A general strategy for the practical synthesis of nojirimycin C-glycosides and analogues. Extension to the first reported example of an iminosugar 1-phosphonate

Article abstract of DOI:10.1021/jo0203903

An efficient and versatile strategy for the synthesis of nojirimycin C-glycosides and related compounds with full stereocontrol is reported. The key steps of the process are the addition of organometallic reagents onto an L-sorbose-derived imine (13) followed by an internal reductive amination. The addition step, which controls the α vs β-configuration at the pseudoanomeric center in the final product, is highly diastereoselective (re-face addition), and the stereoselectivity can be effectively inverted by adding an external monodentate Lewis acid (si-face addition). The complete synthesis could be achieved in 10 steps only from commercially available 2,3;4,6-di-O-isopropylidene-C-L-sorbofuranose and provided α or β-1-C-substituted 1-deoxynojirimycin derivatives in 27-52% overall yield. The strategy was successfully extended to the first example of an iminosugar 1-phosphonate. The methodology provides access to a wide range of biologically relevant glycoconjugate mimetics in which the glycosidic function is replaced by an imino-C-glycosidic linkage.

Full text of DOI:10.1021/jo0203903

A Gen er a l Str a tegy for th e P r a ctica l Syn th esis of Nojir im ycin
C-Glycosid es a n d An a logu es. Exten sion to th e F ir st Rep or ted
Exa m p le of a n Im in osu ga r 1-P h osp h on a te
Guillaume Godin, Philippe Compain, Ge´raldine Masson, and Olivier R. Martin*
Institut de Chimie Organique et Analytique, CNRS - Universite´ d’Orle´ans,
BP 6759, 45067 Orle´ans, France
olivier.martin@univ-orleans.fr
Received J une 10, 2002
An efficient and versatile strategy for the synthesis of nojirimycin C-glycosides and related
compounds with full stereocontrol is reported. The key steps of the process are the addition of
organometallic reagents onto an L-sorbose-derived imine (13) followed by an internal reductive
amination. The addition step, which controls the R- vs â-configuration at the pseudoanomeric center
in the final product, is highly diastereoselective (re-face addition), and the stereoselectivity can be
effectively inverted by adding an external monodentate Lewis acid (si-face addition). The complete
synthesis could be achieved in 10 steps only from commercially available 2,3;4,6-di-O-isopropylidene-
R-L-sorbofuranose and provided R- or â-1-C-substituted 1-deoxynojirimycin derivatives in 27-52%
overall yield. The strategy was successfully extended to the first example of an iminosugar
1-phosphonate. The methodology provides access to a wide range of biologically relevant glycocon-
jugate mimetics in which the glycosidic function is replaced by an imino-C-glycosidic linkage.
CHART 1
In tr od u ction
Since the discovery of nojirimycin 11 as the first glucose
mimetic with nitrogen instead of the ring oxygen (Chart
1), the spectacular development of iminosugars, prompted
primarily by their properties as glycosidase inhibitors,2-4
has opened a dynamic research field at the interface
between glycobiology and organic chemistry. In addition,
the scope of biological activities has been extended in
recent years to the inhibition of glycosyltransferases,5 of
nucleoside6 and glycogen7 phosphorylases, and of sugar
nucleotide mutase (UDP-Galp mutase).8 These remark-
* To whom correspondence should be addressed. Tel: ++ 33 2 38
49 45 81. Fax: ++ 33 2 38 41 72 81.
(1) (a) Inouye, S. E.; Tsuruoka, T.; Ito, T.; Niida, T. Tetrahedron
1968, 24, 2125. (b) Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994,
135.
(2) Stu¨tz, A. E., Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Wiley-VCH: Weinheim, 1999.
(3) (a) Asano, N.; Nash, R. J .; Molyneux, R. J .; Fleet, G. W. J .
Tetrahedron: Asymmetry 2000, 11, 1645. (b) Watson, A. A.; Fleet, G.
W. J .; Asano, N.; Molyneux, R. J .; Nash, R. J . Phytochemistry 2001,
56, 265.
(4) Frankowski, A.; Streith, J . C. R. Acad. Sci., Ser. IIc: Chim. 1998,
1, 681.
(5) (a) For a recent review on carbohydrate mimetic-based glyco-
syltransferase inhibitors, see: Compain, P.; Martin, O. R. Bioorg. Med.
Chem. 2001, 9, 3077. (b) Schuster, M.; Blechert, S. Bioorg. Med. Chem.
Lett. 2001, 11, 1809. (c) Bastida, A.; Fernandez-Mayoralas, A.; Arrayas,
R. G.; Iradier, F.; Carretero, J . C.; Garcia-J unceda, E. Chem. Eur. J .
2001, 7, 2390.
(6) (a) Fedorov, A.; Shi, W.; Kicska, G.; Fedorov, E.; Tyler, P. C.;
Furneaux, R. H.; Hanson, J . C.; Gainsford, G. J .; Larese, J . Z.;
Schramm, V. L.; Almo, S. C. Biochemistry 2001, 40, 853. (b) Miles, R.
W.; Tyler, P. C.; Furneaux, R. H.; Bagdassarian, C. K.; Schramm, V.
L. Biochemistry 1998, 37, 8615. (c) Kline, P. C.; Schramm, V. L.
Biochemistry 1993, 32, 13212.
able properties promise a new generation of iminosugar-
based medicines in a wide range of diseases3,9 such as
diabetes,10 viral infections,11 and tumor metastasis.12 New
(8) (a) Lee, R. E.; Smith, M. D.; Pickering, L.; Fleet, G. W. J .
Tetrahedron Lett. 1999, 40, 8689. (b) Lee, R. E.; Smith, M. D.; Nash,
R. J .; Griffiths, R. C.; McNeil, M.; Grewal, R. K.; Yan, W.; Besra, G.
S.; Brennan, P. J .; Fleet, G. W. J . Tetrahedron Lett. 1997, 38, 6733.
(9) Alper, J . Science 2001, 291, 2338.
(10) (a) Dimitriadis, G. D.; Tessari, P.; Go, V. L. W.; Gerich, J . E.
Metabolism 1985, 34, 261. (b) Bollen, M.; Stalmans, W. Eur. J .
Biochem. 1989, 181, 775. (c) Andersen, B.; Rassov, A.; Westergaard,
N.; Lundgren, K. Biochem. J . 1999, 342, 545.
(11) (a) Ha¨usler, H.; Kawakami, P.; Mlaker, E.; Severn, W. B.;
Wrodnigg, T. M.; Stu¨tz, A. E. J . Carbohydr. Chem. 2000, 19, 435. (b)
Durantel, D.; Branza-Nichita, N.; Carrouee-Durantel, S.; Butters, T.
D.; Dwek, R. A.; Zitzmann, N. J . Virol. 2001, 75, 8987.
(7) J akobsen, P.; Lundbeck, J . M.; Kristiansen, M.; Breinholt, J .;
Demuth, H.; Pawlas, J .; Candela, M. P. T.; Andersen, B.; Westergaard,
N.; Lundgren, K.; Asano, N. Bioorg. Med. Chem. 2001, 9, 733.
10.1021/jo0203903 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/04/2002
6960
J . Org. Chem. 2002, 67, 6960-6970

Synthesis of Nojirimycin C-Glycosides
SCHEME 1
therapeutic applications are being uncovered. For ex-
ample, N-butyl-1-deoxynojirimycin 2 (Chart 1) has been
engaged recently in a clinical trial as a potential therapy
for Gaucher disease, a severe lysosomal storage dis-
order.13-15 The first promising results obtained have
warranted further exploration of N-alkyliminosugars.16
Considering the high potential of azaglycoside mimet-
ics as modified biological substrates, the design of a
general and efficient access to iminosugar C-glycosides
appears to be a major issue in bioorganic and medicinal
chemistry. As stable analogues of azapyranosides, imi-
nosugar C-glycosides have attracted much attention since
the first synthesis17 and isolation18 of R-homonojirimycin
3, the simplest example of this class of compounds. A
diversity-oriented synthesis of iminosugar C-glycosides
would facilitate the exploration of new biological targets,
the finding of more potent/selective inhibitors, and the
elucidation of carbohydrate-processing enzyme mecha-
nisms by probing further their binding specificities.19 In
addition, from a chemical point of view, properly pro-
tected and functionalized iminosugar intermediates could
be particularly useful as building blocks for the synthesis
of more complex targets such as glycosyltransferase
inhibitors (i.e., unreactive sugar nucleotide or bisubstrate
analogues)5 and oligosaccharide or glycoprotein mimetics
(see, for example, 420 and 5,21 Chart 1). Despite a large
amount of synthetic effort in this area,22 there is still a
need for an efficient and general methodology to imino-
sugar C-glycosides of predictable configuration from
simple precursors.
synthesis of various R- and â-1-C-substituted-1-deoxy-
nojirimycins and protected analogues. Extension of the
methodology to a phosphorus nucleophile led to the
synthesis of the first reported example of an iminosugar
1-phosphonate.
Syn th etic Design . Besides the highly oxygenated
piperidine structure of our target I and its five contiguous
stereogenic centers, the main challenge of our synthetic
strategy lies in its generality (Scheme 1). To generate
diversity from advanced intermediates, we concentrated
on three directions: the aglycon part (R), the control of
the R/â configuration at the pseudoanomeric center, and
the rapid access to other series: D-allo, D-galacto, D-
manno, and L-ido.
Our retrosynthetic analysis takes advantage of the
chirality of L-sorbose, which provides three stereogenic
centers (C2, C3, and C4) of our target I and secures the
stereocontrol of the addition reactions.25 The key step of
our synthetic strategy is the diastereoselective chain
extension of imine IV. At this stage, the careful choice
of reaction conditions can give selectively one or the other
of two possible epimers at C6 in III, i.e., the precursors
of the R- or â-epimer of imino-C-glycoside I. In addition,
structural diversity may be introduced at the “anomeric”
position by using the wide library of organometallic
In this context and as part of our continuing studies
on azaglycoside mimics,23 we have designed a versatile
synthetic strategy for the preparation of various types
of iminosugar C-glycosides from L-sorbose based on the
stereoselective addition of organometallic reagents onto
an advanced imine intermediate. In a preliminary study,24
this approach was partially validated with the prepara-
tion of two protected analogues of nojirimycin R-C-
glycosides. Herein, we wish to report the generalization
of this strategy to the stereocontrolled and practical
(12) (a) Goss, P. E.; Baker, M. A.; Carver, J . P.; Dennis, J . W. Clin.
Cancer Res. 1995, 1, 935. (b) Humphries, M. J .; Matsumoto, K.; White,
S. L.; Olden, K. Cancer Res. 1986, 46, 5215. (c) Nishimura, Y.; Satoh,
T.; Adachi, H.; Kondo, S.; Takeuchi, T.; Azetaka, M.; Fukuyasu, H.;
Lizuka, Y. J . Med. Chem. 1997, 40, 2626.
(13) Butters, T. D.; Dwek, A.; Platt, F. M. Chem Rev. 2000, 100,
4683.
(14) Butters, T. D.; van den Broek, L. A. G. M.; Fleet, G. W. J .;
Krulle, T. M.; Wormald, M. R.; Dwek, R. A.; Platt, F. M. Tetrahedron:
Asymmetry 2000, 11, 113.
(15) For a chemical chaperone therapy of another lysosomal storage
disorder (Fabry disease) using iminosugars, see: (a) Fan, J .-Q.; Ishii,
S.; Asano, N.; Suzuki, Y. Nature Med. 1999, 5, 112. (b) Asano, N.; Ishii,
S.; Kizu, H.; Ikeda, K.; Yasuda, K.; Kato, A.; Martin, O. R.; Fan, J . Q.
Eur. J . Biochem. 2000, 267, 4179.
(16) Cox, T.; Lachmann, R.; Hollak, C.; Aerts, J .; van Weely, S.;
Hrebicek, M.; Platt, F.; Butters, T.; Dwek, R.; Moyses, C.; Gow, I.;
Elstein, D.; Zimran, A. Lancet 2000, 355, 1481.
(22) (a) Liotta, L. J .; Lee, J .; Ganem, B. Tetrahedron 1991, 47, 2433.
(b) J ohnson, C. R.; Golebiowski, A.; Sundram, H.; Miller, M. W.;
Dwaihy, R. L. Tetrahedron Lett. 1995, 36, 653. (c) J ohns, B. A.;
J ohnson, C. R. Tetrahedron Lett. 1998, 39, 749. (d) Fuchss, T.;
Streicher, H.; Schmidt, R. R. Liebigs Ann./ Recueil 1997, 1315. (e) Zhu,
Y.-H.; Vogel, P. J . Org. Chem. 1999, 64, 666. (f) Cipolla, L.; Lay, L.;
Nicotra, F.; Pangrazio, C.; Panza, L. Tetrahedron 1995, 51, 4679. (g)
Cipolla, L.; La Ferla, B.; Peri, F.; Nicotra, F. Chem. Commun. 2000,
1289. (h) Duff, F. J .; Vivien, V.; Wightman, R. H. Chem. Commun.
2000, 2127. (i) Cheng, X.; Kumaran, G.; Mootoo, D. R. Chem. Commun.
2001, 811. (j) Dransfield, P. J .; Gore, P. M.; Shipman, M.; Slawin, M.
Z. Chem. Commun. 2002, 150.
(17) Liu, P. S. J . Org. Chem. 1987, 52, 4717.
(23) (a) Martin, O. R. In Carbohydrate Mimics: Concepts and
Methods; Chapleur, Y., Ed.; Wiley-VCH: New York, 1997; p 259-282.
(b) Martin, O. R.; Compain, P.; Kizu, H.; Asano, N. Bioorg. Med. Chem.
Lett. 1999, 9, 3171. (c) Tezuka, K.; Compain, P.; Martin, O. R. Synlett
2000, 1837. (d) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron:
Asymmetry 2001, 12, 1807. (e) Martin, O. R.; Saavedra, O. M.; Xie, F.;
Liu, L.; Picasso, S.; Vogel, P.; Kizu, H.; Asano, N. Bioorg. Med. Chem.
2001, 9, 1269.
(24) Masson, G.; Compain, P.; Martin, O. R. Org. Lett. 2000, 2, 2971.
(25) It is noteworthy that L-sorbose has been used as the starting
material for the first synthesis, as well as for some of the shortest
syntheses, of 1-deoxynojirimycin, but not for the preparation of chain-
extended analogues (see ref 1b).
(18) Kite, G. C.; Fellows, L. E.; Fleet, G. W. J .; Liu, P. S.; Scofield,
A. M.; Smith, N. G. Tetrahedron Lett. 1988, 29, 6483.
(19) (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed.
1999, 38, 750. (b) Withers, S. G.; Namchuk, M.; Mosi, R. In Iminosugars
as Glycosidase Inhibitors: Nojirimycin and Beyond; Stu¨tz, A. E., Ed.;
Wiley-VCH: Weinheim, 1999; pp 188-206. (c) Davies, G.; Sinnott, M.
L.; Withers, S. G. Glycosyl transfer. In Comprehensive Biological
Catalysis; Sinnott, M. L., Ed.; Academic Press Limited: New York,
1997; Chapter 3, pp 119-208.
(20) J ohns, B. A.; Pan, Y. T.; Elbein, A. D.; J ohnson, C. R. J . Am.
Chem. Soc. 1997, 119, 4856.
(21) Fuchss, T.; Schmidt, R. R. Synthesis 2000, 259.
J . Org. Chem, Vol. 67, No. 20, 2002 6961

Godin et al.
SCHEME 2
nucleophiles available. This point is particularly signifi-
cant if one wants to explore the affinity of the aglycon
binding site within a range of glycosidases in order to
increase the selectivity of potential inhibitors. The last
steps of the synthetic plan consisted of generating the
final iminosugar C-glycosidic structure I by way of the
intramolecular reductive amination of the latent keto
function of the aminosorbofuranose derivative, a reaction
that was expected to be highly stereoselective and to give
the desired epimer in the D-series.26 Finally, an orthogo-
nal protecting group strategy was designed to facilitate
the differentiation of the sugar hydroxyl groups, notably
at C3, thus opening the way to oligosaccharide analogues
or to iminosugars of other configurations by controlled
epimerization of one of the OH group (see Scheme 1). The
strategy was first tested for the stereocontrolled synthesis
of R- and â-1-C-substituted-1-deoxynojirimycin I.
in 91% yield using Dess-Martin periodinane in dichlo-
romethane at room temperature.29 This reaction was
readily scaled-up for the preparation of 12 in 10 g
quantities. On the contrary, standard PCC oxidation of
11 was found to be less efficient (85% yield)24 and less
reproducible on a multigram scale. Finally, condensation
of 12 with benzylamine in dichloromethane in the pres-
ence of molecular sieves (4 Å)30 afforded the imine 13 in
quantitative yield, as judged by proton NMR spectros-
copy. In summary, the advanced intermediate 13 was
efficiently prepared on a multigram scale from com-
mercially available 2,3;4,6-di-O-isopropylidene-R-L-sor-
bofuranose in seven steps and 80% overall yield (Scheme
2).
Ster eocon tr olled Ad d ition to Im in e 13. With the
desired imine 13 in hand, the addition of organometallic
nucleophiles to the CdN bond31 was first investigated
without Lewis acid (Table 1, entries 1-5). The allyl- and
vinylmagnesium bromides were chosen because of the
synthetic potential offered by the CdC bond at a later
stage of the synthesis. The reaction was found to be
highly diastereoselective with organolithium as well as
organomagnesium reagents. In a typical experimental
procedure, a solution of 3 equiv of the organometallic
reagent in ether was added dropwise to a cooled solution
(-78 or 0 °C) of the N-benzylimine 13 in ether. The
reaction mixture was slowly warmed to 0 °C (for RLi) or
to room temperature (for RMgBr) and stirred for a few
hours. In each case, 1H NMR analysis of the crude
product after workup revealed the presence of a single
diastereoisomer with the exception of vinylmagnesium
bromide (de ) 90%, Table 1, entry 3). Purification by
flash chromatography afforded amines 14 in good yields
(Table 1, entries 1-5). The absolute configuration of the
newly created stereocenter was unambiguously estab-
lished to be R at the stage of cyclic products 16 and 17.
The high stereoselectivity of the addition of the organo-
metallic species to the re face of imine 13 can be
rationalized by the chelated intermediate A involving as
ligands the nitrogen atom of the N-benzylimine and the
ring oxygen atom of the sorbofuranose moiety (Scheme
Resu lts a n d Discu ssion
P r ep a r a tion of Im in e 13. As our approach required
an easy access to multigram quantities of imine 13, the
first goal of our synthesis was the efficient preparation
of this key intermediate from commercially available
2,3;4,6-di-O-isopropylidene-R-L-sorbofuranose 6.27 We fol-
lowed a protecting group strategy to isolate and then
oxidize the hydroxyl group at C6 (Scheme 2). The
synthesis began with the benzylation of the primary
alcohol at C1, followed by the selective deprotection of
the less stable isopropylidene acetal under aqueous acidic
conditions, in the presence of acetone, to afford the diol
828 in 97% yield from 6. Benzylation of the secondary
hydroxyl group was performed by way of the temporary
protection of the primary hydroxyl group of 8 as a trityl
ether, benzylation of the secondary OH and cleavage of
the trityl group using HBr in glacial acetic acid. This
three-step procedure provided the primary alcohol 11 in
90% yield. The aldehyde 12 was then cleanly generated
(26) (a) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res. 1993,
26, 182. (b) Saavedra, O. M.; Martin, O. R. J . Org. Chem. 1996, 61,
6987.
(27) In our hands, compound 6 could be obtained in one step from
L-sorbose in 80% yield; see: Paulsen, H.; Sangster, I.; Heyns, K. Chem.
Ber. 1967, 100, 802.
(28) Izquierdo, I.; Plaza, M. T.; Kari, N. Carbohydr. Res. 1995, 268,
187.
(29) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(30) Feldman, K. S.; Mingo, P. A.; Hawkins, P. C. D. Heterocycles
1999, 51, 1283.
(31) Bloch, R. Chem. Rev. 1998, 98, 1407.
6962 J . Org. Chem., Vol. 67, No. 20, 2002

Synthesis of Nojirimycin C-Glycosides
TABLE 1
entry
R-M
Lewis acid
T, °C
14/15a
product
yieldb (%)
1
2
3
4
5
6
7
8
9
allylMgBr
nBuLi
vinylMgBr
EtMgBr
Me3SiCtCMgBr
allylMgBr
allylMgBr
nBuLi
0 f rt
-78 f 0
0 f rt
0 f rt
0 f rt
-40 f 0
-78 f 0
-78 f 0
-78 f 0
>98/2
>98/2
95/5
>98/2
>98/2
40/60
20/80
>2/98
>2/98
14a
14b
14c
14d
84
65
90
75
60
90
42
69
72
14e
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
BF3‚Et2O
14a /15a
14a /15a
15b
vinylMgBr
15c
a
b
Diastereomer ratio from 1H and 13C NMR analysis of the crude products. Isolated yield after chromatography on silica gel.
SCHEME 3
pivotal issues of this one-pot process were the critical
acidic hydrolysis of the relatively stable 2,3-O-isopro-
pylidene group35 and the control of the newly created
stereocenter C5 (Table 2). We first focused our attention
on the synthesis of nojirimycin R-C-glycosides from the
6(R) aminosorbose derivatives 14. The optimized experi-
mental conditions for the hydrolysis step consisted in
using 90% aqueous CF3COOH at room temperature at a
substrate concentration of 0.15 M for 30 h.36 After
concentration of the reaction mixture and removal of
solvent traces by coevaporation with toluene, the crude
intermediate was treated with NaBH3CN for the reduc-
tion step. Our previously reported conditions using acetic
acid as the solvent24 were notably improved after careful
optimization: the amount of acetic acid was decreased
to 1 equiv, the solvent changed to methanol, and the
reaction time extended to 24 h (Table 2). This process
afforded diastereomerically pure diols 1637 or fully pro-
tected piperidines 17 after acetylation in very good
overall yields. The relative configurations of the substit-
uents in the piperidine ring system were unambiguously
3). In furanoid systems, it is well established that the
endocyclic oxygen acts as a coordinating Lewis base in
additions of organometallic reagents to 5-aldehydo-pento-
furanose derivatives.32
With the goal of reversing the stereoselectivity of the
addition, we performed the reaction in the presence of 5
equiv of BF3‚Et2O.33 It was expected that imine 13 would
be engaged in an open complex with the monodentate
Lewis acid (open transition state model B)31 and that
chelation effects would be suppressed. According to this
prevision, addition of BuLi or vinylmagnesium bromide
(3 equiv) to a cold solution of imine 13 thus preactivated
provided after purification the epimeric amines 15b,c in
good yield (Table 1, entries 8 and 9) and with a very high
stereoselectivity (si-face addition). In contrast, the addi-
tion of allylmagnesium bromide to imine 13 at 0 °C under
the same conditions gave a separable mixture of the two
amines 14a and 15a with a lower degree of stereoselec-
tivity (Table 1, entry 6). The diastereomeric excess could
be improved by lowering the addition temperature to -78
°C but to the detriment of the yield (Table 1, entry 7).
The lower diastereoselectivity of this process is attributed
to a change in mechanism from inter- to intramolecular
delivery of allylmagnesium reagents as it has been
previously observed for 1,2-diastereoselective addition to
R-alkoxy ketones or aldimines.34
1
established by the H NMR spectra (COSY and NOESY)
of 16 and 17. Removal of the benzyl protecting groups in
16b and 16d by hydrogenolysis provided the expected
R-1-C-butyl-1-deoxynojirimycin 1838 and R-1-C-ethyl-1-
deoxynojirimycin 1938 in very good yields (Scheme 4) (see
1H NMR data for 18 in Table 3). The diastereoselectivity
of the reduction step may be explained by the addition
of hydride to a favorable half-chair conformation of the
cyclic iminium intermediate in which all substituents are
in pseudoequatorial position except the R group (Scheme
5). Hydride delivery in the axial direction is sterically
unhindered and minimizes torsional strain during the
(34) For related examples, see: (a) Akhoon, K. M.; Myles, D. C. J .
Org. Chem. 1997, 62, 6041. (b) Veith, U.; Schwardt, O.; J a¨ger, V.
Synlett 1996, 1181. (c) Compain, P.; Gore´, J .; Vate`le, J .-M. Tetrahedron
Lett. 1995, 36, 4059.
(35) Heyns, K.; Heukeshoven, J . J ustus Liebig Ann. Chem. 1976,
269.
In tr a m olecu la r Red u ctive Am in a tion . The next
key step of the strategy was the intramolecular reductive
amination of the unmasked aminosorbose hemiketal. The
(36) Nortey, S. O.; Wu, W.-N.; Maryanoff, B. E. Carbohydr. Res.
1997, 304, 29.
(32) (a) Inch, T. D. Adv. Carbohydr. Chem. 1972, 27, 191. (b)
Danishefsky, S. J .; DeNinno, M. P.; Phillips, G. B.; Zelle, R. E.; Lartey,
P. A. Tetrahedron 1986, 42, 2809.
(33) van Delft, F. L.; de Kort, M.; van der Marel, G. A.; van Boom,
J . H. J . Org. Chem. 1996, 61, 1883.
(37) Diol 16c with the vinyl group at C1 was found to decompose
after a few days of storage at -20 °C. To avoid this degradation, 16c
was directly acetylated after the reductive amination reaction.
(38) Bo¨shagen, H.; Geiger, W.; J unge, B. Angew. Chem., Int. Ed.
Engl. 1981, 20, 806.
J . Org. Chem, Vol. 67, No. 20, 2002 6963

Godin et al.
TABLE 2
entry
R
reductive amination
NaBH3CN (4 equiv)
NaBH3CN (3 equiv), AcOH (1 equiv)
NaBH3CN (3 equiv), AcOH (1 equiv)
NaBH3CN (4 equiv)
solvent
reaction time (h)
product
yielda (%)
1
2
3
4
5
6
allyl
allyl
butyl
vinyl
vinyl
ethyl
AcOH
MeOH
MeOH
AcOH
MeOH
MeOH
3
24
24
3
24
24
17a
17a
16b
17c
17c
16d
45
75
72
44
72
53
NaBH3CN (3 equiv), AcOH (1 equiv)
NaBH3CN (3 equiv), AcOH (1 equiv)
a
Isolated yield from 14 after chromatography on silica gel.
SCHEME 4
all the substituents are in a pseudoequatorial position,
which generates A1,2 strain between the C1 substituent
and the N-benzyl group (Scheme 7).26a,39 Hydride addition
may thus also occur in the axial direction on the alternate
half-chair conformation B of the iminium ion and thus
lead to a substantial proportion of pseudo-R-L-ido product.
The decisive influence of A1,2 strain was demonstrated
by the dramatic increase of the diastereomeric excess to
70% with the slightly less sterically demanding vinyl
group (sp2 instead of sp3 carbon linked to C1). According
to this analysis, it was predicted that removal of the
N-benzyl group prior to internal reductive amination
would suppress A1,2 strain effects and increase the
stereoselectivity of the reduction toward the desired D
configuration. This hypothesis was verified by performing
the following three-step sequence without purification of
the intermediates: removal of the benzyl protecting
groups of the amino-sorbofuranose derivatives 15b,c by
hydrogenolysis, cleavage of the isopropylidene group, and
reductive amination under classical conditions (Scheme
8). Purification of the product by ion-exchange chroma-
tography provided the expected â-1-C-butyl-1-deoxynojir-
imycin 2238 and â-1-C-ethyl-1-deoxynojirimycin 23 in
good overall yields from 15b and 15c respectively (see
the 1H NMR data for 22 in Table 3). No trace of the other
epimer was detected. This three-step procedure provides
an efficient access to nojirimycin â-C-glycoside analogues
bearing a C1 substituent compatible with catalytic
hydrogenation.
TABLE 3
J (Hz)
18
22
J 1,2
J 2,3
J 3,4
J 4,5
J 5,6A
J 5,6B
5.4
9.8
9.8
9.8
3.0
6.6
9.2-9.4
9.2-9.4
9.2-9.4
9.2-9.4
2.8
8.2
SCHEME 5
Syn th esis of Im in osu ga r 1-P h osp h on a te 25. The
operational simplicity and predictive power of the syn-
thetic strategy outlined in this paper have been success-
fully applied to the efficient synthesis of the first example
of an iminosugar 1-phosphonate. Due to their central role
in the metabolism and the biosynthesis of carbohy-
drates,40,41 glycosyl phosphates represent valuable tools
for the comprehension of such fundamental biological
mechanisms as glycolysis, gluconeogenesis, and glycosy-
lation. The synthesis of glycosyl phosphate mimetics that
could regulate those processes may lead to the discovery
of new carbohydrate-based therapeutics. In the pyranoid
series, several examples of glycosylmethylphosphonates,42
the isosteric and isopolar C-glycosyl equivalents of gly-
transition to the final chair conformation of the piperidine
ring.39
Under the same conditions, the reductive amination
of the 6(S)-epimers 15a ,b afforded quite unexpectedly an
equimolar mixture of the pseudo-â-D-gluco and pseudo-
R-L-ido products 20a ,b and 21a ,b, respectively, as deter-
mined on the basis of mass and NMR spectral data
(Scheme 6). The complete loss of stereoselectivity at C5
may be rationalized by the partial destabilization of the
cyclic iminium ion in conformation A: in this conformer,
(40) Hers, H. G. Biochem. Soc. Trans. 1984, 12, 729.
(41) Macdonald, D. L. In The Carbohydrates: Chemistry and
Biochemistry; Pigman, W., Horton, D., Eds.; Academic Press: New
York, 1972; Vol. 1A, pp 253-277.
(39) Baxter, E. W.; Reitz, A. B. J . Org. Chem. 1994, 59, 3175.
6964 J . Org. Chem., Vol. 67, No. 20, 2002

Synthesis of Nojirimycin C-Glycosides
SCHEME 6
SCHEME 7
was completely lost with the more sterically demanding
phosphorus nucleophile generated from dibenzyl phos-
phite. According to Rees et al.,46 the electrophilicity of
the carbon atom of the CdN bond in this reaction is
increased by the formation of a transient N-silylated
iminium cation. The S configuration of the newly created
stereogenic center may be explained by an open transi-
tion state model of type B having an antiperiplanar
conformation due to steric and electrostatic repulsion
(Scheme 3). The sense of addition could be reversed using
the bidentate Lewis acid ZrCl4 (chelated intermediate of
type A). Following the mild experimental procedure
recently described by Yadav et al.,47 the epimeric R-amino
phosphonate 24b was obtained with a diastereomeric
excess of 85%. Surprisingly, the acetal function of the
R-amino phosphonates 24 was found to be particularly
resistant to various hydrolysis conditions. To overcome
this unexpected difficulty, we took advantage of the
observation that deketalization of 15 was easier after
complete debenzylation of the hydroxyl and amino func-
tions (Scheme 8). We therefore completed the synthesis
of the deprotected iminosugar 1-phosphonate 25 from
24a by way of a one-pot deprotection (acetal and ben-
zyl groups) and intramolecular reductive amination
using hydrogen over a palladium catalyst in aqueous
CF3COOH. This process provided 1-deoxynojirimycin
â-1-phosphonate 25 in a single operation and in 70%
yield, the new stereogenic center (C5) being created with
cosyl phosphates, as well as a number of the isopolar
glycosylphosphonates43 have been reported and prepared
by various routes. While examples of “iminoglycosyl”-
methylphosphonates have been described,44 there has
been no report of the corresponding iminosugar-derived
glycosylphosphonates. Extension of our synthetic strategy
to a phosphorus nucleophile provided access to this new
class of stable glycosyl phosphate mimetics that combine
an iminosugar moiety and a nonisosteric phosphate
analogue (Scheme 9). Compound 25 was designed to
display a strong affinity toward certain carbohydrate-
processing enzymes: the ability of iminosugars to become
protonated in biological medium and to form a cation
which can interact strongly with an anionic group (i.e.,
carboxylate) at the enzyme active site is well established.
In addition, glycosyl phosphate mimetics that consist of
a phosphonate directly bound to the pseudo anomeric
carbon were found to have a polarity similar to that of
the natural sugar 1-phosphates.45 Diethyl phosphite was
converted in situ to its trimethylsilyloxy P(III) derivative
2646 in the presence of TMSCl and then reacted with
imine 13 in CH2Cl2 to afford the R-amino phosphonate
24a as a single diastereoisomer (6S) in high yield
(Scheme 9). It is noteworthy that the diastereoselectivity
1
a diastereomeric excess of 80% according to the H and
31P NMR spectra of the crude product. So far, the
conversion of epimeric 24b into the corresponding 1-deox-
ynojirimycin R-1-phosphonate was unsuccessful, as the
same sequence of reactions led to an unexploitable
mixture of products. As shown clearly by NMR data,
compound 25 has a pseudo-â-D-gluco configuration and
adopts a chair conformation in which all substituents are
in equatorial position.
Con clu sion
The synthetic strategy based on the addition of orga-
nometallic reagents onto the L-sorbose-derived imine 13,
followed by an internal reductive amination, provides an
efficient, practical and general access to nojirimycin
C-glycosides and analogues. The tactical combination of
these two reactions allows the stereocontrolled synthesis
of R- and â-1-C-substituted-1-deoxynojirimycin and pro-
tected analogues in 10 steps and in an overall yield of 27
to 52% from commercially available 2,3;4,6-di-O-isopro-
pylidene-R-L-sorbofuranose 6. Future work will focus on
the extension of this strategy to other series (D-allo,
(42) Nicotra, F. In Carbohydrate Mimics: Concepts and Methods;
Chapleur, Y., Ed.; Wiley-VCH: New York, 1997; pp 67-85.
(43) (a) Vasella, A.; Baudin, G.; Panza, L. Heteroatom Chem. 1991,
2, 151 and references therein. (b) Vaghefi, M. M.; Bernacki, R. J .;
Dalley, N. K.; Wilson, B. E.; Robins, R. K. J . Med. Chem. 1987, 30,
1383. (c) Chmielewski, M.; BeMiller, J . N.; Cerretti, D. P. Carbohydr.
Res. 1981, 97, C1. (d) Meuwly, R.; Vasella, A. Helv. Chim. Acta 1986,
69, 25.
(44) For examples of iminosugar C-glycoside analogues of glycosyl
1-phosphate, see: (a) Reference 5b. (b) Bosco, M.; Bisseret, P.; Bouix-
Peter, C.; Eustache, J . Tetrahedron Lett. 2001, 42, 7949. (c) Schuster,
M.; He, W.-F.; Blechert, S. Tetrahedron Lett. 2001, 42, 2289. (d)
Gautier-Lefebvre, I.; Behr, J .-B.; Guillerm, G.; Ryder, N. S. Bioorg.
Med. Chem. Lett. 2000, 10, 1483. (e) Kajimoto, T.; Chen, L.; Liu, K.
K.-C.; Wong, C.-H. J . Am. Chem. Soc. 1991, 113, 6678.
(45) Briner, K.; Vasella, A. Helv. Chim. Acta 1987, 70, 1341.
(46) Afarinkia, K.; Rees, C. W.; Cadogan, J . I. G. Tetrahedron 1990,
46, 7175.
(47) Yadav, J . S.; Reddy, B. V. S.; Sarita Raj, K.; Bhaskar Reddy,
K.; Prasad, A. R. Synthesis 2001, 2277.
J . Org. Chem, Vol. 67, No. 20, 2002 6965

Godin et al.
SCHEME 8
13C NMR spectra were recorded at 250 or 500 MHz and 62.9
MHz, respectively. Carbon multiplicities were assigned by
distortionless enhancement by polarization transfer (DEPT)
experiments.
SCHEME 9
1-O-Ben zyl-2,3:4,6-d i-O-isop r op ylid en e-r-L-sor bofu r a -
n ose (7).28 To a stirred solution of 6 (40 g, 150 mmol) in
anhydrous THF (40 mL) was added NaH (12.5 g, 312.5 mmol)
at 0 °C. After 30 min at room temperature, benzyl bromide
(30 mL, 250 mmol) and tetrabutylammonium iodide (3 g, 10
mmol) were added. After 3 h, the reaction was quenched by
the careful addition of MeOH (25 mL) and ice (100 g). The
mixture was extracted with CH2Cl2 (2 × 150 mL). The
combined organic layer was washed with water (100 mL), dried
(MgSO4), and concentrated in vacuo. Purification of the
residual product by silica gel chromatography (PE/EtOAc 5:2)
afforded 7 (52.5 g, 98%) as a clear syrup: [R]20 +34.5 (c 1.02,
D
1
CHCl3); H NMR (CDCl3) δ 1.29 (s, 3H), 1.41 (s, 3H), 1.42 (s,
3H), 1.51 (s, 3H), 3.72 (d, 1H, J ) 10.8 Hz), 3.80 (d, 1H, J )
10.8 Hz), 4.02 (m, 2H), 4.09 (d, 1H, J ) 1.7 Hz), 4.30 (d, 1H,
J ) 1.7 Hz), 4.49 (s, 1H), 4.58 (d, 1H, J ) 12.2 Hz), 4.72 (d,
1H, J ) 12.2 Hz), 7.25-7.3 (m, 5H); 13C NMR (CDCl3) δ 26.6,
27.7, 29.0, 60.4, 70.0, 72.2, 73.4, 73.7, 84.4, 97.4, 112.4, 114.2,
127.6, 127.7, 128.4, 138.3; MS m/z 351 (MH+). Anal. Calcd for
C
19H26O6: C, 65.13; H, 7.48. Found: C, 64.74; H, 7.34.
1-O-Ben zyl-2,3-O-isopr opyliden e-r-L-sor bofu r an ose (8).28
To a cold solution (ice bath) of 7 (51.8 g, 148 mmol) in acetone
(530 mL) were cautiously added concentrated H2SO4 (45 mL)
and water (235 mL). After 3 h at room temperature, the
reaction mixture was neutralized by the slow addition of 2 M
aqueous NaOH (500 mL). The mixture was extracted with
EtOAc (3 × 500 mL). The combined organic layer was washed
with water (300 mL), dried (MgSO4), and concentrated to
afforded 8 (45.4 g, 99%) as a white foam. An analytical sample
was obtained by purification by silica gel chromatography (PE/
D-galacto, and D-manno) from diols 16 and to various
types of functionalized nucleophiles. Investigations on the
activity of the synthesized iminosugars as glycosidase
inhibitors, especially in the field of lysosomal storage
disorders, are in progress and will be reported in due
course. The synthesis of potential glycosyltransferase
inhibitors based on a new type of sugar nucleotide
mimetics with an unusual â pseudo-anomeric configura-
tion from 24a is currently being investigated. According
to a remarkable observation reported very recently by
Schmidt et al.,48 such original donor analogues might be
extremely useful to probe the poorly understood mech-
anism of glycosyl transfer by retaining transferases.
EtOAc 1:9): [R]20 +41 (c 1.34, CHCl3); 1H NMR (CDCl3) δ
D
1.30 (s, 3H), 1.50 (s, 3H), 2.1 (m, 1H), 3.63 (d, 1H, J ) 9.8 Hz),
3.73 (d, 1H, J ) 11 Hz), 3.84 (d, 1H, J ) 9.8 Hz), 3.89-3.98
(m, 2H), 4.18 (dd, 1H, J ) 2.7, 10.3 Hz), 4.31 (dt, 1H, J ) 3.1,
5.1 Hz), 4.43 (s, 1H), 4.59 (d, 1H, J ) 11.7 Hz), 4.68 (d, 1H, J
) 11.7 Hz), 7.25-7.37 (m, 5H); 13C NMR (CDCl3) δ 26.5, 27.6,
61.7, 71.8, 74.41, 75.9, 82.1, 87.3, 112.8, 113.0, 128.4, 128.7,
129.1, 137.0; MS m/z 311.5 (MH+). Anal. Calcd for C16H22O6:
C, 61.92; H, 7.15. Found: C 61.84; H, 7.23.
Exp er im en ta l Section
Gen er a l Met h od s. All reactions requiring anhydrous
conditions were carried out under Ar. Diethyl ether and
tetrahydrofuran were freshly distilled from sodium/benzophe-
none under Ar prior to use. Infrared spectra were recorded
using films on NaCl windows or KBr pellets. Mass spectra
(MS) were recorded by ion spray (IS). Melting points were
determined in open capillary tubes and are uncorrected.
Specific rotations were measured at room temperature (20 °C).
Analytical thin-layer chromatography was performed using
silica gel 60F254 precoated plates (Merck). Flash chromatog-
raphy was perfomed on silica gel 60 (230-400 mesh) with ethyl
1-O-Ben zyl-2,3-O-isop r op ylid en e-6-O-tr ip h en ylm eth yl-
r-L-sor bofu r a n ose (9). To a solution of 8 (30 g, 96.6 mmol)
in pyridine (140 mL) was added trityl chloride (30 g, 107.6
mmol) at room temperature. The mixture was stirred for 24 h
at 50 °C. After removal of pyridine by coevaporation with tol-
uene in vacuo, the crude product was taken in CH2Cl2 (200
mL). The solution was washed with saturated aqueous
NaHCO3 (3 × 100 mL), dried (MgSO4), and concentrated in
vacuo. Purification of the residual product by silica gel
chromatography (PE/EtOAc 95:5 to 6:4) afforded 9 (50.6 g,
95%) as a clear syrup: [R]20 +39 (c 1.32, CHCl3); 1H NMR
D
1
acetate (AcOEt) and petroleum ether (PE) as eluants. H and
(CDCl3) δ 1.30 (s, 3H), 1.52 (s, 3H), 3.39 (d, 1H, J ) 2 Hz),
3.42 (s, 1H), 3.64 (d, 1H, J ) 10 Hz), 3.79 (d, 1H, J ) 10.2
Hz), 4.13 (dd, 1H, J ) 2.2, 10.6 Hz), 4.38 (d, 1H, J ) 2.7 Hz),
4.41 (s, 1H), 4.53 (d, 1H, J ) 11.7 Hz), 4.62 (d, 1H, J ) 11.7
Hz), 7.2-7.39 (m, 14H), 7.41-7.59 (m, 6H); 13C NMR (CDCl3)
δ 26.3, 27.4, 61.9, 71.5, 74.1, 75.1, 81.1, 86.5, 87.0, 112.3, 112.8,
127.1, 127.9, 128.2, 128.7, 128.9, 136.9, 144.0; MS m/z 553
(MH+).
(48) Very recently, Schmidt et al. observed that the presence of UDP
on the â-side of the sugar donor moiety of a bisubstrate analogue led
to higher inhibition of a retaining glycosyltransferase (galactosyltrans-
ferase LgtC from Neisseria meningitidis) than when UDP was on the
R-side as in the natural sugar nucleotide donor: Waldscheck, B.;
Streiff, M.; Notz, W.; Kinzy, W.; Schmidt, R. R. Angew. Chem., Int.
Ed. 2001, 40, 4007.
6966 J . Org. Chem., Vol. 67, No. 20, 2002

Synthesis of Nojirimycin C-Glycosides
1,4-Di-O-b en zyl-2,3-O-isop r op ylid en e-6-O-t r ip h en yl-
m eth yl-r-L-sor bofu r a n ose (10). To a solution of 9 (27.2 g,
49.2 mmol) in anhydrous THF (130 mL) was added NaH (3.14
g, 78.5 mmol) at 0 °C. After 30 min at room temperature,
benzyl bromide (7.6 mL, 63.9 mmol) and tetrabutylammonium
iodide (0.9 g, 3 mmol) were added. After 4 h, the reaction was
quenched by the slow addition of MeOH (15 mL) and ice (80
g). The mixture was extracted with CH2Cl2 (3 × 400 mL). The
combined organic layer was washed with water (250 mL), dried
(MgSO4), and concentrated in vacuo. Purification of the
residual product by silica gel chromatography (PE/EtOAc 95:
3.74 (d, 1H, J ) 11 Hz), 3.83 (d, 1H, J ) 11 Hz), 4.16 (d, 1H,
J ) 3.4 Hz), 4.37 (d, 1H, J ) 12 Hz), 4.53 (d, 1H, J ) 12 Hz),
4.58 (d, 1H, J ) 12 Hz), 4.60-4.69 (m, 3H), 4.68 (s, 1H), 4.86
(m, 1H), 7.15-7.31 (m, 15H), 7.79 (d, 1H, J ) 5 Hz); 13C NMR
(CDCl3) δ 26.8, 27.7, 65.0, 70.2, 72.1, 73.8, 82.3, 82.5, 84.7,
112.8, 114.8, 127.0, 127.3, 127.5, 127.7, 127.9, 128.3, 128.5,
128.6, 128.7, 137.4, 138.2, 138.4, 163.2.
Gen er a l P r oced u r e A: Syn th esis of (6R)-6-C-Alk yl-1,4-
di-O-ben zyl-6-ben zylam in o-6-deoxy-2,3-O-isopr opyliden e-
r-L-sor bofu r a n ose (14). To a 0.33 M solution of organolith-
ium reagent (3 equiv) or organomagnesium bromide reagent
(3 equiv) in anhydrous Et2O at -78 or at 0 °C, respectively,
was added slowly a 0.15 M solution of 13 (1 equiv) in
anhydrous Et2O. The mixture was then warmed slowly to 0
°C or to room temperature, respectively, and stirred for 3-12
h. The reaction was quenched by the slow addition of a
saturated aqueous NH4Cl at room temperature. The phases
were separated, the organic layer was dried (MgSO4), and
concentrated under reduced pressure. The product was puri-
fied by flash silica gel chromatography.
Gen er a l P r oced u r e B: Syn th esis of (6S)-6-C-Alk yl-1,4-
di-O-ben zyl-6-ben zylam in o-6-deoxy-2,3-O-isopr opyliden e-
r-L-sor bofu r a n ose (15). To a 0.06 M solution of 13 (1 equiv)
in anhydrous Et2O at -78 °C was added BF3‚Et2O (5 equiv).
After 10 min, a solution of organolithium reagent (3 equiv) or
organomagnesium bromide reagent (3 equiv) in anhydrous
Et2O or THF (1-3 M) was added to the imine solution. After
3 h at 0 °C, the reaction was quenched by the slow addition of
saturated aqueous NH4Cl. The phases were separated, and
the organic layer was dried (MgSO4) and concentrated under
reduced pressure. The product was purified by silica gel flash
chromatography.
5-85:15) afforded 10 (31.4 g, 99%) as a white crystalline
1
material: mp 46-48 °C; [R]20 +23.5 (c 1, CHCl3); H NMR
D
(CDCl3) δ 1.42 (s, 3H), 1.55 (s, 3H), 3.28 (dd, 1H, J ) 6.9, 9.1
Hz), 3.48 (dd, 1H, J ) 6, 9.4 Hz), 3.57 (d, 1H, J ) 11 Hz), 3.72
(d, 1H, J ) 11 Hz), 4.03 (d, 1H, J ) 3.1 Hz), 4.39 (d, 1H, J )
11.9 Hz), 4.46 (ddd, 1H, J ) 3.1, 5.9, 6.2 Hz), 4.50 (d, 1H, J )
12.2 Hz), 4.55 (d, 1H, J ) 11.9 Hz), 4.58 (s, 1H), 4.65 (d,
1H, J ) 12.2 Hz), 7.10 (m, 2H), 7.15-7.35 (m, 17H), 7.38-
7.50 (m, 6H); 13C NMR (CDCl3) δ 26.7, 27.8, 61.5, 70.3, 71.8,
73.6, 80.3, 81.7, 82.1, 87.0, 112.4, 114.0, 127.1, 127.5, 127.6,
127.7, 127.9, 128.4, 128.8, 137.8, 138.3, 144.1; MS m/z 643.5
(MH+).
1,4-Di-O-b en zyl-2,3-O-isop r op ylid en e-r-L-sor b ofu r a -
n ose (11). To a solution of 10 (4.2 g, 6.54 mmol) in acetic acid
(25 mL) was added a 33% (w/v) solution of HBr in acetic acid
(2 mL) at 10 °C. After 2-4 min at 10-15 °C, EtOAc (50 mL)
and cold aqueous NaHCO3 (50 mL) were added quickly to the
reaction mixture. The organic layer was separated, dried
(MgSO4), and concentrated in vacuo. Purification of the
residual product by silica gel chromatography (PE/EtOAc 4:1-
3:2) afforded 11 (2.51 g, 96%) as a colorless oil: [R]20 +33.5
D
(c 1, CHCl3); 1H NMR (CDCl3) δ 1.43 (s, 3H), 1.51 (s, 3H), 3.66
(d, 1H, J ) 11 Hz), 3.78 (d, 1H, J ) 11 Hz), 3.82 (dd, 1H, J )
4.9, 12 Hz), 3.89 (dd, 1H, J ) 5.4, 11.7 Hz), 4.03 (d, 1H, J )
3.4 Hz), 4.37 (dt, 1H, J ) 3.4, 5.3 Hz), 4.40 (d, 1H, J ) 12 Hz),
4.56 (d, 1H, J ) 12.2 Hz), 4.63 (d, 1H, J ) 12 Hz), 4.66 (s,
1H), 4.69 (d, 1H, J ) 11 Hz), 7.20-7.40 (m, 10H); 13C NMR
(CDCl3) δ 27.1, 28.0, 61.5, 70.6, 72.1, 74.0, 81.3, 82.4, 83.1,
112.8, 114.3, 128.0, 128.1, 128.5, 128.7, 129.0, 137.5, 138.5;
MS m/z 401.5 (MH+). Anal. Calcd for C23H28O6: C, 68.98; H,
7.05. Found: C, 69.08; H, 6.97.
(6R)-6-C-Allyl-1,4-d i-O-ben zyl-6-ben zyla m in o-6-d eoxy-
2,3-O-isop r op ylid en e-r-L-sor bofu r a n ose (14a ). Compound
13 (2 g, 4.1 mmol) was treated with allylmagnesium bromide
(12.3 mmol) according to general procedure A. Purification of
the crude product by silica gel chromatography (PE/AcOEt 3:1)
provided 14a (1.82 g, 84%) as a yellow oil: [R]20 -10 (c 1.2,
D
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 1.41 (s, 3H), 1.50 (s, 3H),
2.05 (m, 1H), 2.20 (m, 1H), 3.07 (ddd, 1H, J ) 6.8, 8.7, 14.2
Hz), 3.60 (d, 1H, J ) 11 Hz), 3.73 (d, 1H, J ) 11 Hz), 3.74 (d,
1H, J ) 12.5 Hz), 3.83 (d, 1H, J ) 12.5 Hz), 3.88 (d, 1H, J )
3.2 Hz), 4.16 (dd, 1H, J ) 3.2, 8.8 Hz), 4.36 (d, 1H, J ) 11.5
Hz), 4.55 (d, 1H, J ) 12.2 Hz), 4.64 (d, 1H, J ) 11.5 Hz), 4.66
(d, 1H, J ) 12.2 Hz), 4.67 (s, 1H), 5.01 (ddd, 2H, J ) 2.5, 7,
11.5 Hz), 5.84 (m, 1H), 7.22-7.29 (m, 15H); 13C NMR (CDCl3)
δ 26.8, 27.7, 34.9, 51.8, 55.5, 70.6, 71.4, 73.8, 81.5, 81.7, 83.5,
112.3, 113.6, 116.9, 126.9, 127.7, 128.0, 128.0, 128.4, 128.5,
128.6, 135.5, 137.5, 138.4; MS m/z 530.5 (MH+).
3,6-Di-O-ben zyl-4,5-O-isop r op ylid en e-D-xylo-a ld eh yd o-
h exos-5-u lo-2,5-fu r a n ose (12). To a solution of 11 (4.6 g, 11.5
mmol) in anhydrous CH2Cl2 (60 mL) was added a 15 wt %
Dess-Martin periodinane solution (26.3 mL, 12.65 mmol) in
CH2Cl2. After 30 min, aqueous NaOH (200 mL) and Et2O (400
mL) were added under vigorous stirring. The organic layer was
washed with aqueous NaOH (200 mL) and then with water
(100 mL), dried (MgSO4), and concentrated in vacuo. Purifica-
tion of the residual product by silica gel chromatography (PE/
EtOAc 8:2-1:1) afforded 12 (4.16 g, 91%) as a colorless oil:
(6R)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-C-bu tyl-6-d eoxy-
2,3-O-isop r op ylid en e-r-L-sor bofu r a n ose (14b). Compound
13 (1 g, 2.11 mmol) was treated with butyllithium (6 mmol)
according to general procedure A. Purification of the crude
product by silica gel chromatography (PE/AcOEt 3:1) provided
[R]20 +1 (c 1.02, CHCl3); IR (NaCl, neat) 1736 cm-1; 1H NMR
D
(CDCl3) δ 1.43 (s, 3H), 1.50 (s, 3H), 3.77 (d, 1H, J ) 11 Hz),
3.87 (d, 1H, J ) 11 Hz), 4.34 (d, 1H, J ) 3.8 Hz), 4.40 (d, 1H,
J ) 12 Hz), 4.55 (d, 1H, J ) 12 Hz), 4.58 (d, 1H, J ) 12 Hz),
4.63 (dd, 1H, J ) 1.5, 4.1 Hz), 4.68 (s, 1H), 4.71 (d, 1H, J ) 12
Hz), 7.17-7.32 (m, 10H), 9.61 (d, 1H, J ) 1.6 Hz); 13C NMR
(CDCl3) δ 26.4, 27.5, 69.7, 72.2, 73.7, 81.6, 83.9, 85.1, 113.0,
115.4, 127.6, 127.7, 128.1, 128.3, 128.4, 128.5, 136.4, 137.4,
14b (745 mg, 65%) as a yellow oil: [R]20 -16 (c 1.05, CHCl3);
D
1H NMR (CDCl3) δ 0.85 (t, 3H, J ) 6.5 Hz), 1.20-1.40 (m,
6H), 1.38 (s, 3H), 1.51 (s, 3H), 2.40 (d, 2H, J ) 5.6 Hz), 3.04
(dd, 1H, J ) 3.2, 12 Hz), 3.71 (d, 1H, J ) 12 Hz), 3.73 (d, 1H,
J ) 12.7 Hz), 3.81 (d, 1H, J ) 12 Hz), 3.82 (d, 1H, J ) 12.7
Hz), 3.92 (d, 1H, J ) 3.2 Hz), 4.23 (dd, 1H, J ) 3.2, 8.6 Hz),
4.38 (d, 1H, J ) 11.5 Hz), 4.67 (s, 1H), 4.71 (d, 1H, J ) 11.5
Hz), 7.20-7.32 (m, 15H); 13C NMR (CDCl3) δ 14.4, 23.4, 27.1,
27.8, 27.9, 30.2, 51.4, 58.8, 64.4, 72.0, 82.3, 82.4, 83.7, 112.3,
114.2, 127.3, 128.5, 128.7, 128.8, 128.9, 137.3, 140.8; MS m/z
546.5 (MH+). Anal. Calcd for C34H43NO5: C, 74.83; H, 7.94;
N, 2.57. Found: C, 74.42; H, 7.44; N, 2.68.
200.3; MS m/z 399.0 (MH+). Anal. Calcd for C23H26O6
0.5H2O: C, 67.80; H, 6.68. Found: C, 68.15; H, 6.70.
+
3,6-Di-O-ben zyl-4,5-O-isop r op ylid en e-D-xylo-a ld eh yd o-
h exos-5-u lo-2,5-fu r a n ose N-Ben zylim in e (13). To a solution
of 12 (3.6 g, 9.05 mmol) in anhydrous CH2Cl2 (45 mL) were
added powdered 4 Å molecular sieves (450 mg) and benzyl-
amine (1.04 mL, 9.5 mmol) at room temperature. After 3 h at
4 °C without stirring, the solids were removed by filtration
and washed with anhydrous CH2Cl2 (45 mL). The filtrate was
concentrated in vacuo to afford homogeneous 13 (4.38 g,
quant.) as a colorless oil: [R]20D +43 (c 1.07, CHCl3); IR (NaCl,
neat) 1672 cm-1; 1H NMR (CDCl3) δ 1.42 (s, 3H), 1.50 (s, 3H),
(6R)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-d eoxy-6-C-eth e-
n yl-2,3-O-isop r op ylid en e-r-L-sor bofu r a n ose (14c). Com-
pound 13 (500 mg, 1.05 mmol) was treated with vinylmagne-
sium bromide (3 mmol) according to general procedure A.
Purification of the crude product by silica gel chromatography
(PE/AcOEt 5:1) provided 14c (482 mg, 90%) as a yellow oil:
J . Org. Chem, Vol. 67, No. 20, 2002 6967

Godin et al.
[R]20D -23 (c 1.2, CHCl3); 1H NMR (CDCl3) δ 1.40 (s, 3H), 1.50
(s, 3H), 3.57 (t, 1H, J ) 8.1 Hz), 3.59 (d, 1H, J ) 13 Hz), 3.62
(d, 1H, J ) 11 Hz), 3.73 (d, 1H, J ) 11 Hz), 3.73 (d, 1H, J )
13 Hz), 3.85 (d, 1H, J ) 2.9 Hz), 4.21 (dd, 1H, J ) 2.9, 9.3
Hz), 4.34 (d, 1H, J ) 11.2 Hz), 4.53 (d, 1H, J ) 12.2 Hz), 4.55
(d, 1H, J ) 11.2 Hz), 4.65 (s, 1H), 4.66 (d, 1H, J ) 12.2 Hz),
5.21 (dd, 1H, J ) 1.7, 17.1 Hz), 5.31 (dd, 1H, J ) 1.9, 10.3
Hz), 5.39 (ddd, 1H, J ) 8.1, 10, 17.6 Hz), 7.19-7.59 (m, 15H);
13C NMR (CDCl3) δ 26.8, 27.7, 51.4, 60.4, 69.4, 70.8, 73.7, 81.5,
82.5, 82.9, 112.5, 114.0, 119.3, 126.8, 127.6, 127.7, 127.8, 128.2,
128.3, 128.4, 128.7, 136.4, 137.6, 138.2, 140.4; MS m/z 516.5
(MH+). Anal. Calcd for C32H37NO5: C, 74.54; H, 7.23; N, 2.72.
Found: C, 74.76; H, 7.30; N, 2.77.
(6S)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-C-bu tyl-6-d eoxy-
2,3-O-isop r op ylid en e-r-L-sor bofu r a n ose (15b). Compound
13 (825 mg, 1.7 mmol) was treated with BF3‚Et2O (8.5 mmol)
and butyllithium (5.1 mmol) according to general procedure
B. Purification of the crude product by silica gel chromatog-
raphy (PE/AcOEt 5:1 to 3:1) provided 15b (630 mg, 69%) as a
1
yellow oil: [R]20 +15 (c 1.4, CHCl3); H NMR (CDCl3) δ 0.87
D
(m, 3H), 1.10-1.70 (m, 6H), 1.46 (s, 3H), 1.51 (s, 3H), 3.13 (m,
1H), 3.64 (d, 1H, J ) 11 Hz), 3.74 (d, 1H, J ) 11 Hz), 3.85 (m,
2H), 4.19 (dd, 1H, J ) 2.8, 7.8 Hz), 4.40-4.70 (m, 6H), 7.0-
7.40 (m, 15H); 13C NMR (CDCl3) δ 23.1, 26.8, 27.4, 27.8, 30.8,
51.9, 55.4, 70.6, 71.8, 73.8, 81.5, 82.1, 112.3, 113.7, 127.4, 127.7,
127.8, 128.2, 128.5, 128.5, 128.6, 128.7, 128.8, 138.3; MS m/z
546.5 (MH+).
(6R)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-d eoxy-6-C-eth yl-
2,3-O-isop r op ylid en e-r-L-sor bofu r a n ose (14d ). Compound
13 (500 mg, 1.05 mmol) was treated with ethylmagnesium
bromide (3.15 mmol) according to general procedure A. Puri-
fication of the crude product by silica gel chromatography
(CH2Cl2/MeOH 99:1 to 95:5) provided 14d (410 mg, 75%) as a
yellow oil: [R]20D -11 (c 0.89, CHCl3); 1H NMR (CDCl3) δ 0.93
(t, 3H, J ) 7.4 Hz), 1.30-1.53 (m, 2H), 1.42 (s, 3H), 1.51 (s,
3H), 3.02 (ddd, 1H, J ) 6.1, 9.3, 10 Hz), 3.62 (d, 1H, J ) 11
Hz), 3.70 (d, 1H, J ) 13 Hz), 3.74 (d, 1H, J ) 11 Hz), 3.78 (d,
1H, J ) 13 Hz), 3.87 (d, 1H, J ) 2.7 Hz), 4.22 (dd, 1H, J )
2.9, 9 Hz), 4.34 (d, 1H, J ) 11.5 Hz), 4.52 (d, 1H, J ) 12.3
Hz), 4.55 (d, 1H, J ) 11.2 Hz), 4.67 (s, 1H), 4.66 (d, 1H, J )
12.2 Hz), 7.13-7.40 (m, 15H); 13C NMR (CDCl3) δ 10.2, 23.1,
27.2, 28.1, 51.6, 57.1, 70.9, 71.9, 74.1, 81.9, 82.4, 83.5, 112.5,
113.9, 127.1, 128.0, 128.0, 128.2, 128.3, 128.7, 128.8, 128.8,
128.8, 137.9, 138.7, 141.5; MS m/z 518.5 (MH+). Anal. Calcd
for C32H39NO5: C, 74.25; H, 7.59; N, 2.71. Found: C, 74.50;
H, 7.73; N, 2.84.
(6R)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-d eoxy-2,3-O-iso-
p r op ylid en e-6-C-(t r im et h ylsilylet h yn yl)-r-L-sor b ofu r a -
n ose (14e). To a solution of ethynyltrimethylsilane (580 µL,
4.1 mmol) in anhydrous Et2O (15 mL) was added at 0 °C a
solution of ethylmagnesium bromide in Et2O (1.18 mL, 3.54
mmol). The mixture was stirred at 40 °C for 1 h. Compound
13 (420 mg, 0.86 mmol) was then treated with the solution of
trimethylsilylethynylmagnesium bromide thus prepared ac-
cording to general procedure A. Purification of the crude
(6S)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-d eoxy-6-C-eth e-
n yl-2,3-O-isop r op ylid en e-r-L-sor bofu r a n ose (15c). Com-
pound 13 (830 mg, 1.7 mmol) was treated with BF3‚Et2O (6.13
mmol) and vinylmagnesium bromide (7 mmol) according to
general procedure B . Purification of the crude product by silica
gel chromatography (PE/AcOEt 5:1-1:1) provided 15c (635 mg,
72%) as a yellow oil: [R]20D +7 (c 2.1, CHCl3); 1H NMR (CDCl3)
δ 1.40 (s, 3H), 1.49 (s, 3H), 3.51 (t, 1H, J ) 8.3 Hz), 3.57 (d,
1H, J ) 13.1 Hz), 3.63 (d, 1H, J ) 11.2 Hz), 3.72 (d, 1H, J )
11.2 Hz), 3.78 (d, 1H, J ) 13.1 Hz), 4.09 (d, 1H, J ) 2.9 Hz),
4.13 (dd, 1H, J ) 3.2, 8.5 Hz), 4.43 (d, 1H, J ) 11.7 Hz), 4.55
(d, 1H, J ) 12.2 Hz), 4.62 (d, 1H, J ) 11.7 Hz), 4.65 (s, 1H),
4.66 (d, 1H, J ) 12.2 Hz), 5.22 (m, 2H), 5.77 (ddd, 1H, J )
7.8, 10.7, 18.6 Hz), 7.20-7.28 (m, 15H); 13C NMR (CDCl3) δ
27.0, 28.0, 51.4, 59.6, 70.6, 72.2, 73.9; 81.8, 82.0, 83.6, 112.5,
114.1, 118.2, 127.3, 127.8, 128.0, 128.1, 128.2, 128.5, 128.7,
128.9, 137.9, 138.7; 141.0; MS m/z 516.5 (MH+).
Gen er a l P r oced u r e C: Syn th esis of (1R)-1-C-Alk yl-N-
b en zyl-3,6-d i-O-b en zyl-1,5-d id eoxy-1,5-im in o-D-glu cit ol
(16). A ∼0.15 M solution of precursor 14 in trifluoroacetic acid
was prepared at 0 °C; H2O was then added to form a 9:1 (v/v)
TFA/H2O mixture. The reaction mixture was warmed to room
temperature and stirred for 20-30 h. The solvents were
removed by three coevaporations with toluene, and the re-
sidual product was taken up in MeOH to form a ∼0.05 M
solution. Acetic acid (1 equiv) and NaBH3CN (3 equiv) were
added at 0 °C. The reaction mixture was stirred for 24 h at
room temperature. The mixture was then concentrated under
reduced pressure. The crude product was taken up in CH2Cl2,
and the solution was washed with saturated aqueous NaHCO3
and then with water. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. The product (16)
was purified by silica gel chromatography.
product by silica gel chromatography (EP/AcOEt 4:1) provided
1
14e (300 mg, 60%) as a yellow oil: [R]20 -4 (c 1, CHCl3); H
D
NMR (CDCl3) δ 0.18 (s, 9H), 1.41 (s, 3H), 1.51 (s, 3H), 3.58 (d,
1H, J ) 11 Hz), 3.70 (d, 1H, J ) 11 Hz), 3.82 (d, 1H, J ) 13
Hz), 3.88 (d, 1H, J ) 9.5 Hz), 3.92-4.10 (m, 1H), 4.43 (dd, 1H,
J ) 2.9, 8.3 Hz), 4.46 (d, 1H, J ) 12 Hz), 4.53-4.62 (m, 2H),
4.60 (s, 1H), 4.61 (d, 1H, J ) 12 Hz), 7.13-7.40 (m, 15H);; 13
C
(1R)-1-C-Allyl-N-b en zyl-3,6-d i-O-b en zyl-1,5-d id eoxy-
1,5-im in o-D-glu citol (16a ) a n d Dia ceta te (17a ). Compound
14a (2.4 g, 4.53 mmol) was treated according to general
procedure C. Purification of the crude product by silica gel
chromatography (PE/AcOEt 3:1 to 2:1) provided 16a (1.6 g,
NMR (CDCl3) δ -0.06, 26.5, 27.5, 50.4, 51.3, 70.0, 73.0, 73.6,
81.5, 83.0, 83.1, 89.3, 103.6, 112.2, 114.5, 126.8, 127.5, 127.5,
127.7, 128.2, 128.3, 137.7, 138.1, 139.8; MS m/z 586.5 (MH+).
Anal. Calcd for C35H43NO5Si: C, 71.76; H, 7.40; N, 2.39.
Found: C, 72.01; H, 7.56; N, 2.55.
75%) as a yellow oil: [R]20 +24 (c 1.21, CHCl3); 1H NMR
D
(6S)-6-C-Allyl-1,4-d i-O-ben zyl-6-ben zyla m in o-6-d eoxy-
2,3-O-isop r op ylid en e-r-L-sor bofu r a n ose (15a ). Compound
13 (825 mg, 1.7 mmol) was treated with BF3‚Et2O (8.5 mmol)
and allylmagnesium bromide (5.1 mmol) according to general
procedure B. The isomers were separated by silica gel chro-
matography (PE/AcOEt 4:1). Isomer 6S (15a ) eluted first (300
(CDCl3, 500 MHz) δ 2.36 (m, 2H), 3.02 (dd, 1H, J ) 5.6, 8.1
Hz), 3.07 (ddd, 1H, J ) 13.7, 13.5, 4.6 Hz), 3.69 (d, 1H, J )
4.9 Hz), 3.70 (t, 1H, J ) 8.3 Hz), 3.71 (m, 2H), 3.79 (d, 1H, J
) 13.7 Hz), 3.86 (dd, 1H, J ) 4.9, 8.8 Hz), 4.42 (d, 1H, J )
11.7 Hz), 4.73 (d, 1H, J ) 11.7 Hz), 4.93 (d, 1H, J ) 11.7 Hz),
4.96 (d, 1H, J ) 10.3 Hz), 5.03 (dd, 1H, J ) 10.2, 17.1 Hz),
5.74 (ddd, 1H, J ) 7.8, 10.3, 17.0 Hz), 7.10-7.49 (m, 15H);
13C NMR (CDCl3) δ 29.7, 53.4, 58.1, 59.1, 65.4, 70.3, 72.8, 73.5,
74.6, 83.5, 115.9, 126.9-128.9, 132.1, 137.4, 137.8, 138.8; MS
m/z 474.5 (MH+). Compound 16a (1.3 g, 2.75 mmol) was
acetylated under standard conditions (acetic anhydride/pyri-
dine), and the crude diacetate was purified by silica gel
mg, 33%): yellow oil; [R]20 +24 (c 1.34, CHCl3); 1H NMR
D
(CDCl3) δ 1.41 (s, 3H), 1.50 (s, 3H), 2.33 (m, 1H), 2.46 (m, 1H),
3.18 (dd, 1H, J ) 5.6, 13.5 Hz), 3.60 (d, 1H, J ) 10.9 Hz), 3.73
(d, 1H, J ) 10.9 Hz), 3.72 (d, 1H, J ) 12.7 Hz), 3.91 (d, 1H, J
) 12.7 Hz), 4.10 (s, 1H), 4.13 (dd, 1H, J ) 3.1, 9.1 Hz), 4.44
(d, 1H, J ) 11.6 Hz), 4.55 (d, 1H, J ) 11.6 Hz), 4.64 (d, 1H, J
) 11.6 Hz), 4.68 (d, 1H, J ) 11.6 Hz), 4.66 (s, 1H), 5.04 (ddd,
2H, J ) 2.2, 7.8 Hz, 11 Hz), 5.75 (m, 1H), 7.22-7.29 (m, 15H);
13C NMR (CDCl3) δ 26.8, 27.8, 34.9, 51.7, 54.4, 70.5, 71.8, 73.8,
81.6, 81.9, 82.3, 112.2, 113.6, 118.3, 127.2, 127.7, 127.9, 128.0,
128.1, 128.3, 128.4, 128.5, 128.6, 134.5, 137.6, 138.2; MS m/z
530.5 (MH+). The second fraction contained homogeneous 14a
(80 mg, 9%).
chromatography (PE/AcOEt 4:1) to give 17a (1.53 g, quant)
1
as a yellow oil: [R]20 +26 (c ) 1.2, CHCl3); H NMR (CDCl3)
D
δ 1.89 (s, 3H), 1.95 (s, 3H), 2.24 (m, 1H), 2.37 (m, 1H), 3.19
(m, 2H), 3.58 (m, 2H), 3.80 (t, 1H, J ) 8.3 Hz), 3.96 (s, 2H),
4.33 (s, 2H), 4.62 (d, 1H, J ) 11.7 Hz), 4.66 (d, 1H, J ) 11.7
Hz), 4.96 (dd, 1H, J ) 1.5, 10.3 Hz), 4.99 (dd, 1H, J ) 1.5,
17.1 Hz), 5.15 (dd, 1H, J ) 5.4, 8.8 Hz), 5.23 (t, 1H, J ) 8.5
6968 J . Org. Chem., Vol. 67, No. 20, 2002

Synthesis of Nojirimycin C-Glycosides
Hz), 5.62 (ddd, 1H, J ) 6.8, 10.3, 17.1 Hz), 7.10-7.45 (m, 15H);
13C NMR (CDCl3) δ 21.2, 30.7, 52.6, 55.8, 56.0, 69.6, 71.4, 71.8,
73.2, 74.2, 78.6, 116.1, 126.0-128.5, 136.1, 138.0, 138.4, 140.1,
Hz), 3.88 (dd, 1H, J ) 2.9, 10.7 Hz); 13C NMR (D2O) δ 10.1,
17.4, 54.2, 57.3, 62.1, 72.4, 72.8, 74.4; HR-FABMS (relative
intensity) calcd for C8H18NO4 (MH+) m/z 192.12358, found
192.12314 (100).
170.0, 170.1; MS m/z 558.5 (MH+). Anal. Calcd for C34H39
-
NO6: C, 73.23; H, 7.05; N, 2.51. Found: C, 73.02; H, 7.15; N,
2.61.
(1S)-N-Ben zyl-3,6-d i-O-ben zyl-1,5-d id eoxy-1-C-eth en yl-
1,5-im in o-D-glu citol (20c). Compound 15c (150 mg, 0.29
mmol) was treated according to general procedure C, and the
resulting crude product mixture was filtered through silica gel
to afford 120 mg (90%) of a mixture of 20c and its L-ido epimer
(de 70%): 1H NMR (CDCl3, 500 MHz) δ 2.84 (ddd, 1H, J )
3.9, 4.4, 8.3 Hz), 3.14 (t, 1H, J ) 9.3 Hz), 3.22 (ddd, 0.15H, J
) 3.3, 5.4, 10.3 Hz), 3.30 (dd, 1H, J ) 3.9, 9.8 Hz), 3.44 (dd,
1H, J ) 3.4, 10.3 Hz), 3.55 (t, 1H, J ) 8.3 Hz), 3.75 (dd, 0.15H,
J ) 2.9, 6.3 Hz), 3.89 (d, 1H, J ) 16.1 Hz), 4.03 (d, 1H, J )
16.1 Hz), 4.14 (s, 2H), 4.60 (s, 2H), 5.00 (t, 0.15H, J ) 9.3 Hz),
5.06 (t, 1H, J ) 9.3 Hz), 5.12 (dd, 1H, J ) 1.5, 10.3 Hz), 5.20
(dd, 1H, J ) 1.5, 17.6 Hz), 5.26 (t, 1H, J ) 7.8 Hz), 5.66 (m,
1H), 7.17-7.40 (m, 15H); 13C NMR (CDCl3) δ (major product)
21.0, 21.2, 54.5, 68.5, 68.6, 71.4, 72.8, 73.0, 81.4, 119.7, 126.4-
128.6, 137.9, 138.1, 140.2; MS m/z 460.4 (MH+).
(1R)-N-Ben zyl-3,6-d i-O-b en zyl-1-C-b u t yl-1,5-d id eoxy-
1,5-im in o-D-glu citol (16b). Compound 14b (220 mg, 0.4
mmol) was treated according to general procedure C. Purifi-
cation of the crude product by silica gel chromatography
(PE/AcOEt 2:3) provided 16b (140 mg, 72%) as a yellow oil:
1H NMR (CDCl3) δ 0.85 (t, 3H, J ) 7.3 Hz), 1.16-1.28 (m,
4H), 1.53 (m, 2H), 2.30 (br s, 1H), 2.85 (m, 1H), 3.00 (br s,
1H), 3.08 (m, 1H), 3.52 (t, 1H, J ) 8.5 Hz), 3.70-3.96 (m, 6H),
4.12 (dd, 1H, J ) 7.3, 14 Hz), 4.44 (s, 2H), 4.74 (d, 1H, J )
11.4 Hz), 4.96 (d, 1H, J ) 11.3 Hz), 7.23-7.39 (m, 15H); 13C
NMR (CDCl3) δ 14.2, 14.3, 21.2, 22.8, 24.6, 29.4, 53.3, 57.3,
59.1, 60.5, 69.6, 71.5, 73.0, 73.6, 74.9, 84.3, 126.9, 127.8, 127.9,
127.9, 128.2, 128.3, 128.6, 128.7, 137.7, 139.0, 140.9; MS m/z
490.5 (MH+).
Gen er a l P r oced u r e D: Syn th esis of (1S)-1-C-Alk yl-1,5-
d id eoxy-1,5-im in o-D-glu citol. To a solution of precursor 15
(1 equiv) in MeOH were added 10% Pd/C (0.2 equiv) and two
drops of 5 N aqueous HCl. The flask was purged 3× with Ar
and then filled with H2. After 48 h, the solids were removed
by filtration, and the filtrate was concentrated under reduced
pressure. The crude intermediate was then dissolved in a 9:1
(v/v) mixture of trifluoroacetic acid and H2O (final concentrated
∼0.15 M). The reaction mixture was stirred for 18 h at room
temperature. The solvent was removed under reduced pressure
by coevaporation with toluene (3×), the residual product was
taken in MeOH (to a concentration of ∼0.05 M), and CH3-
COOH (1 equiv) and NaBH3CN (3 equiv) were added. After
12 h, the mixture was concentrated under reduced pressure.
The crude product was filtered through Amberlyst ion-
exchange resin IRA-400(OH-) (elution with H2O), and the
filtrate was concentrated under reduced pressure. The residual
product was purified by chromatography on Amberlyst ion-
exchange resin IR-120(H+) (loading, washing with H2O, elution
with aqueous ammonia (7.5% NH4OH)); the fractions contain-
ing the product were pooled and concentrated under reduced
pressure to afforded pure 1-C-alkyl-1,5-dideoxy-1,5-imino-D-
glucitol.
(1R )-2,4-D i-O -a c e t y l-N -b e n zy l-3,6-d i-O -b e n zy l-1,5-
d id eoxy-1-C-eth en yl-1,5-im in o-D-glu citol (17c). Compound
14c (370 mg, 0.72 mmol) was submitted to deprotection-
reductive amination according to general procedure C. The
resulting crude product (16c) was acetylated under standard
conditions, and the diacetate was purified by silica gel chro-
matography (PE/AcOEt 5:1-3:1), which provided 17c (280 mg,
72%) as a yellow oil: [R]20 + 33.6 (c ) 1.23, CHCl3); 1H NMR
D
(CDCl3) δ 1.86 (s, 3H), 1.90 (s, 3H), 3.16 (dt, 1H, J ) 3.9, 9.8
Hz), 3.51 (d, 2H, J ) 3.9 Hz), 3.59 (dd, 1H, J ) 5.4, 8.8 Hz),
3.68 (d, 1H, J ) 14.2 Hz), 3.76 (t, 1H, J ) 9.5 Hz), 4.08 (d, 1H,
J ) 14.2 Hz), 4.33 (d, 1H, J ) 11.7 Hz), 4.38 (d, 1H, J ) 11.7
Hz), 4.58 (d, 1H, J ) 11.7 Hz), 4.67 (d, 1H, J ) 11.7 Hz), 5.05
(dd, 1H, J ) 5.4, 9.8 Hz), 5.12 (dd, 1H, J ) 10.2, 17.1 Hz),
5.14 (t, 1H, J ) 9.8 Hz), 5.36 (dd, 1H, J ) 10.2, 17.1 Hz), 5.93
(ddd, 1H, J ) 8.8, 10.2, 17.1 Hz), 7.10-7.45 (m, 15H); 13C NMR
(CDCl3) δ 21.0, 52.7, 57.9, 59.8, 69.0, 72.1, 72.8, 73.2, 74.2,
79.1, 121.4, 126.0-128.7, 130.7, 137.9, 138.5, 139.7, 169.8,
170.1; MS m/z 544.5 (MH+). Anal. Calcd for C33H37NO6: C,
72.91; H, 6.86; N, 2.58. Found: C, 72.73; H, 6.98; N, 2.71.
(1R)-1-C-Bu tyl-1,5-d id eoxy-1,5-im in o-D-glu citol (18). To
a solution of 16b (60 mg, 0.12 mmol) in MeOH (4 mL) were
added 10% Pd/C (0.2 equiv) and two drops of 5 N aqueous HCl.
The flask was purged 3× with Ar and then filled with H2. After
48 h, the solids were removed by filtration, and the filtrate
was concentrated under reduced pressure. The crude product
was filtered through Amberlyst ion-exchange resin IRA-400
(OH-) (elution with H2O), and the filtrate was concentrated
under reduced pressure. The residual product was purified by
chromatography on Amberlyst ion-exchange resin IR-120(H+)
(loading, washing with H2O, elution with aqueous ammonia
(7.5% NH4OH)); the fractions containing the product were
pooled and concentrated under reduced pressure to afforded
(1S)-1-C-Bu t yl-1,5-d id eoxy-1,5-im in o-D-glu cit ol (22).
Compound 15b (170 mg, 0.31 mmol) was submitted to general
procedure D, which provided 22 (41 mg, 60%) as a colorless
1
oil: [R]20 +2 (c ) 1.4, H2O); H NMR (CD3OD) δ 0.90 (t, 3H,
D
J ) 6.3 Hz), 1.20-1.40 (m, 5H), 1.80-1.90 (m, 1H), 2.36 (m,
1H), 2.52 (m, 1H), 2.94 (t, 1H, J ) 9.2 Hz), 3.06 (t, 1H, J ) 9.4
Hz), 3.17 (t, 1H, J ) 9.2 Hz), 3.46 (dd, 1H, J ) 8.2, 11 Hz),
3.90 (dd, 1H, J ) 2.8, 10.7 Hz); 13C NMR (CD3OD) δ 14.4, 24.0,
29.0, 32.6, 60.7, 62.4, 63.6, 73.7, 76.6, 80.6; HR-FABMS
(relative intensity) calcd for C10H22NO4 (MH+) m/z 220.1550,
found 220.1548 (100).
pure 18 (21 mg, 77%) as a colorless oil: [R]20 +50 (c ) 0.13,
D
H2O); 1H NMR (D2O, 500 MHz) δ 0.91 (t, 3H, J ) 6.6 Hz),
1.1-1.49 (m, 4H), 1.50-1.70 (m, 2H), 2.92 (ddd, 1H, J ) 3,
6.6, 9.8 Hz), 3.23 (ddd, 1H, J ) 4.6, 5.5, 9.8 Hz), 3.28 (dd, 1H,
J ) 9.5, 9.8 Hz), 3.58 (dd, 1H, J ) 9.5, 9.8 Hz), 3.64 (dd, 1H,
J ) 6.6, 12 Hz), 3.69 (dd, 1H, J ) 5.4, 9.8 Hz), 3.88 (dd, 1H, J
) 2.9, 11.7 Hz); 13C NMR (D2O) δ 13.7, 22.4, 24.1, 28.2, 54.7,
55.9, 61.3, 71.7, 72.3, 74.1. HR-FABMS (relative intensity)
calcd for C10H22NO4 (MH+) m/z 220.1550, found 220.1550 (100).
(1R)-1,5-Did eoxy-1-C-et h yl-1,5-im in o-D-glu cit ol (19).
Compound 14d (300 mg, 0.58 mmol) was submitted to depro-
tection-reductive amination according to general procedure
C. The resulting crude iminoalditol 16d was then debenzylated
and purified as described for 18, which provided 19 (49 mg,
45%) as a colorless oil: [R]20D +52 (c 1.15, H2O); 1H NMR (D2O,
500 MHz) δ 0.95 (t, 3H, J ) 7.5 Hz), 1.50 (m, 1H), 1.70 (m,
1H), 2.70 (ddd, 1H, J ) 3.4, 8.3, 10.7 Hz), 2.91 (ddd, 1H, J )
3.9, 5.4, 9.3 Hz), 3.10 (t, 1H, J ) 9.3 Hz), 3.45 (t, 1H, J ) 9.3
Hz), 3.49 (dd, 1H, J ) 7.8, 10.7 Hz), 3.60 (dd, 1H, J ) 5.4, 9.3
(1S)-1-C-E t h yl-1,5-d id eoxy-1,5-im in o-D-glu cit ol (23).
Compound 15c (146 mg, 0.28 mmol) was submitted to general
procedure D, which provided 23 (33 mg, 62%) as a colorless
1
oil: [R]20 -2 (c ) 0.3, H2O); H NMR (CD3OD) δ 1.02 (t, 3H,
D
J ) 7.6 Hz), 1.66 (m, 1H), 1.96 (m, 1H), 2.89 (m, 1H), 3.03 (m,
1H), 3.31 (m, 2H), 3.50 (t, 1H, J ) 9.5 Hz), 3.86 (m, 2H); 13C
NMR (CD3OD) δ 10.5, 23.9, 58.7, 61.8, 62.1, 69.1, 72.8, 78.2;
HR-FABMS (relative intensity) calcd for C8H18NO4 (MH+) m/z
192.12358, found 192.12389 (23).
(6S)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-d eoxy-2,3-O-iso-
p r op ylid en e-6-C-d iet h ylp h osp h on o-r-L-sor b ofu r a n ose
(24a ). Trimethylsilyl chloride (360 µL, 2.85 mmol) was added
to a mixture of diethyl phosphite (360 µL, 2.85 mmol) and
triethylamine (400 µL, 2.85 mmol) in anhydrous CH2Cl2 (24
mL) at 0 °C. The reaction mixture was stirred for 15 min, and
then 13 (1 g, 2.05 mmol) in anhydrous CH2Cl2 (12 mL) was
added at room temperature. The reaction was warmed to 40
°C during 45 min. The reaction mixture was diluted with
J . Org. Chem, Vol. 67, No. 20, 2002 6969

Godin et al.
CH2Cl2 and washed with 2 M NaOH (2×) and water. The
organic layer was dried (MgSO4) and concentrated under
reduced pressure to provided homogeneous 24a (1.17 g, 91%)
as a yellow oil. For analysis, a small amount of 24a was
NMR (CDCl3) δ 16.3, 26.6, 27.6, 53.2 (d, J ) 160.5 Hz), 53.5,
53.6, 62.4, 70.3, 71.7, 73.6, 80.0, 81.7, 82.6, 112.3, 113.2, 126.7,
127.3, 127.5, 127.5, 128.1, 128.3, 128.3, 128.6, 137.8, 138.1,
140.1; 31P NMR (121.5 MHz, CDCl3{1H}) δ 24.02 (s, 1P), 25.82
(s, 0.082P) de ) 86%; MS m/z 626.5 (MH+). Anal. Calcd for
purified by silica gel chromatography (PE/AcOEt 2:1): [R]20
D
-3.4 (c 1.65, CHCl3); 1H NMR (CDCl3) δ 1.29 (m, 6H), 1.42 (s,
3H), 1.52 (s, 3H), 2.34 (br s, 1H), 3.45 (d, 1H, J ) 7.6 Hz), 3.50
(d, 1H, J ) 7.8 Hz), 3.65 (d, 1H, J ) 11 Hz), 3.77 (d, 1H, J )
11 Hz), 3.85 (d, 1H, J ) 13 Hz), 3.97 (d, 1H, J ) 13 Hz),
4.08-4.18 (m, 4H), 4.29 (d, 1H, J ) 2.8 Hz), 4.50 (ddd, 1H, J
) 2.8, 4, 10.4 Hz), 4.53 (d, 1H, J ) 12.3 Hz), 4.57 (d, 1H, J )
4.7 Hz), 4.62 (d, 1H, J ) 1.6 Hz), 4.65 (d, 1H, J ) 12.3 Hz),
7.21-7.27 (m, 15H); 13C NMR (CDCl3) δ 16.3 (d, J ) 5.9 Hz),
26.6, 27.6, 53.2 (d, J ) 151.3 Hz), 53.5, 53.6, 62.4, 70.3, 71.7,
73.6, 80.0, 81.7, 82.6, 112.3, 113.2, 126.7, 127.3, 127.5, 127.5,
128.1, 128.3, 128.3, 128.6, 137.8, 138.1, 140.1; 31P NMR (121.5
MHz, CDCl3{1H}) δ 25.82 (s); MS m/z 626.5 (MH+). Anal. Calcd
for C34H44NO8P: C, 65.27; H, 7.09, N, 2.24; P, 4.95. Found:
C, 65.13; H, 7.16; N, 2.29; P, 5.07.
C
34H44NO8P: C, 65.27; H, 7.09, N, 2.24. Found: C, 64.56; H,
7.21; N, 2.30.
(1S)-1-C-Dieth ylp h osp h on o-1-d eoxyn ojir im ycin (25).
To a solution of 24a (100 mg, 0.16 mmol) in TFA/H2O 9:1 (3
mL) was added 10% Pd/C (0.2 equiv). The flask was purged
three times with argon and then filled with H2. After 70 h,
the crude mixture was filtered using MeOH, and the filtrate
was concentrated under reduced pressure. The crude product
was filtered through Amberlyst ion-exchange resin IRA-400
(OH-) (elution with H2O), and the filtrate was concentrated
under reduced pressure to provided 25 (33 mg, 70%) (de 80%)
as a colorless oil: 1H NMR (CD3OD) δ 1.32 (t, 6H, J ) 7.1
Hz), 2.53 (dt, 1H, J ) 3, 11 Hz), 2.90 (dd, 1H, J ) 10, 11.7
Hz), 3.07 (t, 1H, J ) 9 Hz), 3.20 (dt, 1H, J ) 1.2, 8.8 Hz), 3.43
(dd, 1H, J ) 2.9, 8.6 Hz), 3.49 (t, 1H, J ) 9 Hz), 3.90 (dd, 1H,
J ) 3.2, 11 Hz), 4.17 (m, 4H); 13C NMR (CD3OD) δ 16.7 (d, J
) 5.4 Hz), 58.0 (d, J ) 158.1 Hz), 63.3, 63.5, 63.6, 64.2-64.5,
72.9 (d, J ) 5.4 Hz), 73.4, 80.8 (d, J ) 19.4 Hz); 31P NMR (121.5
MHz, CD3OD{1H}) δ 25.63 (s, 1P), 26.58 (s, 0.11P); HR-FABMS
(relative intensity) calcd for C10H23NO7P (MH+) m/z 300.12121,
found 300.12050 (100).
(6R)-1,4-Di-O-ben zyl-6-ben zyla m in o-6-d eoxy-2,3-O-iso-
p r op ylid en e-6-C-d iet h ylp h osp h on o-r-L-sor b ofu r a n ose
(24b). To a solution of 13 (490 mg, 1 mmol) were added diethyl
phosphite (175 µL, 1.36 mmol) and ZrCl4 (27 mg, 0.11 mmol)
in anhydrous CH3CN (3 mL), at 0 °C. The reaction mixture
was stirred for 1.5 h at room temperature. Water (5 mL) was
added, and the product was extracted in CH2Cl2 (2×). The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. A 31P NMR spectrum taken before
purification indicated a de of 80%. Purification of the crude
product by silica gel chromatography (PE/AcOEt 3:1-2:1)
Ack n ow led gm en t. G.G. thanks the CNRS and the
council of Re´gion Centre for a fellowship.
provided 24b (475 mg, 76%) as a colorless oil: [R]20 -15 (c 1,
D
CHCl3); 1H NMR (CDCl3) δ 1.29 (m, 6H), 1.42 (s, 3H), 1.53 (s,
3H), 2.33 (br s, 1H), 3.62 (d, 1H, J ) 9.7 Hz), 3.64 (d, 1H, J )
11 Hz), 3.66 (d, 1H, J ) 9.7 Hz), 3.80 (d, 1H, J ) 11 Hz), 4.00
(d, 1H, J ) 14 Hz), 4.12 (d, 1H, J ) 14 Hz), 4.13-4.30 (m,
4H), 4.58 (d, 1H, J ) 12.3 Hz), 4.58-4.72 (m, 3H), 4.71 (d,
1H, J ) 12.3 Hz), 4.73 (s, 1H), 7.14-7.35 (m, 15H); 13C
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for selected compounds (10, 13, 14a , 15a , 16b, 17c,
18, 19, and 22-25). This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0203903
6970 J . Org. Chem., Vol. 67, No. 20, 2002