Access to piperidine imino-C-glycosides via stereoselective thiazole-based aminohomologation of pyranoses

Article abstract of DOI:10.1021/jo060890m

(Chemical Equation Presented) The access to piperidine homoazasugars (dideoxyiminoheptitols) from pyranoses via formal one-carbon chain elongation and exchange of the ring oxygen with the NH group is described. The key process involves the stereoselective

Full text of DOI:10.1021/jo060890m

Access to Piperidine Imino-C-glycosides via Stereoselective
Thiazole-Based Aminohomologation of Pyranoses
Alessandro Dondoni* and Andrea Nuzzi
Dipartimento di Chimica, Laboratorio di Chimica Organica, UniVersita` di Ferrara,
Via L. Borsari 46, 44100 Ferrara, Italy
adn@unife.it
ReceiVed April 28, 2006
The access to piperidine homoazasugars (dideoxyiminoheptitols) from pyranoses via formal one-carbon
chain elongation and exchange of the ring oxygen with the NH group is described. The key process
involves the stereoselective addition of 2-thiazolylmagnesium bromide to an N-glycosylhydroxylamine,
i.e., a hidden open-chain sugar nitrone. The N-thiazolylalkylhydroxylamine formed in this way is reduced
to amine, and this transformed into a substituted piperidine via intramolecular cyclization by an SN2
process. Cleavage of the thiazole residue attached to C2 of the piperidine ring reveals the formyl group,
and this is reduced to hydroxymethyl to give the target homoazasugar. A collection of six stereodiversified
compounds with free OH and NH groups and isolated as hydrochlorides has been prepared.
SCHEME 1a
Introduction
Recent disclosures from these laboratories have shown the
effectiveness of the thiazole-based transformation of 2,3,5-tri-
O-benzyl D- and L-furanoses into N-benzylpyrrolidines bearing
a hydroxymethyl group at the carbon atom adjacent to nitrogen,
namely the so-called pyrrolidine homoazasugars1 (Scheme 1).
The whole procedure can be considered as an aminohomologa-
tion process because it entails the substitution of the furanose
ring oxygen with the NH group and the insertion of a methyl-
ene group into the anomeric C-OH bond. These structural
changes are achieved via a five-step reaction sequence involving
the following: (i) the conversion of the furanose Ia into the
N-benzyl-N-glycosylhydroxylamine IIa; (ii) the stereoselective
addition of 2-lithiothiazole 3 to the minor tautomer of IIa, viz.
an open-chain N-benzyl sugar nitrone (not shown), to give a
mixture of N-thiazolylalkylhydroxylamine diastereoisomers
Th(R)CH*-N(Bn)OH (Th ) 2-thiazolyl; R ) BnOCH2CH(OH)-
CH(OBn)CH(OBn)-); (iii) the separation and reductive N-
dehydroxylation of each isomer to give a secondary amine
Th(R)CH*-NHBn; (iv) the pyrrolidine ring formation via acti-
vation of the free hydroxyl group in the alkyl chain R as a
a Key: (a) N(OH)Bn f NHBn in the open-chain adduct; (b) cyclization
via SN2 of OSO2CH3 by NHBn; (c) one-pot thiazole f CHO f CH2OH.
mesylate and displacement of the latter with the amino group;
(v) the cleavage of the thiazole ring to formyl group and reduc-
tion of the latter to give the target alcohol IIIa. We embarked
(1) (a) Dondoni, A.; Perrone, D. Tetrahedron Lett. 1999, 40, 9375-
9378. (b) Dondoni, A.; Giovannini, P. P.; Perrone, D. J. Org. Chem. 2002,
67, 7203-7214.
10.1021/jo060890m CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/06/2006
7574
J. Org. Chem. 2006, 71, 7574-7582

Thiazole-Based Aminohomologation of Pyranoses
in this research because in the diversity of natural and synthetic
azasugars (alias iminosugars) that have been isolated and
prepared in the last three decades2,3 due to their intense activity
as specific glycosidase and glycosyltransferase inhibitors, those
compounds having a hydroxymethyl group or a polyhydroxyl-
ated carbon chain linked to the carbon adjacent to nitrogen of
either a pyrrolidine or piperidine ring have gained special
importance.4 These homoazasugars have been found to retain
the same type of enzymatic inhibition of the lower homologues
and at the same time exibit higher selectivity and potency.5
Moreover, they present high stability toward chemical and
enzymatic degradation, a serious drawback of the parent
azasugars due to the lability of the O,N-acetal function. In line
with this concept, the synthesis of aza-C-glycosides with various
functional aglycons, suitable for further modification, are attract-
ing great interest as the next generation of glycoprocessing
enzyme inhibitors.4c The thiazole-based aminohomologation
methodology appears to fit quite well in this program because
the mild and neutral reaction conditions of the thiazole-to-formyl
protocol (methylation, reduction, hydrolysis) permit rather
unstable aza-C-glycosyl aldehydes to be isolated and trans-
formed into more complex aza-C-glycosides. We have taken
advantage of this opportunity by performing Wittig-type cou-
pling reactions of 2-formyl N-benzylpyrrolidines with sugar
phosphoranes en route to (1f6)- and (1f5)-linked aza-C-
disaccharides,1 i.e., compounds in which the azasugar moiety
is anomerically linked through an all-carbon tether to a normal
monosaccharide.4c,6
Unfortunately, the use of the above aminohomologation
sequence was restricted to pentofuranoses Ia. Attempts to extend
the methodology to pyranoses Ib to access piperidine homo-
azasugars IIIb met with failure.1 The crucial process involving
the introduction of the thiazole ring at the anomeric carbon of
the N-hexopyranosylhydroxylamine IIb was unsuccessful by the
use of 2-lithiothiazole 3 at -70 °C in Et2O. Performing the
reaction under these conditions was required since substantial
decomposition of 3 occurred at higher temperatures.7 We sought
a simple solution to this shortcoming by the use of another
thiazole-based organometallic reagent that was enough stable
and reactive at higher temperature. Thus, guided by the obser-
vation8 that Grignard reagents reacted with two N-hexopyrano-
sylhydroxylamines IIb, attention was focused on the use of
2-thiazolylmagnesium bromide 4. This was a previously scarcely
exploited organometallic reagent very likely because of the lack
of a standard preparation procedure. Fortunately enough the
preparation of 4 was recently optimized in our laboratory.9 To
our delight, the Grignard reagent 4 reacted smoothly with
N-hexopyranosylhydroxylamines IIb at 0 °C in THF, thus
paving the way to the target piperidine homoazasugars IIIb.
The results of this work are presented below.
(2) Reviews and books: (a) Winchester, B.; Fleet, G. W. J. Glycobiology
1992, 2, 199-210. (b) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem.
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347. (d) Bols, M. Acc. Chem. Res. 1998, 31, 1-8 (e) Sears, P.; Wong,
C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300-2324. (f) Stu¨tz, A. E.
Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-
VCH: Weinheim, Germany, 1999. (g) Butters, T. D.; Dwek, R. A.; Platt,
F. M. Chem. ReV. 2000, 100, 4683-4696. (h) Asano, N.; Nash, R. J.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645-
1680 (i) Ossor, A.; Elbein, A. D. Glycoprotein Processing Inhibitors. In
Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay¨,
P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Part II, Vol. 3, pp 513-
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2002, 102, 515-553. (k) Asano, N. Curr. Top. Med. Chem. 2003, 3, 471-
484. (l) Cipolla, L.; La Ferla, B.; Nicotra, F. Curr. Top. Med. Chem. 2003,
3, 485-511. (m) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003,
3, 541-560. (n) Pearson, M. S. M.; Mathe`-Allainmat, M.; Fargeas, V.;
Lebreton, J. Eur. J. Org. Chem. 2005, 2159-2191.
(3) For selected recent papers (2003-2005), see: (a) Pino-Gonza´les, M.
S.; Assiego, C.; Lo´pez-Herrera, F. J. Tetrahedron Lett. 2003, 44, 8353-
8356. (b) Dransfield, Gore, P. M.; Prokes, I.; Shipman, M.; Slawin, A. M.
Z. Org. Biomol. Chem. 2003, 1, 2723-2733. (c) Pandey, G.; Kapur, M.;
Khan, M. I.; Gaikwad, S. M. Org. Biomol. Chem. 2003, 1, 3321-3326. (d)
Sawada, D.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2003, 44, 3085-
3088. (e) Ayad, T.; Ge´nisson, Y.; Broussy, S.; Baltas, M.; Gorrichon, L.
Eur. J. Org. Chem. 2003, 2903-2910. (f) Xie, J.; Gu¨veli, T.; Hebbe, S.;
Dechoux, L. Tetrahedron Lett. 2004, 45, 4903-4906. (g) Chery, F.; Cronin,
L.; O’Brien, J. L.; Murphy, P. V. Tetrahedron 2004, 60, 6597-6608. (h)
Cren, S.; Gurcha, S. S.; Blake, A. J.; Besra, G. S.; Thomas, N. R. Org.
Biomol. Chem. 2004, 2, 2418-2420. (i) Asano, N.; Yamauchi, T.;
Kagamifuchi, K.; Shimizu, N.; Takahashi, S.; Takatsuka, H.; Ikeda, K.;
Kizu, H.; Chuakul, W.; Kettawan, A.; Okamoto, T. J. Nat. Prod. 2005, 68,
1238-1242. (j) Wang, R.-W.; Qing, F.-L. Org. Lett. 2005, 7, 2189-2192.
(k) Moreno-Vargas, A. J.; Carmona, A. T.; Mora, F.; Vogel, P.; Robina, I.
Chem. Commun. 2005, 4949-4951. (l) Ouchi, H.; Mihara, Y.; Takahata,
H. J. Org. Chem. 2005, 70, 5207-5214. (m) Segraves, N. L.; Crews, P. J.
Nat. Prod. 2005, 68, 118-121. (n) Cren, S.; Wilson, C.; Thomas, N. R.
Org. Lett. 2005, 7, 3521-3523. (o) Chapman, T. M.; Davies, I. G.; Gu, B.;
Block, T. M.; Scopes, D. I. C.; Hay, P. A.; Courtney, S. M.; McNeill, L.
A.; Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc. 2005, 127, 506-507.
(p) Boglio, C.; Stahlke, S.; Thorimbert, S.; Malacria, M. Org. Lett. 2005,
7, 4851-4854. (q) Ouchi, H.; Mihara, Y.; Takahata, H. J. Org. Chem. 2005,
70, 5207-5214.
We considered three model 2,3,4,6-tetra-O-benzyl-D-hexo-
pyranoses (D-gluco 1a, D-manno 1b, D-galacto 1c) as readily
available starting materials to study the feasibility of the thiazole-
based route toward a small yet representative collection of
stereodiversified piperidine homoazasaugars. We were aware
that in the case of a successful synthesis via the reaction
sequence employed for the pyrrolidine homoazasugar synthesis,1
the products will belong to the L-series of carbohydrates.
L-Azasugars which in the past attracted little attention, have been
recently reevaluated because while mimicking L-sugars10 they
have been found to be also noncompetitive inhibitors of
D-glycohydrolases.11 Moreover, it has been recently reported a
(4) Reviews: (a) Martin, O. R. Toward Azaglycoside Mimics: Aza-C-
glycosyl Compounds and Homoazaglycosides. In Carbohydrate Mimics.
Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH: Weinheim,
Germany, 1998; pp 259-282. (b) Dhavale, D. D.; Matin, M. M. ArkiVok
2005, 110-132. (c) Zou, W. Curr. Top. Med. Chem. 2005, 5, 1363-1391.
Recent papers: (d) Dhavale, D. D.; Matin, M. M.; Sharma, T.; Sabharwal,
S. G. Bioorg. Med. Chem. 2003, 11, 3295-3305. (e) Godin, G.; Compain,
P.; Martin, O. R. Org. Lett. 2003, 5, 3269-3272. (f) Chapman, T. M.;
Courtney, S.; Hay, P.; Davis, B. G. Chem. Eur. J. 2003, 9, 3397-3414. (g)
Donohoe, T. J.; Headley, C. E.; Cousins, R. P. C.; Cowley, A. Org. Lett.
2003, 5, 999-1002. (h) Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew.
Chem., Int. Ed. 2003, 42, 5987-5990. (i) Carmona, A. T.; Fuentes, J.;
Robina, I.; Garc´ıa, E. R.; Demange, R.; Vogel, P.; Winters, A. L. J. Org.
Chem. 2003, 68, 3874-3883. (j) Assiego, C.; Pino-Gonza´les, M. S.; Lo´pez-
Herrera, F. J. Tetrahedron Lett. 2004, 45, 2611-2613. (k) Garc´ıa-Moreno,
M. I.; Rodr´ıguez-Lucena, D.; Ortiz Mellet, C.; Garc´ıa-Ferna´ndez, J. M. J.
Org. Chem. 2004, 69, 3578-3581. (l) Fuentes, J.; Sayago, F. J.; Illangua,
J. M.; Gasch, C.; Angulo, M.; Pradera, M. A. Tetrahedron: Asymmetry
2004, 15, 603-615. (m) Dondoni, A.; Giovannini, P. P.; Perrone, D. J.
Org. Chem. 2005, 70, 5508-5518.
(6) Robina, I.; Vogel, P. Synthesis 2005, 675-702.
(7) For the effective in situ generation of 3 from 2-bromothiazole and
subsequent reactions, see: Dondoni, A.; Scherrmann, M.-C. J. Org. Chem.
1994, 59, 6404-6412.
(8) Dondoni, A.; Perrone, D. Tetrahedron 2003, 59, 4261-4273.
(9) Dondoni, A.; Catozzi, N.; Marra, A. J. Org. Chem. 2005, 70, 9257-
9268.
(10) (a) Davis, B. G.; Hull, A.; Smith, C.; Nash, R. J.; Watson, A. A.;
Winkler, D. A.; Griffiths, R. C.; Fleet, G. W. J. Tetrahedron: Asymmetry
1998, 9, 2947-2960. (b) Davis, B.; Bell, A. A.; Nash, R. J.; Watson, A.
A.; Griffiths, R. C.; Jones, M. G.; Smith, C.; Fleet, G. W. J. Tetrahedron
Lett. 1996, 37, 8565-8568.
(11) Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi,
I.; Kato, I.; Ouchi, H.; Takahata, H.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2005, 16, 223-229.
(5) Martin, O. R.; Saavedra, O. M.; Xie, F.; Liu, L.; Picasso, S.; Vogel,
P.; Kizu, H.; Asano, N. Bioorg. Med. Chem. 2001, 9, 1269-1278.
J. Org. Chem, Vol. 71, No. 20, 2006 7575

Dondoni and Nuzzi
TABLE 1. N-Glycosylhydroxylamines 2 Prepareda from Pyranoses 1 and Their Adductsb 5a-c, 6a-c with 2-Thiazolylmagnesium Bromide 4
1
a Neat 1 and BnNHOH at 110 °C, 1 h. b 5 equiv of 4 in THF at 0 °C. c dr ratios determined by H NMR analysis. d Not isolated in pure form.
synthetic azasugar with the L-altro configuration featuring great
potential as immunosuppressive agent.12 Hence compounds
1a-c were conveniently transformed into the corresponding
N-benzyl-N-glycosylhydroxylamines 2a-c (Table 1) on heating
their mixtures with N-benzylhydroxylamine at 110 °C for 1 h
in the absence of solvent. While the â-configuration of the
D-gluco 2a and D-galacto 2c derivatives was previously assigned
on the basis of the J1,2 values,8 the assignment of the anomeric
configuration of the D-manno isomer 2b appeared to be
problematic. In fact, ROESY experiments were inconclusive.
Moreover, the measurement of the 1JC1-H1 (157.5 Hz) appeared
to us of scarce utility because of the unavailable value of the
other anomer and the absence of an extensive set of data for R-
and â-N-glycosylhydroxylamines.13 Therefore, the structure of
2b remains at present unassigned. No one of compounds 2a-c
showed by NMR analysis the presence of the open-chain nitrone
form. Nevertheless treatment of these hydroxylamines with
excess (5.0 equiv) of 2-thiazolylmagnesium bromide 4 in THF
at 0 °C for 2 h afforded three pairs of formal adducts to nitrones,
i.e., the thiazolylalkylhydroxylamine diastereoisomers 5a-6a,
5b-6b, and 5c-6c respectively, in good overall yield but
modest selectivity (Table 1). Unfortunately, attempts to separate
5a and 6a by flash chromatography were unsuccessful. Only a
pure sample of 5a was obtained by preparative TLC. On the
other hand, each isomer of the pairs 5b-6b and 5c-6c was
separated by flash chromatography. The configuration of the
newly formed stereocenter in all compounds 5 and 6 was
established following the conversion of their mixtures or indi-
vidually isolated pure compounds into piperidines (see below).
Thus, it appeared that the major diastereoisomers 5a and 5c
were both syn-adducts, whereas the main product 5b was an
anti-adduct. Evidently, the configuration of the carbon stereo-
center adjacent to the nitrone group affects substantially the
selectivity of these reactions. Variable syn/anti selectivities in
the additions of organometallic reagents to nitrones derived from
chiral polyalkoxy aldehydes and aldehydo sugars were recorded
in a number of cases studied in our14 and other 15 laboratories.
Either the individually isolated hydroxylamines 5 and 6 or
their mixtures were transformed into polyhydroxylated 2-thia-
zolylpiperidines 9 and 10 (Table 2). Improved conditions were
used with respect to those employed for the synthesis of the
pyrrolidine derivatives.1 Specifically, the reductive dehydroxyl-
ation of the N(OH)Bn group was first carried out by Zn-Cu
(OAc)2‚H2O to give the amino alcohols 7 and 8. Attempts of
cyclization of these compounds to piperidine derivatives via
activation of the free hydroxyl group with triflic anhydride as
reported1 gave complex mixtures of products. This crucial oper-
ation was conveniently carried out via O-mesylate formation
at 0-5 °C in toluene employing methanesulfonyl chloride
(MsCl) in the presence of Et3N (1.5 equiv) and catalytic
N,N,N′,N′-tetramethylethylenediamine, TMEDA, as a pro-
moter,16 followed by heating the crude product in MeCN at 85
°C. Under these conditions, the piperidines 9a and 10a (from
D-glucose), 9b (from D-mannose), and 9c, 10c (from D-galactose)
(14) (a) Dondoni, A.; Franco, S.; Junquera, F.; Mercha´n, F. L.; Merino,
P.; Tejero, T.; Bertolasi, V. Chem. Eur. J. 1995, 1, 505-520 (b) Dondoni,
A.; Junquera, F.; Mercha´n, F. L.; Merino, P.; Scherrmann, M.-C.; Tejero,
T. J. Org. Chem. 1997, 62, 5484-5496.
(15) For recent reviews on nucleophilic additions to CdN bonds,
including nitrones, see: (a) Bloch, R. Chem. ReV. 1998, 98, 1407-1438
(b) Lombardo, M.; Trombini, C. Synthesis 2000, 759-774.
(16) Yoshida, Y.; Shimonishi, K.; Sakakura, Y.; Okada, S.; Aso, N.;
Tanabe, Y. Synthesis 1999, 1633-1636.
(12) Ye, X.-S.; Sun, F.; Liu, M.; Li, Q.; Wang, Y.; Zhang, G.; Zhang,
L.;-H.; Zhang, X.-L. J. Med. Chem. 2005, 48, 3688-3691.
(13) It is known that R- and â-mannopyranosides exibit in several cases
1
very close JC1-H1 values. (a) Callam, C. S.; Gadikota, R. R.; Lowary, T.
L. J. Org. Chem. 2001, 66, 4549-4558. (b) Bock, K.; Pedersen, C. J. Chem.
Soc., Perkin Trans. 2 1974, 293-297. (c) Bock, K.; Lundt, I.; Pedersen, C.
Tetrahedron Lett. 1973, 1037-1040. (d) Sparks, M. A.; Panek, J. S.
Tetrahedron Lett. 1989, 30, 407-410.
7576 J. Org. Chem., Vol. 71, No. 20, 2006

Thiazole-Based Aminohomologation of Pyranoses
TABLE 2. Protected (11a-c, 12a-c) and Free (13a-c, 14a-c) Piperidine Homoazasugars Prepared from Sugar Hydroxylamines 5a-c, 6a-c
a A side product (ca. 30%) has been isolated (ref 17).
were obtained as the sole diastereoisomers in good isolated
yields (70-80%). Only the piperidine 10b was obtained in low
yield (52%) because an unexpected byproduct was also formed,
which was characterized as a C-furanosyl substituted thiazolyl-
alkylamine.17 The configuration of the C2 carbon bearing the
thiazole ring in all piperidines 9 and 10 was established by
analysis of their 1H NMR spectra and determination of coupling
constant values of all protons of the heterocyclic ring. Hence,
based on the reasonable assumption that the ring closure reaction
occurred via an SN2 mechanism, the configuration of the
corresponding open-chain amine and hydroxylamine precursors
was assigned with high degree of confidence.
corresponding homoazasugars 11a-12a, 11b-12b, and 11c-
12c commenced by cleavage of the thiazole ring. Although
earlier work in our laboratory showed that the presence of the
NBn group was incompatible with the thiazole-to-aldehyde
unmasking protocol,18 this shortcoming did not occur with the
thiazolyl-piperidines 9 and 10. Hence, these compounds were
subjected to the one-pot sequence consisting of microwave
(MW)-assisted19 methylation (MeI), reduction (NaBH4), and
HgCl2-promoted hydrolysis. Crude piperidine aldehydes thus
formed were reduced by NaBH4 to the corresponding alcohols
11 and 12. The isolated overall yields of these products varied
from 31 to 71% without any apparent reason. Finally, the
removal of the O-Bn and N-Bn protective groups from com-
pounds 11 and 12 by H2 (100psi) and Pd(OH)2/C in the presence
With the three pairs of thiazolylpiperidine epimers 9a-10a,
9b-10b, and 9c-10c in hand, their transformation into the
J. Org. Chem, Vol. 71, No. 20, 2006 7577

Dondoni and Nuzzi
(1.71 g, 13.88 mmol) was stirred at 110 °C for 1 h. The resulting
residue was cooled to room temperature and purified by crystal-
lization.
of HCl afforded the three pairs of epimers, i.e., free dideoxy-
iminoheptitol hydrochlorides 13a-14a, 13b-14b, and 13c-
14c. These salts, with the exception of 13b, were isolated in
very good yields. Compounds 13b20 and 13c21 showed char-
acteristics identical to those of the literature.
In conclusion, the results of the present work demonstrate
the successful extension of the thiazole-based aminohomolo-
gation strategy to pyranoses. The reactions in this sequence
while being nontrivial are operationally simple and do not show
limitations by the structural change of the reactants employed.
Hence, since this methodology works quite well with both
furanoses and pyranoses, we believe that significant collections
of pyrrolidine and piperidine homoazasugars with a wide range
of stereochemical diversity will become accessible.
N-Benzyl N-2,3,4,6-tetra-O-benzyl-D-mannopyranosylhydrox-
ylamine (2b). Crystallization from cyclohexane afforded 2b (4.85
g, 81%) as a white solid. Mp ) 101-103 °C. [R]D ) 16.3 (c 0.6,
CHCl3). 1H NMR (C6D6): δ ) 7.40-7.00 (m, 25 H, Ph), 4.84 and
4.48 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.64 and 4.60 (2 d, 2 H, J )
11.5 Hz, CH2Ph), 4.55 (d, 1 H, J1,2 ) 3.0 Hz, H-1), 4.48 and 4.41
(2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.48 (s, 2 H, CH2Ph), 4.38 and
3.54 (2 d, 2 H, J ) 13.5 Hz, N-CH2Ph), 4.35 (ddd, 1 H, J5,4 ) 8.5
Hz, J5,6a ) 4.0 Hz, J5,6b ) 4.5 Hz, H-5), 4.24 (t, 1 H, J2,1 ) J2,3
)
3.0 Hz, H-2), 4.15 (t, 1 H, J4,3 ) J4,5 ) 8.5 Hz, H-4), 4.11 (s, 1 H,
N(OH)), 4.02 (dd, 1 H, J3,2 ) 3.0 Hz, J3,4 ) 8.5 Hz, H-3), 3.75 (m,
2 H, H-6a and H-6b). 13C NMR (C6D6): δ ) 138.9, 138.1, 137.2,
129.9-127.0, 90.3, 79.9, 75.5, 74.8, 74.3, 73.9, 73.1, 72.6, 70.1,
1
60.1, JC1-H1 ) 157.5 Hz. MALDI-TOF MS: 668.2 (M + Na),
Experimental Section
684.5 (M + K). Anal. Calcd for C41H43NO6 (645.3): C, 76.25; H,
6.71; N, 2.17. Found: C, 76.35; H, 6.63; N, 2.29.
All moisture-sensitive reactions were performed under a nitrogen
atmosphere using oven-dried glassware. Solvents were dried over
standard drying agent and freshly distilled prior to use. Reactions
were monitored by TLC on silica gel 60 F254 with detection by
charring with ethanolic solution of sulfuric acid or ninhydrin. Flash
column chromatography was performed on silica gel 60 (230-
400 mesh). The microwave (MW) irradiation was performed by a
Biotage Initiator apparatus. Optimization experiments were per-
formed in the “single-run” mode, i.e., by manual filling of reaction
vials and by specifying the irradiation time and maximum temper-
ature. Melting points were determined with a capillary apparatus.
Optical rotations were measured at 20 ( 2 °C in the stated solvent;
General Procedure for the Addition of 2-Thiazolylmagnesium
Bromide 4 to N-Benzyl-N-glycosylhydroxylamines 2a-c. To a
cooled (0 °C), stirred mixture of ethylmagnesium bromide (12.9
mL, 38.74 mmol of a 3 M solution in Et2O) and anhydrous THF
(82 mL) was added dropwise a solution of freshly distilled
2-bromothiazole (3.49 mL, 38.74 mmol) in dry THF (15 mL) in
ca. 15 min. The resulting pale yellow-orange solution was kept at
0 °C for an additional 10 min and then warmed to room temperature
and stirred for 1.5-2 h until the color of the solution changed to
red-violet. The mixture was then cooled to 0 °C, and a solution of
N-benzyl-N-glycosyl hydroxylamine 2a-c (5.00 g, 7.75 mmol) in
anhydrous THF (35 mL) was added dropwise in ca. 20 min. The
mixture was stirred at 0 °C for 1-2 h and then quenched with 1 M
aqueous phosphate buffer (25 mL). The layers were separated, and
the aqueous phase was extracted with AcOEt (2 × 50 mL). The
collected organic phases were washed with 1 M aqueous phosphate
buffer (2 × 50 mL), dried over Na2SO4, filtered, and concentrated.
The residue was eluted from a column of silica gel with the suit-
able elution system to give the corresponding thiazolyl derivatives
5a-c, 6a-c.
[R]D values are given in 10-1 deg cm2 g-1. 1H (400 MHz) and 13
C
NMR (100 MHz) spectra were recorded for CDCl3 solutions at
room temperature unless otherwise specified. Assignments were
aided by homo-2D experiments. MALDI-TOF mass spectra were
acquired using 2,6-dihydroxy benzoic acid (DHB) as matrix.
N-Benzyl-N-glycosylhydroxylamines 2a and 2c,8 2,6-dideoxy-2,6-
imino heptitol hydrochloride 13b,20 and the free amine of 13c21
were known compounds.
General Procedure for the Preparation of N-Benzyl-N-glycosyl-
hydroxylamines 2a-c. A mixture of 2,3,4,6-tetra-O-benzylhexo-
pyranose 1a-c (5.00 g, 9.25 mmol) and N-benzylhydroxylamine
(2R,3R,4R,5S,6R)- and (2R,3R,4R,5S,6S)-6-N-Benzylhydroxyl-
amino-1,3,4,5-tetra-O-benzyl-6-thiazolyl-1,2,3,4,5-hexanepen-
tol (5a and 6a). Column chromatography with 3:1 cyclohexane-
AcOEt afforded 5a and 6a (4.54 g, 80%) as a 3:1 unseparable
mixture of diastereoisomers. The above mixture was subjected to
preparative TLC analysis with 4:1 cyclohexane-AcOEt.
Eluted first was 5a. [R]D ) 4.6 (c 0.5, MeOH). 1H NMR
(C6D6): δ ) 7.55 (d, 1 H, J ) 3.2 Hz, Th), 7.40-7.00 (m, 25 H,
Ph), 6.62 (d, 1 H, J ) 3.2 Hz, Th), 6.05 (s, 1 H, N(OH)Bn), 5.04
(d, 1 H, J6,5 ) 6.0 Hz, H-6), 4.76 (s, 2 H, CH2Ph), 4.73 and 4.52
(2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.59 (dd, 1 H, J5,4 ) 5.5 Hz, J5,6
) 6.0 Hz, H-5), 4.49 (s, 2 H, CH2Ph), 4.30 and 4.24 (2 d, 2 H, J )
12.0 Hz, CH2Ph), 4.21 (m, 1 H, H-2), 4.05 (dd, 1 H, J4,3 ) 4.5 Hz,
J4,5 ) 5.0 Hz, H-4), 3.97 and 3.70 (2 d, 2 H, J ) 13.0 Hz, N-CH2-
Ph), 3.87 (dd, 1 H, J3,2 ) 7.0 Hz, J3,4 ) 4.5 Hz, H-3), 3.59 (dd, 1
H, J1a,1b ) 9.5 Hz, J1a,2 ) 3.5 Hz, H-1a), 3.56 (dd, 1 H, J1b,1a ) 9.5
Hz, J1b,2 ) 5.5 Hz, H-1b), 2.85 (s, 1 H, OH). 13C NMR (C6D6): δ
) 164.9, 143.9, 141.7, 139.3, 139.2, 138.9, 138.6, 137.9, 130.1,
128.5-127.6, 120.9, 120.5, 80.8, 79.2, 74.9, 74.3, 74.0, 73.4, 71.6,
67.4, 62.0. MALDI-TOF MS: 731.8 (M), 753.8 (M + Na). Anal.
Calcd for C44H46N2O6S (730.3): C, 72.30; H, 6.34; N, 3.83. Found
C, 72.31; H, 6.36; N, 3.85.
(17) NMR and mass spectral data are consistent with the structure shown
1
below. H NMR (400 MHz, C6D6): δ ) 7.52 (d, 1 H, J ) 3.2 Hz, Th),
7.25-7.00 (m, 20 H, Ph), 6.67 (d, 1 H, J ) 3.2 Hz, Th), 4.57 (dd, 1 H, J4,3
) 2.0 Hz, J4,5 ) 0.5 Hz, H-4), 4.56 (d, 1 H, J2,3 ) 9.0 Hz, H-2), 4.54 and
4.18 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.49 (ddd, 1 H, J6,5 ) 4.5 Hz, J6,7a
) J6,7b ) 6.0 Hz, H-6), 4.35 (dd, 1 H, J3,2 ) 9.0 Hz, J3,4 ) 2.0 Hz, H-3),
4.35 and 4.29 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.10 and 4.02 (2 d, 2 H, J
) 12.0 Hz, CH2Ph), 3.90 (dd, 1 H, J5,4 ) 0.5 Hz, J5,6 ) 4.5 Hz, H-5), 3.82
(dd, 1 H, J7a,6 ) 6.0 Hz, J7a,7b ) 10.0 Hz, H-7a), 3.72 and 3.47 (2 d, 2 H,
J ) 13.5 Hz, N-CH2Ph), 3.71 (dd, 1 H, J7b,6 ) 6.0 Hz, J7b,7a ) 10.0 Hz,
H-7b), 2.84 (bs, 1 H, NH). MALDI-TOF MS: 629.54 (M+Na), 645.46
(M+K). The formation of this compound from the precursor 8b can be
explained to occur by intramolecular C-O bond formation via mesylate
displacement by the OBn group at C2 followed by elimination of the benzyl
cation.
(18) (a) Dondoni, A.; Marra, A. Chem. ReV. 2004, 104, 2557-2600. (b)
Dondoni, A. Synthesis 1998, 1681-1706.
Eluted second was 6a contaminated by 5a. 1H NMR for 6a
(C6D6, selected data): δ ) 7.52 (d, 1 H, J ) 3.2 Hz, Th), 6.60 (d,
1 H, J ) 3.2 Hz, Th).
(19) It is worth pointing out that under these new conditions (i.e., MW,
110 °C, 35 equiv of MeI) the N-methylation of the thiazole ring went to
completion in 10-15 min.
(2R,3R,4R,5R,6R)- and (2R,3R,4R,5R,6S)-6-N-Benzylhydroxyl-
amino-1,3,4,5-tetra-O-benzyl-6-thiazolyl-1,2,3,4,5-hexanepentol
(5b and 6b). Column chromatography with 4:1 cyclohexane-
AcOEt afforded, first, 5b (2.27 g, 40%) as a foam. [R]D ) 14.9
(20) Bruce, I.; Fleet, G. W. J.; Cenci di Bello, I.; Winchester, B.
Tetrahedron Lett. 1989, 51, 7257-7260.
(21) Shilvock, J. P.; Nash, R. J.; Watson, A. A.; Winters, A. L.; Butters,
T. D.; Dwek, R. A.; Winkler, D. A.; Fleet, G. W. J. J. Chem. Soc., Perkin
Trans. 1 1999, 2747-2754.
1
(c 0.3, CHCl3). H NMR (C6D6): δ ) 7.55 (d, 1 H, J ) 3.2 Hz,
7578 J. Org. Chem., Vol. 71, No. 20, 2006

Thiazole-Based Aminohomologation of Pyranoses
Th), 7.40-7.00 (m, 25 H, Ph), 6.64 (d, 1 H, J ) 3.2 Hz, Th), 5.13
(d, 1 H, J6,5 ) 7.5 Hz, H-6), 4.98 and 4.85 (2 d, 2 H, J ) 11.0 Hz,
CH2Ph), 4.90 and 4.65 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.80 (dd,
1 H, J5,4 ) 3.0 Hz, J5,6 ) 7.5 Hz, H-5), 4.57 and 4.46 (2 d, 2 H,
J ) 11.0 Hz, CH2Ph), 4.33 (dd, 1 H, J3,2 ) 12.0 Hz, J3,4 ) 6.0 Hz,
H-3), 4.30 (dd, 1 H, J4,3 ) 6.0 Hz, J4,5 ) 3.0 Hz, H-4), 4.22 (s,
(2R,3S,4R,5R,6S)-N-Benzyl-6-benzyloxymethyl-2-thiazolyl-
3,4,5-tribenzyloxypiperidine and (2S,3S,4R,5R,6S)-N-Benzyl-6-
benzyloxymethyl-2-thiazolyl-3,4,5-tribenzyloxypiperidine (9a and
10a). To a stirred solution of (AcO)2Cu‚H2O (13 mg, 0.11 mmol)
in AcOH (1.0 mL) was added Zn dust (0.36 g, 0.56 mmol) in one
portion. The resulting suspension was vigorously stirred at room
temperature for 10 min, and then a solution of a 3:1 mixture of 5a
and 6a (1.02 g, 1.4 mmol) in AcOH (13.0 mL) and H2O (5.0 mL)
was added dropwise. The resulting mixture was warmed to 80 °C
for 1 h. The suspension was filtered through a pad of Celite,
neutralized with aqueous 3 M NaOH, and extracted with AcOEt
(3 × 25 mL). The organic layer was washed with a saturated
aqueous solution of EDTA (30 mL), dried over Na2SO4, filtered,
concentrated, and eluted from a column of silica gel with 4:1
cyclohexane-AcOEt to afford, first, 7a (0.54 g, 54%) and, second,
8a (0.29 g, 20%), both as syrups.
To a cooled (0 °C), stirred mixture of the above amine 7a or 8a,
anhydrous toluene (6.0 mL), Et3N (0.28 mL, 0.84 mmol), and
TMEDA (9.0 µL, 0.057 mmol) was added MsCl (65 µL, 0.84
mmol) dropwise. The resulting mixture was stirred for 1 h, and
then MeOH (100 µL) and Et3N (0.28 mL) were added in one portion
and the mixture was stirred for an additional 5 min. The solvent
was then evaporated, and the crude was taken up in CH3CN (6.0
mL) and Et3N (0.28 mL, 0.84 mmol). The solution was warmed to
85 °C for 4-20 h. Then, the mixture was cooled to room tem-
perature and concentrated. The resulting crude material was diluted
in AcOEt (10 mL), washed with saturated NaHCO3 (2 × 10 mL),
dried over Na2SO4, filtered, concentrated, and eluted from a column
of silica gel with the suitable elution system to give the corre-
sponding piperidines 9a and 10a.
(2R,3S,4R,5R,6S)-N-Benzyl-6-benzyloxymethyl-2-thiazolyl-
3,4,5-tribenzyloxypiperidine (9a). Column chromatography with
6:1 cyclohexane-AcOEt afforded 9a (321 mg, 80%) as a syrup.
[R]D ) -20.0 (c 1.0, CHCl3). 1H NMR: δ ) 7.80 (d, 1 H, J ) 3.1
Hz, Th), 7.40-7.10 (m, 26 H, 5Ph and Th), 4.87 and 4.82 (2 d,
2 H, J ) 11.0 Hz, CH2Ph), 4.65 and 4.55 (2 d, 2 H, J ) 11.0 Hz,
CH2Ph), 4.50 and 4.43 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.45 (d,
1 H, J2,3 ) 5.5 Hz, H-2), 4.36 (dd, 1 H, J4,3 ) 7.0 Hz, J4,5 ) 8.5
Hz, H-4), 4.23 and 4.16 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.16 and
4.09 (2 d, 2 H, J ) 15.0 Hz, N-CH2Ph), 3.91 (dd, 1 H, J3,2 ) 5.5
Hz, J3,4 ) 7.0 Hz, H-3), 3.83 (dd, 1 H, J5,4 ) 8.5 Hz, J5,6 ) 5.5
Hz, H-5), 3.68 (dd, 1 H, J7a,6 ) 4.5 Hz, J7a,7b ) 9.5 Hz, H-7a),
3.57 (ddd, 1 H, J6,5 ) 5.5 Hz, J6,7a ) 4.5 Hz, J6,7b ) 6.5 Hz, H-6),
3.50 (dd, 1 H, J7b,6 ) 6.5 Hz, J7b,7a ) 9.5 Hz, H-7b). 13C NMR: δ
) 142.1, 139.1-137.9, 128.5-127.1, 119.3, 80.2, 79.9, 79.2, 74.5,
72.8, 72.6, 72.3, 69.4, 59.2, 59.1, 58.1. MALDI-TOF MS: 718.8
(M + Na). Anal. Calcd for C44H44N2O4S (696.3): C, 75.83; H,
6.36; N, 4.02. Found: C, 75.91; H, 6.38; N, 4.03.
2 H, CH2Ph), 4.18 (ddd, 1 H, J2,1a ) 5.5 Hz, J2,1b ) 3.5 Hz, J2,3
)
12.0 Hz, H-2), 3.93 and 3.68 (2 d, 2 H, J ) 13.0 Hz, N-CH2Ph),
3.69 (dd, 1 H, J1a,1b ) 9.0 Hz, J1a,2 ) 3.5 Hz, H-1a), 3.58 (dd, 1 H,
J1b,1a ) 9.0 Hz, J1b,2 ) 5.5 Hz, H-1b). 13C NMR: δ ) 166.6, 141.5,
138.7, 138.5, 138.0, 137.0, 129.3-127.3, 119.9, 81.1, 80.1, 79.5,
74.5, 74.3, 73.5, 73.3, 71.3, 71.2, 67.2, 62.0. MALDI-TOF MS:
752.7 (M + Na). Anal. Calcd. for C44H46N2O6S (730.3): C, 72.30;
H, 6.34; N, 3.83. Found: C, 72.18; H, 6.34; N, 3.84.
Eluted second was a 2:1 mixture of 6a and 6b (0.83 g, 15%).
Eluted third was pure 6b (1.53 g, 27%) as a syrup. [R]D ) -8.8
1
(c 0.8, MeOH). H NMR: δ ) 7.84 (d, 1 H, J ) 3.2 Hz, Th),
7.40-7.10 (m, 26 H, Ph and Th), 5.95 (s, 1 H, N(OH)), 4.90 (d,
1 H, J6,5 ) 5.5 Hz, H-6), 4.72 and 4.68 (2 d, 2 H, J ) 11.0 Hz,
CH2Ph), 4.66 and 4.58 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.58 and
4.46 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.49 and 4.47 (2 d, 2 H, J )
10.0 Hz, CH2Ph), 4.48 (t, 1 H, J5,4 ) J5,6 ) 5.5 Hz, H-5), 4.14 (dd,
1 H, J4,3 ) 4.0 Hz, J4,5 ) 5.5 Hz, H-4), 4.00 (ddd, 1 H, J2,1a ) 3.0
Hz, J2,1b ) 5.5 Hz, J2,3 ) 7.5 Hz, H-2), 3.85 and 3.73 (2 d, 2 H,
J ) 13.5 Hz, N-CH2Ph), 3.73 (dd, 1 H, J3,2 ) 7.5 Hz, J3,4 ) 4.0
Hz, H-3), 3.64 (dd, 1 H, J1a,1b ) 9.5 Hz, J1a,2 ) 3.0 Hz, H-1a),
3.57 (dd, 1 H, J1b,1a ) 9.5 Hz, J1b,2 ) 5.5 Hz, H-1b), 2.90 (s, 1 H,
OH). 13C NMR: δ ) 165.4, 141.8, 138.5, 138.2, 137.9, 137.5,
129.2-127.2, 120.3, 80.9, 79.6, 78.4, 74.2, 73.3, 73.1, 71.2, 70.5,
67.7, 61.4. MALDI-TOF MS: 731.9 (M+H), 753.9 (M + Na).
Anal. Calcd for C44H46N2O6S (730.3): C, 72.30; H, 6.34; N, 3.83.
Found C, 72.13; H, 6.36; N, 3.81.
(2R,3S,4R,5S,6R)- and (2R,3S,4R,5S,6S)-6-N-Benzylhydroxyl-
amino-1,3,4,5-tetra-O-benzyl-6-thiazolyl-1,2,3,4,5-hexanepen-
tol (5c and 6c). Column chromatography with 10:1 CH2Cl2-
isopropyl ether afforded, first, 6c (0.83 g, 15%) as a foam. [R]D )
-18.2 (c 0.5, CHCl3). 1H NMR (C6D6): δ ) 7.60 (d, 1 H, J ) 3.2
Hz, Th), 7.30-6.90 (m, 25 H, 5Ph), 6.66 (d, 1 H, J ) 3.2 Hz, Th),
5.02 (d, 1 H, J6,5 ) 9.0 Hz, H-6), 4.77 and 4.72 (2 d, 2 H, J ) 11.0
Hz, CH2Ph), 4.71 and 4.31 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.66
and 4.43 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.65 (dd, 1 H, J5,4 ) 4.0
Hz, J5,6 ) 9.0 Hz, H-5), 4.50 (dd, 1 H, J4,3 ) 6.0 Hz, J4,5 ) 4.0 Hz,
H-4), 4.43 (ddd, 1 H, J2,1a ) 5.5 Hz, J2,1b ) 7.5 Hz, J2,3 ) 2.0 Hz,
H-2), 4.35 (dd, 1 H, J3,2 ) 2.0 Hz, J3,4 ) 6.0 Hz, H-3), 4.19 and
4.09 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 3.83 and 3.72 (2 d, 2 H, J )
13.0 Hz, N-CH2Ph), 3.52 (dd, 1 H, J1a,1b ) 9.0 Hz, J1a,2 ) 5.5
Hz, H-1a), 3.42 (dd, 1 H, J1b,1a ) 9.0 Hz, J1b,2 ) 7.5 Hz, H-1b),
3.17 (s, 1 H, OH). 13C NMR: δ ) 166.1, 141.6, 138.1, 136.8,
129.5-127.3, 120.2, 100.0, 80.5, 79.8, 77.9, 75.1, 73.6, 73.4, 73.3,
70.7, 69.8, 68.5, 61.7. MALDI-TOF MS: 731.7 (M + H). Anal.
Calcd for C44H46N2O6S (730.3): C, 72.30; H, 6.34; N, 3.83.
Found: C, 72.23; H, 6.33; N, 3.84.
(2S,3S,4R,5R,6S)-N-Benzyl-6-benzyloxymethyl-2-thiazolyl-
3,4,5-tribenzyloxypiperidine (10a). Column chromatography with
6:1 cyclohexane-AcOEt afforded 10a (281 mg, 70%) as a syrup.
1
[R]D ) -28.2 (c 0.94, CHCl3). H NMR: δ ) 7.78 (d, 1 H, J )
Eluted second was a 3:1 mixture of 5c and 6c (1.17 g, 21%).
Eluted third was pure 5c (2.34 g, 41%) as a foam. [R]D ) -8.2
(c 1.0, CHCl3). 1H NMR: δ ) 7.91 (d, 1 H, J ) 3.3 Hz, Th), 7.41
(d, 1 H, J ) 3.3 Hz, Th), 7.35-7.14 (m, 25 H, 5Ph), 6.10 (s, 1 H,
N(OH)), 4.83 and 4.77 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.79 (d,
1 H, J6,5 ) 6.0 Hz, H-6), 4.67 and 4.64 (2 d, 2 H, J ) 11.0 Hz,
CH2Ph), 4.63 and 4.49 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.36 (t,
1 H, J5,4 ) J5,6 ) 6.0 Hz, H-5), 4.23 and 4.18 (2 d, 2 H, J ) 11.5
Hz, CH2Ph), 4.10 (m, 2 H, H-3 and H-2), 3.93 (t, 1 H, J4,3 ) J4,5
) 5.5 Hz, H-4), 3.80 and 3.66 (2 d, 2 H, J ) 13.0 Hz, N-CH2Ph),
3.43 (dd, 1 H, J1a,1b ) 9.0 Hz, J1a,2 ) 5.5 Hz, H-1a), 3.36 (dd, 1 H,
J1b,1a ) 9.0 Hz, J1b,2 ) 7.5 Hz, H-1b), 3.02 (s, 1 H, OH). 13C
NMR: δ ) 164.6, 142.1, 138.6, 138.3, 138.2, 137.6, 137.2, 129.6-
127.3, 120.3, 80.3, 79.8, 75.0, 73.4, 73.1, 72.8, 70.5, 69.4, 67.9,
61.9. MALDI-TOF MS: 768.8 (M + K). Anal. Calcd for
C44H46N2O6S (730.3): C, 72.30; H, 6.34; N, 3.83. Found: C, 72.48;
H, 6.32; N, 3.82.
3.1 Hz, Th), 7.40-6.95 (m, 26 H, 5Ph and Th), 4.93 and 4.78 (2 d,
2 H, J ) 11.0 Hz, CH2Ph), 4.65 (d, 1 H, J2,3 ) 9.0 Hz, H-2), 4.60
and 4.00 (2 d, 2 H, J ) 10.0 Hz, CH2Ph), 4.57 and 4.53 (2 d, 2 H,
J ) 11.0 Hz, CH2Ph), 4.55 (s, 2 H, CH2Ph), 3.96 (t, 1 H, J4,3
)
J4,5 ) 9.0 Hz, H-4), 3.95 and 3.92 (dd, 1 H, J7a,6 ) 5.0 Hz, J7a,7b
) 9.5 Hz, H-7a), 3.89 (t, 1 H, J3,2 ) J3,4 ) 9.0 Hz, H-3), 3.83 (dd,
1 H, J5,4 ) 9.0 Hz, J5,6 ) 2.5 Hz, H-5), 3.79 (dd, 1 H, J7b,6 ) 5.0
Hz, J7b,7a ) 9.5 Hz, H-7b), 3.74 and 3.49 (2 d, 2 H, J ) 14.0 Hz,
N-CH2Ph), 3.31 (ddd, 1 H, J6,5 ) 2.5 Hz, J6,7a ) J6,7b ) 5.0 Hz,
H-6). 13C NMR: δ ) 141.9, 138.9, 138.3, 138.2, 128.3-126.8,
119.8, 85.5, 82.6, 79.8, 75.2, 75.0, 73.3, 72.4, 64.8, 64.6, 56.0, 53.1.
MALDI-TOF MS: 696.4 (M), 720.1 (M + Na). Anal. Calcd for
C44H44N2O4S (696.3): C, 75.83; H, 6.36; N, 4.02. Found: C, 75.74;
H, 6.35; N, 4.02.
General Procedure for the Synthesis of Piperidines 9b-c,
10b-c. To a stirred solution of (AcO)2Cu‚H2O (13 mg, 0.11 mmol)
in AcOH (1.0 mL) was added Zn dust (0.36 g, 0.56 mmol) in one
J. Org. Chem, Vol. 71, No. 20, 2006 7579

Dondoni and Nuzzi
portion. The resulting suspension was vigorously stirred at room
temperature for 10 min, and then a solution of N-benzylhydroxyl-
amines 5b-c, 6b-c (0.41 g, 0.57 mmol) in AcOH (5.0 mL) and
H2O (2.0 mL) was added dropwise. The resulting mixture was
warmed to 80 °C for 1 h. The suspension was filtered through a
pad of Celite, neutralized with aqueous 3 M NaOH, and extracted
with AcOEt (3 × 15 mL). The organic layer was washed with a
saturated aqueous solution of EDTA (30 mL), dried over Na2SO4,
filtered, and concentrated to give crude 7b-c, 8b-c.
To a cooled (0 °C), stirred mixture of the above crude amine,
anhydrous toluene (6.0 mL), Et3N (0.28 mL, 0.84 mmol), and
TMEDA (9.0 µL, 0.057 mmol) was added MsCl (65 µL, 0.84
mmol) dropwise. The resulting mixture was stirred for an additional
1 h, and then MeOH (100 µL) and Et3N (0.28 mL) were added in
one portion and stirred for an additional 5 min. The solvent was
then evaporated, and the crude was taken up in CH3CN (6.0 mL)
and Et3N (0.28 mL, 0.84 mmol). The solution was warmed to 85 °C
for 4-20 h. Then, the mixture was cooled to room temperature
and concentrated. The resulting crude material was diluted in AcOEt
(10 mL), washed with saturated NaHCO3 (2 × 10 mL), dried over
Na2SO4, filtered, concentrated, and eluted from a column of silica
gel with the suitable elution system to give the corresponding
piperidines 9b-c, 10b-c.
J ) 12.0 Hz, CH2Ph), 4.19 (dd, 1 H, J5,4 ) 2.5 Hz, J5,6 ) 8.5 Hz,
H-5), 4.16 and 4.10 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.04 and 3.81
(2 d, 2 H, J ) 16.0 Hz, N-CH2Ph), 3.90 (dd, 1 H, J3,2 ) 3.5 Hz,
J3,4 ) 5.0 Hz, H-3), 3.83 (dd, 1 H, J4,3 ) 5.0 Hz, J4,5 ) 2.5 Hz,
H-4), 3.67 (dd, 1 H, J7a,6 ) 3.5 Hz, J7a,7b ) 10.0 Hz, H-7a), 3.52
(dd, 1 H, J7b,6 ) 3.5 Hz, J7b,7a ) 10.0 Hz, H-7b), 3.26 (ddd, 1 H,
J6,5 ) 8.5 Hz, J6,7a ) J6,7b ) 3.5 Hz, H-6). 13C NMR: δ ) 141.0,
139.1, 138.6, 138.5, 138.4, 138.0, 128.5-126.4, 120.2, 77.3, 74.1,
73.1, 72.8, 72.5, 72.1, 71.9, 67.7, 62.6, 60.5, 57.1. MALDI-TOF
MS: 697.2 (M + H), 719.7 (M + Na). Anal. Calcd for C44H44N2O4S
(696.3): C, 75.83; H, 6.36; N, 4.02. Found: C, 75.75; H, 6.35; N,
4.03.
(2S,3S,4R,5S,6S)-N-Benzyl-6-benzyloxymethyl-2-thiazolyl-
3,4,5-tribenzyloxypiperidine (10c). Column chromatography with
6:1 cyclohexane-AcOEt afforded 10c (282 mg, 70%) as a syrup.
[R]D ) -4.2 (c 1.6, CHCl3). 1H NMR (C6D6, 70 °C): δ ) 7.50-
7.00 (m, 26 H, 5Ph and Th), 6.70 (d, 1 H, J ) 3.1 Hz, Th), 4.79
(dd, 1 H, J3,2 ) 6.5 Hz, J3,4 ) 7.0 Hz, H-3), 4.66 (d, 1 H, J2,3
)
6.5 Hz, H-2), 4.63 and 4.36 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.55
and 4.48 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.46 (s, 2 H, CH2Ph),
4.19 (s, 2 H, CH2Ph), 4.07 (dd, 1 H, J5,4 ) 3.0 Hz, J5,6 ) 5.0 Hz,
H-5), 4.02 and 3.93 (2 d, 2 H, J ) 14.0 Hz, N-CH2Ph), 3.98 (dd,
1 H, J4,3 ) 7.0 Hz, J4,5 ) 3.0 Hz, H-4), 3.78 (q, 1 H, J6,5 ) J6,7a
)
J6,7b ) 5.0 Hz, H-6), 3.61 (dd, 1 H, J7a,6 ) 5.0 Hz, J7a,7b ) 10.0
Hz, H-7a), 3.54 (dd, 1 H, J7b,6 ) 5.0 Hz, J7b,7a ) 10.0 Hz, H-7b).
13C NMR: δ ) 173.5, 141.7, 141.1, 139.3-137.9, 128.5-126.5,
120.3, 119.9, 81.4, 78.2, 76.8, 74.5, 74.2, 73.3, 72.9, 72.6, 72.2,
72.0, 71.6, 70.8, 67.7, 66.4, 63.9, 62.7, 54.5, 52.9. MALDI-TOF
MS: 718.5 (M + Na). Anal. Calcd for C44H44N2O4S (696.3): C,
75.83; H, 6.36; N, 4.02. Found: C, 75.85; H, 6.39; N, 4.00.
General Procedure for the Synthesis of Piperidine Homo-
iminosugars 11a-c, 12a-c. A 2.0-5.0 mL process vial was filled
with piperidine 9a-c, 10a-c (100 mg, 0.14 mmol), MeI (0.45 mL,
7.2 mmol), and CH3CN (4.0 mL). The vial was sealed with a Teflon
septum and aluminum crimp, using an appropriate crimping tool.
The vial was then placed in its correct position in the Biotage
Initiator cavity and irradiated for 15 min at 110 °C. After the full
irradiation sequence was completed, the vial was cooled to room
temperature and then opened. The solution was transferred into a
round-bottom flask, and the solvent was removed under reduced
pressure. The residue was dissolved in a 3:1 mixture of CH2Cl2-
MeOH (2.0 mL), cooled to 0 °C in an ice bath; to the resulting
mixture NaBH4 (30 mg, 0.72 mmol) was added in one portion while
the solution was vigorously stirred. The ice bath was then removed,
and after an additional 40 min the solution was treated with acetone
(1.0 mL) and diluted with CH2Cl2. The resulting mixture was
washed with saturated aqueous NaHCO3, and the extracted organic
phase was dried over Na2SO4, filtered, and concentrated. The resi-
due was taken up in a 10:1 mixture of CH3CN-H2O (2.0 mL)
where some drops of CH2Cl2 were added. Then, HgCl2 (43 mg,
0.16 mmol) was added in one portion. After the mixture was stirred
for 5 min, a 10% aqueous solution of KI (6.0 mL) was added drop-
wise. The solution was stirred for an additional 5 min and then
extracted with CH2Cl2. The organic layer was dried over Na2SO4,
filtered, and concentrated. The residue was taken up in a 3:1 mixture
of CH2Cl2-MeOH (2.0 mL). The solution was cooled to -35 °C,
and NaBH4 (30 mg, 0.72 mmol) was added in one portion. After
being stirred for 40 min, the solution was treated with acetone (1.0
mL) and then diluted with CH2Cl2. The solution was washed with
saturated aqueous NaHCO3 and the extracted organic phase was
dried over Na2SO4, filtered, concentrated, and eluted from a column
of silica gel with the suitable elution system to give the corre-
sponding piperidine homoiminosugars 11a-c, 12a-c.
(2R,3R,4R,5R,6S)-N-Benzyl-6-benzyloxymethyl-2-thiazolyl-
3,4,5-tribenzyloxypiperidine (9b). Column chromatography with
6:1 cyclohexane-AcOEt afforded 9b (282 mg, 70%) as a pale
1
yellow solid. Mp ) 80-82 °C. [R]D ) 24.9 (c 0.7, CHCl3). H
NMR (300 MHz, C6D6, 70 °C): δ ) 7.50-7.00 (m, 26 H, 5Ph
and Th), 6.65 (d, 1 H, J ) 3.1 Hz, Th), 4.76 (d, 1 H, J2,3 ) 6.5 Hz,
H-2), 4.71 and 4.61 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.66 (dd,
1 H, J3,2 ) 6.5 Hz, J3,4 ) 2.5 Hz, H-3), 4.48 (s, 2 H, CH2Ph), 4.35
and 4.26 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.27 (dd, 1 H, J5,4 ) 7.0
Hz, J5,6 ) 4.0 Hz, H-5), 4.17 and 3.91 (2 d, 2 H, J ) 15.0 Hz,
N-CH2Ph), 4.12 (dd, 1 H, J4,3 ) 2.5 Hz, J4,5 ) 7.0 Hz, H-4), 4.08
(s, 2 H, CH2Ph), 3.72 (dd, 1 H, J7a,6 ) 6.5 Hz, J7a,7b ) 9.0 Hz,
H-7a), 3.64 (ddd, 1 H, J6,5 ) 4.0 Hz, J6,7a ) 6.5 Hz, J6,7b ) 6.0
Hz, H-6), 3.46 (dd, 1 H, J7b,6 ) 6.0 Hz, J7b,7a ) 9.0 Hz, H-7b). 13
C
NMR (C6D6): δ ) 173.2, 141.5, 140.1, 139.1, 138.7, 128.4-126.6,
119.2, 79.6, 75.3, 74.1, 72.9, 72.7, 72.4, 72.2, 69.1, 63.0, 60.7, 58.1.
MALDI-TOF MS: 697.55 (M + H), 719.55 (M + Na). Anal. Calcd
for C44H44N2O4S (696.3): C, 75.83; H, 6.36; N, 4.02. Found: C,
75.99; H, 6.38; N, 4.00.
(2S,3R,4R,5R,6S)-N-Benzyl-6-benzyloxymethyl-2-thiazolyl-
3,4,5-tribenzyloxypiperidine (10b). Column chromatography with
6:1 cyclohexane-AcOEt afforded 10b (209 mg, 52%) as a syrup.
1
[R]D ) -26.3 (c 0.6, CHCl3). H NMR (C6D6, 70 °C): δ ) 7.60
(d, 1 H, J ) 3.2 Hz, Th), 7.45-7.00 (m, 25 H, 5Ph), 6.73 (d, 1 H,
J ) 3.2 Hz, Th), 4.96 (d, 1 H, J2,3 ) 3.0 Hz, H-2), 4.91 and 4.58
(2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.66 and 4.59 (2 d, 2 H, J ) 12.0
Hz, CH2Ph), 4.53 and 4.38 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.44
(dd, 1 H, J5,4 ) 9.0 Hz, J5,6 ) 5.0 Hz, H-5), 4.38 (t, 1 H, J3,2 ) J3,4
) 3.0 Hz, H-3), 4.32 (s, 2 H, CH2Ph), 4.06 and 3.95 (2 d, 2 H, J
) 15.0 Hz, N-CH2Ph), 4.02 (dd, 1 H, J4,3 ) 3.0 Hz, J4,5 ) 9.0
Hz, H-4), 3.87 (dd, 1 H, J7a,6 ) 5.0 Hz, J7a,7b ) 10.0 Hz, H-7a),
3.82 (dd, 1 H, J7b,6 ) 4.0 Hz, J7b,7a ) 10.0 Hz, H-7b), 3.68 (ddd,
1 H, J6,5 ) 5.0 Hz, J6,7a ) 5.0 Hz, J6,7b ) 4.0 Hz, H-6). 13C NMR
(C6D6): δ ) 170.5, 142.5, 141.1, 140.2, 139.4, 139.3, 139.1, 138.7,
128.2, 128.1, 128.0, 127.9, 127.7, 127.4, 127.3, 127.2, 127.1, 126.7,
120.2, 80.3, 77.8, 75.9, 74.9, 73.0, 72.8, 72.5, 71.3, 67.0, 63.1, 57.2,
54.3, 51.6. MALDI-TOF MS: 697.1 (M + H), 719.8 (M + Na).
Anal. Calcd for C44H44N2O4S (696.3): C, 75.83; H, 6.36; N, 4.02.
Found: C, 75.97; H, 6.43; N, 4.05.
(2R,3S,4R,5S,6S)-N-Benzyl-6-benzyloxymethyl-2-thiazolyl-
3,4,5-tribenzyloxypiperidine (9c). Column chromatography with
6:1 cyclohexane-AcOEt afforded 9c (305 mg, 76%) as a syrup.
N-Benzyl-2,6-dideoxy-2,6-imino-3,4,5,7-tetra-O-benzyl-L-
glycero-D-ido-heptitol (11a). Column chromatography with 4:1
cyclohexane-AcOEt afforded 11a (52 mg, 56%) as a syrup. [R]D
1
[R]D ) 17.6 (c 0.5, CHCl3). H NMR: δ ) 7.74 (d, 1 H, J ) 3.1
1
Hz, Th), 7.45-7.10 (m, 26 H, 5Ph and Th), 4.72 (d, 1 H, J2,3
)
) -3.8 (c 1.0, CHCl3). H NMR (C6D6): δ ) 7.40-7.00 (m, 25
3.5 Hz, H-2), 4.58 and 4.54 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.51
and 4.45 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.29 and 4.11 (2 d, 2 H,
H, 5Ph), 4.85 and 4.80 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.44 and
4.36 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.39 and 4.34 (2 d, 2 H, J )
7580 J. Org. Chem., Vol. 71, No. 20, 2006

Thiazole-Based Aminohomologation of Pyranoses
11.5 Hz, CH2Ph), 4.32 and 4.21 (2 d, 2 H, J ) 11.5 Hz, CH2Ph),
4.02 (m, 1 H, H-1a), 3.93 (s, 2 H, N-CH2Ph), 3.91 (dd, 1 H, J1b,1a
) 11.5 Hz, J1b,2 ) 8.0 Hz, H-1b), 3.80 (t, 1 H, J4,3 ) J4,5 ) 9.0
Hz, H-4), 3.76 (dd, 1 H, J5,4 ) 10.0 Hz, J5,6 ) 5.0 Hz, H-5), 3.70
644.7 (M + H), 666.6 (M + Na). Anal. Calcd for C42H45NO5
(643.3): C, 78.35; H, 7.05; N, 2.18. Found: C, 78.29; H, 7.11; N,
2.23.
N-Benzyl-2,6-dideoxy-2,6-imino-3,4,5,7-tetra-O-benzyl-L-
glycero-L-gluco-heptitol (11c). Column chromatography with 4:1
cyclohexane-AcOEt afforded 11c (34 mg, 37%) as a syrup. [R]D
) 17.4 (c 0.8, CHCl3). 1H NMR (acetone-d6): δ ) 7.42-7.06 (m,
25 H, 5Ph), 4.72 and 4.64 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.67 (s,
2 H, CH2Ph), 4.62 and 4.57 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.33
and 4.29 (2 d, 2 H, J ) 11.5 Hz, CH2Ph), 4.25 (dd, 1 H, J3,2 ) 4.5
Hz, J3,4 ) 7.5 Hz, H-3), 4.18 and 4.06 (2 d, 2 H, J ) 15.0 Hz,
N-CH2Ph), 4.07 (dd, 1 H, J5,4 ) 3.0 Hz, J5,6 ) 5.5 Hz, H-5), 3.99
(dd, 1 H, J4,3 ) 7.5 Hz, J4,5 ) 3.0 Hz, H-4), 3.71 (dd, 1 H, J1a,1b
) 11.0 Hz, J1a,2 ) 7.0 Hz, H-1a), 3.64 (dd, 1 H, J7a,6 ) 5.0 Hz,
J7a,7b ) 9.5 Hz, H-7a), 3.55 (dd, 1 H, J7b,6 ) 5.5 Hz, J7b,7a ) 9.5
Hz, H-7b), 3.52 (dd, 1 H, J1b,1a ) 11.0 Hz, J1b,2 ) 7.0 Hz, H-1b),
3.38 (ddd, 1 H, J6,5 ) J6,7b ) 5.5 Hz, J6,7a ) 5.0 Hz, H-6), 3.34
(dd, 1 H, J2,1a ) J2,1b ) 7.0 Hz, J2,3 ) 4.5 Hz, H-2). 13C NMR
(C6D6): δ ) 140.8, 139.1, 139.0, 138.8, 138.3, 128.4-126.9, 76.2,
75.9, 73.2, 72.8, 72.1, 72.0, 70.1, 61.5, 61.1, 59.8, 59.5. MALDI-
TOF MS: 666.7 (M + Na). Anal. Calcd for C42H45NO5 (643.3):
C, 78.35; H, 7.05; N, 2.18. Found: C, 78.45; H, 7.03; N, 2.18.
N-Benzyl-2,6-dideoxy-2,6-imino-3,4,5,7-tetra-O-benzyl-L-
glycero-L-manno-heptitol (12c). Column chromatography with 4:1
cyclohexane-AcOEt afforded 12c (46 mg, 50%) as a syrup. [R]D
) -1.6 (c 0.5, CHCl3). 1H NMR (C6D6): δ ) 7.40-7.00 (m, 25 H,
5Ph), 4.74 and 4.53 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.47 and 4.40
(2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.39 (s, 2 H, CH2Ph), 4.13 (s,
2 H, CH2Ph), 4.11 and 3.81 (2 d, 2 H, J ) 14.0 Hz, N-CH2Ph),
4.04 (t, 1 H, J3,2 ) J3,4 ) 7.0 Hz, H-3), 4.00 (dd, 1 H, J5,4 ) 3.0
Hz, J5,6 ) 5.5 Hz, H-5), 3.94 (dd, 1 H, J1a,1b ) 11.0 Hz, J1a,2 ) 5.5
Hz, H-1a), 3.83 (dd, 1 H, J4,3 ) 7.0 Hz, J4,5 ) 3.0 Hz, H-4), 3.74
(dd, 1 H, J1b,1a ) 11.0 Hz, J1b,2 ) 4.5 Hz, H-1b), 3.57 (ddd, 1 H,
J6,5 ) 5.5 Hz, J6,7a ) 5.5 Hz, J6,7b ) 6.0 Hz, H-6), 3.47 (dd, 1 H,
J7a,6 ) 5.5 Hz, J7a,7b ) 11.0 Hz, H-7a), 3.38 (dd, 1 H, J7b,6 ) 5.5
(dd, 1 H, J3,2 ) 6.5 Hz, J3,4 ) 9.0 Hz, H-3), 3.65 (dd, 1 H, J7a,6
)
2.0 Hz, J7a,7b ) 8.0 Hz, H-7a), 3.63 (dd, 1 H, J7b,6 ) 2.0 Hz, J7b,7a
) 8.0 Hz, H-7b), 3.46 (ddd, 1 H, J6,5 ) 5.0 Hz, J6,7a ) J6,7b ) 2.0
Hz, H-6), 3.39 (ddd, 1 H, J2,1b ) 8.0 Hz, J2,3 ) 6.5 Hz, H-2). 13C
NMR: δ ) 139.9, 138.8, 138.1, 137.9, 128.5-127.2, 79.9, 79.6,
79.2, 75.7, 73.4, 73.2, 72.9, 70.2, 61.3, 60.7, 60.4, 57.5. MALDI-
TOF MS: 666.7 (M + Na), 682.7 (M + K). Anal. Calcd for C42H45-
NO5 (643.3): C, 78.35; H, 7.05; N, 2.18. Found: C, 78.43; H,
7.08; N, 2.17.
N-Benzyl-2,6-dideoxy-2,6-imino-3,4,5,7-tetra-O-benzyl-L-
glycero-D-gulo-heptitol (12a). Column chromatography with 6:1
cyclohexane-AcOEt afforded 12a (66 mg, 71%) as a syrup. [R]D
1
) -21.1 (c 0.9, CHCl3). H NMR (acetone-d6): δ ) 7.40-7.20
(m, 25 H, 5Ph), 4.93 and 4.76 (2 d, 2 H, J ) 11.0 Hz, CH2Ph),
4.92 and 4.68 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.55 and 4.51 (2 d,
2 H, J ) 11.5 Hz, CH2Ph), 4.54 (s, 2 H, CH2Ph), 4.22 and 4.00
(2 d, 2 H, J ) 14.0 Hz, N-CH2Ph), 3.96 (dd, 1 H, J1a,1b ) 11.5 Hz,
J1a,2 ) 3.0 Hz, H-1a), 3.95 (dd, 1 H, J7a,6 ) 6.0 Hz, J7a,7b ) 10.5
Hz, H-7a), 3.85 (dd, 1 H, J7b,6 ) 3.0 Hz, J7b,7a ) 10.5 Hz, H-7b),
3.84 (dd, 1 H, J4,3 ) 8.0 Hz, J4,5 ) 9.0 Hz, H-4), 3.84 (dd, 1 H,
J1b,1a ) 11.5 Hz, J1b,2 ) 4.0 Hz, H-1b), 3.68 (dd, 1 H, J5,4 ) 9.0
Hz, J5,6 ) 5.5 Hz, H-5), 3.63 (dd, 1 H, J3,2 ) 9.0 Hz, J3,4 ) 8.5
Hz, H-3), 3.37 (ddd, 1 H, J6,5 ) 5.5 Hz, J6,7a ) 6.0 Hz, J6,7b ) 3.0
Hz, H-6), 3.24 (s, 1 H, OH), 3.10 (ddd, 1 H, J2,1a ) 3.0 Hz, J2,1b
) 4.0 Hz, J2,3 ) 9.0 Hz, H-2). 13C NMR: δ ) 141.7, 140.4, 140.2,
139.8, 139.5, 129.3-127.4, 84.1, 80.2, 79.7, 75.3, 75.1, 73.6, 72.5,
66.7, 61.9, 60.0, 57.1, 53.2. MALDI-TOF MS: 644.8 (M + H),
666.9 (M + Na). Anal. Calcd for C42H45NO5 (643.3): C, 78.35;
H, 7.05; N, 2.18. Found: C, 78.51; H, 7.06; N, 2.19.
N-Benzyl-2,6-dideoxy-2,6-imino-3,4,5,7-tetra-O-benzyl-L-
glycero-D-talo-heptitol (11b). Column chromatography with 6:1
cyclohexane-AcOEt afforded 11b (33 mg, 36%) as a syrup. [R]D
Hz, J7b,7a ) 11.0 Hz, H-7b), 3.03 (ddd, 1 H, J2,1b ) 4.5 Hz, J2,1a
)
5.5 Hz, J2,3 ) 7.0 Hz, H-2). 13C NMR (C6D6): δ ) 140.9, 139.4,
139.3, 139.2, 138.7, 128.9-127.2, 79.4, 77.1, 74.6, 74.1, 73.2, 72.1,
71.8, 68.1, 61.3, 59.9, 56.0, 52.6. MALDI-TOF MS: 644.7 (M +
H), 666.8 (M + Na). Anal. Calcd for C42H45NO5 (643.3): C, 78.35;
H, 7.05; N, 2.18. Found: C, 78.49; H, 7.08; N, 2.17.
1
) 10.3 (c 1.1, CHCl3). H NMR (C6D6): δ ) 7.35-7.00 (m, 25
H, 5Ph), 4.58 and 4.49 (2 d, 2 H, J ) 12.0 Hz, CH2Ph), 4.43 (s,
2 H, CH2Ph), 4.37 and 4.33 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.16
and 4.12 (2 d, 2 H, J ) 11.0 Hz, CH2Ph), 4.10 (dd, 1 H, J5,4 ) 6.0
Hz, J5,6 ) 3.0 Hz, H-5), 4.06 (dd, 1 H, J3,2 ) 8.0 Hz, J3,4 ) 2.5
Hz, H-3), 3.91 and 3.82 (2 d, 2 H, J ) 16.0 Hz, N-CH2Ph), 3.78
(dd, 1 H, J4,3 ) 2.5 Hz, J4,5 ) 6.0 Hz, H-4), 3.76 (dd, 1 H, J1a,1b
) 11.5 Hz, J1a,2 ) 3.5 Hz, H-1a), 3.75 (dd, 1 H, J7a,6 ) 6.0 Hz,
J7a,7b ) 11.5 Hz, H-7a), 3.63 (dd, 1 H, J1b,1a ) 11.5 Hz, J1b,2 ) 4.0
Hz, H-1b), 3.56 (dd, 1H, J7b,6 ) 6.0 Hz, J7b,7a ) 11.5 Hz, H-7b),
3.56 (ddd, 1 H, J6,5 ) 3.0 Hz, J6,7a ) 6.0 Hz, J6,7b ) 6.0 Hz, H-6),
3.29 (ddd, 1 H, J2,1a ) 3.5 Hz, J2,1b ) 4.0 Hz, J2,3 ) 8.0 Hz, H-2),
2.61 (s, 1 H, OH). 13C NMR (75 MHz, C6D6): δ ) 141.7, 139.4,
139.1, 138.8, 128.6-126.9, 76.1, 75.3, 73.7, 73.1, 72.7, 72.2, 70.4,
63.0, 60.5, 59.5, 58.1. MALDI-TOF MS: 667.4 (M + Na). Anal.
Calcd for C42H45NO5 (643.3): C, 78.35; H, 7.05; N, 2.18. Found:
C, 78.26; H, 7.05; N, 2.16.
General Procedure for the Synthesis of 2,6-Dideoxy-2,6-
iminoheptitol Hydrochlorides 13a-c, 14a-c. To a solution of
piperidine homoiminosugar 11a-c, 12a-c (80 mg, 0.12 mmol) in
a 2:1 mixture of MeOH and THF (3.0 mL) was added Pd(OH)2/C
(80 mg). After the reaction flask was purged with hydrogen, 7 drops
of 6 M HCl were added, and the reaction mixture was stirred for
2 days at room temperature under hydrogen (100 psi). The mix-
ture was then filtered through a pad of Celite, concentrated, and
eluted from a column of Sephadex LH-20 (2 × 60 cm) with MeOH
to afford the corresponding pure heptitol hydrochlorides 13a-c,
14a-c.
2,6-Dideoxy-2,6-imino-L-glycero-D-ido-heptitol Hydrochloride
(13a). 13a (26 mg, 92%) as an amorphus solid. [R]D ) 0.0 (c 0.8,
1
N-Benzyl-2,6-dideoxy-2,6-imino-3,4,5,7-tetra-O-benzyl-L-
glycero-D-galacto-heptitol (12b). Column chromatography with 4:1
cyclohexane-AcOEt afforded 12b (29 mg, 31%) as a syrup. [R]D
) -35.8 (c 1.0, CHCl3). 1H NMR: δ ) 7.40-7.15 (m, 25 H, 5Ph),
4.73-4.35 (8 d, 8 H, CH2Ph), 4.12 (dd, 1 H, J3,2 ) J3,4 ) 5.0 Hz,
H-3), 4.05 (t, 1 H, J1a,1b ) J1a,2 ) 10.0 Hz, H-1a), 3.92 and 3.68
(2 d, 2 H, J ) 14.0 Hz, N-CH2Ph), 3.92 (dd, 1 H, J4,3 ) 5.0 Hz,
J4,5 ) 9.0 Hz, H-4), 3.80 (bs, 1 H, H-5), 3.74 (dd, 1 H, J7a,6 ) 6.0
MeOH). H NMR (CD3OD): δ ) 4.02 (t, 1 H, J4,3 ) J4,5 ) 3.0
Hz, H-4), 3.98 (m, 2 H, H-3 and H-5), 3.89 (m, 4 H, H-1a and
H-1b, H-7a and H-7b), 3.55 (m, 2 H, H-2 and H-6). 13C NMR
(CD3OD): δ ) 68.8, 67.7, 59.9, 58.1. MALDI-TOF MS: 193.8
(Mamine), 215.6 (Mamine + Na). Anal. Calcd for C7H16ClNO5
(229.1): C, 36.61; H, 7.02; N, 6.10. Found: C, 36.57; H, 7.03; N,
6.11.
2,6-Dideoxy-2,6-imino-L-glycero-D-gulo-heptitol Hydrochlo-
Hz, J7a,7b ) 9.0 Hz, H-7a), 3.69 (dd, 1 H, J7b,6 ) 6.5 Hz, J7b,7a
)
ride (14a). 14a (25 mg, 89%) as an amorphus solid. [R]D ) -38.2
1
9.0 Hz, H-7b), 3.66 (dd, 1 H, J1b,1a ) 10.0 Hz, J1b,2 ) 4.5 Hz,
(c 0.8, MeOH). H NMR (CD3OD): δ ) 3.99 (dd, 1 H, J1a,1b
)
H-1b), 3.56 (m, 1 H, H-6), 3.10 (ddd, 1 H, J2,1a ) 10.0 Hz, J2,1b
)
13.0 Hz, J1a,2 ) 5.5 Hz, H-1a), 3.97 (dd, 1 H, J7a,6 ) 6.0 Hz, J7a,7b
) 12.5 Hz, H-7a), 3.89 (dd, 1 H, J7b,6 ) 6.5 Hz, J7b,7a ) 12.5 Hz,
H-7b), 3.87 (dd, 1 H, J1b,1a ) 13.0 Hz, J1b,2 ) 3.5 Hz, H-1b), 3.85
(dd, 1 H, J5,4 ) 8.5 Hz, J5,6 ) 5.5 Hz, H-5), 3.68 (t, 1 H, J4,3 ) J4,5
4.5 Hz, J2,3 ) 5.0 Hz, H-2), 2.45 (s, 1 H, OH). 13C NMR: δ )
140.9, 138.4, 128.6, 128.3, 127.7, 127.6, 127.0, 73.3, 73.0, 72.8,
71.5, 68.4, 60.4, 58.5, 53.4, 26.9, 21.0, 14.8. MALDI-TOF MS:
J. Org. Chem, Vol. 71, No. 20, 2006 7581

Dondoni and Nuzzi
) 8.5 Hz, H-4), 3.63 (ddd, 1 H, J6,5 ) 5.5 Hz, J6,7a ) 6.0 Hz, J6,7b
) 6.5 Hz, H-6), 3.61 (t, 1 H, J3,2 ) J3,4 ) 8.5 Hz, H-3), 3.39 (ddd,
1 H, J2,1a ) 5.5 Hz, J2,1b ) 3.5 Hz, J2,3 ) 8.5 Hz, H-2). 13C NMR
(CD3OD): δ ) 73.8, 69.9, 69.3, 58.2, 58.1, 57.5, 57.1. MALDI-
TOF MS: 216.3 (Mamine + Na). Anal. Calcd for C7H16ClNO5
(229.1): C, 36.61; H, 7.02; N, 6.10. Found: C, 36.68; H, 7.01; N,
6.10.
+ Na). Anal. Calcd for C7H16ClNO5 (229.1): C, 36.61; H, 7.02;
N, 6.10. Found: C, 36.58; H, 6.93; N, 6.03.
Compound 13c was previously characterized as a free amine.21
Therefore, the hydrochloride 13c was dissolved in a minimum of
water and stirred with DOWEX 1X8-200 ion-exchange resin until
pH ) 11.55. After filtration, the filtrate was concentrated under
vacuum to give the free amine. [R]D ) -40.7 (c 0.7, H2O) [lit.21
[R]D ) -41.0 (c 0.69, H2O)]. 1H and 13C NMR spectra were iden-
tical to those reported in the literature.21
2,6-Dideoxy-2,6-imino-L-glycero-D-talo-heptitol Hydrochloride
(13b). 13b (16 mg, 56%) as an amorphus solid. [R]D ) 30.8 (c
1
0.9, H2O) [lit.20 [R]D ) 31.1 (c 1.0, H2O)]. H NMR (D2O): δ )
2,6-Dideoxy-2,6-imino-L-glycero-L-manno-heptitol Hydrochlo-
ride (14c). 14c (24 mg, 86%) as an amorphus solid. [R]D ) -19.9
(c 1.6, MeOH). 1H NMR (CD3OD): δ ) 4.04 (dd, 1 H, J5,4 ) 3.0
Hz, J5,6 ) 6.5 Hz, H-5), 4.00 (dd, 1 H, J1a,1b ) 12.0 Hz, J1a,2 ) 8.0
Hz, H-1a), 3.92 (dd, 1 H, J7a,6 ) 4.5 Hz, J7a,7b ) 12.0 Hz, H-7a),
3.90 (t, 1 H, J3,2 ) J3,4 ) 6.5 Hz, H-3), 3.87 (dd, 1 H, J1b,1a ) 12.0
3.96-3.89 (m, 3 H), 3.82-3.62 (m, 4 H), 3.51-3.42 (m, 1 H),
3.24 (m, 1 H). 13C NMR (D2O) spectrum was consistent with that
reported in the literature.20 MALDI-TOF MS: 194.2 (Mamine + H).
Anal. Calcd for C7H16ClNO5 (229.1): C, 36.61; H, 7.02; N, 6.10.
Found: C, 36.59; H, 7.00; N, 6.09.
2,6-Dideoxy-2,6-imino-L-glycero-D-galacto-heptitol Hydro-
Hz, J1b,2 ) 4.0 Hz, H-1b), 3.84 (dd, 1 H, J7b,6 ) 7.0 Hz, J7b,7a )
chloride (14b). 14b (25 mg, 88%) as an amorphus solid. [R]D
)
12.0 Hz, H-7b), 3.80 (dd, 1 H, J4,3 ) 6.5 Hz, J4,5 ) 3.0 Hz, H-4),
3.50 (ddd, 1 H, J6,5 ) 6.5 Hz, J6,7a ) 4.5 Hz, J6,7b ) 7.0 Hz, H-6),
3.36 (m, 1 H, H-2). 13C NMR (CD3OD): δ ) 71.7, 67.9, 67.0,
60.0, 58.4, 57.6. MALDI-TOF MS: 215.7 (Mamine + Na). Anal.
Calcd for C7H16ClNO5 (229.1): C, 36.61; H, 7.02; N, 6.10.
Found: C, 36.69; H, 7.03; N, 6.12.
-39.4 (c 0.7, MeOH). 1H NMR (D2O): δ ) 4.04-3.99 (m, 2 H),
3.85 (dd, 1 H, J ) 4.5 Hz, J ) 12.0 Hz), 3.75-3.60 (m, 5 H), 3.45
(t, 1 H, J3,2 ) J3,4 ) 6.0 Hz, H-3). 13C NMR (D2O): δ ) 69.1,
66.1, 65.9, 58.2, 55.4, 55.3, 55.0. MALDI-TOF MS: 217.7 (Mamine
+ Na). Anal. Calcd for C7H16ClNO5 (229.1): C, 36.61; H, 7.02;
N, 6.10. Found: C, 36.55; H, 6.97; N, 6.01.
2,6-Dideoxy-2,6-imino-L-glycero-L-gluco-heptitol Hydrochlo-
ride (13c). 13c (24 mg, 87%) as an amorphus solid. [R]D ) -20.0
Acknowledgment. This work was financially supported by
MIUR (COFIN 2004).
1
(c 0.3, MeOH). H NMR (CD3OD): δ ) 4.02-3.92 (m, 4 H),
3.87-3.80 (m, 3 H), 3.51 (t, 1 H). 13C NMR (D2O): δ ) 70.6,
68.3, 64.7, 59.9, 59.4, 57.8, 57.1. MALDI-TOF MS: 217.6 (Mamine
JO060890M
7582 J. Org. Chem., Vol. 71, No. 20, 2006