Glycosidase inhibitors: Synthesis of enantiomerically pure aza-sugars from Schiff base amino esters via tandem reduction-alkenylation and osmylation

Article abstract of DOI:10.1021/jo9820115

Nitrogen-in-the-ring 'aza-sugars' have been synthesized in enantiomerically pure form from the amino acid L-alanine in excellent overall yield. The O'Donnell's Schiff base of L-alanine methyl ester 9a was converted to aza-sugar L-fuco-1-deoxy-nojirimycin, 18, and to the epimer L-gulo-1- deoxy-nojirimycin, 20, in eight steps. The overall yields were 20 and 29%, respectively. The methodology for the efficient generation of silyl- and benzyl-protected (E)-3-lithio-2-propen-1-ols, and the use of these alkenyllithiums with iBu₅Al₂H as nucleophiles in the threo-selective tandem reduction-alkenylation of the Schiff base esters is described. Osmium- catalyzed cis-oxygenation of the resulting olefin products was selective for the galacto (fuco) amino polyols in all cases for the acyclic olefins, and was gulo-selective for the cyclic D-4,5-dihydropyridine pivalate, 17c. TEMPO- NaOCl was selective for oxidation of the primary position of the acyclic Schiff bases, and allowed for minimal protection/deprotection of the intermediates. The resulting N-benzhydryl heterocycles were easily deprotected with H₂-Pd at atmospheric pressure.

Full text of DOI:10.1021/jo9820115

J . Org. Chem. 1999, 64, 6147-6158
6147
Glycosid a se In h ibitor s: Syn th esis of En a n tiom er ica lly P u r e
Aza -Su ga r s fr om Sch iff Ba se Am in o Ester s via Ta n d em
Red u ction -Alk en yla tion a n d Osm yla tion
Robin Polt,* Dalibor Sames,† and J ason Chruma
Department of Chemistry, University of Arizona, Tucson, Arizona 85721
Received October 6, 1998
Nitrogen-in-the-ring “aza-sugars” have been synthesized in enantiomerically pure form from the
amino acid L-alanine in excellent overall yield. The O’Donnell’s Schiff base of L-alanine methyl
ester 9a was converted to aza-sugar L-fuco-1-deoxy-nojirimycin, 18, and to the epimer L-gulo-1-
deoxy-nojirimycin, 20, in eight steps. The overall yields were 20 and 29%, respectively. The
methodology for the efficient generation of silyl- and benzyl-protected (E)-3-lithio-2-propen-1-ols,
and the use of these alkenyllithiums with iBu5Al2H as nucleophiles in the threo-selective tandem
reduction-alkenylation of the Schiff base esters is described. Osmium-catalyzed cis-oxygenation
of the resulting olefin products was selective for the galacto (fuco) amino polyols in all cases for the
acyclic olefins, and was gulo-selective for the cyclic D-4,5-dihydropyridine pivalate, 17c. TEMPO-
NaOCl was selective for oxidation of the primary position of the acyclic Schiff bases, and allowed
for minimal protection/deprotection of the intermediates. The resulting N-benzhydryl heterocycles
were easily deprotected with H2-Pd at atmospheric pressure.
In tr od u ction
Glycosidases (glycosylhydrolases) are ubiquitous en-
zymes that are involved not only in the degradation of
carbohydrate foodstuffs1 but also in the processing of
eucaryotic glycoproteins2 and glycolipids.3 These enzymes
are essential for normal cellular development of all organ-
isms. Glycosidases can be classified in various ways:
according to their function, by their location in the organ-
ism, or by their mechanistic characteristics.4 Inhibitors
of glycosylhydrolases have provided mechanistic insight
into these enzymes and have proven to be important tools
for the elucidation of metabolic pathways to the various
glycoforms of glycoproteins and glycolipids.5
Nojirimycin was isolated from a fermentation broth in
19666 (Figure 1). The more stable reduction product,
F igu r e 1. Aza-sugars.
1-deoxy-nojirimycin was initially obtained from nojiri-
mycin by catalytic hydrogenation of the natural product.
possess glucosidase inhibitory activity.7 Significant in-
hibition of glucoamylase, microbial R- and â-glucosidases,
mammalian intestinal oligo- and disaccharidases were
subsequently reported.8 Efforts have focused on struc-
tural and stereochemical modifications of 1-deoxy-nojiri-
mycin for development of antihyperglycemic drugs9 and
have led to glycosidase inhibitors selective for particular
enzymes. “Aza-sugars” or “nitrogen-in-the-ring” sugar an-
alogues can be predicted to possess activity against gly-
cosidases specific for the parent sugars in many cases.15
The first synthesis of 1-deoxy-nojirimycin appeared in
1968 by Inouye et al.,10 required 10 steps and proceeded
in 22% overall yield. Later, Ganem et al.11 synthesized
1-deoxy-nojirimycin and the manno-epimer from the
Subsequently, both nojirimycin and 1-deoxy-nojirimycin
were isolated from other microorganisms and plants. By
1970 nojirimycin and 1-deoxy-nojirimycin were known to
* Correspondence should be addressed to the Department of Chem-
istry, University of Arizona, or to polt@u.Arizona.edu.
† Present address: Department of Chemistry, Columbia University,
New York City, NY 10027. E-mail: sames@chem.columbia.edu.
(1) Marshall, J . J . Adv. Carbohydr. Chem. Biochem. 1974, 30, 257-
370.
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(7) (a) Ishida, N.; Kumagai, K.; Niida, T.; Hamamoto, K.; Shomura,
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10.1021/jo9820115 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/05/1999

6148 J . Org. Chem., Vol. 64, No. 17, 1999
Polt et al.
F igu r e 2. Synthetic approach.
corresponding methyl glycosides in six steps and 28%
overall yield. Alteration of fucose expression12 has been
achieved with azafucose, first synthesized by Fleet, et
al.13 in 15 steps from R-D-methylglucoside. Other ap-
proaches from acyclic and cyclic chiral precursors have
also been employed,14-18 and Nishimura has reviewed
various synthetic approaches to this class of compounds.19
Ta n d em C-C/C-O Ap p r oa ch fr om r-Am in o Ac-
id s. Benzophenone imine-protected esters of R-amino
acids (O’Donnell’s Schiff bases) have been converted to
unsaturated â-amino alcohols via tandem reduction-
alkenylation (C-C bond formation)20,21 (Figure 2). Due
to the pseudosymmetry22 of fucose (6-deoxy-galactose),
exchange of -CH3 for -CH2OH in the amino acid
component (alanine vs serine) and -CH2OH for -CH3
in the alkenyllithium component (LiCHdCHCH3 vs
LiCHdCHCH2-OTBDMS) can provide access to D-fu-
cosamine or L-azafucose from an L-amino acid with the
same stereoselective two-step reaction sequence.
Selection of suitable functional group protection was
crucial for the efficient execution of this approach. The
benzophenone Schiff base protecting group masks the
acidic -NH2 protons in the C-C bond formation step and
also promotes chelation-controlled delivery of Grignards
and alkyllithiums to provide threo-selectivity. The imine
lone pair is similar to pyridine in terms of basicity and
metal-complexing ability23 and is an important stereo-
chemical control element in the tandem reduction-
alkenylation reaction by virtue of its steric bulk and at
the same time is a steric hurdle that inhibits enolization
of the imino ester.24
th r eo Ad d ition of F u n ction a lized Alk en yllith iu m s
(C-C Bon d F or m a tion ). Generation of a suitably pro-
tected 3-oxygenated-(E)-1-lithiopropene species in hydro-
carbon solvent was somewhat problematic. Hydroalumi-
nation25 of propargyl alcohol was unsuccessful due to
multiple additions to the triple bond, and hydroboration
with catechol borane26 did not yield any identifiable
products from the resulting black syrup. Therefore, we
explored hydrostannylation27 methods used by Seebach
et al.28 and J ung et al.29 The (E)-vinylstannanes 1a and
2 were obtained as the predominant products (Scheme
(11) (a) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985, 26,
1123-1126. (b) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985,
26, 4981-4984. For other efficient carbohydrate-based approaches,
see: (c) Vasella, A.; Voeffray, R. Helv. Chim. Acta 1982, 65, 1134-
1144 and references therein.
(12) (a) Hakomori, S. Cancer Res. 1985, 45, 2405-14. (b) Fukushima,
K.; Hirota, M.; Terasaki, P. I.; Wakisaka, A.; Togashi, H.; Chia, D.;
Suyama, N.; Fukushi, Y.; Nudelman, E.; Hakomori, S. Cancer Res.
1984, 44, 5279-5285. (c) Feizi, T. Glycoprotein oligosaccharides as
recognition structures; In Ciba Foundation Symp. Ser.; Wiley: Chich-
ester, 1989, Vol. 145, pp 62-79. (d) Hounsell, E. F.; Davies, M. J .;
Renouf, D. V. Glycoconjugate J . 1996, 13, 19-26. (e) Oettgen, E. F.,
Ed.; Gangliosides and Cancer; VCH Publishers: New York City, NY,
1989.
(13) Fleet, G. W. J .; Shaw, A. N.; Evans, S. V.; Fellows, L. E. J . C.
S. Chem. Commun. 1985; pp 841-842.
(14) For a review of monosaccharide syntheses from non-carbohy-
drate sources, including aza-sugars, see: Hudlicky, T.; Entwistle, D.
A.; Pitzer, K. K.; Thorpe, A. J . Chem. Rev. 1996, 96, 1195-1220.
(15) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1987, 52,
3337-3342.
Sch em e 1. cis- a n d tr a n s-Iod oa lk en es
(16) (a) J ohnson, C. R.; Golebiowski, A.; Schoffers, E.; Sundram, H.;
Braun, M.P. Synlett 1995, 313-314. (b) J ohnson, C. R.; Nerukar, B.
M.; Golebiowski, A.; Sundram, H.; Esker, J . L. J . C. S. Chem. Commun.
1995, 1139-1140. (c) J ohnson, C. R.; Golebiowski, A.; Sundram, H.;
Miller, M. W.; Dwaihy, R. L. Tetrahedron Lett. 1995, 36, 653-654. (d)
J ohns, B. A.; Pan, Y. T.; Elbein, A. D.; J ohnson, C. R. J . Am. Chem.
Soc. 1997, 119, 4856-4865.
(17) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res. 1993,
26, 182-190.
(18) Xu, Y,-M.; Zhou, W.-S. Tetrahedron Lett. 1996, 37, 1461-2.
(19) (a) Nishimura, Y. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed., Elsevier: New York, 1992, Vol. 10 (Part F). Also
see: (b) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199-
210. New “aza-sugars” with glycosidase activity continue to be
discovered as natural products: (c) Asano, N.; Kato, A.; Miyauchi, M.;
Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J .; Fleet, G. W. J . J .
Nat. Prod. 1998, 61, 625-628.
(20) (a) Polt, R.; Peterson, M. A Tetrahedron Lett. 1990, 31, 4985-
4988. (b) Polt, R.; Peterson, M. A.; DeYoung, L. J . Org. Chem. 1992,
57, 5469-5480. Other examples: (c) McGrane, P. L.; Livinghouse, T.
J . Am. Chem. Soc. 1993, 115, 11485-11489. (d) Yong, Y. F.; Lipton,
M. A. Bioorg. Med. Chem. Lett. 1993, 3, 2879-2882. (e) Golebiowski,
A.; J urczak, J . Synlett 1993, 241-245.
(21) (a) Sames, D.; Polt, R. J . Org. Chem. 1994, 59, 4596-4601. (b)
Sames, D.; Polt, R. Synlett 1995, 552-554. (c) Razavi, H.; Polt, R.
Tetrahedron Lett. 1998, 39, 3371-3374.
1). Subsequent iodine-tin exchange was easily accom-
plished with I2 in CH2Cl2 at room temperature with
+
(23) The pKBH of Ph2CdNH has been determined to be ∼7.2: (a)
Culbertson, J . B. J . Am. Chem. Soc. 1951, 73, 4818-4823. For stable
Ni(II) and Cu(II) complexes of these related Schiff bases, see: (b)
Dangel, B.; Clarke, M.; Haley, J .; Sames, D.; Polt, R. J . Am. Chem.
Soc. 1997, 119, 10865-10866. (c) Terekohava, M. I.; Belokon, Y. N.;
Maleev, V. I.; Chernoglazova, N. I.; Kochetkov, K. A.; Belikov, V. M.;
Petrov, E. S. Izv. Akad. Nauk SSSR 1986, 905-909.
(22) For a complete description of “dimensional analysis”, see: (a)
Hudlicky, T.; Natchus, M. G. In Organic Synthesis: Theory and
Applications; Hudlicky, T., Ed.; J AI Press: Greenwich, CT, 1993; pp
1-25. (b) Hudlicky, T. Chem. Rev. 1996, 96, 3-30.
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N.; Knuth, K.; LeClef, B.; Polt, R. L.; Bordwell, F. G.; Mrozack, S. R.;
Cripe, T. A. J . Am. Chem. Soc. 1988, 110, 8520-8525.

Glycosidase Inhibitors: Synthesis of Aza-Sugars
J . Org. Chem., Vol. 64, No. 17, 1999 6149
Sch em e 2. tr a n s-Br om oa lk en es
Sch em e 3. Li-Br a n d Li-I Exch a n ge Rea ction s
apparent retention of configuration, and the (E)-iodoal-
benzyl-protected bromoalkene 6b and the TBDMS-
kenes 3a and 4 were purified by vacuum distillation.
Similarly, the (Z)-iodoalkene 3b was obtained from the
minor (Z)-hydrostannylation product 1b in good yield.
Despite their well-deserved reputation for explosive
decomposition, a method based on 1-haloacetylenes30 also
worked quite well in our hands. Bromination of distilled
propargyl alcohol with potassium hypobromide at -5 °C
gave 1-bromo-propargyl alcohol in good yield, which was
subjected without purification to reduction with “Cl2AlH”
(LiAlH4 + 2 AlCl3) (Scheme 2). Only the (E)-isomer 5 was
obtained in 70% yield on a 30-gram scale. A similar
LiAlH4/AlCl3 reduction protocol of 1-iodo-propynol at
various temperatures resulted only in reductive removal
of iodine. Standard protection protocols yielded the
protected bromoalkene 6a .
Reduction-alkenylation in Et2O or THF has been
shown to result in a dramatic decrease in the stereose-
lectivity of the iBu5Al2H/R-Li addition sequence. Prepa-
ration of the lithio-alkenes in nonpolar solvents such as
hexane or toluene was crucial for preserving the chelation
control in this step. At the outset it was not clear whether
the presence of oxygen substitution on the alkenyllithium
would permit stereoselective reduction-alkenylation of
the Schiff base substrates with these functionalized
nucleophiles.
When the oxygen-substituted bromides 6a and 6b were
treated with tBuLi in hexanes, and subsequently added
to the reaction vessel with the iBu5Al2H‚9a at -78 °C,
only poor yields (∼20%) of the corresponding alcohols 10a
and 11a or 10b and 11b were isolated, and a great deal
of the reduction product 12 was observed (Scheme 3).
Seebach and Neumann31 reported some time ago that
bromoallylic alcohols in THF undergo facile lithiation
with nBuLi at the olefinic position R to the bromine.
Geminal elimination of LiBr then led to a vinylcarbene,
which rearranged to propargyl alcohol.32 Use of the
corresponding iodides proved to be a much more practical
solution in this case.
(25) Klunder, H. C. U.S. Patent 4,197,765, 493, 1978; Chem. Abstr.
1978, 88, P190216n.
(26) (a) Brown, H. C.; Gupta, S. K. J . Am. Chem. Soc. 1972, 94,
4370-4373. (b) Brown, H. C.; Hamaoka, T.; Ravindran, N. J . Am.
Chem. Soc. 1973, 95, 5786-5788.
(27) Groh, B. L. Tetrahedron Lett. 1991, 32, 7647-7650 and refer-
ences therein.
(28) (a) Leusink, A. J .; Budding, H. A.; Marsman, J . W. J . Orga-
nomet. Chem. 1969, 9, 285-294. (b) Meyer N.; Seebach, D. Chem Ber.
1980, 113, 1290-1303. (c) Kitano, Y.; Matsumoto, T.; Okamoto, S.;
Shimazaki, T.; Kobayashi, Y.; Sato, F. Chem. Lett. 1987, 1523-1526.
(29) J ung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851-
3854.
(30) (a) Kruglikova, R. I.; Kravets, L. P.; Unkovskii, B. V. Zh. Org.
Khim. 1975, 11, 263-267. (b) Bohlmann, F.; Rotard, W. Liebigs Ann.
Chem. 1982, 1216-1219.
(31) Neumann, H.; Seebach, D. Chem. Ber. 1978, 111, 2785-2812.
(32) Kobrich, G.; Trapp, H. Chem. Ber. 1966, 99, 680-688.

6150 J . Org. Chem., Vol. 64, No. 17, 1999
Polt et al.
F igu r e 3. Reductive alkenylation provides threo products.
F igu r e 4. “TAI” simplifies stereochemical assignment.
Ta ble 1. Red u ctive Alk en yla tion Yield s
method, which involved removal of the Schiff base with
aqueous HCl and isolation of the â-amino alcohol, fol-
lowed by cyclization to the oxazolidin-2-one (cyclic car-
bamate, Figure 4) with carbonyldiimidazole or another
phosgene equivalent. With care, the J 4,5 coupling constant
of the cyclic carbamate could then be related to the
erythro/ threo identity of the amino alcohol.35 This pro-
cedure was less than satisfactory due to the time involved
as well as to the uncertainty in the observed ratios
following manipulation of the Schiff base and amino
alcohol products.
Trapping of the cyclic oxazolidine form of the crude
â-hydroxy Schiff bases with the very reactive trichloro-
acetylisocyanate (TAI)36 proved to be a rapid and conve-
nient way to examine the pertinent J 4,5 coupling con-
stants. In addition to causing a difference in chemical
shift between the erythro and threo forms, the observed
J 4,5 coupling constant seemed to be consistently larger
for the threo products (Figure 4). The TAI reaction was
complete within seconds, was quantitative, and was
normally performed in the NMR tube just prior to
measurement; and without any of the isolation and
purification steps required in the previous method.
Proton integration of erythro/ threo mixtures was then
performed without the complication introduced by the
In contrast to the bromides, iodoalkenes 3a , 3b, and 4
underwent rapid Li-I exchange with tBuLi in hexanes
to provide stable solutions of 7a , 7b, and 8, which could
be stored and handled in the usual fashion.33 Treatment
of Schiff base 9a or 9b with iBu5Al2H (1:1 mixture of
iBu2AlH + iBu3Al)34 at -78 °C in CH2Cl2, followed by
addition of a lithiopropene provided the threo amino
alcohols 10a -10f in excellent yield and selectivity (>20:
1) (Figure 3). Yields for several reaction partners studied
are depicted in Table 1. In every case studied, the
reduction product corresponding to 12 was also observed,
but if the iBu5Al2H was added slowly with a syringe
pump, the amount of this byproduct was only 5-10%.
The threo selectivity and chemical yields did not suffer
from introduction of the oxygen atom into the alkenyl-
lithium substrates.
(35) Normally, J anti > J syn: (a) Seebach, D.; Beck, A. K.; Mukho-
padhlyay, T.; Thomas, E. Helv. Chim. Acta 1982, 65, 1101-1133. (b)
Kobayashi, S.; Isobe, T.; Ohno, W. Tetrahedron Lett. 1983, 24, 5079-
5082. But these vicinal coupling values may be ambiguous, or even
reversed: (c) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Chem.
Lett. 1987, 1531-1534. (d) Reference 20b.
Initially, the stereochemical configuration of several
amino alcohols was determined following a two-step
(33) Shriver, D. F.; Drezdzon, M. A. The Manipulation of Air-
Sensitive Compounds, 2nd ed.; J ohn Wiley & Sons: New York, 1986.
(34) (a) Eisch, J . J .; Rhee, S. G. J . Organomet. Chem. 1974, 42, C73-
C76. (b) Vestin, R.; Vestin, U.; Kowalewski, J . Acta Chem. Scand. A
1985, 39, 767-773.
(36) Trichloroacetylisocyanate, “TAI” is commercially available from
Aldrich Co. Synthesis: (a) Speziale, A. J .; Smith, L. R. J . Org. Chem.
1962, 27, 3742-3743. Use as in situ derivativation agent for NMR of
alcohols: (b) Goodlett, V.W. Anal. Chem. 1965, 37, 431-432. Thiols:
(c) Butler, P. E.; Mueller, W. H. Anal. Chem. 1966, 38, 1407-1408.

Glycosidase Inhibitors: Synthesis of Aza-Sugars
J . Org. Chem., Vol. 64, No. 17, 1999 6151
F igu r e 5. Osmylation provides galacto amino polyol acetates.
Ta ble 2. Osm yla tion Selectivities a n d Yield s
#
Schiff base
R1
R2
R3
galacto/ido ratioa
galacto product
isolated yieldb (%)
1
2
3
4
5
6
10a
10b
10e
10g
10h
10j
-H
-H
-OTBDMS
-OCH2Ph
-H
-H
6:1
4:1
6:1
3:1
9:1
6:1
13a
13b
13c
13c
13d
13e
60
52
60
60
50c
43
-H
-OTBDMS
-OTBDMS
-H
-H
-H
-OAc
-OPiv
-OPiv
-OTBDMS
-OTBDMS
-OTBDMS
a
b
1H NMR of crude acetate mixture. Isolated as acetates. c +20% recovered starting material.
Schiff base-oxazolidine tautomerism. As determined by
1H NMR of the crude TAI-mixtures, the reduction-
alkenylation methodology provided amino alcohols 10a -
10f with excellent stereoselectivity (>20:1 threo:erythro)
(Table 1).
Oxygen a tion of th e Olefin (C-O Bon d F or m a -
tion ). The well-known Stork/Kishi empirical rules for
substrate-controlled delivery of OsO4 to allylic systems
(“inside alkoxy effect”)37 was of great predictive value in
the stereoselective introduction of the diol to the threo
products 10.38 The exact mechanism of the osmylation
([2 + 2] vs [3 + 2] mechanism), the role of additional
ligands, and the origin of such π-facial differentiation in
oxygenated allylic systems have been debated exten-
sively.39 Kinetic isotope data on the reaction has been
subjected to differing interpretation.40 Stereoelectronic
arguments and the role of Os-substrate complexation
have been advanced.41 Houk suggested σ-acceptors would
F igu r e 6. Osmylation geometries.
occupy antiperiplanar (“outside”) or eclipsed (“inside”)
position and the best σ-donor would be anti to the
electrophile to facilitate olefin HOMO-electrophile LUMO
interactions.42 Most workers have concluded that sterics
have a strong influence on the reaction, and the use of
substrate-controlled delivery of OsO4 with chiral sub-
strates is both predictable and useful.43
The osmylation conditions of Yamamoto, et al.,44 modi-
fied by the addition of 1 equiv of CH3SO2NH2 as described
by Sharpless and Gobel45 were explored (Figure 5 and
Table 2). A mixture of diastereomeric galacto (major) and
ido (minor) configurations was obtained after acylation
of the crude diol or triol mixtures. Both OsO4 and K2-
OsO2(OH)2 (potassium osmate) were used as catalysts
and gave identical results. The reactions did not reach
completion without the addition of CH3SO2NH2. The
substitution of potassium glycolate for CH3SO2NH2 had
a strongly inhibitory effect on the reaction rate, essen-
tially stopping the reaction entirely. The addition of
pyridine, normally required for this reaction, also had a
negative effect on the rate. The basic character of the
aqueous medium was suitable for the acid-sensitive imine
substrates, but the substitution of NaHCO3/K2CO3 for
K2CO3 was superior (vide infra).
(37) (a) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron Lett. 1983,
24, 3943-3946. (b) Stork, G.; Kahn, M. Tetrahedron Lett. 1983, 24,
3951-3954. (c) Cha, J . K.; Kishi, Y. Tetrahedron 1984, 40, 2247-2255.
(d) Houk, K N.; Moses, S. R. Wu, Y-D.; Rondan, N. G.; J ager, V.;
Schohe, R.; Fronczek, R. J . Am. Chem. Soc. 1984, 106, 3880-3882. (e)
Vedejs, E.; McClure, C. K. J . Am. Chem. Soc. 1986, 108, 1094-1096.
(f) Cha, J . K.; Kim, N. S. Chem. Rev. 1995, 95, 1761-17695.
(38) (a) Hauser, F. M.; Ellenberger, S. R.; Clardy, J . C.; Bass, L. S.
J . Am. Chem. Soc. 1984, 106, 2458-2459. (b) Brimacombe, J . S.;
Hanna, R.; Kabir, A. K. M. S.; Bennett, F.; Taylor, I. D. J . Chem. Soc.,
Perkin Trans. 1 1986, 815-828. (c) DeNinno, M. P.; Danishefsky, S.
J .; Schulte, G. J . Am. Chem. Soc. 1988, 110, 3925-3929. (d) Kaldor,
S. W.; Evans, D. A. J . Org. Chem. 1990, 55, 1698-1700. (e) Marshall,
J . A.; Seletsky, B. M.; Luke, G. P. J . Org. Chem. 1994, 59, 3413-3420.
For reviews of earlier osmylations, see: (f) Schroder, M. Chem. Rev.
1980, 80, 187-213. For reviews of ligand-catalyzed osymylations,
see: (g) Kolb, H. C.; Van Nieuwenhze, M.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483-2547.
(39) A Reaction Under Scrutiny; Rouhi, A. M. Chem. Eng. News, 3
November 1997, 23-25.
(40) (a) Corey, E. J .; Noe, M. C.; Grogan, M. J . Tetrahedron Lett.
1996, 37, 4899-48102. (b) Corey, E. J .; Noe, M. C. J . Am. Chem. Soc.
1996, 118, 11038-11053. (c) Nelson, D. W.; Gypser, A.; Ho, P. T.; Kolb,
H. C.; Kondo, T.; Kwong, H.-L.; McGrath, D. V.; Rubin, A. E.; Norrby,
P.-O.; Gable, K. P.; Sharpless, K. B. J . Am. Chem. Soc. 1997, 119,
1840-1858. (d) Gobel, T.; Sharpless, K. B. ref 45. (e) DelMonte, A. J .;
Haller, J .; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner,
T.; Thomas, A. A. J . Am. Chem. Soc. 1997, 119, 9907-9908. For a
review of metallaoxetanes as possible intermediates in oxygen transfer
reactions, see: (f) J orgensen, K. A.; Schiott, B. Chem. Rev. 1990, 90,
1483-1506.
(41) (a) J ohnson, C. R.; Barbachyn, M. R. J . Am. Chem. Soc. 1984,
106, 2459-2461. (b) J ohnson, C. R.; Tait, B. D.; Cieplak, A. S. J . Am.
Chem. Soc. 1987, 109, 5875-5876. (c) Vedejs, E.; Dent, W. H. J . Am.
Chem. Soc. 1989, 111, 6861-6862. (d) Halterman, R. L.; McEvoy, M.
A. J . Am. Chem. Soc. 1992, 114, 980-985.
(42) (a) Houk, K. N.; Duh, H.-Y.; Wu, Y.-D.; Moses, S. R. J . Am.
Chem. Soc. 1986, 108, 2754-2755. (b) Haller, J .; Strassner, T.; Houk,
K. N. J . Am. Chem. Soc. 1997, 119, 8031-8034.
(43) For related osmylation examples see: (a) Hoveyda, A. H.; Hale,
M. R. J . Org. Chem. 1992, 57, 1643-1645. (b) Tschamber, T.;
Backenstrass, F.; Neuburger, M.; Zehnder, M.; Streith, J . Tetrahedron
1994, 50, 1135-1152. (c) Arjona, O.; Candilejo, A.; deDios, A.; de la
Pradilla, R. F.; Plumet, J . J . Org. Chem. 1992, 57, 6097-6099. (d)
Panek, J . S.; Zhang, J . J . Org. Chem. 1993, 58, 294-296. (e) Saito, S.;
Morikawa, Y.; Moriwake, T. J . Org. Chem. 1990, 55, 5424-5426. (f)
King, S. B.; Ganem, B. J . Am. Chem. Soc. 1994, 116, 562-570.
(44) Minato, M.; Yamamoto, K.; Tsuji, J . J . Org. Chem. 1990, 55,
766-768.
(45) Gobel, T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1993,
32, 1329-1331.

6152 J . Org. Chem., Vol. 64, No. 17, 1999
Polt et al.
F igu r e 7. Osmylation of pivalates provides galacto amino polyols with selective protection.
Ta ble 3. Osm yla tion Ad d itive Effects on ga la cto Selectivity
#
Schiff base
R1
additive
none
(DHQ)2-PHAL
none
quinuclidine
(DHQD)2-PHAL
(DHQ)2-PHAL
NaHCO3
galacto/ido ratioa
galacto product
isolated yieldb (%)
1
2
3
4
5
6
7
10h
10h
10i
10i
10i
10i
10i
-H
-H
9:1
14:1
6:1
14d
14d
14e
14e
14e
14e
14e
50
60
43-50
69
60
54-60
67
-OTBDMS
-OTBDMS
-OTBDMS
-OTBDMS
-OTBDMS
9:1
8-9:1
11-20:1
>20:1
a
b
1H NMR of crude alcohol mixture. Isolated as alcohol.
Acylation of 10e provided the imine 10g, which gave
a poorer 3:1 galacto mixture still favoring 13c (entry 4).
Pivalylation of 10a with pivaloyl chloride, pyridine, and
DMAP yielded compound 10h in 89% yield. Osmylation
of this pivalate with 1.2 mol % K2OsO2(OH)2 in the
presence of 1 equiv of MeSO2NH2 yielded 20% of recov-
ered starting material and 50% of the desired galacto
isomer 13e (entry 5). The galacto-ido selectivity was
improved to 9:1. These results can be rationalized by the
oxygenation of the cyclic oxazolidine tautomer46 in entries
1, 2, and 3, which may oxygenate more selectively than
the open-chain compound (TS†-1 vs TS†-2, Figure 6).
Upon O-acylation, this cyclic structure no longer exists,
eliminating TS†-2 as a possibility. The increased steric
bulk of the pivalate would be expected to enhance the
selectivity. Another possibility is that the imine itself
could have directed the osmylation reaction intramolecu-
larly via TS†-3. This possibility was appealing given the
strong negative effect that pyridine had on the reaction
rate. The effect of bulky, sp3-hybridized amine ligands
on the reaction was explored next.
1, entry 6). However, 10i and the pseudo-enantiomeric
(DHQD)2-PHAL also resulted in increased selectivity,
(8-9:1, entry 5). Achiral quinuclidine increased the
selectivity to 9:1 in a similar fashion (entry 4). This result
indicates that, to the extent that the substrate imine
complexed with OsO4,49 it did not aid in the stereoselec-
tivity of diol formation and that it was unlikely that
intramolecular delivery of OsO4 had occurred. It is
possible that the interaction between OsO4 and the Schiff
base nitrogen may unfavorably compete with the stereo-
electronic effects of the allylic ester moiety, and the
presence of tertiary amines may preclude such participa-
tion.
Since Schiff base alcohols exist predominantly in the
cyclic oxazolidine form, the question as to which form is
the actual reactive species must be considered. Clearly,
this complication is eliminated by the protection of the
allylic alcohol group prior to osmylation (substrates 10g,
10h , and 10i). All of the substrates studied gave the same
anti selectivity (galacto product), and these results can
be rationalized by the models proposed by Stork,39b
Kishi,39a,c Vedejs,39e or Houk39d,44b for the osmylation
transition state (Figure 7). The pivaloyl group that
enhances selectivity must be opposite to the osmium
reagent during the initial attack.
Several researchers have used chiral amines for reagent-
controlled osmylation of chiral substrates in an effort to
enhance or override natural substrate reactivity with
various degrees of success.47 The chiral dimeric (DHQ)2-
PHAL ligand48 was added (3 mol %) to the reaction
mixture with 10h , and resulted in an increased chemical
yield of the galacto product (50 f 60%), and an increase
in stereoselectivity (9:1 f 14:1, Entries 1 and 2, Table
3). The C-4 protons (i.e., CH bearing the O-pivaloyl group)
for the galacto and ido diol isomers could be easily
Finally, it should be pointed out that substitution of a
NaHCO3/K2CO3 mixture for K2CO3 (entry 7) slowed the
rate of base-catalyzed pivalate migration from its initial
position on the allylic OH to the newly formed OH groups
introduced by osmylation. This transesterification re-
duced the isolated yield of galacto products, thus reducing
the observable stereoselectivity. Performing the osmyla-
tion at a slightly lower pH (i.e., with NaHCO3/K2CO3)
slowed the rate of the transesterification without ap-
preciably slowing the rate of osmylation.
1
distinguished in the crude H NMR spectra (5.00 vs 5.10
ppm), and quantified by integration for these compounds.
When substrate 10i was osmylated in the absence of a
chiral auxiliary it provided a 6:1 mixture of diastereomers
(entry 3), and as expected in the presence of the (DHQ)2-
PHAL ligand the stereoselectivity was improved (11-20:
Cycliza tion (C-N Bon d F or m a tion ). The base-
stable methoxymethyl (MOM) group was initially chosen
(46) (a) Paukstelis, J . V.; Hammaker, R. M. Tetrahedron Lett. 1968,
3557-3560. (b) Wijayaratne, T.; Collins, N.; Li, Y.; Bruck, M. A.; Polt,
R. Acta Crystallogr. 1993, B49, 316-320.
(49) For examples of N f Os induced chirality, see: (a) Hentges, S.
G.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 4263-4265. (b)
Tokles, M.; Snyder, J . K. Tetrahedron Lett. 1986, 27, 3951-3954. (c)
Yamada, T.; Narasaka, K. Chem. Lett. 1986, 131-134. (d) Tomoika,
K.; Nakajima, M.; Koga, K. J . Am. Chem. Soc. 1987, 109, 6213-6215.
(e) Annuziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, Stefenelli, S.
Tetrahedron Lett. 1987, 28, 3139-3142. (f) Hirama, M.; Oishi, T.; Ito,
S. J . C. S. Chem. Commun. 1989, 665-666. (g) Corey, E. J .; J ardine,
P. D.; Virgil, S.; Yuen, P. W.; Connell, R. D. J . Am. Chem. Soc. 1989,
111, 9243-9244.
(47) (a) Annuziata, R.; Cinquini, M.; Cozzi, F. Tetrahedron 1988,
44, 6897-6902. (b) Oishi, T.; Iida, K.; Hirama, M. Tetrahedron Lett.
1993, 34, 3573-3576. (c) Makoto, I.; Kinsho, T.; Smith, A. B.
Tetrahedron Lett. 1995, 36, 2199-2202.
(48) Amber, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.;
Davis, W. D.; Hartung, J .; J eong, K.-S.; Ogino, Y.; Shibata, T.;
Sharpless, K. B. J . Org. Chem. 1993, 58, 844-849.

Glycosidase Inhibitors: Synthesis of Aza-Sugars
J . Org. Chem., Vol. 64, No. 17, 1999 6153
Sch em e 4. Red u ctive Am in a tion w ith MOM P r otection (fu co-Nor jir im ycin )
Sch em e 5. Selective Oxid a tion of “Nea r ly Na k ed Tr iol”
Sch em e 6. Red u ctive Am in a tion of En a l (gu lo-Nor jir im ycin )
for protection of the newly formed diol. (Scheme 4)
Fluoride-catalyzed desilylation of 14d proceeded to give
the crystalline triol 15b. Without purification, the nearly-
naked triol was subjected to oxidation with TEMPO/
NaOCl50 to provide the fucose derivative 16b. This
compound could be isolated, but the best yields were
obtained when it was immediately subjected to the next
reaction. Reduction of this intermediate at pH 5 as before
led to imine reduction and cyclization to produce the aza-
fucose diol 17b. Saponification of the pivalate and hy-
drogenolysis of the N-benzhydryl protection was straight-
forward, leading to L-fuco-1-deoxy-nojirimycin,13 18 in
excellent yield.
To illustrate a slightly different approach to aza-
sugars, the geometric isomer, 10d , was converted to
L-gulo-1-deoxy-nojirimycin in seven steps (Scheme 6).
Pivaloylation led to the compound 10j, which was depro-
tected and oxidized to enal 16c in excellent yield. Reduc-
tive amination as before provided the unsaturated pi-
Treatment of diol 14d with MOM-Cl in CH2Cl2 and
Hu¨nig’s base in the normal fashion resulted in rapid
acetal formation at one hydroxyl, but proceeded slowly
to the desired fully protected amino tetrol 15a . De-
silylation and Swern oxidation proceeded smoothly to the
aminofucose derivative 16a . While the cyclization pro-
tocol was successful, protection of the vicinal diol system
was not very efficient.
The reduction of benzophenone imines to the corre-
sponding N-benzhydrylamines with NaBH3CN at pH 7
works well when a reducible aldehyde is not present. At
this pH, the aldehyde of 16a is selectively attacked. By
running this same reaction under acidic conditions (pH
5), the resulting iminium ion was reduced selectively in
the presence of the aldehyde. This led to rapid cyclization
and further reduction (reductive amination) to the pro-
tected aza-fucose 17a . Given the problems involved in
MOM protection, we abandoned this approach for a more
adventurous route that omitted protection and deprotec-
tion of the 2,3-diol functionality entirely. (Scheme 5).
(50) (a) Siedlecka, R.; Skarzewski, Mlochowski, J . Tetrahedron Lett.
1990, 31, 2177-2180. (b) Leanna, M. R.; Savin, T. J .; Morton, H. E.
Tetrahedron Lett. 1992, 33, 5029-5032.

6154 J . Org. Chem., Vol. 64, No. 17, 1999
Polt et al.
4: 1H NMR (250 MHz, CDCl3) δ E-isomer 7.39-7.25 (m,
5H), 6.66 (dt, J ) 14.6, 5.7 Hz, 1H), 6.40 (dt, J ) 14.6, 1.5 Hz,
1H), 4.51 (s, 2H), 3.95 (dd, J ) 5.6, 1.5 Hz, 2H); Z-isomer: 4.22
(dd, J ) 5.3, 1.8 Hz, 2H); terminal isomer 4.15 (t, J ) 1.8 Hz,
2H).
(E)-3-Br om o-2-p r op en e-1-ol (5). Essentially, the proce-
dure of Kruglikova, et al.30 was used. CAUTION: 1-Halo-
propynes are potentially explosive. Do not heat these com-
peridine 17c. Osmylation led to diol 19 possessing the
gulo configuration. Deprotection as before led to the
epimeric L-gulo-deoxy-nojirimycin, 20.
Con clu sion s
Stereoselective tandem reduction-alkenylation of
O’Donnell’s Schiff bases, followed by pivaloylation and
osmylation of the resulting allylic threo amino alcohols
is a chemically efficient and stereoselective approach to
aza-sugars (1-deoxy-norjirimycins) of the galacto config-
uration. In summary, the synthesis of L-fuco-1-deoxy-
nojirimycin, 18, was accomplished in eight steps from the
Schiff base 9a in 20% yield. Similarly, L-gulo-1-deoxy-
nojirimycin, 20, was synthesized from the same starting
material in 29% yield in 8 steps by varying only the olefin
geometry in the starting material and the order of the
chemical operations. This work demonstrates the syn-
thetic utility inherent in amino acid-based acyclic ste-
reocontrol facilitated by the benzophenone Schiff bases
and appropriately functionalized organometallics. This
work illustrates a powerful approach to amino polyols
and related complex natural products.
pounds. Perform these operations behind
a blast shield.
Molecular Br2 (48.0 g, 300 mmol) was added to a vigorously
stirring solution of 45 g KOH in 120 mL of water at -5 °C.
The yellow solution was kept at 0 °C and added dropwise to
propargyl alcohol (17.83 g, 1.06 equiv; freshly distilled) in 39
mL of H2O at -7-0 °C. The addition took approximately 3 h.
The mixture was warmed to 10 °C and then extracted 4 times
with Et2O. The ether layer was washed with Na2S2O3 and
dried over K2CO3, and the solvent was removed to provide
28.50 g of the crude 1-bromopropyne-3-ol. DO NOT DISTILL!
A 2L flask was charged with LiAlH4 (20.3 g, 2.0 equiv) and
AlCl3 (53.5 g, 1.0 equiv). Anhydrous Et2O (270 mL, distilled
from K/Na/benzophenone) was carefully added at -5 °C with
stirring. The crude bromoacetylene (DO NOT DISTILL!),
prepared in the first step, was added dropwise, and the
mixture was refluxed for 4 h. The reaction was quenched with
200 mL of wet Et2O (H2O saturated), followed by 20 mL of
H2O and 20 mL of 5% NaOH at -10 °C. An additional 60 mL
of H2O was added to break up the solid mass. The liquid was
decanted and extracted three times with Et2O. The Et2O layer
was dried over K2CO3 and the solvent was removed. The crude
material was vacuum distilled (67 °C, 84 mmHg) to yield pure
bromoalkene 5 (27.7 g, 70% from propargyl alcohol).
Exp er im en ta l Section
Gen er a l Meth od s. All air- and moisture-sensitive reactions
were performed under an argon atmosphere in flame-dried
reaction flasks using modified Schlenk methods. All solvents
were dried over the standard drying agents and freshly
distilled prior to use. For flash chromatography, 400-230 mesh
silica gel 60 was employed. All compounds described were
characterized by IR as well as 1H (250 or 300 MHz for 1-D
spectra, COSY were obtained at 500 MHz) and 13C NMR
spectroscopy (62.9 MHz). Optical rotations were measured
using the Na-D line. Elemental analyses (CHN) were per-
formed by Desert Analytics, Tucson, AZ.
5: 1H NMR (250 MHz, CDCl3) δ 6.36 (m, 2H), 4.13 (apparent
d, 2H), 2.51 (1H, OH).
(E)-3-ter t-Bu tyldim eth ylsilyloxy-1-lith io-1-pr open e (7a).
Distilled E-TBDMSO-CH2CHdCH-I, 3a (4.00 mmol, 1.20 g)
and 8 mL of hexane were cooled to 0 °C, and tBuLi (4.8 mL,
1.7 M in pentane, 2.04 equiv) was added dropwise with
vigorous stirring. After 30 min at O° C a white precipitate
(LiBr) was observed. It is strongly recommended to monitor
temperature inside the reaction vessel for larger scales.
(Z)-3-ter t-Bu tyldim eth ylsilyloxy-1-lith io-1-pr open e (7b).
A solution of 7b was prepared from Z-TBDMSO-CH2CHd
CH-I, 3b (4.00 mmol, 1.20 g), using the same protocol used
to prepare 7a .
(E)-3-Ben zyloxy-1-lith io-1-p r op en e (8). A solution of 8
was prepared from E-PhCH2O-CH2CHdCH-I, 4 (4.00 mmol,
1.10 g), using the same protocol used to prepare 7a .
Meth yl N-(d ip h en ylm eth ylen e)-L-a la n in a te (9a ), m eth -
yl O-ter t-bu tyldim eth ylsilyl-N-diph en ylm eth ylen e-L-ser i-
n a te (9b): prepared as previously described.20b,51
(E)-1-ter t-Bu tyld im eth ylsilyloxy-3-iod o-2-p r op en e (3a ),
(Z)-1-ter t-Bu tyld im eth ylsilyloxy-3-iod o-2-p r op en e (3b).
O-tert-butyldimethylsilylpropynol (20.0 g, 117 mmol), nBu3-
SnH (63.2 mL, 153 mmol, 1.3 equiv) and AIBN (150 mg) were
stirred and heated at 110-130 °C for 2 h.28,29 The mixture was
distilled in vacuo. An excess of nBu3SnH can be separated as
the first fraction (65-70 °C, 0.4 mmHg). The second fraction
(100-130 °C) yielded 53.68 g (99%) of a mixture of vinylstan-
nanes ((E)-1a :(Z)-1b:terminal 69:16:15). The mixture of vinyl-
stannanes (53.68 g, 116 mmol) was dissolved in 700 mL of
CH2Cl2, and a solution of I2 in CH2Cl2 (32.41 g, 1.1 equiv in
900 mL of CH2Cl2) was added dropwise at rt until the solution
remained brown. The mixture was washed with saturated
Na2S2O3 and H2O and dried over K2CO3. The solvent was
removed, and the crude product was purified by Kugelrohr
distillation. The first fraction (58-61 °C, 0.4 mmHg) yielded
21.0 g of vinyliodides ((E)-3a :(Z)-3b:terminal 3:1:1) and the
second (61-65 °C, 0.4 mmHg) yielded E-enriched vinyliodides
((E)-3a :(Z)-3b:terminal 8:1:1). Total yield was 84%. A second
distillation through a 2-cm column provided reasonably pure
3a . The product was stored in a brown reagent bottle under
argon at low temperature (-20 °C) in the dark (freezer) with
a piece of copper wire.
(4S,5S,2E)-5-Am in o-N-d ip h en ylm eth ylen e-1-O-ter t-bu -
tyld im eth ylsilyl-2-h exen -1,4-d iol (10a ). Schiff base ester 9a
(22.3 mmol, 6.63 g) and 220 mL of CH2Cl2 were cooled to -78°
with stirring and 1.1 equiv iBu5Al2H (49.0 mL of 0.5 M solution
in hexane) was added via syringe pump over 2 h. After the
iBu5Al2H addition was complete, 3.0 equiv E-1-lithio-3-tert-
butyldimethylsilyloxy-1-propene, 7a (20.0 g 3a , 80.2 mL 1.7
M tBuLi, 133 mL of hexanes) was slowly cannulated into the
reaction flask. The reaction was stirred overnight at -78 °C
and then warmed to rt. After stirring 3 h at rt, the reaction
was cooled to 0 °C and quenched by cautious addition of wet
ether followed by 20 mL of 1% NaHCO3. The reaction mixture
was extracted with Et2O, dried over K2CO3 and filtered
through Celite, and the solvent was removed in vacuo. The
product was purified via flash chromatography (20% EtOAc/
hexanes/0.1%NEt3) to provide pure 10a (6.40 g, 70%).
1
E-3a : H NMR (250 MHz, CDCl3) δ 6.58 (dt, J ) 14.3, 4.4
Hz, 1H), 6.27 (dt, J ) 14.5, 1.8 Hz, 1H), 4.09 (dd, J ) 4.7, 1.8
Hz, 2H), 0.88 (s, 9H), 0.05 (s, 6H).
Z-3b: 4.22 (dd, J ) 5.3, 1.8 Hz, 2H).
1
10a : H NMR (Table 4); 13C NMR (Table 5); IR (neat) νmax
Ter m in a l isom er : 4.15 (t, J ) 1.8 Hz); 13C NMR (250 MHz,
CDCl3) δ 136.69 (C3), 106.06 (C2), 63.24 (C1), 25.80 (tBu),
-5.40 (SiMe).
3315.1, 3048.3, 2937.3 (C-H), 1662.9 (CdC), 1584.3, 1350.0
(C-O); [R]D 4.4° (c ) 0.1, CHCl3).
(4S,5S,2E)-5-Am in o-N-d ip h en ylm eth ylen e-1-O-ben zyl-
2-h exen -1,4-d iol (10b). The Schiff base ester 9a (1.0 mmol,
(E)-1-Ben zyloxy-3-iod o-2-p r op en e (4). Prepared from
PhCH2OCH2CCH (2 f 4) by following the same procedure
used for the TBDMS-protected vinyliodide 3a . The product
(105 °C, 0.5 mmHg) was obtained in 80% yield as an 8:1
mixture of E- and Z-isomers.
(51) O’Donnell, M. J .; Polt, R. L. J . Org. Chem. 1982, 47, 2663-
2666.

Glycosidase Inhibitors: Synthesis of Aza-Sugars
Ta ble 4. 1H NMR Da ta for Acyclic Com p ou n d s (250 MHz, CDCl3)
Chemical Shifts (ppm)
J . Org. Chem., Vol. 64, No. 17, 1999 6155
10a
10b
10d
10h
10i
13a
13b
14d
14e
15a
15b
16a
16c
H1
H′1
H2
H3
H4
H5
H6
4.13
4.13
5.79
5.51
3.89
2.95
1.19
4.00
4.00
5.87
5.60
3.92
3.00
1.21
4.46
4.36
5.72
5.22
5.62
3.56
1.14
4.17
4.17
5.84
5.64
5.45
3.57
1.13
4.11
4.11
5.75
5.60
5.44
3.71
3.78
3.56
3.43
5.13
5.40
5.24
3.64
0.91
3.47
3.39
5.35
5.43
5.25
3.64
1.19
3.68
3.68
3.48
4.17
4.94
3.92
1.13
3.66
3.69
3.46
4.04
5.00
4.00
3.87
3.62
3.62
3.73
4.01
5.51
3.86
1.1
3.86
3.71
3.93
4.15
4.94
3.52
1.12
9.63
10.14
3.88
4.16
5.41
3.94
1.10
6.01
6.29
6.01
3.62
1.08
Coupling Constants (Hz)
J H,H
10a
10b
10d
10h
10i
13a
13b
14d
14e
15a
15b
16a
16c
1,1′
1′,2
1,2
2,3
3,4
4,5
5,6
13.8
5.9
5.7
11.2
8.8
7.6
10.4
5.8
5.3
2.7
7.5
4.4
nd
10.3
6.1
5.2
2.8
7.6
4.5
6.5
11.3
5.7
4.4
nd
9.6
3.8
6.6
5.6
5.6
15.4
7.7
4.0
6.3
4.3
4.3
15.3
6.9
7.2
6.5
4.5
15.4
7.9
7.9
6.3
4.0
15.2
6.4
nd
7.2
0.5
9.5
3.7
6.3
6.6
nd
1.0
2.7
5.8
5.8
6.5
7.8
11.4
9.4
nd
6.6
∼0
3.6
3.6
7.3
6.5
9.3
3.5
6.2
6.7
nd
Ta ble 5. 13C NMR Sh ifts for Acyclic Com p ou n d s (62.5 MHz, CDCl3)
10a
10b
10d
10h
13a
13b
14d
15a
15b
16a
16c
C-1
C-2
C-3
C-4
C-5
C-6
63.0
131.2
134.7
70.0
59.7
16.0
69.9
73.9
nd
nd
75.0
60.1
17.9
63.0
129.8
133.6
77.5
60.2
18.3
67.3
72.6
73.1
70.2
55.9
17.9
68.6
73.1
73.4
70.1
56.9
18.5
63.8
70.0
71.4
68.6
58.3
15.2
62.6
74.9
76.2
78.5
57.3
18.7
65.3
69.6
71.1
71.6
58.4
14.9
201.7
82.3
76.2
74.5
56.5
16.6
191.5
136.4
139.3
73.0
59.6
17.7
130.0
131.7
72.1
59.7
16.0
1
267 mg) and 10 mL of CH2Cl2 were cooled to -78° and 1.1
equiv iBu5Al2H (2.2 mL of 0.5 M solution in hexane) was added
via syringe pump over 15-20 min. After addition was com-
plete, 3.0 equiv (E)-1-lithio-3-benzyloxy-1-propene, 8, was
slowly cannulated into the reaction flask. The reaction was
stirred for 1 h at -78 °C, then warmed to rt. After stirring 1
h at rt, the reaction was cooled and quenched by adding wet
ether (saturated with H2O) and 1 mL of 1% NaHCO3. The
reaction mixture was extracted with Et2O, dried over K2CO3
and filtered through Celite, and the solvent was removed in
vacuo. The product was purified via flash chromatography
(20% EtOAc/hexanes/0.1%NEt3) to provide pure 10b (259 mg,
60%).
10j: H NMR (CDCl3) δ 7.60-7.15 (m, 10H), 5.72 (pseudo
q, 1H), 5.61 (pseudo t, J ) 8.8 Hz, 1H), 4.46 (ddd, J ) 1.7, 5.9,
1
13.8 Hz, /2AB, 1H), 4.36 (ddd, J ) 1.8, 5.7, 13.8 Hz, 1/2AB),
3.56 (pseudo q, 1H), 1.14 (d, CH3), 1.11 (s, 9H), 0.88 (s, 9H),
0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3) δ 177.16 (CdO),
136.67, 135.70, 129.90, 128.49, 128.40, 127.96, 127.72, 125.34
(aromatic), 74.97 (CH-O), 73.94 (CH2-O), 60.06 (CH-N),
27.19 (tBu), 25.90 (tBu), 17.93 (CH3), -5.19 (SiCH3); IR (neat)
νmax 2956.3 (C-H), 1731.7 (CdO), 1631.3 (CdC), 1352.1 (C-
O); [R]D 7.3 (c ) 0.07, CHCl3).
(4S,5R)-4-Meth yl-5-[(E)-1-p r op en -1-yl]-2-oxa zolid in on e
(see F igu r e 4). Imino alcohol 10f (251 mg, 0.90 mmol) was
hydrolyzed with 3% HCl in 1 mL THF for 1 h, extracted with
CH2Cl2 to remove Ph2CdO, made basic with NaOH, and
extracted with CH2Cl2. After drying and filtration, solvent was
removed in vacuo, a portion (45 mg, 0.39 mmol) was dissolved
in 1.5 mL of dry THF, and carbonyldiimidazole (CDI, 91 mg,
0.56 mmol) was added. After stirring for 2 days at rt (TLC),
the solvent was removed, and the crude material was purified
via flash chromatography (50% EtOAc/hexanes) to yield the
pure oxazolidinone (47 mg, 85%) as a colorless oil. 1H NMR
(250 MHz, CDCl3) δ 5.85 (ddq, J ) 15.2, 6.6, 0.7 Hz), 5.51 (m,
1H), 4.41 (pseudo t, J ) 7.7 Hz; J 4,5 ) 7.5 Hz determined via
decoupling of the 1.24 ppm CH3); 3.61 (m, 1H), 1.72 (dd, J )
6.6, 1.4 Hz, 3H); 1.24 (d, J ) 6.2 Hz, 3H); 13C NMR (APT,
CDCl3) δ 132.65, 126.67 (CHdCH), 85.08 (CH-O),54.14 (CH-
N), 19.26, 17.76 (Me).
1
10b: H NMR (Table 4); 13C NMR (Table 5); IR (neat) νmax
3152.3 (C-H), 2930.2 (C-H), 1645.5 (CdC), 1326.7 (C-O). [R]D
+3.1° (c ) 0.1, CHCl3).
(4S,5S,2E)-5-Am in o-1-O-ter t-b u t yld im et h ylsilyl-N-d i-
ph en ylm eth ylen e-4-O-pivaloyl-2-h exen -1,4-diol (10h ). The
alcohol 10a (820 mg, 2.0 mmol) and DMAP (48.8 mg, 0.40
mmol) were dissolved in 8 mL of pyridine. Pivaloyl chloride
(1.48 mL, 12 mmol) was added dropwise via syringe while
stirring the mixture at rt. Stirring was continued until
completion (2 days). The mixture was poured into water and
ice, and the aqueous solution was extracted 3× with CH2Cl2.
The organic solution was dried (MgSO4) and filtered through
Celite, and the solvent was removed in vacuo. The crude
sample was flash chromatographed on SiO2 (5-10% EtOAc/
hexanes) to yield pure 10h (880 mg, 89%) as a colorless oil.
1
10h : H NMR (Table 4); 13C NMR (Table 5); IR (neat) νmax
(4S,5R)-2,2-Dip h en yl-4-m eth yl-5-[(E)-1-p r op en -1-yl]-N-
(tr ich lor o-a cetylca r ba m oyl)-oxa zolid in e (see F igu r e 4).
The compound was prepared in situ by the addition of one drop
of trichloroacetylisocyanate (TAI)36 to the NMR sample of
alcohol 10f (5 mg in 0.5 mL of CDCl3). The cyclic product was
formed instantaneously and quantitatively. 1H NMR (250
MHz, CDCl3) δ 7.81-7.21 (m, 10H), 5.81 (dq, J ) 15.2, 6.4
Hz), 5.61 (ddd, J ) 15.2, 7.8, 1.4 Hz, 1H), 4.15 (dq, J ) 8.6,
6.1 Hz, 1H), 3.82 (dd, J ) 8.2 Hz; J 2,3 ) 8.7 Hz, determined
via decoupling of the 1.36 ppm CH3), 1.73 (dd, J ) 6.4, 1.4 Hz,
3H), 1.36 (d, J ) 6.1 Hz, 3H); 13C NMR (APT, CDCl3) δ 139.56,
138.78 (q aromatic), 133.22 130.42, 130.04, 129.36, 128.89,
128.71, 128.38, 128.27, 128.16, 128.03, 127.78, 126.57 (aro-
matic), 82.98 (CH-O), 60.00 (CH-N), 17.91, 16.31 (Me).
3250.1, 2945.3 (C-H), 1729.5 (CdO), 1345.1, 1215.3 (C-O);
[R]D 5.60 (c ) 0.5, CHCl3). Elemental anal.: C30H43NO3Si
theoretical C, 72.98; H, 8.78. Found: C, 73.10; H, 8.72.
(4S,5S,2Z)-5-Am in o-1-O-ter t-b u t yld im et h ylsilyl-N-d i-
p h en ylm eth ylen e-4-O-p iva loyl-2-h exen -1,4-d iol (10j). The
alcohol 10d was prepared from 9a (1.0 mmol, 267 mg) and 7b
by means of the same protocol used to prepare 10a as a
colorless oil (280 mg, 68%) after chromatography (10%-20%
EtOAc/hexanes/0.1%NEt3). The product was immediately
treated with (CH3)3CCOCl (0.740 mL, 6.0 mmol), 2 mg DMAP
in 2.0 mL pyridine for 12 h at rt. Chromatography (30% EtOAc/
hexane/0.1%NEt3) provided pure 10j as an oil. (280 mg, 0.567
mmol, 83%).

6156 J . Org. Chem., Vol. 64, No. 17, 1999
Polt et al.
(4S,5R)-2,2-Dip h en yl-4-(ter t-bu tyld im eth ylsiloxym eth -
yl)-5-[(E)-1-p r op en -1-yl]-N-(t r ich lor oa cet ylca r b a m oyl)-
oxa zolid in e (see F igu r e 4). The compound was prepared in
situ by the addition of one drop of trichloroacetylisocyanate
(TAI)36 to the NMR sample of alcohol 10e (5 mg in 0.5 mL of
CDCl3). The cyclic product was formed instantaneously and
quantitatively as judged by NMR. 1H NMR (250 MHz, CDCl3)
δ 7.54-7.17 (m, 10H), 5.82 (dq, J ) 15.4, 6.5 Hz, 1H), 5.64
(ddd, J ) 15.3, 7.4, 1.5 Hz, 1H), 4.35 (apparent t, J ) 7.7 Hz,
3 mol %) in 6.7 mL of H2O was prepared. Compound 10e (204.8
mg, 0.50 mmol) was dissolved in 3 mL of tBuOH and added to
the aqueous solution. The mixture was stirred vigorously at
rt. After 24 h the reaction was complete (TLC). Na2SO3 (0.375
g) was added, and the mixture was stirred for 20 min. The
phases were separated, and the aqueous layer was extracted
with three portions of CHCl3. The combined organic phases
were dried (MgSO4), filtered through Celite, and dried in
vacuo. Without purification the mixture was dissolved in 1 mL
of pyridine, catalytic amount of DMAP was added, and the
mixture was chilled to 0 °C. One milliliter of Ac2O was added
dropwise. The reaction was complete in 3 h. Solvent was
removed, and the mixture of 13c and the ido-isomer was
separated by flash chromatography (5-25% EtOAc/hexanes)
to yield pure 13c (170 mg, 60%) and pure ido-isomer (28 mg,
9.8%) as colorless oils.
1
1H), 4.16 (ddd, J ) 8.2, 5.9, 3.5 Hz, 1H), 3.94 (m, 1H, /2 AB),
3.82 (dd, J ) 10.3, 5.9 Hz, 1H), 1.72 (dd, J ) 6.3, 1.3 Hz, 3H),
0.75 (s, 9H), -0.05 (s, 6H); 13C NMR (APT, CDCl3) δ 139.83,
138.67 (q aromatic), 132.15, 130.32, 130.04, 129.22, 128.83,
128.69, 128.24, 128.15, 127.77, 127.72, 127.56 (aromatic), 79.25
(CH-O), 64.66 (CH2-O), 60.96 (CH-N), 25.76 (tBu), 17.85
(Me), -5.39 (SiMe), -5.54 (SiMe).
13c: 1H NMR (250 MHz, CDCl3) δ -0.07 (s, 3H, SiCH3), 0.00
(s, 3H, SiCH3), 0.84 (s, 9H, tBu), 1.09 (d, 3H, J ) 6.4 Hz, CH3),
1.85 (s, 3H, Ac), 1.97 (s, 3H, Ac), 2.06 (s, 3H, Ac), 3.65-3.69
(m, 1H, unresolved, CH-N), 3.72-3.85 (m, 2H, unresolved,
CH2O), 5.13 (dq, 1H, J ) 3.65, 6.5 Hz, C(5)H-OAc), 5.20 (dd,
1H, J ) 3.6, 7.0 Hz, C(4)H-OAc), 5.39 (dd, 1H, J ) 3.3, 7.0
Hz, C(3)H-OAc), 7.23-7.58 (m, 10H, unresolved); 13C NMR
(CDCl3) δ -5.48 (CH3Si), 16.6 (CH3), 20.84 (acetate CH3), 20.97
(acetate CH3), 21.06 (acetate CH3), 25.85 (tBu), 63.43 (CH2O),
63.62 (CH3-N), 68.22 (CH-OAc), 70.54 (CH-OAc), 72.93
(CH-OAc),127.94, 128.22, 128.51, 128.62, 128.71, 130.04
(aromatic CH), 135.92 (q aromatic), 140.20 (q aromatic), 169.85
(acetate CdO), 170.00 (acetate CdO), 170.25 (acetate CdO);
IR (neat) νmax 3058.0, 3023.9, 2928.1, 2856.9, 1742.2, 1698.9,
1625.0, 1578.1 cm-1; MS (CI) 570 (MH+), 512 (MH - (CH3)3-
CH), 424 (MH - TBDMS-OMe), 364 (MH - (TBDMS-OMe)
- CH3COOH), 338 (TBDMS-OCH2dNdCPh2), 280 (338 -
(CH3)3CH); [R]D +2.15° (c ) 0.04, CHCl3).
P r oced u r e A: Ca ta lytic Dih yd r oxyla tion in th e Ab-
sen ce of a Ch ir a l Au xilia r y. A flask was charged with 5 mL
of water, 5 mL of tert-butyl alcohol, 0.98 g of K3Fe(CN)6 (3
mmol), 0.42 g K2CO3 (3 mmol), 10.8 mg of K2OsO2(OH)4 (3 mol
%), and 95 mg of MeSO2NH2. The mixture was stirred at rt
until both phases were clear. The olefin (1 mmol) was added,
and the heterogeneous mixture was vigorously stirred at rt
until the substrate was consumed (TLC). Na2SO3 (2.3 g) was
added, and the mixture was stirred for 20 min. The phases
were separated, and the aqueous layer was extracted 3× with
CHCl3. The combined organic phases were dried (MgSO4),
filtered through Celite, and dried in vacuo to give a crude
mixture of diastereomeric triols.
2,3,4-Tr i-O-a cetyl-5-a m in o-1-O-ter t-bu tyld im eth ylsilyl-
N-d ip h en ylm eth ylen e-5-d eoxy-L-ga la ctitol (13a ). Com-
pound 10a was oxidized following procedure A. Without
purification, the crude product mixture was dissolved in 2 mL
of pyridine, a catalytic amount of DMAP was added, and the
mixture was cooled to 0 °C. Two milliliters of Ac2O were added
dropwise. The reaction was allowed to stand in the refrigerator
overnight. Solvent was removed in vacuo, and the mixture of
13a and the ido-isomer (6:1) was separated by gradient flash
chromatography.
id o-Isom er : 1H NMR (CDCl3) δ -0.05 (s, 3H, SiCH3), 0.01
(s, 3H, SiCH3), 0.86 (s, 9H, tBu), 1.23 (d, 3H, J ) 6.4 Hz, CH3),
3.63-3.70 (m, 1H, unresolved, CH-N), 3.74-3.77 (m, 2H,
unresolved, CH2-O), 4.89 (quintet, 1H, J ) 6.6 Hz, C(5)H-
OAc), 5.25 (dd, 1H, J ) 3.6, 6.9 Hz, CH-OAc), 5.50 (dd, 1H, J
1
13a : H NMR (Table 4); 13C NMR (Table 5); IR (neat) νmax
) 3.6, 7.0 Hz), 7.20-7.62 (m, 10H, unresolved, aromatic); 13
C
2953.1 (C-H), 1740.1 (CdO), 1365.3, 1262.1, 1250.1, 1212.3
(C-O). [R]D +5.4° (c ) 0.4 CHCl3). Elemental anal.: calcd for
NMR (CDCl3) δ -5.5 (CH3Si), 16.42 (CH3), 20.41 (CH3COO),
20.92 (2 CH3COO), 25.80 (tBu), 63.35 (CH2O), 63.65 (CH-N),
69.15 (CH-OAc), 70.76 (CH-OAc), 73.15 (CH-OAc), 127.99,
128.17, 128.29, 128.40, 128.62 (aromatic CH), 130.14 (q
aromatic), 167.75 (CH3COO), 169.95 (2 CH3COO).
C
31H43NO7Si C, 65.35; H, 7.61. Found C, 65.39; H, 7.65.
P r oced u r e B: Ca ta lytic Dih yd r oxyla tion in th e P r es-
en ce of a (DHQ)2P HAL [or (DHQD)2P HAL]. A container
was charged with 5 mL of H2O, 5 mL of tert-butyl alcohol, K3-
Fe(CN)6 (0.98 g, 3 mmol), K2CO3 (0.42 g, 3 mmol), K2OsO2-
(OH)4 (4.3 mg, 1.2 mol %), and MeSO2NH2 (95 mg, 1 mmol)
and (DHQ)2PHAL (23.8 mg, 3 mol %). The mixture was stirred
at rt until both phases were clear and then added to the olefin
(1 mmol). The heterogeneous mixture was vigorously stirred
at rt until consumption of starting material (TLC). Solid Na2-
SO3 (2.3 g) was added, and the mixture was stirred for 20 min.
Two phases were separated and the aqueous layer extracted
3× with CHCl3. The combined organic phases were dried
(MgSO4), filtered through Celite, and dried in vacuo to give a
crude mixture of diastereomeric triols.
5-Am in o-1-O-ter t-bu tyld im eth ylsilyl-N-d ip h en ylm eth -
ylen e-4-O-p iva loyl-5-d eoxy-L-ga la ctitol (14d ). From 10h
using procedure A. Provided a colorless oil.
14d : 1H NMR (Table 4); 13C NMR (Table 5); IR νmax 3500.0
(OH), 2957.3, 2930.2, 2856.9 (C-H), 1732.3 (CdO), 1151.7 (C-
O); [R]D +37.6°. Elemental anal.: calcd for C30H45N5Si C, 71.53;
H, 9.00. Found C, 71.58; H, 9.06.
5-Am in o-N-d ip h en ylm eth ylen e-4-O-p iva loyl-5-d eoxy-
L-ga la ctitol (15b). (TBAF Dep r otection of ter t-Bu tyld i-
m eth ylsilyl gr ou p .) The tert-butyldimethylsilyl group (TB-
DMS) was deprotected under standard conditions.52 Diol 14d
(1 mmol) was dissolved in THF (4 mL), nBu4N+F-, (TBAF),
(1.1 mmol) was added as a 1.0 M solution in THF, and the
mixture stirred at rt to completion (2-3 h). The solvent was
removed in vacuo to provide a colorless oil. Normally, the
resulting triol 15b was carried on to the oxidation step without
purification. In one case the residue was purified via flash
chromatography on silica gel (6% MeOH/CH2Cl2) to provide
crystalline triol 15b.
15b: White crystals, mp 92-94 °C (recrystallized from
hexane/EtOAc); 13C NMR (CDCl3) δ 177.13 (CdO), 138.63 (q
aromatic), 134.69 (q aromatic), 130.90, 128.60, 128.56, 128.31,
127.66 (aromatic), 71.59 (CH-O), 71.09 (CH-O), 69.60 (CH-
O), 65.32 (CH2-O), 58.38 (CH-N), 38.80 (q Bu), 27.04 (tBu),
14.95 (Me); IR νmax 3213.4-3425.1 (broad, OH), 1732.2 (Cd
O), 1274.2 (C-O); [R]D +51.3° (c ) 1, CHCl3).
2,3,4-Tr i-O-acetyl-5-am in o-1-O-ben zyl-N-diph en ylm eth -
ylen e-5-d eoxy-L-ga la ctitol (13b). Compound 10b (150 mg,
0.388 mmol) was oxidized following procedure A. Without
purification, the crude product mixture was dissolved in 2 mL
of pyridine. A catalytic amount of DMAP was added, and the
mixture was cooled to 0 °C. Two milliliters of Ac2O were added
dropwise. The reaction was complete within 3 h. Solvent was
removed in vacuo, and the mixture of 13b and the ido-isomer
(4:1) was separated by gradient flash chromatography (5-20%
EtOAc/hexanes) to yield pure 13b (110 mg, 52%) and pure ido-
isomer (28 mg, 13%) as a colorless oil.
1
13b: H NMR (Table 4); 13C NMR (Table 5); IR (neat) νmax
2983.1 (C-C), 1745.1 (CdO), 1665.8 (aromatic), 1358.7, 1261.3
(C-O).
3,4,5-Tr i-O-a cetyl-2-a m in o-1-O-ter t-bu tyld im eth ylsilyl-
N-d ip h en ylm eth ylen e-2-d eoxy-D-ga la ctitol (13c). Proce-
dure A. A mixture of K3Fe(CN)6 (0.49 g, 1.5 mmol, 3 equiv),
K2CO3 (0.21 g, 1.5 mmol, 3 equiv), and K2OsO2(OH)4 (5.6 mg,
(52) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991.

Glycosidase Inhibitors: Synthesis of Aza-Sugars
J . Org. Chem., Vol. 64, No. 17, 1999 6157
Ta ble 6. 1H NMR a n d 13C NMR Da ta for Cyclic
Com p ou n d s
(4S,5S,2Z)-5-Am in o-N-d ip h en ylm eth ylen e-4-p iva loyl-
oxyh ex-2-en -1-a l (16c) (Sw er n Oxid a tion ). Oxalyl chloride
(28 µL, 0.32 mmol) and 0.55 mL of dry CH2Cl2 were mixed in
a flask under an argon atmosphere. The mixture was cooled
to -65 °C (CHCl3, solid CO2) and DMSO (40 µL, 0.56 mmol)
in 110 µL of CH2Cl2 was added. The reaction was stirred for 2
min at -65 °C and 100 mg (∼0.26 mmol) of the crude alcohol
resulting from the desilylation of 10j (see procedure for 14d
f 15b, above) in 0.22 of mL of CH2Cl2 was added. The reaction
was stirred at -65 °C for 15 min, and 154 µL of NEt3 was
added. After stirring for an additional 10 min, the mixture
was allowed to warm to rt and quenched with 6 mL of water.
The mixture was extracted 2× with CHCl3. The combined
CHCl3 extracts were subsequently washed with 3% NaHCO3
and dried (MgSO4), and the solvent was removed in vacuo to
provide the crude aldehyde 16c as an oil (87 mg, 70% for both
steps).
16c: 1H NMR (Table 4); 13C NMR (Table 5).
(2S,3R,4R,5S)-5-Am in o-N-d ip h en ylm et h ylen e-2,3-bis-
m eth oxym eth oxy-4-p iva loyloxy-1-h exa n a l or 5-Am in o-
N-d ip h en ylm eth ylen e-2,3-bis-O-m eth oxym eth yl-4-O-p i-
va loyl-5,6-d id eoxy-L-ga la ctose (16a ). Aldehyde 16a was
prepared from 15a by desilylation (see procedure for 14d f
15b), and Swern oxidation (see procedure for 10j f 16c) to
provide a colorless oil in 75% yield.
1
16a : H NMR (Table 4); 13C NMR (Table 5).
(2S,3R,4R,5S)-5-Am in o-N-diph en ylm eth ylen e-4-pivaloyl-
oxy-2,3,4-tr ih yd r oxy-h exa n -1-a l or 5-Am in o-N-d ip h en yl-
m eth ylen e-2,3-bis-O-m eth oxym eth yl-4-O-pivaloyl-6-deoxy-
L-ga la ctose (16b) (TEMP O Oxid a tion ). Triol 15b (0.53
mmol, 220 mg) was dissolved in 1.4 mL of CH2Cl2, TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxide) (1 mol %, 0.8 mg, 320
µL of a solution of 5 mg TEMPO in 2 mL of CH2Cl2), 0.87 mL
of saturated NaHCO3 containing 5.3 mg of KBr and 7.3 mg of
tetrabutylammonium chloride hydrate were added. The mix-
ture was cooled to -5 °C (ice/MeOH). While stirring vigorously
a mixture of 1.56 mL of NaOCl (4% solution, Aldrich), 0.76
mL of saturated NaHCO3, and 1.49 mL of brine was added
dropwise to the cooled flask. The addition time was 12-15 min.
Extension of this addition time resulted in deactivation of the
catalyst. At the end of the reaction (TLC) the mixture was
diluted with excess CH2Cl2, dried (MgSO4), and filtered, and
solvent was removed in the dark at 0-10 °C. The unstable
crude aldehyde 16b (210 mg, 96%) was used immediately for
the next reaction, and a complete spectral characterization was
not done.
N -Dip h en ylm et h yl-2,3-bis-O-m et h oxym et h yl-4-O -p i-
va loyl-L-(-)-1-d eoxyfu con ojir im ycin (17a ). Aldehyde 16a
(90 mg, 0.18 mmol) in 0.52 mL of anhydrous CH3CN was
acidified with glacial HOAc (8-10 equiv) to maintain pH 5-6.
Solid NaBH3CN (12.4 mg, 0.197 mmol) was added to the
mixture at once. The reaction was complete in 10 min (TLC).
The mixture was diluted with H2O and extracted with EtOAc.
The organic layer was dried and evaporated to provide the
crude diol (48 mg), which was purified via flash chromatog-
raphy (50% EtOAc/hexanes) to yield the pure heterocycle 17a
(34 mg, 88%) as a colorless oil.
the gulo isomer 19 was detected in the crude 1H NMR
spectrum.
1
19: White crystals, mp 151-3 °C; H NMR and 13C NMR
(Table 6); IR νmax 3462.2 (OH), 2992.2 (C-H), 1743.2 (CdO),
1143.3 (C-O); [R]D -85.40 (CHCl3). Calcd for C27H31NO4 C,
74.80; H, 7.21. Found C, 74.89; H, 7.30.
1-d eoxy-L-(-)-Aza fu cose (L-(-)-1-d eoxyfu con ojir im y-
cin ) (18). Dep r ot ect ion of P iva la t e a n d Ben zh yd r yl
Gr ou p s. N-Diphenylmethyl-4-pivaloyl-L-azasugar 17b (313.4
mg, 1 mmol) was dissolved in 10 mL of dioxane and 6.5 mL of
H2O. An aqueous solution of nBu4NOH (720 µL, 1.1 mmol) was
added at 0 °C. The mixture was stirred until completion (TLC,
5% MeOH/CH2Cl2), and diluted with excess CH2Cl2. The
aqueous layer was extracted 3× with CH2Cl2. The combined
organic phases were washed with brine (H2O generated an
emulsion), dried (MgSO4), and evaporated. When necessary,
the crude material was purified via gradient flash chroma-
tography (2-5% MeOH/CH2Cl2) to yield a pure N-benzhydryl
triol (typically 85%), which was submitted to hydrogenolysis
in MeOH. A portion of the triol (56.0 mg, 0.179 mmol) was
dissolved in 2 mL EtOAc, and the solution was added to an
argon-purged flask (omission of argon leads to the N-methyl-
ated impurity) with 50 mg of 5% Pd/C catalyst and 50 mL of
MeOH in the presence of H2. Hydrogen was applied via rubber
balloon. The mixture was vigorously stirred at rt for 3 h, and
then it was filtered and evaporated to dryness. The residue
was dissolved in H2O, acidified with HCl (2 mmol), and washed
2× with hexane to remove diphenylmethane. The aqueous
solution was lyophilized, and the crude sample was purified
via ion exchange. An aqueous solution (∼1 mL) was taken to
pH 9-10 with 1 N NaOH, applied to Dowex (H+form), washed
with H2O, and eluted with 10 mL of MeOH/H2O/NH3 (MeOH:
3 M NH3:H2O, 2:5:3 by volume) to yield the pure azasugar 18
(typically 95% for the second step).
17a : 1H NMR and 13C NMR (Table 6); IR νmax 2972.7, 2891.7
(C-H), 1730.4 (CdO), 1479.6, 1165.5, 1033.9; [R]D -55.3°
(CHCl3).
N-Dip h en ylm eth yl-4-O-p iva loyl-L-(-)-1-d eoxyfu con o-
jir im ycin (17b). Crude aldehyde 16b was converted to
azafucose 17b (80% yield) following the same protocol as for
16a f 17a .
18: 1H NMR and 13C NMR (Table 6); [R]D -50° (c ) 1, D2O).
Calcd for C6H12NO3: C, 48.96; H, 8.22. Found: C, 49.01; H,
8.25.
17b: 1H NMR and 13C NMR (Table 6); IR νmax 3443.4 (OH),
2976.5 (C-H), 1728 (CdO), 1165.15 (C-O); [R]D -41°.
(2S,3S)-N-Dip h en ylm et h yl-2-m et h yl-3-p iva loyloxy-D-
4,5-tetr a h yd r op yr id in e (17c). Crude aldehyde 16c yielded
17c (85% yield) following the same protocol as for 16a f 17a .
1-d eoxy-L-(-)-Aza gu lose (L-(-)-1-Deoxygu lon ojir im y-
cin ) (20). N-Diphenylmethyl-4-pivaloyl-L-azasugar 19 (27 mg,
0.068 mmol) was dissolved in 0.3 mL of dioxane and 0.2 mL
of H2O. An aqueous solution of nBu4NOH (150 µL) was added
at 0 °C. The mixture was stirred until completion (TLC, 5%
MeOH/CH2Cl2), and the mixture was diluted with an excess
of CH2Cl2. The aqueous layer was extracted 3× with CH2Cl2.
The combined organic phases were washed with brine (H2O
generated an emulsion), dried (MgSO4), and evaporated. The
crude material was purified via gradient flash chromatography
1
17c: H NMR and 13C NMR (Table 6); IR νmax 2974.6 (C-
H), 1728.4 (CdO), 1157.4 (C-O), [R]D +58.6°.
N-Diph en ylm eth yl-4-O-pivaloyl-L-(-)-gu lo-1-deoxyn ojir -
im ycin (19). Cyclic alkene 17c was converted to azagulose
19 (80% yield) by following the osmylation procedure A. Only

6158 J . Org. Chem., Vol. 64, No. 17, 1999
Polt et al.
(2-5% MeOH/CH2Cl2) to yield the pure triol as snow-white
crystals (mp 147-148 °C). Hydrogenation of 13 mg of this
material in 2 mL EtOAc and 50 mL MeOH with 50 mg 5%
Pd-C as before yielded 8.0 mg of 20‚HCl after lyophylization.
20‚HCl: 1H NMR and 13C NMR (Table 6); [R]D +13.5° (c )
0.33, H2O/MeOH 1:1). Calcd for C6H13NO3Cl: C, 39.46; H, 7.17.
Found: C, 39.46; H, 7.22.
Barry M. Goldwater Scholarship and Excellence in Edu-
cation Foundation for an undergraduate scholarship.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
(250 or 300 MHz) are available for olefin 10h , diol 14d (crude
reaction mixture showing ido-galacto mixture), cis-enal 16c,
and cyclic products 17a , 17b, 17c, 18, 19, and 20 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the National Science Foundation
(CHE-9526909 and CHE-9201112). J .C. thanks the
J O9820115