Chemical synthesis of β-homonojirimycin, of its N-butyl derivative, and of 'methyl homoazacellobioside'

Article abstract of DOI:10.1021/jo960362i

β-Homonojirimycin (2) was prepared by the highly stereoselective double reductive amination of a 2,6-heptodiulose derivative (6 or 13) using ammonium formate and NaBH₃CN. The process was unsuccessful with primary amines. The synthesis of N-buty

Full text of DOI:10.1021/jo960362i

J . Org. Chem. 1996, 61, 6987-6993
6987
Ch em ica l Syn th esis of â-Hom on ojir im ycin , of Its N-Bu tyl
Der iva tive, a n d of “Meth yl Hom oa za cellobiosid e”
Oscar M. Saavedra and Olivier R. Martin*
Department of Chemistry, State University of New York, P.O. Box 6016, Binghamton,
New York 13902-6016
Received February 21, 1996X
â-Homonojirimycin (2) was prepared by the highly stereoselective double reductive amination of a
2,6-heptodiulose derivative (6 or 13) using ammonium formate and NaBH3CN. The process was
unsuccessful with primary amines. The synthesis of N-butyl-â-homonojirimycin (19) was achieved
by the N-butanoylation of a derivative of 2 followed by the reduction of the resulting tertiary amide.
Compound 19 was found to be completely devoid of anti-HIV activity, in marked contrast with
N-butyl-1-deoxynojirimycin. The coupling of the 1-O-p-toluenesulfonyl derivative of 2, compound
20, with methyl 2,3,6-tri-O-benzyl-R-D-glucopyranoside, followed by a deprotection step, provided
pseudodisaccharide 23, the “homoaza” analog of methyl R-cellobioside and a potential inhibitor of
â-glucan-processing enzymes.
In tr od u ction
J udging by their potent biological activities, most
prominently as glycosidase inhibitors, azasugars1 con-
stitute undoubtedly the most remarkable class of “gly-
comimetics” designed by Nature. As a result of the
lability of the O/N-acetal function2 that would character-
ize glycosides of azasugars, most natural and non-natural
piperidine azasugars,1c,3 including the archetypal 1-deoxy-
nojirimycin, are, in fact, derivatives of 1,5-dideoxy-1,5-
iminohexitols and lack a substituent at the “anomeric”
position. The concept of C-glycosidation, now extensively
developed in furanoid and pyranoid systems,4 becomes
particularly significant in azasugar chemistry: the re-
placement of the anomeric oxygen atom in azaglycosides
by a methylene group or the insertion of a methylene
group into the “glycosidic” linkage provides means of
generating stable analogs of such elusive species as, for
example, azadisaccharides.5 Several types of significant
azasugar-containing pseudoglycoconjugates become ac-
cessible by way of this structural modification. The so-
called homoazasugars (e.g., 1 and 2) represent the
simplest examples of aza-C-glycosyl compounds. The
isolation of 1 (R-homonojirimycin) from the moth Urania
fulgens6a and from its larval food plant Omphalea
diandra6b prompted the synthesis of several homoaza-
sugars including 1,7-9 the homo analogs of mannojiri-
mycin,9-11 of L-fuconojirimycin,12 and, recently, of galac-
tostatin in our laboratory.13 A number of pyrrolidine
homoazasugars have also been reported,10,14,15 and one
of them has been used for the construction of a homo-
azanucleoside.14a While retaining the powerful biological
activity of the parent azasugars, homoazasugars were
shown in several instances6a,9 to exhibit greater selectiv-
ity in their inhibition of glycosidases. The addition of a
substituent recognizing the aglycon-binding site of the
enzyme is expected to further increase this selectivity,
for example, toward oligosaccharidases. This proposition
is supported by the potent activity of the 7-O-â-D-
glucopyranosyl derivative of 17 toward intestinal sucrase
and other disaccharidases of the digestive system. Few
other types of aza-C-glycosyl compounds have been
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) (a) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199-
210. (b) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res. 1993,
26, 182-190. (c) Van den Brook, L. A. G. M.; Vermaas, D. J .; Heskamp,
B. M.; van Boeckel, C. A. A.; Tan, M. C. A. A.; Bolscher, J . G. M.;
Ploegh, H. L.; van Kemenade, F. J .; de Goede, R. E. Y.; Miedema, F.
Recl. Trav. Chim. Pays-Bas 1993, 112, 82-94. (d) Legler, G. Adv.
Carbohydr. Chem. Biochem. 1990, 48, 319-384.
(2) (a) Smith, P. A. S. The Chemistry of Open-Chain Organic
Nitrogen Compounds; Benjamin: New York, 1965. (b) Houben-Weyl,
Methoden der Organischen Chemie; Thieme Verlag: Stuttgart, 1991;
Bd E14a/2 (O/N-Acetale).
(3) Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994, 11, 135-162.
(4) (a) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca
Raton, FL, 1995. (b) Levy, D. E.; Tang, C. The Chemistry of C-
Glycosides; Elsevier Science: Oxford, 1995.
(5) Interestingly, disaccharides having NH in the interglycosidic
linkage have been reported. (a) Barker, S. A.; Murray, K.; Stacey, M.
Nature 1961, 191, 142-143. (b) Micheel, P.; Heinemann, K. H.;
Schwieger, K. H.; Frowein, A. Tetrahedron Lett. 1965, 3769-3771. (c)
Linek, K.; Alfo¨ldi, J .; Defaye, J . Carbohydr. Res. 1987, 164, 195-205.
(6) (a) Kite, G. C.; Horn, J . M.; Romeo, J . T.; Fellows, L. E.; Lees,
D. C.; Scofield, A. M.; Smith, N. G. Phytochemistry 1990, 29, 103-
105. (b) Kite, G. C.; Fellows, L. E.; Fleet, G. W. J .; Liu, P. S.; Scofield,
A. M.; Smith, N. G. Tetrahedron Lett. 1988, 29, 6483-6486.
(7) Liu, P. S. J . Org. Chem. 1987, 52, 4717-4721.
(8) (a) Anzeveno, P. B.; Creemer, L. J .; Daniel, J . K.; King, C.-H.
R.; Liu, P. S. J . Org. Chem. 1989, 54, 2539-2542. (b) Aoyagi, S.;
Fujimaki, S.; Kibayashi, C. J . Chem. Soc., Chem. Commun. 1990,
1457-1459.
(9) Bruce, I.; Fleet, G. W. J .; Cenci di Bello, I.; Winchester, B.
Tetrahedron 1992, 48, 10191-10200.
(10) Myerscough, P. M.; Fairbanks, A. J .; J ones, A. H.; Bruce, I.;
Choi, S.-M. S.; Fleet, G. W. J .; Al-Daher, S. S.; Cenci di Bello, I.;
Winchester, B. Tetrahedron 1992, 48, 10177-10190.
(11) (a) Holt, K. E.; Leeper, F. J .; Handa, S. J . Chem. Soc., Perkin
Trans. 1 1994, 231-234. (b) Henderson, I.; Laslo, K.; Wong, C.-H.
Tetrahedron Lett. 1994, 35, 359-362.
(12) (a) Fleet, G. W. J .; Namgoong, S. K.; Barker, C.; Baines, S.;
J acob, G. S.; Winchester, B. Tetrahedron Lett. 1989, 30, 4439-4442.
(b) Andrews, D. M.; Bird, M. I.; Cunningham, M. M.; Ward, P. Bioorg.
Med. Chem. Lett. 1993, 3, 2533-2536.
(13) Martin, O. R.; Xie, F.; Liu, L. Tetrahedron Lett. 1995, 36, 4027-
4030.
(14) (a) Wong, C.-H.; Provencher, L.; Porco, J . A., J r.; J ung, S.-H.;
Wang, Y.-F.; Chen, L.; Wang, R.; Steensma, D. H. J . Org. Chem. 1995,
60, 1492-1501. (b) Hiranuma, S.; Shimizu, T.; Nakata, T.; Kajimoto,
T.; Wong, C.-H. Tetrahedron Lett. 1995, 36, 8247-8250.
(15) Campanini, L.; Dure´ault, A.; Depezay, J .-C. Tetrahedron Lett.
1995, 36, 8015-8018.
S0022-3263(96)00362-3 CCC: $12.00 © 1996 American Chemical Society

6988 J . Org. Chem., Vol. 61, No. 20, 1996
Saavedra and Martin
described so far:16-20 therefore particularly noteworthy
are the recent first examples of aza-C-disaccharides.19,20
We report in this article21 the first chemical synthesis
of the â-epimer of 1, namely â-homonojirimycin (2), of
its N-butyl derivative 19, and of the pseudodisaccharide
Sch em e 1
23, the “homoaza” analog of methyl R-cellobioside.
A
chemoenzymatic preparation of 2 was recently reported
by Holt and co-workers,11a but no physical data on this
compound were given. Compound 19 is the homolog of
N-butyl-1-deoxynojirimycin, the azasugar exhibiting the
strongest inhibition of HIV-induced cytopathogenicity;1c
compound 23 is the first example of a homoaza analog
of a natural disaccharide and constitutes a potential
selective inhibitor of cellobiohydrolases and cellulases.
Resu lts a n d Discu ssion
Our synthesis of â-homonojirimycin (2) and its deriva-
tives relies on the double reductive amination22 of a 2,6-
heptodiulose. This strategy appeared to be particularly
well suited to the preparation of an all-equatorial pip-
eridine derivative. From the results of extensive studies
on the synthesis of 1-deoxynojirimycin by internal reduc-
tive amination1b,23 as well as from dicarbonyl sugars,22b
the reduction step was expected to provide predomi-
nantly, if not exclusively, the desired configuration at C-2
and C-6.
Horii27 to produce related diketones. As a result of the
tendency of 1,5-diketones such as 6 to undergo internal
aldol reaction,27 compound 6 was immediately submitted
to reductive amination using ammonium formate in the
presence of NaBH3CN. This process afforded the desired
â-homonojirimycin derivative 7 in 50% yield (from 5a /
5b) as a single stereoisomer. Thorough analysis of the
reaction mixture did not reveal the presence of any other
isomer. Although no evidence is available on the nature
of the intermediates involved in this multistep process,
the very high degree of stereoselectivity observed appears
to exclude the amination of one of the carbonyl groups
of the diketone in the open chain form that would produce
an aminoheptulose in the first step. Rather, the reaction
involves probably only cyclic intermediates (starting with
a bis-hemiaminal and the corresponding cyclic imine/
iminium salt) and the stereoselectivity of the hydride
addition (axial attack) appears to be due primarily to
torsional effects.1b,22b
Two different approaches to the required D-xylo-2,6-
heptodiulose were investigated: (i) the addition of an
(alkoxyalkyl)lithium reagent to a D-gluconolactone de-
rivative (3) and (ii) a Wittig chain extension of tetra-O-
benzyl-D-glucopyranose (9) followed by the dihydroxyla-
tion of the resulting heptenitol. Both approaches were
designed to provide a differentially protected 2,6-hepto-
diulose and, ultimately, nonsymmetric â-homonojirimycin
derivatives having different protecting groups at C-1 and
C-7.
In approach i (see Scheme 1), tetra-O-benzyl-D-glucono-
1,5-lactone 3 was treated with ((methoxymethoxy)meth-
yl)lithium24 under the conditions described by Shiozaki;25
the resulting R-D-gluco-heptulopyranose derivative 4 was
reduced in high yield to a mixture of heptitols 5a and 5b
(∼1:1 ratio) using LiAlH4. The configuration26 of these
epimers was determined as described later in the discus-
sion. The oxidation of the mixture of 5a and 5b to the
heptodiulose 6 was achieved using DMSO-trifluoroacetic
anhydride, conditions that were used by Fukase and
Cleavage of the MOM group of 7 under mildly acidic
conditions gave the amino alcohol 8, a key precursor of
â-(D)-homonojirimycin derivatives (see below). Deben-
zylation of 8 by catalytic hydrogenation, by treatment
with Li/NH3, or with iodotrimethylsilane gave â-homonojir-
imycin (2), the best results being obtained using the latter
(16) Bo¨shagen, H.; Geiger, W.; J unge, B. Angew. Chem., Int. Ed.
Engl. 1981, 20, 806-807.
(17) Liotta, L. J .; Lee, J .; Ganem, B. Tetrahedron 1991, 47, 2433-
2447.
(18) Liu, P. S.; Rogers, R. S.; Kang, M. S.; Sunkara, P. S. Tetrahe-
dron Lett. 1991, 32, 5853-5856.
1
reagent. The simple H and 13C NMR spectra of 2 (five
(19) (a) J ohnson, C. R.; Miller, M. W.; Golebiowski, A.; Sundram,
H.; Ksebati, M. B. Tetrahedron Lett. 1994, 35, 8991-8994. (b) Baudat,
A.; Vogel, P. Tetrahedron Lett. 1996, 37, 483-484.
(20) Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett. 1996, 37,
1991-1994.
and four signals, respectively) and the absence of optical
activity were evidence for its symmetrical structure, and
3
the magnitude of the J H,H coupling constants between
(21) For a preliminary communication, see: Martin, O. R.; Saavedra,
O. M. Tetrahedron Lett. 1995, 36, 799-802.
the ring protons (9.5 Hz) confirmed its all-equatorial
configuration.
The reductive amination of 6 was also attempted with
primary alkylamines (benzylamine, butylamine) in the
presence of acetic acid and NaBH3CN. However, these
reactions were completely unsuccessful.
(22) (a) Abe, K.; Okumura, H.; Tsugoshi, T.; Nakamura, N. Synthesis
1984, 597-598. (b) Baxter, E. W.; Reitz, A. B. J . Org. Chem. 1994, 59,
3175-3185.
(23) Straub, A.; Effenberger, F.; Fischer, P. J . Org. Chem. 1990, 55,
3926-3932.
(24) Organic Synthesis; Overman, L. E., Ed.; Wiley: New York, 1992;
Vol. 71, pp 140-145.
In approach ii (see Scheme 2), the chain extension was
achieved by the efficient Wittig reaction of tetra-O-
(25) Shiozaki, M. J . Org. Chem. 1991, 56, 528-532.
(26) As a result of the preferred configurational prefix, the new
chiral center is C-2 in 5a (D-glycero-D-gulo) and C-6 in 5b (D-glycero-
L-gulo, not D-glycero-D-ido). For the relevant rule of carbohydrate
nomenclature, see: Biochemistry 1971, 10, 3983-4004.
(27) Fukase, H.; Horii, S. J . Org. Chem. 1992, 57, 3642-3650.

Chemical Synthesis of â-Homonojirimycin
J . Org. Chem., Vol. 61, No. 20, 1996 6989
Sch em e 2
Sch em e 3
Sch em e 4
benzyl-D-glucopyranose 9 with Ph3PdCH2.28 The result-
ing heptenitol 10 was submitted to dihydroxylation using
catalytic OsO4, which afforded the D-glycero-D-gulo- and
D-glycero-L-gulo-heptitols 11a and 11b in a ratio of 10:1;
the major stereoisomer was the one predicted from the
Kishi empirical rule.29 Selective silylation of the mixture
of epimers gave primary silyl ethers 12a and 12b, which
could be readily separated by flash chromatography at
this stage. Oxidation of 12a /12b and reductive amina-
tion of the resulting 2,6-heptodiulose 13 gave â-homonojir-
imycin derivative 14 in 58% overall yield, again as a
single stereoisomer. Desilylation of 14 led to 8, thus
completing this alternative synthesis of â-homonojirimy-
cin. Overall, the second approach is the preferred one
for both better yields and simpler experimental condi-
tions.
With pure 12a and 12b available, their configuration
could be determined as follows (see Scheme 3): desily-
lation of 12a and 12b, separately, afforded pure samples
of 11a and 11b. The two triols were then perbenzy-
lated: compound 11a led to 15, a heptitol derivative
exhibiting simple NMR spectra and zero optical activity,
and 11b led to 16, an optically active compound exhibit-
ing seven 13C signals for its heptitol chain. On the basis
of these data, the D-glycero-D-gulo and D-glycero-L-gulo
configurations (see footnote 26) were assigned unambigu-
ously to 11a and 11b.
benzoyl group underwent immediate N f O migration.30
These preliminary investigations indicated the route to
follow for the preparation of 19 (see Scheme 4): butanoy-
lation of the magnesium amide derived from 7 gave 17
in 70% yield. The amide was then reduced to the
corresponding tertiary amine by treatment of 17 with the
BH3‚THF complex, and the protecting groups were
removed in two steps. This lengthy procedure provided
N-butyl-â-homonojirimycin (19). N-Alkylation of 2 pro-
moted a marked change of conformation about the C(1)-
C(2) and C(6)-C(7) bonds: while the conformation of the
hydroxymethyl groups in 2 appears to be flexible, with
two predominant forms for each group, compound 19 has
clearly both hydroxymethyl groups in the unusual
gauche-gauche conformation (both values of 3J ) 1.7 Hz).
The preparation of N-substituted derivatives of 2 met
with considerable difficulties: for example, the N-ben-
zylation of precursor 7 could not be achieved under any
of the direct benzylation conditions attempted. N-Ben-
zoylation was successful if the amine was first deproto-
nated with a Grignard reagent. Upon cleavage of the
MOM group from the N-benzoyl derivative of 7, the
It has been suggested that this conformation is an
important structural feature of azasugar derivatives
exhibiting antiviral activity.1c Compound 19 was found,
however, to be completely devoid of anti-HIV activity (in
vitro screening at the National Cancer Institute), in
marked contrast with N-butyl-1-deoxynojirimycin.1c
The low reactivity of the amino function in 2 and its
derivatives is clearly due to steric effects: the substitu-
(28) Pougny, J . R.; Nassr, M. A. M.; Sinay¨, P. J . Chem. Soc., Chem.
Commun. 1981, 375-376.
(29) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron Lett. 1983, 24,
3943-3946.
(30) Hill, R. K.; Chan, T. H.; J oule, J . A. Tetrahedron 1965, 21, 147-
161 and references cited.

6990 J . Org. Chem., Vol. 61, No. 20, 1996
Saavedra and Martin
Spectrometry in the FAB mode [matrix: 3-nitrobenzyl alcohol
in the absence or in the presence of an alkali metal cation (Li+,
Na+)].
Sch em e 5
Analytical TLC was performed on precoated glass plates
with silica gel 60 F-254 as the adsorbant (layer thickness: 0.25
mm). The developed plates were air-dried, exposed to UV light
for inspection, sprayed with a solution of ammonium phos-
phomolybdate, and heated to 120-140 °C. Flash chromatog-
raphy was performed using silica gel 60 (230-400 mesh). The
following hexane-ethyl acetate solvent systems were used: A,
1:1; B, 2:1; C, 3:1; D, 4:1; E, 5:1.
Separations by HPLC were achieved using a preparative
HPLC system equipped with a gradient programmer, a vari-
able wavelength UV detector, and a 21.2 × 250 mm prepara-
tive column containing silica gel 60 (10 µm).
Solvents were evaporated under reduced pressure below 40
°C. Catalytic hydrogenations and hydrogenolyses were per-
formed in a stainless steel benchtop pressure reactor equipped
with a magnetic stirring drive and a pressure and tempera-
ture controller (maximum pressure: 2000 psi).
Hep titols 5a a n d 5b. 3,4,5,7-Tetra-O-benzyl-1-O-(meth-
oxymethyl)-R-D-gluco-2-heptulopyranose (4) was prepared in
70% yield by the reaction of ((methoxymethoxy)methyl)lithium
[from ((methoxymethoxy)methyl)tributylstannane24
]
with
ents at C-2 and C-6 reduce the accessibility to nitrogen.
Steric factors may also be responsible for the failure of
the double reductive amination with alkylamines:31 the
presence of a substituent at nitrogen makes the ring
closure substantially less favorable than that without a
substituent.
2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (3),34 as described
by Shiozaki.25 To 4 (3.56 g, 5.8 mmol) was added dropwise a
1 N solution of LiAlH4 in THF (15 mL), and the mixture was
stirred overnight at room temperature. Excess LiAlH4 was
then destroyed by the careful addition of EtOAc (10 mL). An
additional volume of EtOAc (150 mL) was added, and the
resulting mixture was washed with 2 N aqueous HCl (75 mL);
the organic phase was separated, washed successively with
saturated aqueous NaHCO3 (75 mL) and brine (75 mL), dried
(Na2SO4), and concentrated, thus affording a homogeneous
mixture of heptitols 5a and 5b (3.46 g, 98%; 1:1 ratio). A small
sample of the mixture was resolved by flash chromatography
(solvent A).
Advantage was taken of this low reactivity at nitrogen
to prepare derivatives of 2 at O-1: tosylation of amino
alcohol 8 afforded exclusively the reactive O-tosylate 2032
(see Scheme 5). Compound 20 constitutes a convenient
precursor for the preparation of a wide variety of â-linked
“homoazadisaccharides”: upon reaction with methyl
2,3,6-tri-O-benzyl-R-D-glucopyranoside (21), compound 20
gave the expected pseudodisaccharide 22 in 49% yield,
without rearrangement of the piperidine ring.33 Com-
pound 22 was deprotected to afford 23, the homo analog
of an elusive azacellobioside; it is the first example of an
homoaza analog of a natural disaccharide and constitutes
a potential inhibitor of â-glucan-processing enzymes.
In conclusion, we have developed an efficient method
for the chemical synthesis of symmetric â-homonojiri-
mycin (2) and of optically active derivatives. These
derivatives are convenient precursors of homoaza analogs
of â-linked disaccharides, a class of significant glycomi-
metics. Investigations on the activity of the new aza-
sugar derivatives as glycosidase inhibitors are in progress
and will be reported in due course.
3,4,5,7-Te t r a -O-b e n zyl-1-O-(m e t h oxym e t h yl)-D -gly-
cer o-D-gu lo-h ep titol (5a ): syrup; [R]D +1.74 (c 3.5, CHCl3);
IR νmax (film) 3462 (OH) cm-1; lH NMR (CDCl3) δ 2.95 (br s, 1
H, OH), 3.12 (br, 1 H, OH), 3.32 (s, 3 H, OCH3), 3.60-3.74 (m,
4 H, H-1A, 1B, 7A, 7B), 3.82 (dd, 1 H, J ) 6.8, 4.5 Hz) and
3.88 (dd, 1 H, J ) 6.5, 4.6 Hz) (H-3, 5), 3.98 (t, 1 H, J 3,4 = J 4,5
) 4.5 Hz, H-4), 3.99-4.06 (m, 2 H, H-2, 6), 4.51 (AB, 2 H),
4.60 (AB, 2 H), 4.61 (s, 2 H), 4.64 (s, 2 H), and 4.67 (s, 2 H) (4
OCH2Ph, OCH2OCH3), 7.20-7.35 (m, 20 H, 4 C6H5); 13C NMR
(CDCl3) δ 55.36 (OCH3), 69.79 [(-), C-7], 71.12 (2 C, C-2, 6),
71.19 [(-), C-1], 73.37, 73.61 (2 C), and 74.22 [all (-), 4 OCH2-
Ph], 77.67 and 77.82 (C-3, 5), 79.05 (C-4), 97.12 [(-), OCH2O],
127.64-128.37 (Ar CH), 138.14 and 138.21 (Ar C). Anal.
Calcd for C37H44O8: C, 72.06; H, 7.19. Found: C, 71.88; H,
7.27.
1,3,4,5-Tetr a -O-ben zyl-7-O-(m eth oxym eth yl)-D-glycer o-
L-gu lo-h ep titol (5b): syrup; [R]D +2.5 (c 2.5, CHCl3); IR νmax
(film) 3450 (OH) cm-1; lH NMR (CDCl3) δ 2.75 (br s, 1 H, OH),
2.95 (br s, 1 H, OH), 3.30 (s, 3 H, OCH3), 3.42 (dd, 1 H, J )
10.0, 5.5 Hz), 3.51 (dd, 1 H, J ) 10.0, 6.7 Hz), and 3.66 (narrow
ABX, 2 H) (H-1A, 1B, 7A, 7B), 3.75 (dd, 1 H, J ) 7.2, 3.0 Hz)
and 3.90 (dd, 1 H, J ) 7.8, 1.9 Hz) (H-3, 5), 4.09 (dd, 1 H, J )
7.7, 2.7 Hz, H-4), 3.85 (br m, 1 H) and ∼4.05 (br m, 1 H) (H-2,
6), 4.48-4.85 (5 AB, 10 H, 4 OCH2Ph, OCH2OCH3), 7.22-7.35
(m, 20 H, 4 C6H5); 13C NMR (CDCl3) δ 55.31 (OCH3), 69.79
[(-), C-1], 69.95 and 70.63 (C-2, 6), 71.26 [(-), C-7], 73.15,
73.44, 74.70, and 74.89 [all (-), 4 OCH2Ph], 77.48, 78.44, and
79.17 (C-3-5), 96.87 [(-), OCH2O], 127.72-128.32 (Ar CH),
137.95, 138.00, 138.06, and 138.14 (Ar C).
Exp er im en ta l Section
Optical rotations were measured with an automatic pola-
rimeter for solutions in a 0.1 dm cell at 22 ( 3 °C. lH and 13C
NMR spectra were recorded at 360 and 90 MHz, respectively,
using chloroform-d as the solvent unless otherwise indicated.
Chemical shifts (in ppm) and coupling constants (in Hz) were
obtained from first-order analysis of the spectra. A minus sign
(-) is used to designate those signals that are negative in 13C
NMR spectra acquired in the DEPT mode (θy ) 135°). Mass
spectra were recorded at the Nebraska Center for Mass
3,4,5,7-Tetr a -O-ben zyl-1-O-(m eth oxym eth yl)-D-xylo-2,6-
h ep tod iu lose (6). To a solution of DMSO (2.3 mL) in
anhydrous CH2Cl2 (21 mL) at -78 °C was added dropwise,
under N2, a solution of trifluoroacetic anhydride (3.4 mL, 24.1
mmol) in CH2Cl2 (2.5 mL), and the mixture was stirred for 20
min at low temperature. A solution of a mixture of diols 5a
and 5b (3.26 g, 5.3 mmol) in CH2Cl2 (21 mL) was then added
(31) By contrast with 6, both 2,5-hexodiuloses and hexos-5-uloses
(e.g., “5-keto-D-glucose”) undergo double reductive amination with
primary alkylamines. For several examples, see: ref 22b.
(32) A small amount of the dimer resulting from the reaction of 8
with 20 could be detected in the mass spectrum of 20. This byproduct
was not apparent in the NMR spectra of 20.
(33) Expansion of the six-membered ring was observed in related
systems carrying a tertiary nitrogen atom: Martin O. R.; Liu, L.
Unpublished results.
(34) Hanessian, S.; Ugolini, A. Carbohydr. Res. 1984, 130, 265-275.

Chemical Synthesis of â-Homonojirimycin
J . Org. Chem., Vol. 61, No. 20, 1996 6991
dropwise; the temperature of the reaction mixture was main-
tained below -60 °C during the addition. The mixture was
stirred for 1.5 h at -78 °C. A solution of Et3N (6 mL) in CH2-
Cl2 (21 mL) was then added dropwise, and the mixture was
allowed to warm to room temperature. After 30 min, the
solvents were removed in vacuo, and the residue (crude 6) was
a column of Dowex 1X2-200 (OH-) ion-exchange resin. The
product was eluted with water (40 mL), and the fractions
containing 2 were combined and lyophilized to afford 2 (16
mg, 69.5%) as a solid: mp > 200 °C (dec); [R]D 0 (c 1.4, H2O);
lH NMR (D2O, CH3OD internal standard at δ 3.35) δ 2.65 (ddd,
2 H, J ) 2.8, 6.6, and 9.5 Hz, H-2, 6), 3.25 (t, 2 H, J ) 9.5 Hz,
H-3, 5), 3.39 (t, 1 H, J ) 9.0 Hz, H-4), 3.63 (dd, 2 H, J ) 6.6
and 11.6 Hz, H-1A, 7A), 3.88 (dd, 2 H, J ) 2.8 and 11.6 Hz,
H-1B, 7B); 13C NMR (D2O, CH3OD internal standard at δ 49.6)
δ 60.37 (C-2,6), 62.14 [(-), C-1,7], 72.16 (C-3,5), 78.88 (C-4);
FABMS (rel intensity) 200 (100, [M + Li]+); HR-FABMS calcd
for C7H15NO5Li m/ z 200.1110, found 200.1104.
Hep titols 11a a n d 11b. To a solution of heptenitol 10 (ref
28) (1.03 g, 1.9 mmol) in acetone (4 mL) were added water (1
mL), 4-methylmorpholine N-oxide (225 mg, 1.92 mmol), and
a 2.5% (w/v) solution of OsO4 in t-BuOH (0.2 mL). The mixture
was stirred overnight at room temperature. A solution of
NaHSO3 (300 mg) in water (20 mL) was then added, and the
resulting mixture was passed through a bed of Florisil. The
Florisil layer was washed with EtOAc (20 mL), and the eluate
was collected in the flask containing the aqueous phase. The
aqueous phase was acidified with dilute H2SO4. The organic
phase was then separated, and the aqueous phase was
extracted again with two 20 mL portions of fresh EtOAc. The
organic phases were combined, washed with brine (50 mL),
dried (Na2SO4), and concentrated to afford a homogeneous
mixture of epimers 11a and 11b (∼10:1, 1.07 g, 98%). These
epimers could be separated after silylation (see below).
Silyla tion of 11a a n d 11b. To a solution of 11a and 11b
(∼10:1, 1.0 g, 1.75 mmol) in anhydrous CH2Cl2 (6.7 mL) were
added tert-butyldimethylsilyl chloride (316 mg, 2.1 mmol),
DMAP (51 mg), and Et3N (0.4 mL). The mixture was stirred
overnight at room temperature. CH2Cl2 (100 mL) was then
added, and the solution was washed successively with 2 N
aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL),
and brine (50 mL), dried (Na2SO4), and concentrated. The
residue was submitted to flash chromatography (solvent E)
which afforded 12a (767 mg, 64%, Rf 0.25) and 12b (72 mg,
6%, Rf 0.12).
3,4,5,7-Tetr a -O-ben zyl-1-O-(ter t-bu tyld im eth ylsilyl)-D-
glycer o-D-gu lo-h ep titol (12a ): syrup; [R]D +4.4 (c 5.9, CHCl3);
IR νmax (film) 3476 (OH) cm-1; lH NMR (CDCl3) δ 0.18 (s, 6 H)
and 1.02 (s, 9 H) (OSiMe2-t-Bu), 2.98 (br d, 1 H, OH), 3.13 (br
d, 1 H, OH), 3.71-3.89 (2 narrow ABX, 4 H, H-1A, 1B, 7A,
7B), 3.96-4.03 (m, 3 H), 4.10 (t, 1 H, J ) 4.2 Hz) and ∼4.17
(br m, 1 H) (H-2-6), 4.62 (AB, 2 H, J ) 11.9 Hz), 4.73 (AB, 2
H, J ) 11.4 Hz), 4.76 (s, 2 H), and 4.79 (s, 2 H) (4 OCHAHB-
Ph), 7.35-7.45 (m, 20 H, 4 C6H5); 13C NMR (CDCl3) δ -5.45,
-5.38, 18.16, and 25.83 (SiMe2-t-Bu), 63.99 [(-), C-1], 71.20
[(-), C-7], 71.16 and 72.13 (C-2, 6), 73.28, 73.56, 73.65, and
74.25 [all (-), 4 OCH2Ph], 77.42, 77.92, and 79.23 (C-3-5),
127.54-128.28 (Ar CH), 137.86, 138.03, and 138.15 (2 C) (Ar
C). Anal. Calcd for C41H54O7Si: C, 71.69; H, 7.92. Found:
C, 71.58; H, 7.96.
used without further purification in the following step.
A
sample of crude product 6 was rapidly processed (extraction
with aqueous NaHCO3 and brine) for analysis by NMR: 13C
NMR (CDCl3) (content of diketone 6 > 90%) δ 55.49 (OCH3),
71.62, 73.19, 73.83, 73.91, 74.25, and 74.45 [all (-), C-1, 7; 4
OCH2Ph], 80.67, 81.03, and 81.07 (C-3-5), 96.51 [(-), OCH2O],
127.8-128.5 (Ar CH), 136.75 (3 C) and 137.33 (Ar C), 206.22
and 206.38 (C-2, 6).
3,4,5,7-Tetr a-O-ben zyl-2,6-dideoxy-2,6-im in o-1-O-(m eth -
oxym eth yl)-D-glycer o-D-gu lo-h ep titol (7). To a mixture of
crude 6 (product from previous reaction, 5.3 mmol scale), dry
ammonium formate (630 mg, 10 mmol), and powdered 3 Å
molecular sieves (0.5 g) in MeOH (45 mL) was added NaBH3-
CN (720 mg, 11.5 mmol) in one portion. The reaction mixture
was stirred for 30 min at room temperature.35 The solids were
then removed by filtration through a Celite bed, the solids were
washed with CH2Cl2 (100 mL), and the filtrate was concen-
trated. The residue was dissolved in EtOAc (150 mL). The
solution was washed successively with saturated aqueous
NaHCO3 (75 mL) and with brine (75 mL), dried (Na2SO4), and
concentrated. Crude 7 thus obtained was purified by flash
chromatography (solvent A) in a yield of 1.57 g (50%): mp 83-
84 °C (EtOH-water 1:1); [R]D +10.3 (c 5.6, CHCl3); IR νmax
(KBr) 3338 cm-1 (w, NH); 13C NMR (CDCl3) δ 55.34 (OCH3),
58.74 and 58.79 (C-2, 6), 67.92 [(-), C-7], 69.94 [(-), C-1],
73.28, 75.02 (2 C), and 75.53 [all (-), 4 OCH2Ph], 80.50 (2 C,
C-3, 5), 88.15 (C-4), 96.86 [(-), OCH2O], 127.6-128.5 (Ar CH),
138.24, 138.47 (2 C), and 138.92 (Ar C). FABMS (rel intensity)
598 (100, [M + H]+), 522 (18, [M - CH2OMOM]+), 476 (37, [M
- CH2OBn]+); HR-FABMS calcd for C37H44NO6 (MH+) m/ z
598.3168, found 598.3167. Anal. Calcd for C37H43NO6: C,
74.34; H, 7.25; N, 2.34. Found: C, 74.23; H, 7.26; N, 2.33.
3,4,5,7-Tetr a -O-ben zyl-2,6-d id eoxy-2,6-im in o-D-glycer o-
D-gu lo-h ep titol (8). A suspension of 7 (370 mg, 0.62 mmol)
in a mixture of THF (0.7 mL), water (3.4 mL), and 6 N aqueous
HCl (8.4 mL) was stirred overnight at 50 °C. Solid NaHCO3
was then added to neutralize the mixture, followed by water
(30 mL). The mixture was extracted with CH2Cl2 (2 × 60 mL),
the organic phases were combined, washed with brine (30 mL),
dried (Na2SO4), and concentrated to afford homogeneous 8 (320
mg, 93%): mp 129-130 °C (MeOH-water 1:1); [R]D + 7.0 (c
6.1, CHCl3); IR νmax (KBr) 3281 (w, NH), 3143 (m, OH) cm-1
;
lH NMR (CDCl3) δ 2.36 (br s, 2 H, NH, OH), 2.66 (ddd, 1 H,
J 1A,2 ) 4.9 Hz, J 1B,2 ) 3.0 Hz, J 2,3 ) 9.5 Hz, H-2), 2.80 (ddd, 1
H, J 5,6 ) 9.5 Hz, J 6,7A ) 6.0 Hz, J 6,7B ) 2.5 Hz, H-6), 3.39 (t, 2
H, J 3,4 ) 9.5 Hz, J 4,5 ) 9.5 Hz, H-3, 5), 3.52 (dd, 1 H, J 7A,7B
)
9.0 Hz, H-7A), 3.16 (dd, 1 H, J 1A,1B ) 11.0 Hz, H-1A), 3.63 (t,
1 H, H-4), 3.67 (dd, 1 H, H-7B), 3.74 (dd, 1 H, H-1B), 4.45 (AB,
2 H, J ) 12.0 Hz), 4.49 (d, 1 H, J ) 10.9 Hz), 4.65 (d, 1 H, J
) 11.0 Hz), 4.83 (d, 1 H, J ) 11.0 Hz), 4.88 (d, 1 H, J ) 11.0
Hz), and 4.90 (s, 2 H) (4 OCHAHBPh), 7.14-7.38 (m, 20 H, 4
C6H5); 13C NMR (CDCl3; assignments verified by H,C-COSY)
δ 58.79 (C-6), 60.11 (C-2), 62.42 [(-), C-1], 70.02 [(-), C-7],
73.41, 75.04, 75.07, and 75.55 [all (-), 4 OCH2Ph], 80.11 and
80.41 (C-3, 5), 88.02 (C-4), 127.3-130.5 (Ar CH), 137.60, 137.73
(2 C), and 137.91 (Ar C); FABMS (rel intensity) 554 (100, [M
+ H]+). Anal. Calcd for C35H39NO5: C, 75.92; H, 7.10; N, 2.53.
Found: C, 75.70; H, 7.07; N, 2.47.
1,3,4,5-Tetr a -O-ben zyl-7-O-(ter t-bu tyld im eth ylsilyl)-D-
glycer o-L-gu lo-h ep titol (12b): syrup; [R]D +2.3 (c 8.5, CHCl3);
IR νmax (film) 3456 (OH) cm-1; lH NMR (CDCl3) δ 0.08 (s, 6 H)
and 0.91 (s, 9 H) (OSiMe2-t-Bu), ∼2.65 (br, 1 H, OH), ∼3.05
(br, 1 H, OH), 3.48 (dd, 1 H, J ) 9.7, 6.6 Hz), 3.64 (dd, 1 H, J
) 9.7, 6.7 Hz), and 3.66-3.74 (narrow ABX) (H-1A, 1B, 7A,
7B), ∼3.82 (m, 1 H) and ∼4.14 (m, 1 H) (H-2, 6), 3.83 (dd, 1 H,
J ) 7.3, 3.0 Hz) and 4.04 (dd, 1 H, J ) 7.8, 1.6 Hz) (H-3, 5),
4.17 (dd, 1 H, J ) 7.8, 3.0 Hz, H-4), 4.58 (AB, 2 H, J ) 11.9
Hz), 4.65 (s, 2 H), 4.70 and 4.91 (2 d, 2 H, J ) 11.3 Hz), and
4.73 and 4.83 (2 d, 2 H, J ) 11.2 Hz) (4 OCHAHBPh), 7.30-
7.42 (4 C6H5); 13C NMR (CDCl3) δ -5.46, 18.15, and 25.84
(SiMe2-t-Bu), 64.08 [(-), C-7], 70.55 and 71.25 (C-2, 6), 71.25
[(-), C-1], 73.08, 73.37, 74.61, and 74.87 [all (-), 4 OCH2Ph],
77.45, 77.69, and 79.25 (C-3-5), 127.64-128.29 (Ar CH),
137.97, 138.02, 138.11, and 138.27 (Ar C). Anal. Calcd for
2,6-Did eoxy-2,6-im in o-D-glycer o-D-gu lo-h ep t it ol
(â-
h om on ojir im ycin ) (2). To a solution of 8 (65.5 mg, 0.118
mmol) in CH2Cl2 (3.5 mL) was added, dropwise at 0 °C,
iodotrimethylsilane (0.13 mL). The reaction mixture was
allowed to warm up to room temperature and stirred for 12 h.
Water (25 mL) and ether (25 mL) were then added, the organic
phase was separated, and the aqueous phase was extracted
with another 25 mL portion of ether. The aqueous phase was
then concentrated to 2 mL, and the solution was submitted to
C
41H54O7Si: C, 71.69; H, 7.92. Found: C, 71.84; H, 8.04.
3,4,5,7-Tetr a -O-ben zyl-D-glycer o-D-gu lo-h ep titol (11a ).
To a solution of 12a (102.5 mg, 0.15 mmol) in anhydrous THF
(1 mL) was added a 1 M solution of tetra-n-butylammonium
fluoride in THF (0.3 mL). The mixture was stirred for 2 h at
(35) It is imperative to use anhydrous conditions. Otherwise, the
reaction is slow and the yields are lower.

6992 J . Org. Chem., Vol. 61, No. 20, 1996
Saavedra and Martin
0 °C. The solvent was then evaporated, the residue dissolved
in EtOAc (50 mL), and the resulting solution was washed with
brine (25 mL), dried (Na2SO4), and concentrated. The product
was purified by flash chromatography (solvent A) which
afforded 11a (74.7 mg, 87%) as a syrup: [R]D - 0.7 (c 4.4,
CHCl3); IR νmax (film) 3445 (OH) cm-1; lH NMR (CDCl3) δ 2.90
(br, 1 H, OH), ∼3.38 (v br, 1 H, OH), 3.62 (d, 2 H, J ) 4.6 Hz),
∼3.63 (dd, 1 H, J ) ?, 4.3 Hz), and 3.71 (dd, 1 H, J ) 11.4, 3.3
Hz) (2 H-1, 2 H-7), 3.81 (dd, 1 H, J ) 7.3, 4.9 Hz), 3.87 (m, 2
H), 3.93 (t, 1 H, J = 4 Hz), and 4.05 (br q, 1 H) (H-2-6), 4.52
(narrow AB, 2 H, J ) 11.8 Hz), 4.59 (narrow AB, 2 H), 4.595
(s, 2 H), and 4.62 (narrow AB, 2 H, J ) 11.3 Hz) (4 OCHAHB-
Ph), 7.22-7.35 (m, 20 H, 4 C6H5); 13C NMR (CDCl3) δ 63.65
[(-), C-1], 70.89 and 72.00 (C-2, 6), 71.13 [(-), C-7], 73.50,
73.60, 73.87, and 74.00 [all (-), 4 OCH2Ph], 77.16, 77.63, and
79.01 (C-3-5), 127.82-128.47 (Ar CH), 137.49, 137.77, 137.84,
and 137.96 (Ar C). Anal. Calcd for C35H40O7: C, 73.40; H,
7.04. Found: C, 73.31; H, 7.13.
and 75.69 [all (-), 4 OCH2Ph], 80.37 and 80.68 (C-3, 5), 88.19
(C-4), 127.54-128.39 (Ar CH), 138.46-138.76 (Ar C). Anal.
Calcd for C41H53NO5Si: C, 73.72; H, 8.00; N, 2.10. Found: C,
73.80; H, 8.03; N, 2.15.
Com p ou n d 8 fr om 14. To a solution of 14 (398 mg, 0.596
mmol) in THF (4 mL) was added, at 0 °C, a 1 N solution of
tetrabutylammonium fluoride in THF (1.2 mL), and the
mixture was stirred for 4 h at 0 °C. The solvent was then
evaporated and the residue taken up in CH2Cl2 (20 mL). The
solution was washed with brine (15 mL), dried (Na2SO4), and
concentrated. Crystallization of the residue from EtOH-water
(1:1) afforded pure 8 (260 mg). The mother liquors were
concentrated, and the residue was submitted to flash chro-
matography (solvent B) which gave an additional sample of
pure 8 (32 mg; overall yield of 88%).
3,4,5,7-Tetr a -O-ben zyl-N-bu ta n oyl-2,6-d id eoxy-2,6-im i-
n o-1-O-(m et h oxym et h yl)-D-glycer o-D-gu lo-h ep t it ol (17).
To a solution of 7 (103.3 mg, 0.17 mmol) in anhydrous THF
(0.5 mL) was added dropwise 3 N methylmagnesium bromide
in THF (0.08 mL), and the mixture was stirred for 5 min (room
temperature). Butanoyl chloride (0.04 mL) was then added,
and the mixture was stirred for 2 h at room temperature. The
solvent was evaporated, and the residue was taken up in CH2-
Cl2 (25 mL). The resulting mixture was washed with brine
(15 mL), dried (Na2SO4), and concentrated. The crude product
was submitted to flash chromatography (solvent C) which
afforded 17 (80.1 mg, 70%) as a syrup: [R]D +4.0 (c 18.5,
1,3,4,5-Tetr a -O-ben zyl-D-glycer o-L-gu lo-h ep titol (11b).
Compound 12b (65 mg, 0.094 mmol) was desilylated under
the same conditions as 12a to provide heptitol 11b (39.2 mg,
72%) as a syrup: [R]D -3.7 (c 3.8, CHCl3); IR νmax (film) 3440
l
(OH) cm-1; H NMR (CDCl3) δ 2.94 (br, OH), 3.35 (dd, 1 H, J
) 11.2, 4.6 Hz), 3.48 (dd, 1 H, J ) 11.2, 6.3 Hz), 3.62 (br m, 1
H), 3.66 (∼d, 2 H), 3.74 (2 dd overlapping, 2 H), and 4.05 (dd
overlapping br m, 2 H, J ) 7.4, 3.3 Hz) (2 H-1, H-2-6, 2 H-7),
4.49-4.81 (4 AB, 8 H, 4 OCHAHBPh), 7.22-7.35 (m, 20 H, 4
C6H5); 13C NMR (CDCl3) δ 64.17 [(-), C-7], 70.64 and 71.15
(C-2, 6), 71.17 [(-), C-1], 73.19, 73.48, and 74.79 (2 C) [all (-),
4 OCH2Ph], 77.39, 78.93, and 79.00 (C-3-5), 127.79-128.47
(Ar CH), 137.83 (2 C) and 137.89 (2 C) (Ar C).
CHCl3); IR νmax (film) 1651 (s, CdO, doublet) cm-1 13C NMR
;
(∼1:1 mixture of amide rotamers; CDCl3) δ 13.88, 18.71 [(-)],
and 35.54 [(-), CH3CH2CH2CO], 55.48 (OCH3), 55.50, 55.92,
58.07, and 58.15 (C-2, 6), 66.16, 68.43, and 69.79 [(-), C-1, 7],
71.89, 72.13, 73.11, 73.31, 73.53, 73.78, 74.40, and 74.48 [all
(-), OCH2Ph], 75.41, 75.71, 80.00, 80.67, 82.98, and 83.18 (C-
3-5), 96.55 [(-), OCH2O], 127.6-128.3 (Ar CH), 138.03-138.4
(Ar C), 173.40 (CO). Anal. Calcd for C41H49NO7: C, 73.74;
H, 7.40; N, 2.10. Found: C, 73.46; H, 7.45; N, 1.99.
Hep ta -O-ben zyl-D-glycer o-D-gu lo-h ep titol (15). Com-
pound 11a (32.4 mg, 0.057 mmol) was benzylated under
standard conditions (NaH, BnBr in DMF). Purification of the
product by flash chromatography (solvent E) afforded perben-
zylated heptitol 15 (41 mg, 86%) as a syrup: [R]D 0 (c 4.0,
CHCl3); 13C NMR (CDCl3) δ 70.27 [(-), 2 C, C-1,7], 72.03 (2
C), 73.31 (2 C), 74.01 (2 C), 75.07 (1 C) [all (-), 7 OCH2Ph],
79.64 (4 C, C-2,3 and 5,6), 80.06 (1 C, C-4), 127.24-128.43
(Ar CH), 138.51, 138.84 (Ar C). Anal. Calcd for C56H58O7: C,
79.78; H, 6.93. Found: C, 79.62; H, 7.00.
3,4,5,7-Tetr a -O-ben zyl-N-bu tyl-2,6-d id eoxy-2,6-im in o-
D-glycer o-D-gu lo-h ep titol (18). A solution of 17 (76.1 mg,
0.11 mmol) in anhydrous THF (1 mL) was added to a 1 N
solution of BH3 in THF (0.2 mL) at 0 °C, and the mixture was
heated under reflux for 1.5 h. The mixture was treated with
6 N aqueous HCl (1 mL). The acid was neutralized after 10
min by the addition of solid NaHCO3. The aqueous phase was
extracted with CH2Cl2 (2 × 15 mL), and the organic phases
were combined, dried (Na2SO4), and concentrated. The residue
was purified by flash chromatography (solvent D) to afford the
MOM derivative of 18 (61.2 mg, 82%) as a solid: mp 66-67
°C; [R]D +0.9 (c 13, CHCl3). The MOM group was cleaved
under the same conditions as that of 7 (see preparation of 8),
and the product was purified by flash chromatography (solvent
B) to afford 18 in 75% yield: mp 53-54 °C; [R]D +7.5 (c 6.9,
Hep ta -O-ben zyl-D-glycer o-L-gu lo-h ep titol (16). Com-
pound 11b (22.9 mg, 0.040 mmol) was benzylated under
standard conditions (NaH, BnBr in DMF). Purification of the
product by flash chromatography (solvent E) afforded perben-
zylated heptitol 16 (28 mg, 83%) as a syrup: [R]D -4.5 (c 2.4,
CHCl3); 13C NMR (CDCl3) δ 70.26 and 70.52 [(-), C-1, 7], 71.93,
72.94, 73.20, 73.30, 73.83, 74.62, and 74.72 [all (-), 7 OCH2-
Ph], 78.10, 78.94, 79.11, 79.29, and 79.51 (C-2-6), 127.24-
128.18 (Ar CH), 138.5-139.5 (Ar C). Anal. Calcd for
C56H58O7: C, 79.78; H, 6.93. Found: C, 79.39; H, 7.28.
3,4,5,7-Tetr a -O-ben zyl-1-O-(ter t-bu tyld im eth ylsilyl)-D-
xylo-2,6-h ep tod iu lose (13). A mixture of epimers 12a and
12b (883 mg, 1.28 mmol) was submitted to the same oxidation
procedure as the 5a /5b mixture. The resulting crude diketone
13 was used in the following step without further purification.
For 13: 13C NMR (CDCl3) δ 205.88 and 207.05 (C-2, 6).
3,4,5,7-Tet r a -O-b en zyl-1-O-(ter t-b u t yld im et h ylsilyl)-
2,6-d id eoxy-2,6-im in o-D-glycer o-D-gu lo-h ep titol (14). Re-
ductive amination of crude 13 (prepared from 1.28 mmol of
11a /11b) using ammonium formate (155 mg) and NaBH3CN
(176 mg) in MeOH (11 mL) (see preparation of 7) followed by
purification of the product by flash chromatography (solvent
E) afforded compound 14 (497 mg, 58% from 12a /12b) as a
solid: mp 88-89 °C (EtOH-water 1:1); [R]D +8.9 (c 3.1,
CHCl3); IR νmax (KBr) 3342 (NH) cm-1; lH NMR (CDCl3) δ 0.05
(s, 3 H) and 0.89 (s, 9 H) (OSiMe2-t-Bu), 2.66 (m, 1 H) and
2.78 (m, 1 H) (H-2, 6), 3.43 (t, 1 H, J ) 9.4 Hz), and 3.47 (t, 1
H, J ) 9.5 Hz) (H-3, 5), 3.60-3.68 [ABX and t (δ ) 3.65, J =
9 Hz), 3 H, H-4, 2 H-1 or H-7], 3.73 (dd, 1 H, J ) 9.8, 4.8 Hz)
and 3.79 (dd, 1 H, J ) 9.8, 2.4 Hz) (2 H-7 or H-1), 4.46 (AB, 2
H, J ) 11.9 Hz), 4.53 (d, 1 H, J ) 11.0 Hz), 4.62 (d, 1 H, J )
11.0 Hz), 4.87 (d, 1 H), 4.89 (d, 1 H), and 4.91 (s, 2 H) (4
OCHAHBPh), 7.22-7.35 (m, 20 H, 4 C6H5); 13C NMR (CDCl3)
δ -5.47, -5.39, 18.13, and 25.82 (SiMe2-t-Bu), 58.53 and 59.84
(C-2, 6), 62.65 [(-), C-1], 69.75 [(-), C-7], 73.18, 75.08 (2 C),
CHCl3); IR νmax (KBr) 3441 (m, OH) cm-1 13C NMR (CDCl3) δ
;
13.86, 20.30 [(-)], 26.63 [(-)], and 49.39 [(-), C4H9N], 58.74
[(-), C-1], 62.09 and 62.85 (C-2, 6), 68.04 (C-7), 73.25, 74.22,
74.36, and 74.69 [all (-), 4 OCH2Ph], 78.04 and 78.48 (C-3,
5), 86.63 (C-4), 127.4-128.3 (Ar CH), 137.85, 138.39, 138.43,
and 138.60 (Ar C). Anal. Calcd for C39H47NO5: C, 76.82; H,
7.77; N, 2.30. Found: C, 76.56; H, 7.67; N, 2.21.
N-Bu tyl-2,6-d id eoxy-2,6-im in o-D-glycer o-D-gu lo-h ep ti-
tol (N-Bu tyl-â-h om on ojir im ycin ) (19). Compound 18 (67.8
mg, 0.11 mmol) was hydrogenolyzed in EtOH (40 mL) in the
presence of 10% palladium-on-carbon (100 mg) under H2 (120
psig) for 12 h at 50 °C. The solid was removed by filtration,
and the filtrate was concentrated. The residue was dissolved
in water (1 mL), and the solution was passed through LC-8
reverse phase silica gel (1 mL Supelclean extraction tube,
Supelco; H2O eluant). Concentration of the fractions contain-
ing the product afforded 19 (19.7 mg, 72%) as a solid: [R]D
0
l
(c 1.6, H2O); H NMR (D2O) δ 0.93 (t, 3 H, J ) 7.4 Hz), 1.33
(sextet, 2 H, J ) 7.4 Hz), 1.55 (quintet, 2 H), and 3.12 (br t, 2
H) (CH3CH2CH2CH2N), 2.88 (br d, 2 H, J ) 9.8 Hz, H-2, 6),
3.42 (t, 1 H, J ) 9.3 Hz, H-4), 3.56 (t, 2 H, J ) 9.7 Hz, H-3, 5),
3.98 (narrow ABX, 4 H, J AX = J BX = 1.7 Hz, J AB = 11.4 Hz,
H-1A, 7A and H-1B, 7B); 13C NMR (D2O) δ 13.71, 20.23 [(-)],
23.77 [(-)], and 47.78 [(-), C4H9N], 57.12 [(-), C-1, 7], 64.60
(C-2, 6), 68.88 (C-3, 5), 77.87 (C-4); FABMS (rel intensity) 250

Chemical Synthesis of â-Homonojirimycin
J . Org. Chem., Vol. 61, No. 20, 1996 6993
l
(100, [M + H]+); HR-FABMS calcd for C11H24NO5 m/ z 250.1654,
found 250.1652.
3355 (w, NH) cm-1; H NMR (C6D6; assignments verified by
H,H-COSY) δ 2.91-2.98 (2 overlapping m, 2 H, H-2′, 6′), 3.17
(OCH3), 3.46 (t, 1 H, J ) 9.4 Hz, H-3′), 3.51 (t, 1 H, J = 9.5
Hz, H-5′), 3.52 (dd, 1 H, J 1,2 ) 3.4 Hz, J 2,3 ) 9.3 Hz, H-2), 3.55
(dd, 1 H, J 6′,7′A ) 6.4 Hz, J 7′A,7′B = 9 Hz, H-7′A), 3.67-3.76 (m,
4 H, H-4, 4′, 6A, 7′B), 3.83-3.90 (m, 3 H, H-1′A, 5, 6B), 4.18
(t, 1 H, J ) 9.3 Hz, H-3), 4.45 (dd, 1 H, J 1′B,2 ) 2.4 Hz, H-1′B),
4.65 (d, 1 H, H-1), 4.20 (AB, 2 H, J ) 12.0 Hz), 4.39-4.60
(several d and AB, 6 H), 4.85-4.94 (2 d, AB, 4 H), and 4.99 (s,
2 H) (7 OCHAHBPh), 7.05-7.50 (m, 35 H, 7 C6H5); 13C NMR
(C6D6; assignments verified by H,C-COSY) δ 54.93 (OCH3),
59.33 and 59.80 (C-2′, 6′), 69.71 [(-), C-6], 70.96 [(-), C-7′],
71.14 (C-5), 73.69 [(-), C-1′], 72.92, 73.24, 73.55, 74.82, 74.97,
and 75.51 (2 C) [all (-), 7 OCH2Ph], 78.67 (C-4), 81.16, 81.26,
and 81.40 (C-2, 3′, 5′), 81.97 (C-3), 88.84 (C-4′), 98.38 (C-1),
127.4-128.6 (Ar CH), 138.8-139.9 (Ar C); FABMS (rel inten-
sity) 1022 (100, [M + Na]+), 1000 (30, [M + H]+). Anal. Calcd
for C63H69NO10: C, 75.65; H, 6.95; N, 1.40. Found: C, 75.52;
H, 6.99; N, 1.35.
3,4,5,7-Tet r a -O-b en zyl-2,6-d id eoxy-2,6-im in o-1-O-(p -
tolu en esu lfon yl)-D-glycer o-D-gu lo-h ep titol (20). To a solu-
tion of 8 (60.2 mg, 0.11 mmol) in CH2Cl2 (1 mL) were added
p-toluenesulfonyl chloride (31.1 mg), Et3N (0.03 mL), and
DMAP (3 mg). The mixture was stirred for 2 h at room
temperature. The solvent was then evaporated, and the
residue was submitted to flash chromatography (solvent B)
which afforded 20 (57.4 mg, 73%) as a solid: mp 138-139 °C
(EtOH); [R]D +4.0 (c 2.5, CHCl3); IR νmax (KBr) 3343 (w, NH),
l
1365, 1175 (s, SO2) cm-1; H NMR (CDCl3) δ 2.40 (s, 3 H,
ArCH3), 2.70 (ddd, 1 H, J ) 2.6, 5.3, 9.6 Hz) and 2.77 (ddd, 1
H, J ) 2.6, 5.1, 9.8 Hz) (H-2, 6), 3.32 (t, 1 H, J ) 9.5 Hz) and
3.39 (t, 1 H, J ) 9.5 Hz) (H-3, 5), 3.515 (A of ABX, 1 H, J 6,7A
) 5.3 Hz, J 7A,7B ) 9.2 Hz, H-7A), 3.57 (t, 1 H, J = 9.2 Hz,
H-4), 3.585 (B of ABX, 1 H, J 6,7B ) 2.8 Hz, H-7B), 4.13 (A of
ABX, 1 H, J 1A,2 ) 5.1 Hz, J 1A,1B ) 9.6 Hz, H-1A), 4.18 (B of
ABX, 1 H, J 1B,2 ) 2.5 Hz, H-1B), 4.41-4.51 (m, 4 H) and 4.78-
4.91 (m, 4 H) (4 OCHAHBPh), 7.14 (∼d, 2 H) and 7.75 (∼d, 2
H) (pCH3C6H4SO2), 7.22-7.36 (m, 20 H, 4 C6H5); 13C NMR
(CDCl3) δ 21.57 (ArCH3), 57.73 and 58.72 (C-2, 6), 69.44 and
70.13 (C-1, 7), 73.35, 74.98, 75.09, and 75.53 (4 OCH2Ph), 79.36
and 80.19 (C-3, 5), 87.95 (C-4), 127.53-129.85 (Ar CH), 132.66,
137.87, 137.91, 138.14, 138.56, and 144.87 (Ar C); FABMS (rel
intensity) 708.7 (26, [M + H]+), also observed 554.7 (28, [8 +
H]+). Anal. Calcd for C42H45NO7S: C, 71.26; H, 6.41; N, 1.98;
S, 4.53. Found: C, 71.32; H, 6.44; N, 1.91; S, 4.32.
Met h yl 4-O-(2,6-Did eoxy-2,6-im in o-D-glycer o-D-gu lo-
h ep tit-1-yl)-r-D-glu cop yr a n osid e (23). To a solution of 22
(98.2 mg, 0.098 mmol) in EtOH (60 mL) were added AcOH (3
mL) and 10% palladium-on-carbon (200 mg). The mixture was
stirred under hydrogen (140 psig) for 12 h at 50 °C. The
catalyst was then removed by filtration, and the filtrate was
concentrated. The residue was washed with CH2Cl2 (5 mL),
dried, and then dissolved in water (5 mL). The product was
loaded on a column of Dowex 50X8 (H+) ion-exchange resin
(100-200 mesh, 2 mL), the column was washed with water
(50 mL), and the product was eluted with 2% aqueous NH3 to
afford homogeneous 23 (28.2 mg, 84%): [R]D +65.9 (c 0.9,
H2O); 13C NMR (D2O; CH3CN internal standard at δ 1.49) δ
55.69 (OCH3), 58.91 and 60.36 (C-2′, 6′), 60.97 and 61.29 [(-),
C-6, 7′], 71.17, 71.35, 71.66, 71.98 (2 C including C-1′), 73.42,
78.53, and 78.73 (C-2, 3, 3′, 4, 4′, 5, 5′), 99.83 (C-1); FABMS
(rel intensity) 392 (100 [M + Na]+); HR-FABMS calcd for
C14H27NO10Na m/ z 392.1533, found 392.1538.
Meth yl 2,3,6-Tr i-O-ben zyl-4-O-(3,4,5,7-tetr a -O-ben zyl-
2,6-d id eoxy-2,6-im in o-D-glycer o-D-gu lo-h ep t it -1-yl)-r-D-
glu cop yr a n osid e (22). To a solution of methyl 2,3,6-tri-O-
benzyl-R-D-glucopyranoside (21)36 (105.6 mg, 0.23 mmol) was
added NaH (20 mg), and the mixture was stirred for 20 min
at room temperature. A solution of 20 (155.4 mg, 0.22 mmol)
in DMF (1.5 mL) was then added, and the mixture was stirred
for 2 h. MeOH (0.5 mL) was then carefully added, followed
by water (20 mL); the mixture was extracted with ether (2 ×
25 mL), and the organic phases were combined, washed with
brine (15 mL), dried (Na2SO4), and concentrated. The residue
was submitted to flash chromatography (solvent C) which
afforded pseudodisaccharide 22 (107 mg, 49% based on 20) as
a solid: mp 88-89 °C; [R]D +20.0 (c 1.3, CHCl3); IR νmax (KBr)
Ack n ow led gm en t. Support of this research by a
grant from the National Institutes of Health (DK35766)
is gratefully acknowledged. O.S. thanks Fulbright-
LASPAU for a fellowship.
(36) Garegg, P. J .; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982,
108, 97-101.
J O960362I