The efficient, enantioselective synthesis of aza sugars from amino acids. 1. The polyhydroxylated pyrrolidines

Article abstract of DOI:10.1021/jo962028s

Beginning with (+)-serine or (-)-serine, as appropriate, convenient, high-yield, enantioselective synthesis of all eight stereoisomeric 2-hydroxymethyl-3,4-dihydroxypyrrolidines (the enantiomeric pairs of iminoribitol, -arabinitol, -xylitol, and -lyxitol) can be effected. The absolute configuration of the starting amino acid defines the set of azasugars produced.

Full text of DOI:10.1021/jo962028s

372
J . Org. Chem. 1997, 62, 372-376
Th e Efficien t, En a n tioselective Syn th esis of Aza Su ga r s fr om
Am in o Acid s. 1. Th e P olyh yd r oxyla ted P yr r olid in es
Yifang Huang1 and David R. Dalton*
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
Patrick J . Carroll2
Chemistry Department, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Received October 30, 1996X
Beginning with (+)-serine or (-)-serine, as appropriate, convenient, high-yield, enantioselective
synthesis of all eight stereoisomeric 2-hydroxymethyl-3,4-dihydroxypyrrolidines (the enantiomeric
pairs of iminoribitol, -arabinitol, -xylitol, and -lyxitol) can be effected. The absolute configuration
of the starting amino acid defines the set of azasugars produced.
Sch em e 1a
In tr od u ction
It is now clear that carbohydrates mediate the related
properties of cell-cell recognition (necessary for cellular
aggregation and differentiation)3 and cell-cell fusion
(necessary for the subsequent transmission of informa-
tion).4 Glycosidases,5 intimately involved in those and
related processes, have been shown to be inhibited by
some of the members of the group of eight stereoisomeric
2-(hydroxymethyl)-3,4-dihydroxypyrrolidines, 1, and re-
lated nitrogenous materials. It has even been suggested4
that these and other aminosugars could bind directly to
viral or host-cell carbohydrate receptors to produce the
results of their biological activity. Exploration of their
mode(s) of action has only begun.6
a
DIBAL-H, ROH quench; (b) (C6H5)3PdCHCO2CH3.
-xylitol,11,12 and -lyxitol.13,14 In general, the routes are
complex and it is possible that this may have impeded
exploration of their full potential.
Both carbohydrate and noncarbohydrate precursors
have been employed in syntheses of the members of the
pairs of enantiomers of iminoribitol,7,8 -arabinitol,9,10
We report here high-yield, convenient, short, stereo-
selective syntheses to all of the isomers of 1, the final
stereochemistry of which is defined by the enantiomer
of methyl serinate, 2, with which the synthesis is begun.15
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
(1) Present address: SmithKline Beecham Pharmacetuicals, 1250
South Collegeville Rd., P.O. Box 5089, Collegeville, PA 19426-0989.
(2) To whom inquiries concerning X-ray crystallography should be
addressed.
(3) Provencher, L.; Steensma, D. H.; Wong, C.-H. Bioorg. Med. Chem.
1994, 2, 1179.
(4) Karpas, A.; Fleet, G. W. J .; Dewk, R. A.; Petrusson, S.; Mangoong,
S. K.; Ramsden, J . G.; J acob, G. S.; Rademacher, T. W. Proc. Nat. Acad.
Sci. U.S.A. 1988, 85, 9229.
Resu lts a n d Discu ssion
As shown in Scheme 1, when the known,16 readily
available 4-(carbomethoxy)-2-phenyl-∆2-oxazoline, 3, de-
(5) (a) Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319.
(b) Sinnott, L. M. Chem. Rev. 1990, 90, 1171. (c) Kajimoto, T.; Liu, K.
K.-C.; Pederson, R. L.; Zhong, Z.; Ichikawa, Y.; Porco, J . A.; Wong, C.-
H. J . Am. Chem. Soc. 1991, 113, 6187. (d) Andrews, C. W.; Fraser-
Reid, B.; Bowen, J . P. J . Am. Chem. Soc. 1991, 113, 8293. (e) Liu, K.
K.-C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C.-H. J .
Org. Chem. 1991, 56, 6280. (f) Horenstein, B. A.; Zabinski, R. F.;
Schramm, V. L. Tetrahedron Lett, 1993, 34, 7213. (g) Provencher, L.;
Steensma, D. H.; Wong, C.-H. Bioorg. Med. Chem. 1994, 2, 1179. (h)
Boutellier, M.; Horenstein, B. A.; Semenyaka, A.; Schramm, B. L.;
Ganem, B. Biochemistry 1994, 33, 3994. (i) Deng, H.; Chan, A. W.-Y.;
Bagdassarian, C. K.; Dstupin˜a´n, B.; Banem, B.; Callender, R. H.;
Schramm, V. L. Biochemistry 1996, 35, 6037.
(6) The Amino Sugars; the Chemistry and Biology of Compounds
Containing Aminosugars; J eanloz, R. W., Balazs, D. A., Eds.; Academic
Press: New York, 1965-1966; Vols. IA, IB, IIA, IIB.
(7) For a preparation of D-iminoribitol [(2R,3R,4S)-3,4-dihydroxy-
2-(hydroxymethyl)pyrrolidine] see Fleet, G. W. J .; Son, J . C. Tetrahe-
dron 1988, 44, 2647.
(8) For a preparation of L-iminoribitol [(2S,3S,4R)-3,4-dihydroxy-2-
(hydroxymethyl)pyrrolidine] see Fleet, G. W. J .; Son, J . C.; Green, D.
St. C.; Cenci di Bello, I.; Winchester, B. Tetrahedron 1988, 44, 2649.
(9) For preparation of D-iminoarabinitol [(2R,3R,4R)-3,4-dihydroxy-
2-(hydroxymethyl)pyrrolidine] see (a) Fleet, G. W. J .; Smith, P. W.
Tetrahedron 1986, 42, 5685. (b) Ziegler, T.; Straub, A.; Effenberger,
F. Angew. Chem., Int. Ed. Engl. 1988, 27, 716. (c) Fleet, G. W. J .; Witty,
D. R. Tetrahedron: Asym. 1990, 1, 119. (d) Kajimoto, T.; Chen, L.; Liu,
K. K-C.; Wong, C.-H. J . Am. Chem. Soc. 1991, 113, 6678.
(10) For preparation of L-iminoarabinitol [(2S,3S,4S)-3,4-dihydroxy-
2-(hydroxymethyl)pyrrolidine] see (a) J ones, D. W. C.; Nash, R. J .; Bell,
E. A.; Williams, J . M. Tetrahedron Lett. 1985, 26, 3125. (b) Reference
3a.
(11) For a preparation of D-iminoxylitol [(2R,3S,4S)-3,4-dihydroxy-
2-(hydroxymethyl)pyrrolidine] see Ikota, N. Chem. Pharm. Bull. 1989,
37, 3399.
(12) For preparation of L-iminoxylitol [(2S,3R,4R)-3,4-dihydroxy-2-
(hydroxymethyl)pyrrolidine] see (a) Buchanan, J . G.; Lumbard, K. W.;
Sturgeon, R. J .; Thompson, D. K.; Wightman, R. H. J . Chem. Soc.,
Perkin Trans. 1 1990, 699. (b) Meng, Q.; Hesse, M. Helv. Chim. Acta
1991, 74, 445.
(13) For preparation of D-iminolyxitol [(2R,3S,4R)-3,4-dihydroxy-2-
(hydroxymethyl)pyrrolidine] see (a) reference 3a. (b) Austin, G. N.;
Baird. P. D.; Fleet, G. W. J . Peach, J . M.; Smith, P. W.; Watkin, D. J .
Tetrahedron 1987, 43, 3095. (c) Han, S.-Y.; Liddell, P. A.; J oullie, M.
M. Synth. Commun. 1988, 18, 275. (d) Reference 6a. (e) Meyers, A. I.;
Andres, C. J .; Resek, J . E.; McLaughlin, M. A.; Woodall, C. C.; Lee, P.
H. J . Org. Chem. 1996, 61, 2586.
(14) For a preparation of L-iminolyxitol [(2S,3R,4S)-3,4-dihydroxy-
2-(hydroxymethyl)pyrrolidine] see Thompson, D. K.; Hubert, C. N.;
Wightman, R. H. Tetrahedron 1993, 49, 3827.
(15) Within experimental error, both L- and D-serine yield compa-
rable results. The graphics present the synthetic route showing only
the L-isomer for purposes of clarity.
S0022-3263(96)02028-2 CCC: $14.00 © 1997 American Chemical Society

Enantioselective Synthesis of Aza Sugars from Amino Acids
J . Org. Chem., Vol. 62, No. 2, 1997 373
Sch em e 2a
Sch em e 3a
a
OsO4 and NMO or (DHQ)2PHAL [(DHQD)2PHAL].
rived from L-serine15 methyl ester, 2, is treated with a
slight excess of DIBAL-H at low temperature, reduction
to the aldehyde occurs. As the aldehyde is labile, an
alcohol quench of the reaction mixture is followed, in the
same flask, by direct addition of (carbomethoxymethyl-
ene)triphenylphosphorane. This results in the formation
of a mixture of (S)-(+)-methyl (E)-3-(4,5-dihydro-2-phen-
yl-4-oxazolyl)-2-propenoate, 4, ([R]20D ) +60.2°, c ) 0.018
in CHCl3), and the corresponding (S)-(-)-methyl (Z)-
a
Aqueous HCl; (b) B2H6/THF.
Sch em e 4a
isomer 5, ([R]20 ) -49.5°, c ) 0.094 in CHCl3).
D
Interestingly, the total yield of the mixture of isomers,
and their ratio can be varied by altering the conditions
of the alcohol quench and the subsequent Wittig reaction.
For example, if the reaction mixture is quenched with
tert-butanol before (carbomethoxymethylene)triphen-
ylphosphorane is added, 4 and 5 are produced in an
overall yield of 83% and in a 1.5:1 ratio, respectively.
Alternatively, quenching the reaction with methanol but
holding everything else the same, provides a 72% yield
of the mixture of 4 and 5 but now in a 1:8.5 ratio.
The isomeric alkenes are easily separated by column
chromatography.
a
OsO4 and NMO or (DHQ)2PHAL [(DHQD)2PHAL].
tively to yield the known10 L-iminoarabinitol [(2S,3S,4S)-
3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine], 1, ([R]20
)
D
-11.9°, c ) 0.044 in CH3OH; with the corresponding
hydrochloride salt, [R]20D ) -28.8°, c ) 0.049 in H2O; for
the enantiomer9a [R]20 ) +7.8°, c ) 0.46 in H2O and for
As shown in Scheme 2, treatment of the (E)-isomer, 4,
in aqueous acetone with a catalytic amount of osmium
tetraoxide and the N-oxide of N-methylmorpholine (NMO)
at room temperature yields (71%) a mixture of the diol
D
the enantiomeric hydrochloride salt,9a [R]20D ) + 37.9°, c
) 0.53 in H2O).
A diastereomer of L-iminoarabinitol, the known12 L-
iminoxylitol [(2S,3R,4R)-3,4-dihydroxy-2-(hydroxymeth-
esters 6 (2R,3S,4S; [R]20 ) -1.2°, c ) 0.006 in CH3OH)
D
yl)pyrrolidine], 1, ([R]20 ) -4.4°, c ) 0.010 in CH3OH;
and 7 (2S,3R,4S; [R]20 ) +73.9°, c ) 0.009 in CH3OH)
D
D
for the corresponding hydrochloride salt, [R]20 ) -8.6°,
in a 1.6:1 ratio. The diastereomers are readily separated
by column chromatography.
D
c ) 0.010 in H2O; lit.12b [R]22 ) -1.3°, c ) 0.540 in H2O)
D
is obtained in 91% yield from 9 in the same way. Then,
in direct compliment to the above sequence of reactions,
treatment of the (Z)-isomer 5 with osmium tetraoxide as
shown in Scheme 4 produces a mixture of the diol esters
Several attempts to induce preferential formation of
one of the diastereomers through stereoselective oxida-
tion of 4 with the quinine-derived, commercially available
(DHQ)2PHAL17 reagent in the presence of osmium tet-
raoxide produced, in the best case, 65% of 6 and less than
5% of 7. Interestingly, similar results anticipated with
the related (DHQD)2PHAL reagent were not observed
and improvement (both yield and stereochemical out-
come) over NMO/OsO4 was not achieved.
11 (2R,3R,4S; [R]20 ) +48.3°, c ) 0.009 in CH3OH) and
D
10 (2S,3S,4S; [R]20 ) +51.8°, c ) 0.007 in CH3OH) in a
D
3.2:1 ratio (73% overall). As before, these isomers are
readily separated by column chromatography.
Here too, several attempts to induce preferential
formation of one of the diastereomers through stereose-
lective dihydroxylation met with limited success. Thus,
treatment of 5 with (DHQD)2PHAL17 yields 85% of the
isomer 11. However, use of (DHQ)2PHAL produces only
17% of 10 and 64% of 11!
As shown in Scheme 5, on treatment of the diol 10 with
aqueous acid, hydrolysis and recyclization to the
3,4-dihydroxy-5-(hydroxymethyl)pyrrolidone benzoate
(3S,4S,5S)-12 occurs in 98% yield.19 The diastereomeric
diol 11 produces the corresponding ester ([R]20D ) -35.9°,
c ) 0.005 in CH3OH) (3R,4R,5S)-13 in 97% isolated yield
under the same conditions.
As shown in Scheme 3, when the diol 6 is treated with
aqueous acid, hydrolysis of the oxazoline and recycliza-
tion to the 3,4-dihydroxy-5-(hydroxymethyl)pyrroli-
done benzoate ([R]20 ) -47.6°, c ) 0.006 in CH3OH)
D
(3R,4S,5S)-8 occurs in 61% yield. The structure of 8 is
confirmed by X-ray crystallography.18 The diastereomer
of 6, the diol 7, produces the corresponding ester ([R]20
D
) -110°, c ) 0.006 in CH3OH) (3S,4R,5S)-9 under the
same conditions in 60% isolated yield.
Then, the lactam-ester 8, with an excess of borane in
tetrahydrofuran, cleanly undergoes reduction of both
carbonyl functionalities simultaneously and quantita-
Then, reduction of the lactam and removal of the
benzoate is accomplished with borane in THF in 86%
yield to produce the known8 L-iminoribitol [(2S,3S,4R)-
(16) Tkaczuk, P.; Thornton, E. R. J . Org. Chem. 1981, 46, 4393.
(17) Morikawa, K.; Sharpless, K. B. Tetrahedron Lett. 1993, 34, 5575
(18) The X-ray crystal structure of 8 is particularly interesting as
there are four molecules in the asymmetric unit. Complete details are
provided in the Supporting Information. The author has deposited
atomic coordinates for this structure with the Cambridge Crystal-
lographic Data Centre. The coordinates can be obtained, on request,
from the Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK.
(19) This isomer is extraordinarily insoluble in a variety of common
and uncommon solvents and its optical rotation was not taken.
(20) 1H and 13C NMR spectra for intermediates and IR spectra for
intermediates and azasugars 1 are provided at: http://astro.ocis.tem-
ple.edu/∼dalton/azasugar_1.html.

374 J . Org. Chem., Vol. 62, No. 2, 1997
Huang et al.
Sch em e 5a
methanol (700 mL) with stirring. Ten minutes later, with
continued stirring, D-serine (49.0 g, 0.472 mol) was added in
one portion and the reaction mixture brought to reflux on the
steambath. Heating was continued for 2.5 h, the solvent
removed at reduced pressure, and the resulting methyl ester
hydrochloride (73.5 g, 100%) recrystallized from methanol.
Oxa zolin e Meth yl Ester , 3. L-Serine methyl ester hydro-
chloride (25 g, 161 mmol) was suspended in dry methylene
chloride (350 mL) and triethylamine (28 mL, 20.3 g, 200 mmol)
added. When the dissolution of the amine hydrochloride was
complete, benzimino ethyl ether hydrochloride (29.8 g, 162
mmol) was added as one portion. The reaction mixture was
heated at reflux on the steambath for 4 h and then stirred at
room temperature, under argon, overnight. The pink reaction
mixture was extracted twice with saturated sodium bicarbon-
ate, and the combined aqueous extracts were back washed
twice with half its volume of methylene chloride. The com-
bined methylene chloride extracts were washed with brine,
dried over magnesium sulfate, and filtered, and the solvent
was removed at reduced pressure. Flash chromatography on
silica gel (eluted with 1:1 ether:petroleum ether) provided the
known16 oxazoline methyl ester in 80% yield (26.4 g, 128.8
a
Aqueous HCl; (b) B2H6/THF.
3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine], 1, ([R]20
)
D
-30.5, c ) 0.039 in CH3OH; and for the corresponding
mmol, [R]20 ) +117.2°, c ) 0.053 in CHCl3). 1H NMR
hydrochloride salt [R]20 ) -62.3, c ) 0.006 in H2O, lit.8
D
D
(2HCCl3) δ 7.98-8.01 (m, 2H); 7.48-7.54 (m, 1H); 7.39 -7.45
(m, 2H); 4.97 (dd, J ) 7.8, 10.5, 1H); 4.71 (dd J ) 8.7, 8.1,
1H); 4.60 (dd, J ) 10.5, 8.7, 1H); 3.83 (s, 3H).
) -59.0, c ) 0.59 in H2O). Its diastereomer, the known14
L-iminolyxitol [(2S,3R,4S)-3,4-dihydroxy-2-(hydroxymeth-
yl)pyrrolidine], 1, ([R]20 ) -12.9°, c ) 0.039 in CH3OH;
D
(S)-(+)-m eth yl (E)-3-(4,5-Dih yd r o-2-p h en yl-4-oxa zolyl)-
2-p r op en oa te (4) a n d (S)-(-)-Meth yl (Z)-3-(4,5-Dih yd r o-
2-ph en yl-4-oxazolyl)-2-pr open oate (5). The oxazoline meth-
yl ester 3 (26.5 g, 129 mmol) in dry toluene (800 mL) was
cooled to -78 °C under an argon atmosphere and DIBAL-H
(1.5 M, 137 mL) was added slowly, keeping the temperature
of the toluene solution below -70 °C throughout. After stirring
at -78 °C for an additional 3 h, methanol (100 mL) was added,
again keeping the temperature below -70 °C, to terminate
the reaction, and 30 min later, (carbomethoxymethylene)-
triphenylphosphorane (48.5 g, 150 mmol) in methanol (300
mL) was added and the reaction solution allowed to warm to
room temperature. After stirring overnight, the solution was
diluted with diethyl ether (600 mL) and extracted (2 × 150
mL) with aqueous sodium hydroxide (15%), twice (2 × 150 mL)
with saturated sodium bicarbonate, and twice (2 × 150 mL)
with brine. The solvent mixture was removed at reduced
pressure and the residue suspended in light petroleum ether
(300 mL). The crystalline triphenylphosphine oxide was
removed by filtration and the residue, after removal of the
solvent, chromatographed on silica gel, eluting with 80:20
ether:petroleum ether. The mixture (72% of theory) was 64%
5 (19.0 g) and 8.4% 4 (2.5 g). Use of tert-butyl alcohol changes
the ratio of 4:5 to 1.5:1 (83% total yield).
for the hydrochloride salt, [R]20 ) -13.2, c ) 0.014 in
D
H2O; lit.14 [R]20 ) -17.2°, c ) 0.4 in H2O) is obtained in
D
96% yield from 13 with the same reagents.
Con clu sion
The synthesis of all eight (8) isomeric 2-(hydroxy-
methyl)-3,4-dihydroxypyrrolidines (the enantiomeric pairs
of iminoribitol, -arabinitol, -xylitol, and -lyxitol) from L-
or D-serine methyl ester has been effected. Although
separation of isomers has proved simple in both of the
steps in the syntheses where two compounds form (a
single isomer forming in each of the others), it has also
been shown that the composition of the mixture can be
adjusted by changing the conditions under which the
reaction is carried out. In the first of the two isomer-
generating steps, the Wittig reaction, simply modifying
the solvent substantially changes the (E)/(Z) ratio. In
the second isomer-generating step, suprafacial dihy-
droxylation of the each of the alkenes (separately) has
also been shown to be amenable to adjustment. Again,
although it is clear that the ratio can be modified,
significant developmental work remains.
For the E isomer, 4, colorless oil, Rf 0.17, silica gel, 20:80
diethyl ether:petroleum ether, [R]20 ) +60.2°, c ) 0.018 in
D
CHCl3. 1H NMR (2HCCl3) δ 7.96-8.00 (m, 2H); 7.49-7.54 (m,
1H); 7.40-7.46 (m, 2H); 7.00 (dd, J ) 6.3, 15.6, 1H); 6.11 (dd,
J ) 1.5, 15.6, 1H); 4.95-5.03 (m, 1H); 4.62 (dd, J ) 9.9, 10.2,
1H); 4.20 (dd, J ) 8.1, 8.4, 1H); 3.75 (s, 3H). 13C NMR (2HCCl3)
δ 166.58, 165.33, 146.67, 131.75, 128.39, 127.12, 122.14, 71.72,
66.74, 51.68. IR (neat film, cm-1) 1722.2, 1650.9, 1603.1,
1580.0, 1495.6, 1450.3, 1359.6, 1280.5, 1192,8, 1082.4, 1025.5,
974.4, 923.7, 864.9, 781.5, 756.0, 696.7. HRMS calcd for
C13H13NO3 231.0895. Found [M]+ 231.0888.
Exp er im en ta l Section
Gen er al. Satisfactory elementary analysis (Galbraith Labo-
ratories, Knoxville, TN) and/or high resolution mass spectro-
metric analysis (The Pennsylvania State University, College
Park, PA or Drexel University, Philadelphia, PA) have been
obtained for all new compounds. 1H NMR spectra were
obtained at 300 MHz and 13C NMR at 75 MHz, and chemical
shifts are reported in parts per million (ppm), δ, from TMS )
0.00 ppm. NMR spectra of the imino-sugars 1, along with the
X-ray crystallographic data are provided in the Supporting
Information. Infrared (FT-IR) spectra were taken as neat oils
(for noncyrstalline materials) or as KBr pellets for crystalline
samples, and those spectra along with the 1H and 13C NMR
spectra of the reported intermediates can be obtained by mail
or from the website of the senior author (http://astro.ocis.tem-
ple.edu/∼dalton). Solvents, reactive reagents, and column
materials were purchased from Acros Chemical, Fisher Sci-
entific, and/or Aldrich Chemical Companies. Solvents were
distilled under argon prior to use. L- and D-serine were
obtained from Acros Chemical Co., through Fisher Scientific,
Pittsburgh, PA.
For the Z isomer, 5, colorless oil, Rf 0.39, silica gel, 20:80
diethyl ether:petroleum ether, [R]20 ) -49.5°, c ) 0.094 in
D
CHCl3. 1H NMR (2HCCl3) δ 7.96-7.99 (m, 2H); 7.48-7.52 (m,
1H); 7.40-7.46 (m, 2H); 6.44 (dd, J ) 7.2, 11.1, 1H); 5.92 (dd,
J ) 11.4, 1.8, 1H); 5.71-5.80 (m, 1H); 4.87 (dd, J ) 9.9, 10.5,
1H); 4.10 (dd, J ) 8.4, 8.7, 1H); 3.76 (s, 3H). 13C NMR (2HCCl3)
δ 166.17, 165.29, 151.10, 131.50, 128.31, 127.52, 120.03, 73.38,
65.15, 51.44. IR (neat film, cm-1) 1717.9, 1651.4, 1603.1,
1580.0, 1496.1, 1449.8, 1396.3, 1356.3, 1204.9, 1084.3, 1026.0,
965.2, 896.3, 819.6, 780.5, 696.2. HRMS calcd for C13H13NO3
231.0895. Found [M]+ 231.0888.
F or (R)-(-)-Meth yl (E)-3-(4,5-Dih yd r o-2-p h en yl-4-ox-
a zolyl)-2-p r op en oa te (en t-4) a n d (R)-(+)-Meth yl (Z)-3-
(4,5-Dih yd r o-2-p h en yl-4-oxa zolyl)-2-p r op en oa te (en t-5)
fr om D-Ser in e. Prepared as with the L-isomer of serine, ent-4
D-Ser in e Meth yl Ester Hyd r och lor id e. Acetyl chloride
(100 g, 1.27 mol) was slowly added, dropwise, to cold (ice-bath)
has [R]20 ) -51.5°, c ) 0.010 in CHCl3. HRMS calcd for
D

Enantioselective Synthesis of Aza Sugars from Amino Acids
J . Org. Chem., Vol. 62, No. 2, 1997 375
C13H13NO3 231.0895. Found [M]+ 231.0884. For ent-5, [R]20
266.1028478. Found [M + H]+ 266.103391. Anal. Calcd for
C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C, 59.33; H,
5.86; N, 5.20.
D
) +47.7°, c ) 0.013 in CHCl3. HRMS calcd for C13H13NO3
231.0895. Found [M]+ 231.0894.
P r ep a r a tion of th e Diol Ester s 6 a n d 7. The E-alkene
4 (2.14 g, 9.3 mmol) in acetone (40 mL) and water (10 mL)
was treated with N-methylmorpholine N-oxide (NMO) mono-
hydrate (1.63 g, 12.0 mmol) and osmium tetraoxide (1.0 mL
of a 4% aqueous solution). Stirring was continued for 36 h at
room temperature, and the reaction was terminated by adding
a saturated sodium bisulfite solution (5.0 mL) and stirring the
resulting reaction mixture for an additonal 30 min. The
products were isolated by extracting the aqueous solution with
an equal volume of ethyl acetate in three portions, combining
the resulting solutions of organic solvents, drying them over
sodium sulfate, filtering, and removing the solvent at reduced
pressure.
Diol 10, mp 157 °C, 2.15 g, 8.1 mmol 17.5%, [R]20D ) +51.8°,
c ) 0.007 in CH3OH. 1H NMR (C2H3O2H): 7.93-7.97 (m, 2H),
7.50-7.55 (m, 1H), 7.40-7.45 (m, 2H), 4.50-4.66 (m, 3H), 4.42
(dd, J ) 7.8, 7.8, 1H), 3.75 (s, 3H); 13C NMR (C2H3O2H): 173.8,
165.8, 131.3, 128.1, 128.0, 127.3, 73.0, 72.4, 69.2, 66.9, 51.0;
IR (KBr pellet, cm-1) 3393.5, 1710.7, 1640.4, 1449.4, 1373.2,
1238.2, 1063.6, 1034.7, 954.7, 687.5. HRMS calcd for [C13H15
-
NO5 + H] 266.1028478. Found [M + H]+ 266.102911. Anal.
Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C,
59.25; H, 5.80; N, 5.22. Diols 10 and 11 were separated and
purified by flash chromatography (eluting with 98.5:1.5 CH3-
Cl:CH3OH).
Asym m etr ic Dih yr oxyla tion of 5 w ith (DHQD)2P HAL.
The alkene 5 (290 mg, 1.25 mmol), (DHQD)2PHAL (Aldrich,
9.8 mg, 12.5 × 10-3 mmol), K3Fe(CN)6 (1.24 g, 3.77 mmol),
potassium carbonate (520 mg, 3.8 mmol), and methansulfona-
mide (89 mg, 0.94 mmol) were dissolved in tert-butanol (5.0
mL) and water (5.0 mL) at room temperature with stirring.
With stirring, osmium tetraoxide (4% in water, 74 µL) was
added and stirring was continued at 0 °C for 18 h before
saturated sodium bisulfite solution was added to quench the
reaction. After stirring for an additional 20 min, the aqueous
solution was extracted with three times its volume of ethyl
acetate in three portions. The combined organic extracts were
dried over sodium sulfate and filtered and the solvent evapo-
rated. The diol 11 (vide supra) (281 mg, 1.06 mmol, 84.8%)
was purified by silica gel flash column chromatography by
elution with 98:2 CHCl3:CH3OH.
P r ep a r a tion of th e La cta m 8. With stirring, the diol 6
(2.646 g, 99.4 mmol) in THF (100 mL) was treated with
aqueous hydrochloric acid solution (1.5 M, 20 mL). After 24
h at room temperature, the reaction mixture was neutralized
by addition of solid sodium bicarbonate, the solvent removed
at reduced pressure, and the product isolated and purified from
the residue by flash column chromatography over silica gel.
The elution was begun with 10:90 CH3OH:CHCl3 mixture and
this was followed by a mixture of 60:20:10:10 CH2Cl2:CH3CH2-
OH:CH3OH:NH4OH. Lactam 9, a white solid (1.5148 g, 60.4%,
mp 138 °C was recrystallized in acetone/chloroform. Rf ) 0.17
in 10:90 CH3OH:CHCl3, [R]20D ) -47.6° (c ) 0.006, methanol).
1H NMR (C2H3O2H): 8.04-8.08 (m, 2H), 7.58-7.63 (m, 1H),
7.44-7.49 (m, 2H), 4.60 (dd, J ) 11.7, 3.0, 1H), 4.32 (dd, J )
12.0, 5.4, 1H), 4.17 (d, J ) 7.5, 1H), 4.05 (dd, J ) 7.2, 7.5,
1H), 3.63 (ddd, J ) 7.2, 5.4, 3.0, 1H); 13C NMR (C2H3O2H):
175.0, 166.3, 133.0, 129.5, 129.1, 128.2, 75.8, 75.5, 63.4, 56.3;
IR (KBr pellet, cm-1) 3369.4, 3289.4, 1672.1, 1600.8, 1453.8,
1384.8, 1323.1, 1280.6, 1129.2, 1102.2, 891.0, 707.8, 630.6.
HRMS calcd for [C12H13NO5 + H] 252.0871978. Found [M +
H]+ 252.087132. Anal. Calcd for C12H13NO5: C, 57.37; H,
5.22; N, 5.58. Found: C, 57.19; H, 5.43; N, 5.50.
Diol 6, mp 183 °C, from ethanol, 1.06 g, 4 mmol, 43%, [R]20
D
) -1.2°, c ) 0.006 in CH3OH. 1H NMR (C2H3O2H): 7.91-
7.95 (m, 2H), 7.50-7.56 (m, 1H), 7.14-7.47 (m, 2H), 4.44-
4.63 (m, 4H), 4.00 (dd, J ) 5.7, 2.1, 1H), 3.76 (s, 3H); 13C NMR
(C2H3O2H): 173.4, 165.7, 131.5, 128.1, 128.0, 127.1, 73.7, 72.1,
69.5, 67.8, 51.1; IR (KBr pellet, cm-1) 3330.8, 1748.4, 1643.2,
1449.4, 1363.6, 1274.9, 1218.9, 1142.7, 1104.2, 736.8, 694.3.
HRMS calcd for [C13H15NO5 + H] 266.1028478. Found [M +
H]+ 266.103644. Anal. Calcd for C13H15NO5: C, 58.86; H,
5.70; N, 5.28. Found: C, 58.96; H, 5.87; N, 5.21.
Diol 7, mp 106 °C, 668.5 mg, 2.5 mmol, 27%, [R]20D ) +73.9°,
c ) 0.009 in CH3OH. 1H NMR (C2H3O2H): 7.91-7.95 (m, 2H),
7.50-7.56 (m, 1H), 7.14-7.47 (m, 2H), 4.48-4.56 (m, 3H), 4.34
(d, J ) 3.0, 1H), 3.99 (dd, J ) 5.1, 3.0, 1H), 3.76 (s, 3H); 13C
NMR (C2H3O2H): 173.1, 165.7, 131.5, 128.1, 128.0, 127.1, 73.1,
71.9, 69.3, 68.6, 51.2; IR (KBr pellet, cm-1) 3356.9, 1732.9,
1656.8, 1449.4, 1359.7, 1244.0, 1139.8, 1093.6, 1045.3, 967.2,
808.1, 770.5, 694.3. HRMS calcd for [C13H15NO5 + H]
266.1028478. Found [M + H]+ 266.103622. Anal. Calcd for
C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C, 58.86; H,
5.78; N, 5.07.
The diols 6 and 7 were separated and purified by silica gel
flash column chromatography (eluting with 98:2 CH3Cl:CH3-
OH).
Asym m etr ic Dih yr oxyla tion of 4 w ith (DHQ)2P HAL.
The alkene 4 (216 mg, 0.94 mmol), (DHQ)2PHAL (Aldrich, 7.3
mg, 9.4 × 10-3 mmol), K3Fe(CN)6 (823 mg, 2.84 mmol),
potassium carbonate (387.3 mg, 2.8 mmol), and methansul-
fonamide (89 mg, 0.94 mmol) were dissolved in tert-butanol
(5.0 mL) and water (5.0 mL) at room temperature with stirring.
With stirring, osmium tetraoxide (4% in water, 70 µL) was
added and stirring was continued at room temperature for 48
h before saturated sodium bisulfite solution was added to
quench the reaction. After stirring for an additional 20 min,
the aqueous solution was extracted with three times its volume
of ethyl acetate in three portions. The combined organic
extracts were dried over sodium sulfate and filtered and the
solvent evaporated. The diols 6 (vide supra) (166 mg, 0.63
mmol, 67%) and 7 (11 mg, 0.04 mmol, 4.5%) ratio 15:1 were
separated and purified by silica gel flash column chromatog-
raphy by elution with 98:2 CHCl3:CH3OH.
P r ep a r a tion of th e Diol Ester s 10 a n d 11. The Z-alkene
5 (10.67 g, 46.2 mmol) in acetone (80 mL) and water (10 mL)
was treated with N-methylmorpholine N-oxide (NMO) mono-
hydrate (9.35 g, 69.2 mmol) and osmium tetraoxide (6.8 mL
of a 4% aqueous solution). Stirring was continued for 16 h at
0 °C, and the reaction was terminated by adding a saturated
sodium bisulfite solution (10.0 mL) and stirring the resulting
reaction mixture for an additional 30 min. The products were
isolated by extracting the aqueous solution with an equal
volume of ethyl acetate in four portions, combining the
resulting solutions of organic solvents, drying them over
sodium sulfate, filtering, and removing the solvent at reduced
P r ep a r a tion of La cta m 9. The diol 7 (95.2 mg, 0.36 mmol)
was dissolved in methanol (3 mL) at room temperature and
aqueous 1 N HCl (1.0 mL) added. The resulting solution was
permitted to stir at room temperature for 20 h and then
neutralized by addition of solid sodium bicarbonate. The
solvent was evaporated, and the product was isolated and
purified by flash column chromatography over silica gel,
initially eluted with 10:90 CH3OH:CHCl3 and then a 60:20:
10:10 mixture of CH2Cl2:CH3CH2OH:CH3OH:NH4OH. Lactam
9, a white solid (59.8 mg, 66.1%, mp 192 °C, was recrystallized
in ethanol, Rf ) 0.15 (CH3OH(10)/CHCl3(90), [R]20 ) -110°
D
(c ) 0.006, methanol). 1H NMR (C2H3O2H): 8.00-8.04 (m,
2H), 7.58-7.63 (m, 1H), 7.46-7.50 (m, 2H), 4.54 (dd, J ) 11.7,
3.3, 1H), 4.33 (dd, J ) 11.7, 4.8, 1H), 4.38 (dd, J ) 7.5, 8.1,
1H), 4.29 (d, J ) 8.1, 1H), 3.93 (ddd, J ) 7.5, 4.8, 3.3, 1H); 13
C
NMR (C2H3O2H): 175.0, 166.2, 133.0, 129.3, 129.0, 128.2, 74.5,
74.2, 63.0, 54.4; IR (KBr pellet, cm-1) 3408.9, 3209.4, 1722.3,
1665.4, 1600.6, 1434.0, 1377.1, 1317.3, 1264.2, 1124.4, 1089.7,
1019.3, 920.0, 787.6, 707.8. HRMS calcd for [C12H13NO5 + H]
252.0871978. Found [M + H]+ 252.087232. Anal. Calcd for
C12H13NO5: C, 57.37; H, 5.22; N, 5.58. Found: C, 57.32; H,
5.30; N, 5.40.
pressure. Diol 11, mp 159 °C, 6.79 g, 25.6 mmol, 55.5%, [R]20
D
) +48.3°, c ) 0.009 in CH3OH. 1H NMR (C2H3O2H): 7.89-
7.93 (m, 2H), 7.50-7.56 (m, 1H), 7.40-7.45 (m, 2H), 4.44-
4.60 (m, 3H), 4.28 (d, J ) 4.8, 1H), 4.05 (dd, J ) 4.2, 4.2, 1H),
3.75 (s, 3H); 13C NMR (C2H3O2H): 172.9, 165.5, 131.4, 128.0,
127.9, 127.2, 73.7, 73.1, 68.6, 67.1, 51.0; IR (KBr pellet, cm-1
)
3444.6, 1736.8, 1644.2, 1450.4, 1370.3, 1296.0, 1238.2, 1109.0,
989.4, 949.9, 730.9, 694.3. HRMS calcd for [C13H15NO5 + H]
P r ep a r a tion of La cta m 12. Lactam 12 (3.16 g, 126 mmol,
98% of theory) was obtained from diol 10 (3.40 g, 128 mmol)

376 J . Org. Chem., Vol. 62, No. 2, 1997
Huang et al.
by the same procedure used in the preparation of lactam 9
from diol 7 above. The product was recrystallized from
methanol/diethyl ether with difficulty because of its limited
solubility. Optical rotation was not taken because of its limited
solubility.
For 12, mp 212 °C, 1H NMR (C2H3O2H): 8.00-8.05 (m, 2H),
7.58-7.65 (m, 1H), 7.40-7.52 (m, 2H), 4.47 (dd, J ) 11.4, 4.5,
1H), 4.35 (dd, J ) 11.4, 5.1, 1H), 4.33 (d, J ) 5.7, 1H), 4.27
(dd, J ) 5.7, 1.5, 1H), 3.80 (ddd, J ) 5.1, 4.5, 1.5, 1H); 13C
NMR (C2H3O2H): 176.5, 166.0, 133.0, 129.4, 129.1, 128.3, 70.0,
69.9, 64.2, 59.0; IR (KBr pellet, cm-1) 3242.1, 1719.4, 1690.5,
1438.6, 1264.2, 1146.6, 1102.2, 767.6, 706.8. HRMS calcd for
[C12H13NO5 + H] 252.0871978. Found [M + H]+ 252.087255.
Anal. Calcd for C12H13NO5: C, 57.37; H, 5.22; N, 5.58.
Found: C, 57.07; H, 5.38; N, 5.59.
exchange chromatography on DOWEX 50WX8-100 and a final
flash-chromatographic purification over a short silica gel
column where it was eluted with a 50:20:20:10 mixture of CH2-
Cl2:CH3CH2OH:CH3OH:NH4OH to yield material with [R]20
D
) -4.4°, c ) 0.010 in CH3OH. 1H NMR (C2H3O2H): 4.13 (m,
1H), 4.07 (m, 1H), 3.75 (dd, J ) 11.4, 6.3, 1H), 3.63 (dd, J )
11.4, 67.2, 1H), 3.35 (m, 1H), 3.28 (dd, J ) 12.9, 5.1, 1H), 2.78
(dd, J ) 12.9, 1.8, 1H); 13C NMR (C2H3O2H): 75.9, 75.6, 61.7,
58.8, 50.6; IR(neat film, cm-1) 3380, 1654.8, 1420.5, 1048.2.
HRMS calcd for [C5H11NO3 + H] 134.0817184. Found [M +
H]+ 134.081675. The hydrochloride, obtained on treatment
of the free base with 6 N HCl and recrystallized from
methanol/acetone had [R]20 ) -8.6°, c ) 0.010 in H2O; 1H
D
NMR (2H2O): 4.32 (d, br, J ) 3.3, 1H), 4.25 (s, br, 1H), 3.95
(dd, J ) 15.3, 8.7, 1H), 3.83 (m, 2H), 3.60 (dd, J ) 12.9, 4.2,
1H), 3.23 (d, br, J ) 12.9, 1H); 13C NMR (2H2O): 74.3, 74.2,
63.0, 57.2, 50.5. IR (KBr pellet, cm-1) 3383, 1625.9, 1412.8,
1308.6, 1101.3, 1047.3, 978.8, 913.2.
P r ep a r a tion of La cta m 13. Lactam 13, a white solid (20.0
mg, 0.08 mmol), was obtained from diol 11 (21.8 mg, 0.08
mmol, 98%) by the same procedure which was used in the
preparation of lactam 9. It was recrystallized in acetone/
hexanes. Rf ) 0.20 in 10:90 CH3OH:CHCl3. For 13, mp 145
°C, [R]20D ) -35.9° (c ) 0.005, methanol), 1H NMR (C2H3O2H):
8.06-8.09 (m, 2H), 7.58-7.63 (m, 1H), 7.45-7.51 (m, 2H), 4.60
(dd, J ) 11.4, 5.1, 1H), 4.43 (dd, J ) 5.4, 3.6, 1H), 4.40 (dd, J
) 11.1, 7.8, 1H), 4.27 (d, J ) 5.1, 1H), 3.95 (ddd, J ) 7.8, 5.1,
3.6, 1H); 13C NMR (C2H3O2H): 176.7, 166.4, 132.9, 129.7,
L-Im in or ibitol [(2S,3S,4R)-3,4-Dih yd r oxy-2-(h yd r oxy-
m eth yl)p yr r olid in e, 1]. As described above for L-iminoara-
binatol and L-iminoxylitol, L-iminoribitol (152 mg, 1.13 mmol,
86%) [R]20 ) -30.5°, c ) 0.039 in CH3OH. 1H NMR
D
(C2H3O2H): 4.06 (ddd, J ) 5.1, 5.1, 3.9, 1H), 3.79 (dd, J ) 6.9,
5.1, 1H), 3.66 (dd, J ) 11.7, 4.2, 1H), 3.54 (dd, J ) 11.7, 6.0,
1H), 3.26 (s, NH), 3.09 (dd, J ) 12.3, 5.1, 1H), 3.00 (ddd, J )
6.9, 6.0, 4.2, 1H), 2.75 (dd, J ) 12.3, 3.9, 1H); 13C NMR
129.3, 128.1, 71.3, 69.1, 63.8, 54.4; IR (KBr pellet film, cm-1
)
3365.5, 1706.9, 1448.4, 1281.6, 1162.4, 1120.5, 712.5. HRMS
calcd for [C12H13NO5 + H] 252.0871978. Found [M + H]+
252.087147; Anal. Calcd for C12H13NO5: C, 57.37; H, 5.22; N,
5.58. Found: C, 56.31; H, 5.31; N, 5.38.
(C2H3O2H): 73.0, 71.1, 62.3, 61.8, 49.9; IR (neat film, cm-1
)
3380, 1651.9, 1532.3, 1426.2, 1346.2, 1103.2. HRMS calcd for
[C5H11NO3 + H] 134.0817184. Found [M + H]+ 134.081789.
The hydrochloride salt, obtained with 6 N HCl in ethanol had
[R]20D ) -62.3°, c ) 0.006 in H2O. 1H NMR (2H2O): 4.31 (ddd,
J ) 3.9, 3.9, 1.8, 1H), 4.13 (dd, J ) 8.7, 3.9, 1H), 3.90 (dd, J )
12.3, 3.3, 1H), 3.75 (dd, J ) 12.3, 6.0, 1H), 3.56 (ddd, J ) 8.7,
6.0, 3.3, 1H), 3.43 (dd, J ) 12.9, 3.9, 1H), 3.30 (dd, J ) 12.9,
1.8, 1H); 13C NMR (2H2O): 71.1, 69.4, 61.7, 57.9, 49.5. IR (KBr
pellet, cm-1) 3395, 163.5, 1418.5, 1339.4, 1141.8, 106.1, 1043.4.
L-Im in oar abin itol [(2S,3S,4S)-3,4-Dih ydr oxy-2-(h ydr oxy-
m et h yl)p yr r olid in e, 1]. Lactam 8 (252 mg, 1.0 mmol) in
THF (5.0 mL) at 0 °C was treated with borane in THF (1.0 M,
15 mL, 15 mmol) and the reaction, under an atmosphere of
argon, brought to reflux and heated, with stirring, overnight.
The solvent was removed at reduced pressure and methanol
added to destroy unreacted borane. The methanol solution
was treated with aqueous hydrogen chloride (6 N, 1 mL),
slowly added dropwise, and, at room temperature, the solution
was stirred for an additional 30 min. Then, solid sodium
hydroxide was added until the solution was basic and the
product directly isolated (133 mg, 96% of theory) by aqueous
solution ion-exchange chromatography on DOWEX 50WX8-
100 and a final flash-chromatographic purification over a short
silica gel column where it eluted with a 50:20:20:10 mixture
of CH2Cl2:CH3CH2OH:CH3OH:NH4OH to yield material with
L-Im in olyxitol [(2S,3R,4S)-3,4-Dih ydr oxy-2-(h yd r oxym -
eth yl)p yr r olid in e, 1]. As described above for L-iminoarabi-
natol, L-iminoxylitol, and L-iminoribitol (24.9 mg, 0.18 mmol,
96%, [R]20 ) -12.9°, c ) 0.014 in CH3OH. 1H NMR
D
(C2H3O2H): 4.42 (ddd, J ) 7.5, 7.2, 3.9, 1H), 4.27 (dd, J ) 4.2,
3.9, 1H), 3.91(dd, J ) 12.0, 5.1, 1H), 3.81 (dd, J ) 12.0, 8.4,
1H), 3.66 (ddd, J ) 8.4, 5.1, 3.9, 1H), 3.45 (dd, J ) 12.0, 7.5,
1H), 3.12 (dd, J ) 12.0, 7.2, 1H); 13C NMR (C2H3O2H): 70.0,
69.8, 62.4, 57.7, 47.0; IR (neat film, cm-1) 3318.3, 1770.5,
1634.5, 1418.5, 1133.1. HRMS calcd for [C5H11NO3 + H]
134.0817184. Found [M + H]+ 134.081579) was obtained from
the lactam 13 (48.9 mg, 0.194 mmol).
([R]20 ) -11.9°, c ) 0.044 in CH3OH; for the enantiomer7a
D
[R]20 ) +7.8°, c ) 0.46 in H2O). 1H NMR (C2H3O2H): 4.06
D
(ddd, J ) 5.7, 3.9, 3.9, 1H), 3.77 (dd, J ) 3.9, 3.9, 1H), 3.67
(dd, J ) 11.4, 4.8, 1H), 3.58 (dd, J ) 11.7, 6.6, 1H), 3.25 (s,
NH), 3.08 (dd, J ) 12.3, 5.7, 1H), 2.97 (ddd, J ) 6.6, 4.8, 3.9,
1H), 2.80 (dd, J ) 12.3, 3.9, 1H); 13C NMR (C2H3O2H): 78.5,
77.0, 65.3, 61.5, 50.4; IR (neat film, cm-1) 3423, 1645.2, 1530.4,
1422.4, 1206.4, 1115.7. HRMS calcd for [C5H11NO3 + H]
134.0817184. Found [M + H]+ 134.081568. Found [M + H]+
134.081568. The hydrochloride, obtained on treatment of the
free base with 6 N HCl and recrystallized from methanol/
The hydrochloride obtained with 6 N HCl in ethanol had
[R]20D ) -13.2°, c ) 0.014 in H2O. 1H NMR (2H2O): 4.44 (ddd,
J ) 8.2, 4.8, 3.9, 1H), 4.29 (dd, J ) 4.2, 3.9, 1H), 3.93 (dd, J )
12.0, 4.8, 1H), 3.84 (dd, J ) 12.0, 8.2, 1H), 3.69 (ddd, J ) 8.2,
4.8, 4.2, 1H), 3.48 (dd, J ) 12.0, 7.5, 1H), 3.27 (s, NH), 3.15
(dd, J ) 12.0, 7.5, 1H); 13C NMR (2H2O): 70.0, 69.8, 62.5, 57.6,
47.0; IR (KBr pellet, cm-1) 3423.4, 1612.4, 1406.9, 1341.4,
1137.9, 1101.2, 1041.5.
acetone had [R]20 ) -28.8°, c ) 0.049 in H2O (lit.7a for the
D
enantiomeric hydrochloride salt, [R]20 ) +37.9°, c ) 0.53 in
D
H2O); H NMR (2H2O): 4.26 (ddd, J ) 4.5, 3.3, 2.4, 1H), 4.02
1
(dd, J ) 3.6, 3.3, 1H), 3.88 (dd, J ) 12.0, 5.7, 1H), 3.76 (dd, J
) 12.3, 8.1, 1H), 3.55 (ddd, J ) 8.1, 5.7, 3.9, 1H), 3.51 (dd, J
) 12.6, 4.5, 1H), 3.29 (dd, J ) 12.6, 2.4, 1H); 13C NMR (2H2O):
75.7, 74.3, 66.5, 58.9, 50.0; IR (KBr pellet, cm-1) 3352, 1625.9,
1112.8, 1059.4, 1019.3.
L-Im in oxylitol [(2S,3R,4R)-3,4-Dih yd r oxy-2-(h yd r oxy-
m eth yl)p yr r olid in e], 1. Lactam 9 (58.4 mg, 0.23 mmol) in
THF (6.0 mL) at 0 °C was treated with borane in THF (1.0 M,
3.5 mL, 3.5 mmol, 15 equiv) and the reaction, under an
atmosphere of argon, brought to reflux and heated, with
stirring, for 5 h. The solvent was removed at reduced pressure
and methanol added to destroy unreacted borane. The metha-
nol solution was treated with aqueous hydrogen chloride (6
N, 1 mL), slowly added dropwise, and, at room temperature,
the solution was stirred for an additional 30 min. Then, solid
sodium hydroxide was added until the solution was basic and
the product directly isolated (21.8 mg, 91% of theory) by ion-
Ack n ow led gm en t. We thank Professor G. W. J .
Fleet for providing authentic spectra and Professor F.
Davis both for fruitful discussions and use of a micropo-
larimeter.
Su p p or tin g In for m a tion Ava ila ble: The X-ray crystal
structure data for the lactam 8 and 1H and 13C NMR spectra
for the isomers 1 (free bases and hydrochloride salts) (see ref
20) (21 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O962028S