Highly stereocontrolled synthesis of gem-difluoromethylenated azasugars: D- and L-1,4,6-trideoxy-4,4-difluoronojirimycin

Article abstract of DOI:10.1021/ol050558h

(Chemical Equation Presented) D-1,4,6-Trideoxy-4,4-difluoronojirimycin and L-1,4,6-trideoxy-4,4-difluoronojirimycin, a novel series of gem-4,4- difluoromethylenated azasugars, were synthesized from CF₃CH ₂OH in 10 steps. A key step w

Full text of DOI:10.1021/ol050558h

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2189-2192
Highly Stereocontrolled Synthesis of
gem-Difluoromethylenated Azasugars:
D- and
L
-1,4,6-Trideoxy-4,4-difluoronojirimycin
Ruo-Wen Wang† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, and College
of Chemistry and Chemical Engineering, Donghua UniVersity, 1882 West Yanan Lu,
Shanghai 200051, China
flq@mail.sioc.ac.cn
Received March 15, 2005
ABSTRACT
D-1,4,6-Trideoxy-4,4-difluoronojirimycin and L-1,4,6-trideoxy-4,4-difluoronojirimycin, a novel series of gem-4,4-difluoromethylenated azasugars,
were synthesized from CF3CH2OH in 10 steps. A key step was the highly diastereoselective construction of the piperidine ring via reductive
amination.
Azasugars (iminosugars) are polyhydroxylated piperidines
that frequently act as strong and specific inhibitors of
carbohydrate-processing enzymes (i.e., glycosidases and
glycotransferases).1 Notable in this category are natural
1-deoxynojirimycin (DNJ) 1 and L-1-deoxyfuconojirimycin
2 (Figure 1), both of which are excellent inhibitors of
glucosidase and fucosidase, respectively.2 Since glycosidases
are essential for the normal cellular development of all
organisms, azasugars have tremendous potential as thera-
peutic agents in a wide range of diseases.3 For example,
N-butyl-1-DNJ (Zavesta) 3 and N-hydroxyethyl-DNJ (Migli-
tol) 4 (Figure 1) have both been approved as medicines.4
Fucosyltransferases are involved in a number of essential
physiological or pathological processes such as fertilization,
cancer, and apoptosis;5 thus they have been valid targets for
* To whom correspondence should be addressed. Fax: 86-21-64166128.
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
(1) (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. ReV. 2000, 100,
4683-4696. (b) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38,
2301-2324.
(2) (a) Reese, E. T.; Parrish, F. W.; Ettlinger, M. Carbohydr. Res. 1971,
18, 381-388. (b) Fleet, G. W. J.; Shaw, A. N.; Evans, S. V.; Fellows, L.
E. F. J. Chem. Soc., Chem. Commun. 1985, 841-842.
Figure 1. Structures of compounds 1-4.
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the development of potent inhibitors. With regard to the
development of new inhibitors, much effort has been devoted
to the synthesis and structural modification of 1,6 but only
several azasugars have been shown to possess fucosidase or
fucosyltransferase inhibitory activity.7 We therefore decided
to design new potential inhibitors of fucosyltransferases by
structural modification of compound 2, since 2 has proved
to be an excellent inhibitor of both fucosidases and
fucosyltransferases.2b,5a According to past structure-activity
relationships for various azasugars,4,8 both the C2-OH and
the C3-OH groups are important for a good inhibitor binding
to the carbohydrate-processing enzymes, whereas the C4-
OH group is not essential for biological activity. We
wondered if the presence of a CF2 group in the C-4 position
of the piperidine would affect the biological activity of the
interesting analogues D-1,4,6-trideoxy-4,4-difluoronojirimy-
cin 5 and L-1,4,6-trideoxy-4,4-difluoronojirimycin 6 (Figure
2).
have ever been reported because of the difficulties of their
synthesis. Herein, we report a concise and highly stereocon-
trolled route to D-1,4,6-trideoxy-4,4-difluoronojirimycin 5
and L-1,4,6-trideoxy-4,4-difluoronojirimycin 6 using Percy’s
method.
Recently Percy has developed methodologies for prepara-
tion of gem-difluoromethylenated compounds from trifluo-
roethanol via [2,3]-Wittig rearrangement of difluoroallylic
ethers.10 He also described that the Sharpless asymmetric
dihydroxylation (AD) of gem-difluoromethylenated olefins
led to gem-difluoromethylenated analogues of carbohy-
drates.11 We were interested in extending Percy’s reaction
for the synthesis of target molecules 5 and 6. Accordingly,
the synthesis of azasugar 5 and 6 began from trifluoroethanol
(Scheme 1), which was initially protected with MEMCl.
Scheme 1. Preparation of Alcohol 9
Figure 2. Design of gem-difluoromethylenated azasugars 5 and
6.
Treatment with 2 equiv of LDA then brought about elimina-
tion and vinyl anion formation. Addition of an approximately
0.6 M solution of monomeric formaldehyde gave alcohol
7,10a which was purified by vacuum distillation on multigram
scale. Alcohol 7 was then converted to its O-allyl ether 8,
and a sigmatropic rearrangement of this compound was
brought about by adding its THF solution to 2.2 equiv
solution of LDA in THF at -78 °C. Alcohol 9 was obtained
in 32% yield from trifluoroethanol (four steps).10b
Many fluorinated azasugars have been prepared for the
biochemical investigations of azasugars; most of these have
been monofluorinated compounds bearing a fluorine at C-2
or C-3.9 Only a few gem-difluoromethylenated azasugars
(3) (a) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.;
Namgoong, S. K.; Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc.
Natl. Acad. Sci., U.S.A. 1988, 85, 9229-9233. (b) Goss, P. E.; Baker, M.
A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935-944. (c)
Karlsson, G. B.; Butters, T. D.; Dwek, R. A.; Platt, F. M. J. Biol. Chem.
1993, 268, 570-576.
(4) Butters, T. D.; Dwek, R. A.; Platt, F. M.Curr. Top. Med. Chem. 2003,
3, 561-574.
(5) (a) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541-
560. (b) Staudacher, E.; Altmann, F.; Wilson, I. B. H. Biochim. Biophys.
Acta 1999, 1473, 216-236.
With alcohol 9 in hand, initial effort was focused on the
separation of the enantiomer 9 by transesterification-based
enzymatic resolution12 and kinetic resolution via Sharpless
epoxidation,13 but this turned out to be unsuccessful.14
(6) For representarive examples, see: (a) McDonnell, C.; Cronin, L.;
O’Brien, J. L.; Murphy, P. V. J. Org. Chem. 2004, 69, 3565-3568. (b)
Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Org. Lett. 2003, 5, 2527-
2529. (c) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401-404.
(d) Xu, Y.-M.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1997, 741-
746. (e) Rudge, A. J.; Collins, I.; Holmes, A. B.; Baker, R. R. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2320-2322. (f) Kajimoto, T.; Liu, K. K. C.;
Pederson, R. L.; Zhong, Z. Y.; Ichikawa, Y.; Porco, J. A.; Wong, C.-H. J.
Am. Chem. Soc. 1991, 113, 6187-6196. (g) Kajimoto, T.; Chen, L.; Liu,
K. C.; Wong, C.-H. J. Am. Chem. Soc. 1991, 113, 6678-6680. For reviews,
see: (h) Cipolla, L.; Ferla, B. L.; Nicotra, F. Curr. Top. Med. Chem. 2003,
3, 485-511. (i) Ganem, B. Acc. Chem. Res. 1996, 29, 340-347.
(7) (a) Wong, C.-H.; Dumas, D. P.; Ichikawa, Y.; Koseki, K.; Danishef-
sky, S. J.; Weston, B. W.; Lowe, J. B. J. Am. Chem. Soc. 1992, 114, 7321-
7322. (b) Jefferies, I.; Bowen, B. R. Bioorg. Med. Chem. Lett. 1997, 7,
1171-1174. (c) Qiao, L.; Murray, B. W.; Shimazaki, M.; Schultz, J.; Wong,
C.-H. J. Am. Chem. Soc. 1996, 118, 7653-7662. (d) Liu, H.; Liang, X.;
Søhoel, H.; Bulow, A.; Bols, M. J. Am.Chem. Soc. 2001, 123, 5116-5117.
(e) Mitchell, M. L.; Tian, F.; Wong, C.-H. Angew. Chem., Int. Ed. 2002,
41, 3041-3044.
(9) (a) Arnone, A.; Bravo, P.; Donadelli, A.; Resnati, G. J. Chem. Soc.,
Chem. Commun. 1993, 984-986. (b) Lee, C.-K.; Jiang, H.; Koh, L. L.;
Xu, Y. Carbohydr. Res. 1993, 239, 309-315. (c) Reymond, J.-L.; Pinkerton,
A. A.; Vogel, P. J. Org. Chem. 1991, 56, 2128-2135. (d) Kim, D.-K.;
Kim, G.; Kim, Y.-W. J. Chem. Soc., Perkin Trans. 1 1996, 803-808. (e)
Kilonda, A.; Compernolle, F.; Hoornaert, G. J. J. Org. Chem. 1995, 60,
5820-5824. (f) Arnone, A.; Bravo, P.; Donadelli, A.; Resnati, G.
Tetrahedron 1996, 52, 131-142. (g) Szarek, M. A.; Wu, X.; Szarek, W.
A. Carbohydr. Res. 1997, 299, 165-170.
(10) (a) Patel, S. T.; Percy, J. M.; Wilkes, R. D. Tetrahedron 1995, 51,
9201-9216. (b) Patel, S. T.; Percy, J. M.; Wilkes, R. D. J. Org. Chem.
1996, 61, 166-173. (c) Kariuki, B. M.; Owton, W. M.; Percy, J. M.; Pintat,
S.; Smith, C. A.; Spencer, N. S.; Thomas, A. C.; Watson, M. Chem.
Commun. 2002, 228-229. (d) Broadhurst, M. J.; Brown, S. J.; Percy, J.
M.; Prime, M. E. J. Chem. Soc., Perkin Trans. 1 2000, 3217.
(11) (a) Cox, L. R.; DeBoos, G. A.; Fullbrook, J. J.; Percy, J. M.; Spencer,
N. S.; Tolley, M. Org. Lett. 2003, 5, 337-339. (b) Audouard, C.; Fawcett,
J.; Griffith, G. A.; Kerouredan, E.; Miah, A.; Percy, J. M.; Yang, H. Org.
Lett. 2004, 6, 4269-4272.
(8) Butters, T. D.; Broek, L. A. G. M.; van den; Fleet, G. W. J.; Krulle,
T. M.; Wormald, M. R.; Dwek, R. A.; Platt, F. M. Tetrahedron: Asymmetry
2000, 11, 113-124.
(12) (a) Otera, J. Chem. ReV. 1993, 93, 1449-1470. (b) Burgess, K.;
Lee, D. J. J. Am. Chem. Soc. 1991, 113, 6129-6139.
2190
Org. Lett., Vol. 7, No. 11, 2005

Alcohol 9 was therefore converted to the mesylated product
10 by treatment with mesyl chloride and Et3N in CH2Cl2 at
room temperature. When a mixture of 10, NaN3, and catalytic
Pd(PPh3)4 was stirred for 10 h in THF/H2O (4:1) at room
temperature, a smooth and regioselective Pd(0)-catalyzed
allylic substitution took place and azide 11 was obtained as
a clear liquid in 96% yield. Conversion of the azide 11 into
the N-Cbz-amine 12 was accomplished by treatment with
PPh3 in dry THF followed by hydrolysis of the intermediary
phosphoryl imine and addition of CbzCl. The N-protected
amine 12 was obtained in 90% yield (Scheme 2).
with good ee’s (82-84%) using either (DHQ)2PHAL or
(DHQD)2PHAL as the ligand, respectively (Scheme 4).
Scheme 4. Preparation of 16 and 17 by AD Reactions
Scheme 2. Synthesis of Imine 12
Careful analysis of 16 and 17 revealed that these products
were contaminated with MeSO2NH2 in the ratio of 2:1. This
1
finding was supported by H NMR from the chemical shift
and the integral (3.10 ppm, 3/2 H) of the Me of MeSO2-
NH2. Moreover, IR spectroscopy confirmed the existence of
sulfamide (1329, 1152 cm-1). On the basis of these data and
combustion microanalytical data, we believe that a sandwich
structure has been created that is held together by weak
hydrogen bonds (Figure 3).
Initially we planned to prepare 14 and 15 directly by the
Sharpless asymmetric dihydroxylation (AD) of compound
13. Therefore, compound 12 was treated with SOCl2 in CH3-
OH to obtain ketone 13 in 88% yield. Then the AD of 13
was carried out. As a result of the strong electron-withdraw-
ing effect of the CF2 group, the reaction occurred slowly to
give cyclic hemiketals 14 and 15 in low enantiomeric
excesses (ee’s) (47-62%) (Scheme 3).
Figure 3. Sandwich structure of compound 17 with MeSO2NH2.
Scheme 3. Preparation of 14 and 15 from 13
Treatment of diol 16 with SOCl2 in CH3OH for about 12
h followed by the removal of CH3OH in vacuo provided a
Scheme 5. Preparation of Azasugars 5 and 6
Fortunately, the AD reaction of compound 12 could be
carried out selectively and diols 16 and 17 were obtained
(13) (a) Finn, M. G.; Sharpless, K. B. In Asymmetric Synthesis; Morrison,
J. D., Ed.; Academic Press: New York, 1985. (b) Martin, V. S.; Woodard,
S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem.
Soc. 1981, 103, 6237-6240.
(14) When 9 was subject to the standart conditions of transesterification-
based enzymatic resolution and kinetic epoxidation resolution, no reaction
was observed.
Org. Lett., Vol. 7, No. 11, 2005
2191

Figure 4. Demonstration of diastereoselective hydrogenation.
residue. The residue was dissolved in ethyl acetate and
washed with saturated aqueous K2CO3. Then ethyl acetate
was removed in vacuo, and the residue was mixed with 10%
Pd/C in methanol and hydrogenated at 80 psi of H2 for 12
h. The desired azasugar 5 was obtained as a white solid in
43% yield (two steps). Following the same procedure,
azasugar 6 was obtained from diol 17 in 46% yield (two
steps) (Scheme 5).
Figure 5. ORTEP drawing of the X-ray crystallographic structure
of 6.
The hydrogenation showed excellent diastereoselectivity.
No diastereomer has ever been detected by 19F NMR
immediately after the reaction. The diastereoselectivity of
the hydrogenation reaction, as depicted by Wong,6g can be
rationalized by invoking intermediates 19 and 20 (Figure 4).
Taking intermediate 19 as an example, an axial attack of
hydrogen from the top face is hindered by the C4 fluorine
on the six-membered ring. Therefore, attack exclusively
occurs from the bottom face, thus leading to the desired
product 5.
The relative configuration of azasugar 6 was determined
by X-ray crystallography (Figure 5). The diastereoselectivity
of the hydrogenation was also confirmed by this result.
In conclusion, we have designed and completed a 10-step
synthesis of D-1,4,6-trideoxy-4,4-difluoronojirimycin 5 in
7.0% overall yield and L-1,4,6-trideoxy-4,4-difluoronojiri-
mycin 6 in 6.3% overall yield from trifluoroethanol.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China, Ministry of Education of China,
and Shanghai Municipal Scientific Committee for funding
this work.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H NMR spectra for all
new compounds; crystallographic data for compound 6 in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
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