 (m, 1H), 7.92 (m, 2H); 13C NMR (δ/ppm, CDCl3): 22.6,
23.3, 49.8, 53.8, 62.1, 66.4, 126.3, 127.4, 128.7, 137.23, 130.3,
147.9, 162.1. Anal. Calcd for C15H16N2O2: C 70.29, H 6.52, N
10.92. Found: C 70.18, H 6.39, N 10.73.
(EtOH), [R]20 ) -31.4 (c 1,CHCl3); 1H NMR (δ/ppm, J /Hz,
D
CDCl3): 1.31 (d, J ) 7.35 Hz, 3H), 4.72, 5.2 (d, J ) 18.63, 2H),
5.18 (q, J ) 5.49 Hz, 1H), 7.17 (m, 2H), 7.28 (m, 2H), 7.33 (m,
1H), 7.38 (m, 2H, 7.54 (m, 2H), 7.77 (m, 1H); 13C NMR (δ/ppm,
CDCl3): 16.0, 42.7, 58.6, 127.2, 127.6, 129.6, 129.7, 132.5,
132.6, 133.5, 139.1, 176.4, 189.2. Anal. Calcd for C19H16
-
(6S,7R)-6-Met h yl-2-p h en yl-5-(p h en ylsu lfon yl)-4,5,6,7-
tetr a h yd r o[1,3]th ia zolo[4,5-c]p yr id in -7-ol (19a ). The prod-
uct 19a (439 mg, 84% yield) had the following data: mp 92-
N2O3S2: C 59.21, H 4.19, N 7.29, S 16.64. Found C 58.69, H
4.45, N 7.31, S 16.60.
93 °C (EtOAc:hexane ) 1.5:1); pale yellow crystals; [R]20
)
(6S)-6-Met h yl-2-(4-m or p h olin o)-5-p h en ylsu lfon yl-5,6-
d ih yd r o[1,3]th ia zolo[4,5-c] p yr id in -7(4H)-on e (18c). The
product 18c (610 mg, 86% yield) had the following data:, Rf )
0.52 (CH2Cl2:acetone ) 97:3); light yellow crystals; mp 48 °C
(with [R]20D ) -33.67 (c 1.2, CHCl3); 1H NMR (δ/ppm, CDCl3):
1.30 (d, J ) 7.23 Hz, 3H), 3.49 (t, J ) 4.80 Hz, 4H), 3.69 (t, J
) 5.01 Hz, 4H), 4.32, 4.90 (d, J ) 18.59 Hz, 2H), 4.50 (q, J )
7.20 Hz, 1H), 7.34 (m, 2H), 7.41 (m, 1H), 7.61 (m, 2H); 13C
NMR (δ/ppm, CDCl3): 15.9, 42.1, 48.5, 57.8, 65.8, 116.6, 138.9,
162.2, 175.6, 187.0; MS, m/z (%): 393.08 (M, 11.62), 252 (100),
211 (69), 171.2 (13), 142.05 (14), 113.1 (27), 77 8 (39), 57 (19),
45 8 (19). Anal. Calcd for C17H19N3O4S2: C 51.90, H 4.87, N
10.69, S 16.27. Found C 52.3, H 5.10, N 10.70, S 16.05.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5 a n d 19.
To a solution of 4 and 18 (1.36 mmol) in THF/EtOH (1:1, 20
mL) was added NaBH4 (2.72 mmol), and the mixture was
stirred for 2 h at room temperature. The resulting solution
was concentrated, and the crude product was partitioned
between CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (20
mL). The organic layer was dried (Na2SO4) and the solvent
evaporated. The crude materials were chromatographed on
silica gel affording pure products.
D
1
-7.1 (c 1, CHCl3); H NMR (δ/ppm, J /Hz, CDCl3): 0.85 (d, J
) 6.76 Hz, 3H), 3.02 (br, 1H), 4.05,4.82 (d, J ) 16.01 Hz, 2H),
4.65 (m, 1H), 5.03 (m, 1H), 7.33 (2H), 7.41 (2Hr), 7.43 (1H),
7.46 (2H), 7.50 (2H), 7.79 (1H); 13C NMR (δ/ppm, CD3-
COCD3): 9.6, 42.3, 52.6, 67.2, 126.7, 127.4, 129.4, 129.7, 130.7,
131.8, 133.7, 147.3, 168.8; MS, m/z (%): 386.05 (M, 1.15),
217.10 (39.3), 203 (100), 184.05 (26), 141.0 (24), 121.00 (12),
104.1 (67), 100 (20.6), 77.1 (77), 45 (32); HRMS Calcd for
C
19H18N2O3S2: 386.0760. Found: 386.0756.
(6S,7R)-6-Meth yl-2-(4-m or p h olin o)-5-(p h en ylsu lfon yl)-
4,5,6,7-t et r a h yd r o[1,3]t h ia zolo[4,5-c]p yr id in -7-ol (19c).
The product 19c (505 mg, 94% yield) had the following data:
Rf ) 0.46 (CH2Cl2:acetone ) 95:5); colorless crystals; mp 165-
166 °C, [R]D20) -16.7 (c 1.05, CHCl3); 1H NMR (δ/ppm, J /Hz,
CDCl3): 0.83 (d, J ) 6.80 Hz, 3H), 3.3 (t, J ) 4.0, 4H), 3.6 (t,
J ) 5.0 Hz, 4H), 3.7, 4.5 (d, J ) 14.42 Hz, 2H), 4.3 (m, 1H),
4.85 (m, 1H), 7.17 (m, 1H), 7.45 (m, 2H), 7.7 (m, 2H); 13C NMR
(δ/ppm, CDCl3): 9.2 (CH3), 41.7, 48.3, 52.2, 65.8, 66.3, 118.9,
127.1, 129.2, 132.8, 139.8, 142.7, 171.2; MS, m/z (%): 395.1
(M, 15), 254.1 (30), 212 (100), 155.0 (14), 77 (30), 51.0 (11);
HRMS Calcd for C17H21N3O4S2: 395.0975. Found: 395.0975.

3190 J . Org. Chem., Vol. 67, No. 10, 2002
Swaleh and Liebscher
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p on d s
6a , epi-6f or 20a , 20c). Meth od A. A solution of 5(a ,f) (1.7
mmol) or 19(a ,c) in a mixture of DMSO (10 mL) and DMF (10
mL) was added to barium oxide (2.25 g, 14.7 mmol) and barium
hydroxide octahydrate (1.23 g, 3.90 mmol) at 0 °C. Subse-
quently dimethyl sulfate (3.31 mL, 350 mmol) was added
dropwise at 0 °C under argon. After stirring for 18 h at
ambient temperature under argon, concentrated aqueous
ammonia solution (3.3 mL) was added dropwise over 0.25 h
and subsequently 4 N hydrochloric acid (3.5 mL) at 0 °C over
0.25 h. The mixture was poured in water and extracted with
ethyl acetate (3 × 50 mL). The organic layer was washed with
water and brine and was dried. Evaporation of the solvent in
vacuo gave crude products, which were purified by column
chromatography to afford the final methyl ethers in pure form.
Met h od B. Compound 5(a ,f) or 19(a ,c) (10.2 mmol) was
added to a cooled suspension of NaH (270 mg, 11.25 mmol of
a 60% dispersion in oil) in THF (30 mL) at 0 °C under argon.
The reaction mixture was stirred at room temperature for 30
min, and MeI (4.34 g, 1.90 mL 30.6 mmol) was then added in
one portion. After 2 h the reaction was quenched by addition
of saturated aqueous NH4Cl (10 mL), and CH2Cl2 (100 mL)
was added. The organic layer was washed with water and
brine and dried with MgSO4. The solvent was removed in
vacuo to give crude materials that were chromatographed to
obtain pure products.
°C) of 5b, 5c, 5f) or 19b, 19c (2.16 mmol) in DMF (15 mL)
followed immediately with dropwise addition of benzyl bromide
(0.59 mL, 4.97 mmol), respectively. The reaction mixture was
stirred for 2 h when TLC (CH2Cl2:acetone ) 97:3) showed a
major fast moving product. The solution was poured into ice-
cold water. The product was extracted with CH2Cl2 (3 × 40
mL), and the combined organic layers were washed with water
and brine and were dried with Na2SO4 and concentrated. The
resulting syrup was purified by passage through a column of
silica gel affording pure product.
(6S,7R)-7-(Ben zyloxy)-6-m eth yl-2-p h en yl-5-(p h en ylsu l-
fon yl)-4,5,6,7-tetr a h yd r o[1,3]oxa zolo[4,5-c]p yr id in e (6b).
The product 6b (865 mg, 87% yield) had the following data:
Rf ) 0.48 (CH2Cl2:acetone ) 99:1); yellow oil; [R]20 ) +26.0
D
1
(c 1.15 CHCl3); H NMR (δ/ppm, J /Hz, CDCl3): 0.90 (d, J )
6.34 Hz, 3H), 3.9, 3.97 (d, J ) 15.74 Hz, 2H,), 4.55 (m, 1H),
4.60 (m, 1H), 4.65, 4.74 (d, J ) 6.16 Hz, 2H), 7.21 (m, 2H),
7.23 (m, 2H), 7.41 (m, 1H), 7.29 (m, 2H), 7.31 (m, 1), 7.35 (m,
1H), 7.67 (m, 2H), 7.84 (m, 2H), 7.86 (m, 1H); 13C NMR (δ/
ppm, CDCl3): 10.6, 39.5, 50.9, 70.7, 72.5, 126.3, 126.9, 127.1,
127.8, 128.1, 128.6, 128.8, 129.3, 130.6, 132.9, 133.2, 137.3,
139.9, 144.6, 162.3. Anal. Calcd for C26H24N2O4S: C 67.80, H
5.26, N 6.09, S 6.95. Found: C 67.62, H 5.20, N 6.21, S 7.11.
(6S,7R)-7-(Ben zyloxy)-6-({[ter t-b u t yl(d im et h yl)silyl]-
o x y }m e t h y l)-2-p h e n y l-5-(p h e n y ls u lfo n y l)-4,5,6,7-
tetr a h yd r o[1,3]oxa zolo[4,5-c]p yr id in e (6c). The product 6c
(1.21 g, 95% yield) had the following data: Rf ) 0.46 (pentane:
(6S,7R)-7-Meth oxy-6-m eth yl-2-p h en yl-5-(p h en ylsu lfo-
n yl)-4,5,6,7-t et r a h yd r o[1,3]oxa zolo[4,5-c]p yr id in e (6a )
(Meth od B). The product 6a (3.81 g, 97% yield) had the
following data: Rf ) 0.45 (CH2Cl2:acetone ) 98:2); yellow oil;
[R]20D ) -12.1 (c 1 EtOH); 1H NMR (δ/ppm, J /Hz, CDCl3): 0.79
(d, J ) 6.83 Hz, 3H), 3.44 (s, 3H), 3.87 (m, 1H), 4.58(m, 1H),
4.10, 4.63 (d, J ) 13.33 Hz, 2H), 7.27 (m, 2H), 7.35 (m, 2H),
7.41 (m,1H), 7.72 (m, 2H), 7.82 (m, 2H), 7.86 (m,1H); 13C NMR
(δ/ppm, CDCl3): 10.3, 39.9, 50.8, 58.4, 73.5, 126.6, 127.3,
127.4: 133.2, 133.3, 140.1, 144.9, 162.3. Anal. Calcd for
CH2Cl2:EtOAc ) 10: 3 0.5:1.5); yellow oil; [R]20 ) +2.0 (c 1.
D
CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): -0.41, 0.00 (s, 6H),
0.83 (s, 9H), 3.8, 4.2 (d, J ) 8.42 Hz, 2H), 4.7, 4.85 (d, J )
11.86 Hz, 2H), 4.7 (m, 1), 4.8 (m,1H), 7.4 (m, 2H), 7.44 (m,
2H), 7.47 (m, 1H), 7.48 (m, 2H), 7.51 (m,1H), 7.84 (m, 2H),
7.87 (m, 1H), 8.01 (m, 2H), 8.02 (m, 2H); 13C NMR (δ/ppm,
CDCl3): -5.6, -5.5, 18.2, 25.8, 40.6, 56.5, 59.1, 69.7, 73.1,
126.3, 127.1, 127.9, 128.6, 129.0, 130.6, 132.6, 134.0: 137.3,
140.6, 144.7, 161.6; MS, m/z (%): C32H38N2O5SSi, 533.2 (M -
57, 1.4), 277.1 (6), 105 (11), 77 (22), 57 (10), 45 (14).
C
20H20N2O4S: C 62.48, H 5.25, N 7.29, S 8.32. Found: C 62.33,
H 5.18, N 7.22, S 8.45.
(8aS,9S)-9-(Ben zyloxy)-2-ph en yl-4,6,7,8,8a,9-h exah ydr o-
[1,3]oxa zolo[4,5-f]in d olizin e (epi-6g). The product 6g (688
mg, 92% yield) had the following data: Rf ) 0.49 (CHCl3:
MeOH ) 95:5); pale yellow wax; sweet smell; mp 37 °C (with
decomposition), [R]20D ) -22.7 (c 1.3, CHCl3); 1H NMR (δ/ppm,
J /Hz, CDCl3): 1.74 (m, 2H,), 1.96 (m, 1H), 2.42, 2.74 (q, J )
8.86 Hz, 2H), 3.24 (q, J ) 6.53 Hz, 1H), 3.42, 3.9 (d, J ) 15.58
Hz, 2H,), 3.99 (d, J ) 13.98 Hz, 1H), 4.89, 5.10 (d, J ) 11.70
Hz, 2H), 7.36 (m, 2H), 7.42 (m, 2H), 7.47 (m, 1H), 7.52 (m,
1H), 8.13 (m, 2H); 13C NMR (δ/ppm, CDCl3): 22.7, 29.4, 49.5,
53.6, 66.5, 72.1, 126.2, 127.6, 127.7, 127.7, 130.2, 137.6, 138.1,
147.1, 161.5; MS, m/z (%): 346.2 (M, 49%), 277.1 (16), 255.1
(8a S,9S)-9-Met h oxy-2-p h en yl-4,6,7,8,8a ,9-h exa h yd r o-
[1,3]oxa zolo[4,5-f]in d olizin e (ep i-6f) (Met h od B). The
product epi-6f (2.09 g, 76% yield) had the following data: Rf
) 0.43 (CHCl3:MeOH ) 95:5); pale yellow wax; [R]20D ) +20.0
1
(c 1.2, CHCl3); H NMR (δ/ppm, J /Hz, CDCl3): 1.89 (m, 2H),
1.98 (m, 1H), 2.48 (m, 2H), 3.26 (q, J ) 6.68 Hz, 1H, CHN),
3.35, 4.3 (d, J ) 14.02 Hz, 2H), 3.74 (s, 3H), 4.39 (d, 1H, J )
6.25 Hz), 7.48 (m, 2H), 8.07 (m, 1H), 8.11 (m, 2H); 13C NMR
(δ/ppm, CDCl3), 22.6, 29.1, 49.3 (CH2N), 53.5, 66.3, 76.7, 126.2,
127.5, 128.6, 130.1, 137.5, 146.9, 161.5; HRMS Calcd for
C
16H18N2O2: 270.1369. Found. 270.1372.
(6S,7R)-7-Meth oxy-6-m eth yl-2-p h en yl-5-(p h en ylsu lfo-
(100), 186 (40), 91.1 (100), 77 (20); HRMS Calcd for C22
22N2O2: 346.1682. Found: 346.1685.
(6S,7R)-7-(Ben zyloxy)-6-m eth yl-2-p h en yl-5-(p h en ylsu l-
-
n yl)-4,5,6,7-tetr a h yd r o[1,3]th ia zolo[4,5-c]p yr id in e (20a )
(Meth od A). The product 20a (571 mg, 84% yield) had the
following data: Rf ) 0.38 (CH2Cl2:acetone ) 95:5); yellow oil;
[R]20D ) -5.5 (c 1 CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): 0.71
(d, J ) 6.79 Hz, 3H), 3.4 (s, 3H), 4.0-4.8 (dd, 2H), 4.48 (m,
1H), 4.67 (m, 1H), 4.63(m, 2H, 7.27 (m, 2H), 7.35 (m, 2H), 7.29
(m, 2H), 7.42 (m, 2H), 7.44 (m,1H), 7.74 (m,1H), 7.77 (m, 2H),
7.94 (m, 2H); 13C NMR (δ/ppm, CDCl3): 9.3, 42.4, 49.6, 57.7,
76, 126.6, 126.7, 127.4, 129.3, 129.7, 130.3: 130.6, 133.4, 140.1,
147.0, 168.7. Anal. Calcd for C20H20N2O3S2: C 59.99, H 5.04,
N 7.00, S 15.98. Found: C 59.72, H 5.09, N 7.12, S 15.82.
(6S,7R)-7-Meth oxy-6-m eth yl-2-(4-m or p h olin o)-5-(p h en -
ylsu lfon yl)-4,5,6,7-t e t r a h yd r o[1,3]t h ia zolo[4,5-c]p yr i-
d in e (20c) (Meth od B). The product 20c (4.17 g, 100% yield)
had the following data; Rf ) 0.35 (CH2Cl2:acetone ) 95:5); pale
yellow oil; [R]20D ) -13.7 (c 1.3, CHCl3); 1H NMR (δ/ppm, J /Hz,
CDCl3): 0.73 (d, J ) 6.76 Hz, 3H), 3.31 (t, J ) 3.75 Hz, 4H),
3.34 (s, 3H), 3.64 (t, J ) 4.92 Hz, 4H), 3.8, 4.5 (d, J ) 15.88
Hz, 2H), 4.48 (m, 1H), 4.6 (m, 1H), 7.45 (m, 2H), 7.74 (m, 2H),
7.77 (m, 1H); 13C NMR (δ/ppm, CDCl3): 8.8, 41.8, 48.3, 49.3,
56.9, 75.2, 117.2, 127.1, 129.2, 132.8, 142.3, 171; HRMS Calcd
for C18H23N3O4S2: 409.1132. Found: 409.1136.
H
fon yl)-4,5,6,7-tetr ah ydr o[1,3]th iazolo[4,5-c]pyr idin e (20b).
The product 20b (864 mg, 84% yield) had the following data:
Rf ) 0.39 (CH2Cl2:acetone ) 97:3); yellow oil; 1H NMR (δ/ppm,
J /Hz, CDCl3): 0.82 (d, J ) 6.52 Hz, 3H), 4.0, 4.84 (d, J ) 14.79
Hz, 2H), 4.55 (m, 2H), 4.62 (m, 1H), 4.67 (m, 1H), 7.29 (m,
2H), 7.37 (m, 2H), 7.39 (m, 2H), 7.43 (m, 1H), 7.46 (m, 1H),
7.74 (m, 1H), 7.75 (m, 2H), 7.77 (m, 1H); 13C NMR (δ/ppm,
CDCl3): 9.5, 42.0, 49.6, 71.6, 73.1, 126.3, 126.4, 127.0, 127.8,
128.2, 128.7, 128.8, 129.3, 129.8, 130.2, 132.9, 132.9, 133.4,
137.2, 139.7, 146.8, 168.2; MS, m/z (%): 476 (M, 1), 386.05
(1), 293 (3), 91 (100), 77 (31), 65 (15), 43 (8). Anal. Calcd for
C
26H24N2O3S2: C 65.53, H 5.08, N 5.88, S 13.43. Found: C
65.36, H 5.01, N 5.70, S 13.69.
(6S,7R)-7-(Benzyloxy)-6-methyl-2-(4-morpholino)-5-(phen-
ylsu lfon yl)-4,5,6,7-tetr a h yd r o[1,3]th ia zolo[4,5-c]p yr id in e
(20d ). The product 20d (849 mg, 81% yield) had the following
data: Rf ) 0.58 (CH2Cl2:acetone ) 98:2); pale yellow wax; [R]20
D
1
) -4.35 (c 2.3, CHCl3); H NMR (δ/ppm, J /Hz, CDCl3): 0.95
(d, J ) 6.38 Hz, 3H), 3.43 (t, J ) 2.48 Hz, 4H), 3.78 (t, J ) 4.9
Hz, 4H), 3.93-4.59 (dd, 2H), 4.66 (m, 1H), 4.69 (s, 3H), 7.39
(1H), 7.40 (2H), 7.46 (m, 2H), 7.5 (m, 2H), 7.58 (m, 1H), 7.8
(m, 1H); 13C NMR (δ/ppm, CDCl3): 9.5 (CH3), 41.8, 48.3, 49.6,
66.1, 71.2, 72.8, 117.4, 127.0, 128.0, 128.6, 129.2, 132.8, 137.4,
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
6b, 6c, 6g a n d 20b, 20d . Sodium hydride (9.29 mmol of a 60%
dispersion in oil) was added portionally to a cooled solution (0

Synthesis of Iminoglycitols from Amino Acids
J . Org. Chem., Vol. 67, No. 10, 2002 3191
139.8, 142.4, 171.5; HMRS Calcd for C24H27N3O4S2: 485.1445.
Found: 485.1443.
to 0 °C, and methyl triflate (262 mg, 0.180 mL, 1.60 mmol)
was added in one portion. The solution was left to stir until
all starting material had been consumed. The reaction mixture
was then concentrated and the residue washed severally with
diethyl ether (3 × 15 mL). The crude products were further
used without prior purification.
Ben zyl (6S,7R)-7-Met h oxy-6-m et h yl-2-p h en yl-6,7-d i-
h yd r o[1,3]oxa zolo[4,5-c]p yr id in e-5(4H)-ca r boxyla te (7e).
To the N2-purged solution of 0.1 M SmI2 in THF (10 mL) was
added a solution of 6a (665 mg, 1.73 mmol in 5 mL of THF)
followed by DMPU (10 mL). The mixture was refluxed under
N2 for 5 h while the violet color completely faded. The solution
was then cooled and quenched with saturated aqueous NH4-
Cl (100 mL). Subsequently it was extracted with CH2Cl2 (2 ×
100 mL). The organic layer was washed with water (2 × 100
mL), 5% Na2S2O3 (2 × 100 mL), and brine (2 × 100 mL) and
dried with MgSO4, and finally the solvent was evaporated. To
a chilled solution of the crude product 430 mg, 1.70 mmol) and
dibenzyl dicarbonate (650 mg, 2.20 mmol) in THF (10 mL) was
added Et3N (350 mg, 40.0 mmol) dropwise. The reaction
mixture was stirred at ambient temperature for 24 h. The
resulting solution was concentrated in a vacuum to an oily
residue. The crude product was purified by column chroma-
tography on SiO2 (CH2Cl2:acetone ) 95:5) to afford 7 (433 mg,
(6S,7R)-7-Met h oxy-3,6-d im et h yl-2-p h en yl-5-(p h en yl-
su lfon yl)-4,5,6,7-tetr a h yd r o[1,3]oxa zolo[4,5-c]p yr id in e-3-
iu m Tr ifla te 8a (Meth od B). The product 8a (566 mg, 86%
yield) had the following data: Rf ) 0.28 (CHCl3:MeOH ) 9:1);
1
pale yellow oil; H NMR (δ/ppm, J /Hz, DMSO-d6): 0.76 (d, J
) 6.43 Hz, 3H), 3.54 (s, 3H), 4.00 (s, 3H), 4.16, 5.04 (d, J )
14.25 Hz, 2H), 4.74 (m, 1H), 4.79 (m, 1H), 7.67 (m, 2H), 7.74
(m, 2H), 7.83 (m,1H), 7.96 (m, 2Hr), 7.99 (m, 2H), 8.02 (m, 2H);
13C NMR (δ/ppm, DMSO-d6): 9.4, 35.5, 36.7, 50.3, 58.1, 71.9,
120.2, 127.3, 128.1), 130.2, 130.1, 130.2, 134.1, 135.3, 139.0
(Cq/ar), 146.6, 161.5.
(6S,7R)-7-(Ben zyloxy)-3,6-d im eth yl-2-p h en yl-5-(p h en -
ylsu lfon yl)-4,5,6,7-tetr a h yd r o[1,3]oxa zolo[4,5-c]p yr id in e-
3-iu m Tr ifla te 8b (Meth od B). The product 8b (570 mg, 76%
yield) had the following data: Rf ) 0.28 (CHCl3:MeOH ) 6:4);
(66.1% yield Rf ) 0.62) as a pale yellow oil: [R]20 ) -24.8 (c
D
1
1
1, CHCl3); H NMR (δ/ppm, J /Hz, CDCl3): 1.24 (d, J ) 6.63
pale yellow oil; H NMR (δ/ppm, J /Hz, DMSO-d6): 0.74 (d, J
Hz, 3H), 3.69 (s, 3H), 4.2,4.96 (d, J ) 16.63 Hz, 2H), 4.6, 5.2
(d, J ) 10.82 Hz, 2H), 5.2 (m, 1H), 5.26 (m, 1H), 7.4 (m, 2H),
7.43 (m, 4H), 7.48 (m, 2H), 8.1 (m, 2H); 13C NMR (δ/ppm,
CDCl3): 12.0 (CH3), 38.7, 49.0, 58.0 (OCH3), 67.7, 72.6, 126.3,
127.2 (CHar), 127.9, 128.4, 130.5, 132.2,), 137.1, 145.3, 155.3,
162.8. Anal. Calcd for C22H22N2O4: C 69.83, H 5.86, N 7.40.
Found: C 69.77, H 5.76, N 7.29.
) 6.28 Hz, 3H), 3.32 (m, 1H), 3.58 (m, 2H), 3.86 (s, 3H), 4.70
(m, 2H), 4.90 (m, 1H), 7.2-7.98 (15H).
(6S,7R)-7-(Ben zyloxy)-6-(h yd r oxym eth yl)-3-m eth yl-2-
ph en yl-5-(ph en ylsu lfon yl)-4,5,6,7-tetr ah ydr o[1,3]oxazolo-
[4,5-c]p yr id in e-3-iu m Met h yl Su lfa t e (8d ) (Met h od A).
The product 8d (313 mg, 52% yield) had the following data:
1
Rf ) 0.43 (CHCl3:MeOH ) 8:2); pale yellow oil; H NMR (δ/
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
12. To a solution of Ph3P (1.02 g, 2.90 mmol) in THF (10 mL)
was added DEAD (0.60 mL, 3.9 mmol) dropwise at 0 °C. After
5 min stirring, benzoic acid (480 mg, 3.90 mmol) or phthal-
imide (570 mg, 3.90 mmol) in THF (1 mL) and compound 5a
(362 mg, 1.0 mmol) in THF (2 mL) were successively added
dropwise. The reaction mixture was stirred for 15 h at 0 °C
for 12a or overnight at room temperature for 12b. If the
reaction was not complete (monitoring by TLC), 1 equiv or
more of each reagent was added. The reaction mixture was
then concentrated under vacuum. The residue dissolved in
EtOAc was filtered through a silica pad, concentrated under
vacuum, and the crude materials were chromatographed on
silica gel, affording pure products.
ppm, J /Hz, DMSO-d6): 2.99 (br, 1H), 3.39 (d, J ) 6.95 Hz,
2H), 3.44 (m, 2H), 3.69 (s, 3H), 3.74 (m, 1H), 3.99 (d, J ) 8.5
Hz,), 4.35, 4.40 (dd, 2H), 7.29-7.99 (15H); 13C NMR (δ/ppm,
DMSO-d6): 36.8, 56.1, 58.1, 61.3, 72.4, 119.9, 127.1, 128.1,
128.4 128.6, 129.3, 129.4, 12.9, 129.9, 133.3, 134.7, 137.1,
139.6, 146.3, 162.2.
(6S,7R)-7-(Ben zoyloxy)-3,6-d im eth yl-2-p h en yl-5-(p h en -
ylsu lfon yl)-4,5,6,7-tetr a h yd r o[1,3]oxa zolo[4,5-c]p yr id in e-
3-iu m Meth yl Su lfa te (13a ) (Meth od A). The product 13a
(427 mg, 71% yield) had the following data: Rf ) 0.24 (CHCl3:
MeOH ) 6:4); brown crystals; mp 105-106 °C (EtOH/ether),
1H NMR (δ/ppm, J /Hz, DMSO-d6): 0.81 (d, J ) 6.95 Hz, 3H),
3.19 (s, 3H), 3.80 (s, 3H), 4.11-5.0 (d, J ) 16.77 Hz, 2H), 3.80
(s, 3H), 4.53 (m, 1H), 5.80 (m, 1H), 7.10 (m, 2H), 7.30 (m, 2H),
7.42 (m, 1H), 7.48 (m, 1H), 7.50 (m, 2H), 7.60 (m, 2H), 7.71(m,
1H), 7.73 (m, 2H), 7.78 (m, 2H), 7.79 (m, 2H); 13C NMR (δ/
ppm, DMSO-d6): 13.1, 35.8, 37.0, 53.6, 66.4, 126.5, 127.0,
128.9, 129.5 (2xCHar), 129.7, 129.8, 120.2, 133.7, 134.1, 135.1,
139.4, 143.7, 162, 165.0.
(6S,7S)-6-Met h yl-2-p h en yl-5-(p h en ylsu lfon yl)-4,5,6,7-
tetr a h yd r o[1,3]oxa zolo[4,5-c]p yr id in -7-yl Ben zoa te (12a ).
The product 12a (455 mg, 98% yield) had the following data:
Rf ) 0.35 (pentane:EtOAc:CH2Cl2 ) 10:1.5:3.5); pale yellow
1
wax: mp 113-115 °C, [R]20 ) +77.5 (c 1, CHCl3); H NMR
D
(δ/ppm, J /Hz, CDCl3): 1.12 (d, J ) 7.0 Hz, 3H), 4.11, 4.73 (d,
J ) 16.19 Hz, 2H), 4.69 (q, J ) 7.15 Hz, 1H), 5.8 (d, J ) 3.48
Hz, 1H), 7.22 (2H), 7.25 (2H), 7.30 (1H), 7.34 (1H), 7.43 (2H),
7.47 (2H), 7.7 (1H) 7.8 (2H), 7.9 (2H);13C NMR (δ/ppm,
CDCl3): 14.4, 39.1, 53.4, 67.2, 126.2, 126.3, 126.5, 128.4, 128.7
(2 × CHar), 128.8, 130.6, 132.0, 133.2, 136.1, 140.0, 140.8,
162.8, 165.6. Anal. Calcd for C26H22N2O5S: C 68.62, H 5.12,
N 5.93, S 6.79. Found: C 68.59, H 5.09, N 5.88, S 6.68.
(6S,7S)-6-Meth yl-2-ph en yl-5-(ph en ylsu lfon yl)-7-ph th a l-
im id o-4,5,6,7-tetr a h yd r o[1,3]oxa zolo[4,5-c]p yr id in e (12b).
The product 12b (465 mg, 95% yield) had the following data:
(6S,7R)-7-Met h oxy-3,6-d im et h yl-2-p h en yl-5-(p h en yl-
su lfon yl)-4,5,6,7-tetr a h yd r o[1,3]th ia zolo[4,5-c]p yr id in e-
3-iu m Meth yl Su lfa te (21a ) (Meth od A). The product 21a
(458 mg, 87% yield) had the following data: Rf ) 0.26 (CHCl3:
MeOH ) 9:1); white crystals; mp 158-161 °C (EtOH), 1H NMR
(δ/ppm, J /Hz, DMSO-d6): 0.7 (d, J ) 6.61 Hz, 3H), 3.55 (s,
3H), 3.72 (s, 3H), 3.9 (s, 3H), 4.23, 5.00 (d, J ) 16.52 Hz, 2H,),
4.75 (m, 1H), 4.84 (m, 1H), 7.67 (m, 2H), 7.73 (m, 2H), 7.76
(m,1H), 7.97 (m,2H), 7.80 (m, 2H); 13C NMR (δ/ppm, DMSO-
d6): 8.7, 38.8 39.2, 49.7, 57.6, 73.8, 125.2, 127.5, 130.1, 130.2,
130.4, 132.8, 133.8, 134.2, 139.1, 140.8, 169.9. Anal. Calcd for
Rf ) 0.22 (CH2Cl2:acetone); pale yellow oil; [R]20 ) +7.344 (c
C22H26N2O7S3: C 50.18, H 4.98, N 5.32, S 18.23. Found: C
50.31, H 5.07, N 5.37, S 18.32.
D
1, CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): 1.28(d, J ) 6.06
Hz, 3H), 4.27, 4.98 (d, J ) 15.72 Hz, 2H), 4.56 (d, J ) 6.47 Hz,
1H), 5.09 (m, 1H), 7.25-8.0 (14H); 13C NMR (δ/ppm, CDCl3):
15.4, 39.7, 49.3, 123.4, 126.43, 126.7, 127.0, 128.8, 128.9, 130.7,
131.4, 132.4, 133.9, 135.9, 138.5, 139.8, 162.5, 167.1.
(6S,7R)-7-(Ben zyloxy)-3,6-d im eth yl-2-p h en yl-5-(p h en -
ylsu lfon yl)-4,5,6,7-tetr a h ydr o[1,3]th ia zolo[4,5-c]p yr id in e-
3-iu m Meth yl Su lfa te (21b) (Meth od A). The product 21b
(536 mg, 89% yield) had the following data: Rf ) 0.24 (CHCl3:
1
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
8, 13, a n d 21. Meth od A: A neat mixture of 6, 12, or 20 (1
mmol) and dimethyl sulfate (252 mg, 0.190 mL, 2.00 mmol)
or methyl tosylate (372 mg, 0.300 mL, 2.00 mmol) in the case
of 6a were heated at 100 °C for 3 h under argon atmosphere.
The resulting viscous oil was washed several times with
diethyl ether. NMR of the crude samples indicated the
expected products with >95% purity. Solids could be recrystal-
lized from ethanol and diethyl ether. Meth od B: A solution
of 6 or 20 (1.2 mmol) in anhydrous CH2Cl2 (5 mL) was cooled
MeOH ) 6:4); pale yellow oil; H NMR (δ/ppm, J /Hz, DMSO-
d6): 0.77 (d, J ) 6.34 Hz, 3H), 3.97 (s, 3H), 4.3, 5.0 (d, J )
15.67 Hz, 2H), 4.75, 4.89 (d, J ) 6.43 Hz, 2H), 4.82 (m, 1H),
7.36 (m, 2H), 7.40 (m, 2H), 7.54 (m, 1H), 7.67 (m, 2H), 7.68(m,
2H), 7.74 (m, 2H), 7.76 (m, 2H), 7.78 (m, 1H), 7.98 (m, 2H):
13C NMR (δ/ppm, DMSO-d6): 9.1, 38.7, 40.3, 49.2, 61.2, 71.5,
124.9, 127.1, 128.2, 128.6, 129.8, 129.9, 130.1, 132.7, 133.3,
133.7, 137.1, 140.6, 169.7;
(6S,7R)-7-Met h oxy-3,6-d im et h yl-2-(4-m or p h olin o)-5-
(p h en ylsu lfon yl)-4,5,6,7-t et r a h yd r o[1,3]t h ia zolo[4,5-c]-

3192 J . Org. Chem., Vol. 67, No. 10, 2002
Swaleh and Liebscher
p yr id in e-3-iu m Tr ifla te (21c) (Meth od B). The product 21c
(130 mg, 71% yield) had the following data: white crystals;
mp 34-36 °C (EtOH), [R]20D ) -13.7 (c 1.05, MeOH); 1H NMR
(δ/ppm, J /Hz, DMSO-d6): 1.00 (d, J ) 6.81 Hz, 3H), 3.70 (s,
3H), 3.80 (t, J ) 4.91,4H), 3.97 (s, 3H), 4.10 (t, J ) 4.81 Hz,
4H), 4.23, 5.00 (d, J ) 13.93 Hz, 2H), 4.65 (m,1H), 4.97 (m,
1H), 7.85 (m, 2H), 7.9 (m, 2H), 8.2 (m,1H); 13C NMR (δ/ppm,
DMSO-d6): 8.9, 37.8, 39.9, 50., 53.5 (CH2)2N), 57.9, 75.1, 122.7,
128.4, 130.9, 134.7, 135.9, 140.7, 175.2.
N-[(3S,5R,6S)-5-(Ben zyloxy)-6-(h yd r oxym eth yl)-4-oxo-
1-(p h en ylsu lfon yl)p ip er id in yl]-N-m eth ylben za m id e (9d )
(Meth od A). The product 9d (234 mg, 46% yield) had the
following data: Rf ) 0.25 (CH2Cl2:acetone ) 93:7); waxy
1
substance; H NMR (δ/ppm, J /Hz, CDCl3): 2.1 (br, 1H), 3.10
(s, 3H),), 3.60, 3.83 (d, J ) 14.43 Hz, 2H), 3.70(m, 1H), 4.0,
4.3 (d, J ) 12.30 Hz, 2H), 4.4 (m, 2H), 4.8 (m, 1H), 5.2 (t, J )
1H,), 7.2 (m, 2H), 7.26 (m, 2H), 7.28 (m, 1H), 7.3 (m, 1H), 7.34
(m, 1H), 7.37 (m, 2H), 7.38 (m, 1H), 7.68 (m, 2H), 7.70 (m,
2H); 13C NMR (δ/ppm, CDCl3): 44.3, 57.4, 58.0, 59.1, 72.2, 72.8,
76.8, 126.2, 126.7, 127.1, 127.7, 128.6, 128.69, 129.4, 126.6,
129.9, 133.2, 135.4, 137.1, 139.9, 172.8, 199.6; HMRS Calcd
for C27H28N2O6S: 508.1669. Found: 508.1672.
(6S,7R)-7-(Ben zyloxy)-3,6-d im eth yl-2-(4-m or p h olin o)-
5-(p h en ylsu lfon yl)-4,5,6,7-tetr a h yd r o[1,3]th ia zolo[4,5-c]-
p yr id in e-3-iu m Tr ifla te (21d ) (Meth od B). The product 21d
(538 mg, 69% yield) had the following data: Rf ) 0.29 (CHCl3:
1
MeOH ) 6:4); pale yellow oil; H NMR (δ/ppm, J /Hz, DMSO-
Ben zyl (2S,3R,5S)-5-[Ben zoyl(m eth yl)a m in o]-3-m eth -
oxy-2-m eth yl-4-oxo-1-piper idin ecar boxylate (9e) (Meth od
B). The product 9e (304 mg, 74% yield) had the following
d6): 1.02 (d, J ) 6.74 Hz, 3H,), 3.7 (t, J ) 7.08 Hz, 4H), 3.9 (s,
3H), 4.0 (t, J ) 4.9 Hz, 4H), 4.3, 5.11 (d, J ) 16.47 Hz, 2H),
4.6 (m, 1H), 4.8 (m,1H), 4.99 (m, 1H), 7.54 (m, 2H), 7.76 (m,
1H), 7.79 (m, 1H), 7.81 (m, 2HH), 8.0 (m, 2H), 8.12 (m, 2H);
13C NMR (δ/ppm, DMSO-d6): 9.8 (CH3), 35.6, 38.1, 48.5, 53.5,
66.5, 72.1, 73.0, 119.8, 128.3, 135.0,136.0, 138.0, 140.6, 174.7.
(8a S,9R)-5-Ben zyl-9-(ben zyloxy)-2-p h en yl-4,6,7,8,8a ,9-
h exah ydr o[1,3]oxazolo[4,5-f] in dolizin e-5-iu m Iodide (epi-
11). A mixture of compound 6g (550 mg, 1.61 mmol) and benzyl
iodide (390 mg, 1.77 mmol) in ethanol was stirred at ambient
temperature for 24 h. The resulting reaction mixture was then
concentrated under reduced pressure. The crude product was
recrystallized from absolute ethanol to afford epi-11 (870 mg,
97% yield, Rf ) 0.25 (CHCl3:MeOH ) 9:1) as needlelike
crystals: cis:trans ) 56:44, mp 103-105 °C, 1H NMR (δ/ppm,
J /Hz, DMSO-d6): 2.44 (m, 2H), 2.53 (m, 2H,), 3.28(m, 2H), 3.3,
3.40 (d, J ) 14.0 Hz, 2H), 4.25-4.37 (dd, 2H), 4.45 (m, 1H),
4.85-4.99 (dd, 2H), 5.23 (d, 1H, J ) 6.09 Hz), 7.24-8.04 (15H);
13C NMR (δ/ppm, DMSO-d6): 19.8, 22.9, 49.1, 54.1, 59.3, 69.5,
72.5, 74.4, 126.3, 126.4, 127.3, 128.6, 128.2, 128.5, 128.6, 129.2,
129.4, 130.7, 131.6, 137.6, 141.5, 145.3, 163.2.
data: Rf ) 0.42 (CHCl3:MeOH ) 99:1); waxy substance; [R]20
D
1
) +28.1 (c 1, CHCl3); H NMR (δ/ppm, J /Hz, CDCl3) 1.21 (d,
J ) 6.78 Hz, 3H),), 3.18 (s, 3H), 3.32 (s, 3H), 3.5 (m, 1H), 3.7
(m, 1H), 3.8, 4.10 (d, J ) 18.64 Hz, 2H), 4.1 (m, 1H), 5.2 (m,
2H), 7.29 (m, 1H,), 7.32 (m, 1H), 7.40 (m, 2H), 7.44 (m, 2H),
7.47 (m, 1H), 7.50 (m, 2H), 7.60(m, 1H); 13C NMR (δ/ppm,
CDCl3): 12.6, 35.4, 40.5, 46.3, 57.0, 67.5, 73.1, 126.5, 126.7,
127.6, 128.5, 128.6, 129.9, 136.1, 147.5, 155.1, 172.6, 201.7;
Calcd for C23H26N2O5: 410.1843. Found: 410.1840.
N-[(3S,5S,6S)-5-Hyd r oxy-6-m eth yl-4-oxo-1-(p h en ylsu l-
fon yl)p ip er id in yl]-N-m eth ylben za m id e (14a ) (Meth od
B). The product 14a (197 mg, 49% yield) had the following
data: Rf ) 0.32 (CHCl3:MeOH ) 9:1); white wax; 1H NMR
(δ/ppm, J /Hz, CDCl3), 1.22 (d, J ) 6.33 Hz, 3H), 2.97 (s, 3H),
3.66 (m, 1H), 3.85, 3.99 (d, J ) 7.83 Hz, 2H), 4.28 (m, 1H),
5.20 (m, 1H), 7.19-7.98 (10H); 13C NMR (δ/ppm, CDCl3): 14.3,
38.2, 41.4, 53.9, 76.7, 85.5, 126.2, 127.2, 128.4, 129.4, 132.8,
133.6, 135.2, 140.3, 172.3, 194.1; HRMS Calcd for C20H22
N2O5S: 402.1251. Found: 402.1253.
-
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
9, 14, a n d 23: Meth od A. To an aqueous solution of 8 or 21
(1.0 mmol) was added a 1 M solution of potassium hydroxide
until the mixture was slightly alkaline to test paper (pH 9-11).
The solution was extracted with CH2Cl2 (3 × 20 mL) and the
organic layer dried. The crude material was chromatographed
on silica gel, affording pure product.
Meth od B. To a solution of 7 or the quaternary salts 8 or
13 (1.0 mmol) in CH2Cl2 was added a 1 M solution of potassium
hydroxide until the pH of the organic phase was alkaline to
test paper. The organic layer was separated and extracted with
water and dried (Na2SO4). The solvent was evaporated and
the residue chromatographed on silica column.
N-[(5S,6R)-4-{[(2S,3R)-5-[Benzoyl(methyl)amino]-3-meth-
oxy-2-m eth yl-1-(ph en ylsu lfon yl)-1,2,3,6-tetr ah ydr o-4-pyr -
idin yl]disu lfan yl}-5-m eth oxy-6-m eth yl-1-(ph en ylsu lfon yl)-
1,2,5,6-tetr a h ydr o-3-p yr idin yl]-N-m eth ylben za m id e (23a )
(Meth od A). The product 23a (486 mg, 56% yield) had the
following data: Rf ) 0.42 (hexane:EtOAc:CH2Cl2 ) 7:3:5); pale
yellow wax; 1H NMR ((δ/ppm, J /Hz, CHCl3): 0.782 (d, J ) 6.69
Hz, 3H,), 3.03 (s, 3H), 3.27 (s, 3H), 3.44, 3.7 (d, J ) 13.1 Hz,
2H), 3.61 (d, J ) 2.34 Hz, 1H), 4.20 (m, 1H), 7.1-7.80 (m, 10H);
13C NMR (δ/ppm, CHCl3): 9.8, 30.1, 43.5, 50.2, 58.9, 78.6,
127.4-134.1, 132.3, 136.1, 172.2.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
10 a n d 15. A solution of 9 or 14 (1 mmol) in MeOH (5 mL)
was cooled to 0 °C and treated with NaBH4 (0.08 g, 2.2 mmol).
After stirring at room temperature for 3 h, the solvent was
evaporated and the residue was partitioned between CH2Cl2
(10 mL) and saturated aqueous NaHCO3 (10 mL). The organic
layer was dried and the solvent evaporated under reduced
pressure. The crude materials was chromatographed on silica
column affording pure product.
N-[(3S,5R,6S)-5-Meth oxy-6-m eth yl-4-oxo-1-(p h en ylsu l-
fon yl)p ip er id in yl]-N-m eth ylben za m id e (9a ) (Meth od B).
The product 9a (254 mg, 63% yield) had the following data:
Rf ) 0.35 (CH2Cl2:acetone ) 95:5); colorless crystals; mp 225-
227 °C, [R]20 ) +54.1 (c 1, MeOH); 1H NMR (δ/ppm, J /Hz,
D
CDCl3): 0.94 (d, J ) 6.82 Hz, 3H), 2.86 (s,3H), 3.39 (s, 3H),
3.62 (t, J ) 11.85 Hz,1H), 3.85 (m, 1H), 4.24 (m, 1H), 4.57,
4.83 (d, J ) 6.95 Hz, 2H), 7.24 (2H), 7.34 (2H), 7.36 (1H), 7.50
(2H), 7.58 (2H), 7.85 (1H); 13CNMR (δ/ppm CDCl3): 12.1, 37.2,
41.7, 53.7, 59.2, 61.5, 127.3, 127.6, 128.9, 130.0, 130.5, 133.7,
133.7, 135.7, 140.2, 175, 200.9; MS, m/z (%): 416.1 (M, 0.32),
275 (2), 222 (4), 175 (13), 112 (27), 105 (100), 77 (63), 56 (139),
42 (17). Anal. Calcd for C20H24N2O5S: C, 60.56, H, 5.81, N,
6.73, S, 7.68. Found: C, 60.50, H, 5.94, N, 6.91, S, 7.59.
N-[(3S,5R,6S)-5-(Ben zyloxy)-6-m eth yl-4-oxo-1-(p h en yl-
su lfon yl)p ip er id in yl]-N-m eth ylben za m id e (9b) (Meth od
B). The product 9b (256 mg, 52% yield) had the following
data: Rf) 0.3 (CH2Cl2:acetone ) 95:5); waxy substance; 1H
NMR (δ/ppm, J /Hz, CDCl3): 1.03 (d, J ) 6.83 Hz, 3H), 2.80
(s, 3H), 3.05 (m, 2H), 4.2 (m, 1H), 4.3 (t, J ) 12.0 Hz, 1H), 4.4,
4.7 (d, J ) 6.07 Hz, 2H), 4.53 (m, 1H), 7.43 (m, 2H), 7.17 (m,
2H), 7.25(m, 1H), 7.26 (m, 1H), 7.33 (m, 2H), 7.36 (m, 2H),
7.41 (m, 2H), 7.43 (m, 2H), 7.47 (m, 2H), 7.72 (m, 1H); 13C NMR
(δ/ppm, CDCl3): 12.3, 36.6, 41.3, 53.9, 60.7, 72.3, 80.9, 126.8,
127.2, 127.8, 128.0, 128.5, 128.6, 129.6, 130.1, 135.2, 137.5,
140.1, 167.5, 200.8; HMRS Calcd for C27H28N2O5S: 492.1720.
Found: 492.1723.
N -[(3S ,4S ,5R ,6S )-4-H yd r oxy-5-m e t h oxy-6-m e t h yl-1-
(p h en ylsu lfon yl)p ip er id in yl]-N-m eth ylben za m id e (10a ).
The product 10a (314 mg, 75% yield) had the following data:
Rf ) 0.36 (CH2Cl2:acetone ) 94:6); colorless crystals; mp 142-
143 °C (EtOAc:hexane ) 2:1), [R]20 ) -14.1 (c 1, MeOH); 1H
D
NMR (δ/ppm, J /Hz, CD3COCD3): 1.18 (d, J ) 7.02 Hz, 3H),),
2.89 (s, 3H), 3.10 (s, 3H), 3.32 (m, 1H), 3.69 (t, J ) 12.26 Hz,
1H), 3.83 (m,1H), 3.88, 4.37, (d, J ) 4.96 Hz, 2H), 4.30 (m,
1H), 7.43 (m, 2H), 7.45 (m, 2H), 7.64 (m, 1H), 7.66 (m, 2H),
7.73 (m, 1H), 7.88 (m, 2H); 13C NMR (δ/ppm, CD3OD): 13.6,
36, 38 1, 52.3, 54.1, 57.2, 72.1, 79.7, 128., 130.1, 131, 131.3,
134.4, 138.1, 144.3, 175.2; MS, m/z (%), 419.1 (M, 1.2), 277
(7), 142 (12), 104 (100), 76.9 (77), 71 (15), 55 (11), 41 (11). Anal.
Calcd for C21H26N2O5S: C 60.27, H 6.26, N 6.57, S 7.65.
Found: C 60.07, H 6.21, N 6.69, S 7.63.
N-[(3S,4S,5R,6S)-5-(Ben zyloxy)-4-h yd r oxy-6-m eth yl-1-
(p h en ylsu lfon yl)p ip er id in yl]-N-m eth ylben za m id e (10b).
The product 10b (314 mg, 70% yield) had the following data:
Rf ) 0.33 (CH2Cl2:acetone ) 94:6); white crystals: mp 44-45
°C, [R]20 ) -3.1 (c 1, CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3):
D

Synthesis of Iminoglycitols from Amino Acids
J . Org. Chem., Vol. 67, No. 10, 2002 3193
0.78 (d, J ) 6.87 Hz, 3H), 2.05 (br, 1H), 2.96 (s, 3H), 3.56 (d,
J ) 11.50 Hz, 2H), 3.7 (m, 1H), m, 2H), 4.31 (m, 1H), 4.4 (m,
1H), 7.18 (m, 2H), 7.25 (m, 1H), 7.27 (m, 1H), 7.29 (m, 2H7.35
(m, 2H), 7.41 (m, 2H), 7.44(m, 2H), 7.46 (m, 2H), 7.68 (m, 1H);
13C NMR (δ/ppm, CDCl3): 12.97, 35.1, 36.7, 50.2, 52.5, 70.3,
71.2, 75.1, 126.7, 126.9, 127.7, 128.1, 128.5, 128.6, 129.3, 129.6,
132.2, 136.2, 137.2, 144.0, 172.0; MS, m/z (%): 494 (M, 2%),
493 (M - 1, 8%), 437 (205), 403 (52), 353 (30), 218 (50), 91
(100), 56.0 (15). Anal. Calcd for C27H30N2O5S: C 65.56, H 6.12,
N 5.67, S 6.47. Found: C 65.41, H 6.18, N 5.59, S 6.56.
N-[(3S,4S,5R,6S)-5-(Ben zyloxy)-4-h yd r oxy-6-(h yd r oxy-
m et h yl)-1-(p h en ylsu lfon yl)p ip er id in yl]-N-m et h ylb en z-
a m id e (10d ). The product 10d (206 mg, 51% yield) had the
following data: Rf ) 0.52 (CH2Cl2:acetone ) 2:1); wax sub-
15.10 Hz), 3.48 (m, 1H), 4.23 (m, 1H), 4.43 (s, 1H), 7.23 (2H),
7.32 (2H), 7.47, 7.51 (2H), 7.77 (2H), 7.84; 13C NMR (δ/ppm,
CD3COCD3): 8.9, 37.2, 38.9, 46.6, 48.9, 57.9, 67.7, 73.9, 82.6,
126.9, 127.2, 127.5, 128.4, 129.2, 132.5, 140.4, 140.6; MS, m/z
(%): 418 (M, 1), 277 (25), 220 (10), 217 (20), 149.0 (10),
126.0 (20), 77 (100), 69 (32), 42.0 (58); HRMS Calcd for
C
21H26N2O3S2: 418.1351. Found: 418.1350.
(3a S,6S,7R,7a S)-7-(Ben zyloxy)-3,6-d im eth yl-2-p h en yl-
5-(p h e n ylsu lfon yl)oct a h yd r o[1,3]t h ia zolo[4,5-c]p yr i-
d in e (24b). The product 24b (138 mg, 56% yield) had the
following data: Rf ) 0.36 (hexane: EtOAc: CH2Cl2 ) 10:1.5:
3.5); pale yellow oil; [R]20 ) -15.16 (c 1, CHCl3): 1H NMR
D
(δ/ppm, J /Hz CDCl3): 1.07 (d, J ) 6.95 Hz, 3H), 2.02 (s, 3H),
2.65 (m, 1H)), 3.22, 4.09, (d, J ) 15.53 Hz, 2H), 3.24 (m, 1H),
3.68 (m, 1H), 4.13 (m, 2H), 4.34, 4.48 (d, J ) 11.91 Hz, 2H),
4.39 (s, 1H), 7.08 (1H), 7.15 (2H), 7.20 (2Hr), 7.25 (2H), 7.31
(2H), 7.36 (1H), 7.44 (2Hr), 7.49 (2Hr), 7.7 (1H); 13C NMR (δ/
ppm, CDCl3): 9.5, 37.2, 38.7, 46.8, 48.2, 67.8, 71.9, 73.9, 79.5,
127.1, 127.3, 127.8, 128.2, 128.3, 128.7, 128.9, 129.1, 132.3,
137.1, 137.5, 140.4, 140.6; MS, m/z (%), C27H30N2O3S2, 494.2
(M, 0.32), 353.1 (1.02), 245 (10.83), 148 (179, 90 (100), 76.9
(61.83), 57 (30.8), 42 (23.95); HRMS calcd for C27H30N2O3S2:
494.1700. Found: 494.1704.
stance; [R]20 ) +2.3 (c 2, CHCl3); 1H NMR (δ/ppm, J /Hz,
D
CDCl3) 3.0 (s, 3H), 3.2 (br, 1H), 3.5 (m, 2H), 3.8 (m, 1H), 3.9
(m, 1H), 4.01 (m, 1H), 4.06 (d, J ) 17.16 Hz, 2H), 4.22 (m,
1H), 4.40, 4.49 (d, J ) 11.52 Hz, 2H), 7.26(m, 2H), 7.28 (m,
2H), 7.29 (m, 1H), 7.33 (m, 2H), 7.37 (m, 2H), 7.39 (m, 1H),
7.44 (m, 2H), 7.50 (m, 1H), 7.72 (m, 2H); 13C NMR (δ/ppm,
CDCl3): 38.3, 52.1, 55.3, 59.8, 69.3, 71.2, 75.4, 77.2, 126.8,
127.8, 128.2, 128.5, 129.4, 129.7, 130.1, 133.2, 136.1, 137.2,
140.2, 172.4; HRMS Calcd for
Found: 404.1408.
C20H24N2O5S: 404.1407.
3a S ,6S ,7R ,7a S )-7-Me t h oxy-3,6-d im e t h yl-5-(p h e n yl-
su lfon yl)octa h yd r o[1,3]th ia zolo[4,5-c]p yr id in e (24c). The
product 24c (75.3 mg, 44% yield) had the following data: Rf
Ben zyl (2S,3R,4S,5S)-5-[Ben zoyl(m eth yl)a m in o]-4-h y-
dr oxy-3-m eth oxy-2-m eth yl-1-piper idin ecar boxylate (10e).
The product 10e (214 mg, 54% yield) had the following data:
) 0.43 (pentane:EtOAc:CH2Cl2 ) 7:3:5); light yellow oil; [R]20
D
Rf ) 0.35 (CHCl3:MeOH ) 90:10); light yellow oil; [R]20
)
) -49.67 (c 1.2, CHCl3); H NMR (δ/ppm, J /Hz CDCl3): 0.86
1
D
+30.0 (c 1, CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3): 0.78 (d, J
) 6.83 Hz, 3H), 1.17 (br, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.3
(m, 1H), 3.62 (m, 2H), 3.9(m 1H), 4.07 (m, 1H), 4.5(m, 1H),
5.03(m, 2H), 7.0 (m, 1H), 7.03 (m, 2H), 7.10 (m, 2H), 7.20 (m,
1H), 7.26 (m, 2H), 7.35 (m, 1H), 7.4 (m, 1H); 13C NMR (δ/ppm,
CDCl3): 11.2, 35.3, 40.5, 46.3, 57.2, 57.6, 67.2, 67.5, 73.1, 126.9,
127.8, 128.0, 128.6, 129.7, 129.9, 136.2, 147.5, 155.3, 171.9;
HRMS Calcd for C23H28N2O5: 412.1999. Found: 412.1998.
N-[(3S,4R,5S,6S)-4,5-Dih yd r oxy-6-m eth yl-1-(p h en ylsu l-
fon yl)p ip er id in yl]-N-m eth ylben za m id e (15). The product
15a (250 mg, 62% yield) had the following data: Rf ) 0.32
(CHCl3:MeOH ) 9:1); colorless wax; mp 74-75 °C (EtOH),
(d, J ) 6.96 Hz, 3H), 2.31 (s, 3H), 2.5 (m, 1H), 3.08, 3.88 (d, J
) 6.83 Hz, 2H), 3.28 (s, 3H), 3.32 (m, 1H), 3.40, 4.00 (d, J )
6.83 Hz, 2H), 4.23 (m, 1H), 7.43 (m, 2H), 7.46 (m, 2H), 7.49
(m, 1H), 7.79 (m, 2H), 7.81 (m, 2H,); 13C NMR (δ/ppm,
CDCl3): 8.9, 38.8, 39.6, 47.5, 49.7, 57.6, 57.8, 82.0, 126.6, 127.2
(2XCHar), 132.6, 140.2; MS, m/z (%): 342.1 (M, 0.5), 285 (5),
201 (90), 169 (100), 141 (30), 77 (40), 42 (25); HRMS cacld for
C
15H22N2O3S2: 342.1074. Found: 342.1076.
(3a S,6S,7R,7a S)-7-(Ben zyloxy)-3,6-d im eth yl-5-(p h en yl-
su lfon yl)octa h yd r o[1,3]th ia zolo[4,5-c]p yr id in e (24d ). The
product 24d (87.4 mg, 42% yield) had the following data: Rf
) 0.35 (pentane:EtOAc:CH2Cl2 ) 7:3:5); pale yellow oil; [R]20
D
[R]20 ) +3.42 (c 1, CHCl3); 1H NMR (δ/ppm, J /Hz, CDCl3):
) -95.2 (c 3, CHCl3); 1H NMR (δ/ppm, J /Hz CDCl3): 0-90 (d,
J ) 6.96 Hz, 3H), 2.30 (s, 3H), 2.49 (m, 1H), 3.07 (m, 2H),
3.26 (m, 1H), 3.40-3.97 (d, J ) 6.79 Hz, 2H), 3.58 (m, 1H),
4.14 (m, 1H), 4.46 (s, 2H), 7.18 (m, 2H), 7.23 (m, 1H), 7.39 (m,
2H), 7.42 (m, 2H,), 7.47 (m, 2H), 7.74 (m, 1H); 13C NMR (δ/
ppm, CDCl3): 9.3, 38.7, 39.5, 47.7, 50.5, 57.7, 66.9 (CHNCH3),
72.5, 127.2, 127.8, 127.8, 128.5, 129.1, 132.5, 137.9, 140.2; MS,
m/z (%): 418 (M + 1, 50), 417 (M, 49), 277 (67), 327 (48),
169 (80), 91.1 (10), 77 (32), 42 (16); HRMS Calcd for
D
0.79 (d, J ) 6.95 Hz, 3H), 2.96 (s, 3H), 3.16 (m, 1H), 3.27 (dq,
J ) 24.24 Hz, 1H), 3.67 (t, J ) 12.24, 1H), 3.78 (br, 1H), 4.00
(t, J ) 7.14, 1H), 4.03 (m, 2H), 4.12 (m, 1H), 7.2 (2H), 7.3 (2H),
7.41 (2H), 7.67 (2H), 7.8; 13C NMR (δ/ppm, CDCl3): 14.2, 27.5,
29.7, 52.1, 54.6, 72.6, 77.1, 126.8, 127.1, 129.1, 131.4, 132.6,
140.7, 171.2; MS, m/z (%): 404 (M, 0.3), 296 (2), 212 (1), 112
(21), 105 (100), 77 (75), 56.1 (16), 42 (15.). Anal. Calcd for
C
20H24N2O5S: C 59.39, H 5.99, N 6.93, S 7.91. Found: C 59.23,
H 6.07, N 7.06, S 7.98.
C
21H26N2S2O3: 418.1387. Found: 418.1384.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th ia zoli-
d in es 24. A solution of 21 (0.500 mmol) in MeOH (8 mL) was
cooled to 0 °C and treated with NaBH4 (60 mg, 1.6 mmol). The
mixture was stirred for 10 min at room temperature, the
solvent was evaporated, and the crude product obtained was
partitioned between CH2Cl2 (10 mL) and saturated aqueous
NaHCO3 (10 mL). The organic layer was dried (Na2SO4) and
the solvent evaporated under reduced pressure. The crude
products were chromatographed on a silica column.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from DAAD and the Fonds der Che-
mischen Industrie. We thank Dr. Burkhard Ziemer,
Humboldt-Universita¨t Berlin, for providing X-ray crys-
tal analyses and Degussa-Hu¨ls AG for a generous
donation of amino acids and Prof. Horst Hartmann for
providing 2-morpholino-3-methyl-1,3-thiazole.
(3a S,6S,7R,7a S)-7-Met h oxy-3,6-d im et h yl-2-p h en yl-5-
(phenylsulfonyl)octahydro[1,3]thiazolo[4,5-c]pyridine (24a).
The product 24a (144 mg, 69% yield) had the following data:
Rf ) 0.35 (hexane:EtOAc:CH2Cl2 ) 10:1.5:3.5); pale yellow oil
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal analy-
sis of 5f, 10a , and 21c. 1H NMR data of 3c, 3f, 4e, 4f, 5a ,
epi-5f, epi-6f, epi-6g, 9e, 10e, 17a , 17c, 19a , 19c, 20c, 24a ,
24b, 24c, 24d . Experimental procedure for 3c. This material
is available free of charge via the Internet at http://pubs.acs.org.
with an unpleasant smell; [R]20 ) -10.54 (c 1, CHCl3); 1H
D
NMR (δ/ppm, J /Hz CDCl3): 0.96 (d, J ) 6.99 Hz, 3H), 2.07 (s,
3H), 2.64 (m, 1H), 3.17 (m, 1H), 3.23 (s, 3H), 3.44, 4.0 (d, J )
J O010665Z