Divergent approach to imino sugar C-glycosides using imino glycals: Application to the stereocontrolled synthesis of (+)-deoxoprosophylline

Article abstract of DOI:10.1039/b110035a

Tri-O-acetyl imino glucal 2 is readily made and shown to undergo a variety of Lewis acid mediated carbon-carbon bond forming reactions at C-1 of the piperidine nucleus. In all the reactions studied, the β-anomer is predominant.

Full text of DOI:10.1039/b110035a

Divergent approach to imino sugar C-glycosides using imino glycals:
application to the stereocontrolled synthesis of (+)-deoxoprosophylline
Paul J. Dransfield,a Paul M. Gore,b Michael Shipmana* and Alexandra M. Z. Slawinc
a School of Chemistry, University of Exeter, Exeter, Devon, UK EX4 4QD. E-mail: m.shipman@exeter.ac.uk;
Fax: +44 1392 263434, Tel: +44 1392 263469
b GlaxoSmithKline, Medicines Research Centre, Stevenage, UK SG1 2NY
c
School of Chemistry, University of St. Andrews, Purdie Building, St. Andrews, Fife, UK KY16 9ST
Received (in Cambridge, UK) 5th November 2001, Accepted 3rd December 2001
First published as an Advance Article on the web 9th January 2002
Tri-O-acetyl imino glucal 2 is readily made and shown to
undergo a variety of Lewis acid mediated carbon–carbon
bond forming reactions at C-1 of the piperidine nucleus. In
all the reactions studied, the b-anomer is predominant.
aluminium hydride as reducing agent, this provided 5 as an
inseparable 77+23 mixture of isomers in favour of the required
(6R)-diastereoisomer. Whilst stereocontrolled reduction in
favour of this diastereomer might be expected on the basis of
literature precedent,3,4 this assignment was later confirmed by
an X-ray crystal structure of a derived imino sugar (vide infra).
After the PMB ether protecting groups had been changed to
acetates, triacetate 6 could be separated from its C-6 epimer by
preparative MPLC. Completion of the synthesis of 2 was then
achieved by ozonolytic cleavage of the terminal double bond of
diastereomerically pure 6, followed by dehydration of the
resulting hemiacetal using oxalyl chloride.
Imino glucal 2 participates in a wide variety of Lewis acid
mediated C–C bond forming reactions by allylic displacement
of the C-3 acetate group. Treatment of 2 with allyl trimethylsi-
lane and BF3·Et2O at 250 °C provides, after Fmoc deprotec-
tion, piperidine 7a in 78% yield along with small amount of
the readily separable a-anomer 8a (eqn. (1) and Table 1).‡
3,4,6-Tri-O-acetyl -glucal 1 is an extremely useful starting
D
material for the preparation of monosaccharides, oligosacchar-
ides and other enantiomerically enriched organic molecules
(Fig. 1). Significantly, as well as participating in simple addition
reactions across the glycal double bond, the presence of a good
leaving group at C-3 facilitates SNA reactions allowing for the
introduction of a wide variety of nucleophiles at C-1 of the sugar
nucleus with concomitant migration of the double bond.1 As
part of our ongoing studies to devise general methods for the
assembly of imino sugars, important inhibitors of the glycosi-
dase enzymes,2 we wondered whether an aza analogue of 1 such
as tri-O-acetyl imino glucal 2 might behave similarly, and hence
provide a convenient route to a diverse range of C-1 substituted
imino sugars.3 In this communication, we describe the success-
ful preparation of 2 and demonstrate that it can be used in a
number of C–C bond forming reactions at C-1 of the piperidine
nucleus.
(1)
Table 1 Lewis acid mediated additions to imino glycal 2
c
Entry Conditionsa,b
b+a
Products (% yield)d
1
2
3
4
H2CNCHCH2SiMe3, BF3·Et2O
Et2Zn, BF3.Et2O
H2CNC(OSiMe3)Ph, BF3·Et2O
Methylenecyclohexane, SnBr4
79+21
67+33
62+38
86+14
7a (78); 8a (18)
7b (63); 8b (27)
7c (64); 8c (31)
7d (80)
Fig. 1 3,4,6-Tri-O-acetyl D-glucal and 3,4,6-tri-O-acetyl imino D-glucal.
Imino glucal 2 was made from -glucal as outlined in Scheme
D
1.†‡ Protection of the hydroxy groups as p-methoxybenzyl
ethers followed by hydration of the double bond gave
hemiacetal 3. Wittig olefination with methylenetriphenylphos-
phorane followed by TPAP oxidation of the resulting secondary
alcohol furnished ketone 4, which was converted into amine 5
by reduction of the corresponding oxime. Using lithium
a All reactions performed using 1.0–1.5 equiv of Lewis acid and 1.2–1.5
equiv. of nucleophile in CH2Cl2 at the temperature indicated in the text.
Reactions warmed to rt or 0 °C and quenched by addition of aq NaHCO3.
b Crude products treated with piperidine in CH2Cl2 for 1–2 h to remove the
Fmoc group. c Ratio determined by 1H NMR analysis prior to purification.
d Isolated yields after silica gel chromatography.
Similarly, BF3·Et2O promoted addition of diethylzinc at
220 °C, and 1-phenyl-1-(trimethylsiloxy)ethylene at 245 °C,
yield 7b and 7c respectively as the major products. Fur-
thermore, Prins-type addition of methylenecyclohexane medi-
ated by SnBr4 at rt gives 7d in excellent yield. In all these
examples, the b-anomer was produced as the major product.§
Intriguingly, this facial selectivity is the reverse of that observed
when the same nucleophiles are added to 3,4,6-tri-O-acetyl -
D
glucal 1 under comparable conditions.5 Whilst the origin of this
reversal is unclear at present, Craig has noted a similar trend
studying Lewis acid mediated additions to 4-(arylsulfonyl)gly-
cals and 1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines.6
As a demonstration of the utility of this chemistry, we have
applied it to the stereocontrolled synthesis of deoxoprosophyl-
line 9,7 a reduction product of prosophylline, itself isolated from
Prosopis africana.8 Addition of 3-(trimethylsilyl)dodec-1-ene7c
Scheme 1 Reagents and conditions: (a) NaH, PMBCl, DMF; (b) Hg(OAc)2,
THF–H2O then NaBH4; (c) Ph3PNCH2, toluene; (d) TPAP, NMO, 4 Å
sieves, CH2Cl2; (e) HONH2·HCl, pyridine, EtOH, 60 °C; (f) LiAlH4, Et2O,
rt; (g) FmocCl, K2CO3, THF–H2O (3+1); (h) CF3CO2H, CH2Cl2; (i) Ac2O,
pyridine, rt; (j) O3, 278 °C, CH2Cl2 then Me2S, rt; (k) (COCl)2, Et3N, DMF,
CH2Cl2.
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CHEM. COMMUN., 2002, 150–151
This journal is © The Royal Society of Chemistry 2002

to 2 smoothly gave piperidine 10 in 78% yield, after Fmoc
deprotection and chromatographic separation from traces of the
minor a-anomer (Scheme 2).§ 1H NMR analysis of the mixture
prior to chromatography reveals that the addition of this silane
occurs with very high levels of stereocontrol (b+a = 9+1).
Hydrogenation of 10 followed by removal of the acetate groups
provides (+)-deoxoprosophylline 9, whose physical and spec-
troscopic data are in accordance with those previously de-
scribed.‡
synthesis. Work in this direction is ongoing in our laborato-
ries.
We are indebted to EPSRC and GlaxoSmithKline for
financial support. We thank the EPSRC National Mass
Spectrometry Centre for performing some of the mass spec-
trometry.
Notes and references
† All new compounds have been fully characterised using standard
spectroscopic and analytical methods.
‡ Selected physical and spectroscopic data: 2: mp 47–50 °C; dH (400 MHz;
d6-DMSO at 100 °C) 7.84 (2H, d, J 7.5 Hz), 7.60 (2H, d, J 7.5 Hz), 7.41 (2H,
t, J 7.5 Hz), 7.32 (2H, t, J 7.5 Hz), 6.90 (1H, d, J 8.4 Hz), 5.13 (1H, m), 5.03
(1H, m), 4.92 (1H, m), 4.61 (1H, dd, J 10.6, 6.3 Hz), 4.53 (1H, dd, J 10.6,
6.0 Hz), 4.46 (1H, m), 4.33 (1H, br t, J 6.3), 4.15 (1H, dd, J 11.2, 7.2 Hz),
4.02 (1H, m), 1.98 (3H, s), 1.97 (3H, s), 1.96 (3H, s); Anal. Calc. for
C27H27NO8: C, 65.41; H, 5.43; N, 2.77%. Found: C, 65.71; H, 5.51; N,
2.84%. 7a: dH (400 MHz; CDCl3) 5.80–5.67 (2H, m), 5.63 (1H, m),
5.16–5.06 (3H, m), 4.18 (1H, dd, J 11.4, 2.9), 4.01 (1H, dd, J 11.4, 6.1 Hz),
3.46 (1H, m), 3.00 (1H, ddd, J 9.1, 6.1, 2.9 Hz), 2.41 (1H, br s), 2.20 (2H,
t, J 7.0 Hz), 2.04 (3H, s), 2.02 (3H, s); Observed: 254.1386 (MH+);
C
13H20NO4 requires 254.1392. 9: mp 84–85 °C (lit. mp 83 °C7f); [a]D24+12.5
(c 0.24, CHCl3) {lit. [a]20 +13 (c 0.22, CHCl3)7f}.
§ Strong reciprocal NOEDenhancements were observed between H-1 and H-
5 in 7a–d, 10 and 11.
Scheme 2 Reagents and conditions: (a) BF3·Et2O, CH2Cl2, H2CNCHCH(Si-
Me3)(CH2)8CH3, 260?0 °C, 3 h; (b) piperidine, CH2Cl2, rt, 1 h; (c) H2, Pt/
C, EtOH, 1.5 h; (d) LiOH, THF–H2O, 2.5 h.
¶ Crystallographic data for 11: X-ray diffraction studies on a colourless
crystal grown from Et2O–petrol (40–60) were performed at 293 K using a
Bruker SMART diffractometer with graphite-monochromated Mo-Ka
radiation (l = 0.71073 Å). The structure was solved by direct methods.
By combining the carbon–carbon bond forming reactions of
imino glucal 2 with dihydroxylation chemistry, it is possible to
make more highly oxygenated imino sugar C-glycosides. For
example, 2 can be converted into readily separable piperidines
11 and 12 by ethylation, dihydroxylation, acetylation and Fmoc
deprotection without recourse to chromatographic purification
of any of the intermediates (Scheme 3).§ Dihydroxylation of
both alkene intermediates (i.e. N-Fmoc protected forms of 7b
and 8b), proceeds stereoselectively anti- to the ethyl group at C-
1. The relative stereochemistry within 11 has been unambigu-
ously established by X-ray crystallography (Fig. 2).¶ In addition
to verifying the facial selectivity of the dihydroxylation, this
crystallographic determination confirms our earlier stereochem-
ical assignments. Since many other transformations of 1 are
known, it is anticipated that imino glucal 2 (and its various
stereoisomers) could find other applications in imino sugar
C16H25N1O8, M = 359.37, orthorhombic, space group P212121, a =
8.8915(4), b = 9.2151(3), c = 45.8131(19) Å, U = 3753.7(3) Å3, Z = 8
(2 independent molecules), Dc = 1.272 Mg m23, m = 0.102 mm21, F(000)
= 1536, crystal size = 0.26 3 0.15 3 0.1 mm, Flack parameter 0.2(14). Of
16307 measured data, 5410 were unique (Rint = 0.0510) and 4108 observed
(I > 2s(I)]) to give R1 = 0.0538 and wR2 = 0.1252. C(28) in the second
molecule was disordered into 2 orientations of 75 and 25%. The 25%
hydrogens on C(28B) and C(27) were not allowed for in the refinement. All
non-hydrogen atoms were refined with anisotropic displacement parame-
ters; both NH protons were located from a DF map and allowed to refine
isotropically subject to a distance constraint (N–H = 0.98 Å). All remaining
hydrogen atoms bound to carbon were idealised and fixed. Structural
refinements were by the full-matrix least-squares method on F2. CCDC
173804. See http://www.rsc.org/suppdata/cc/b1/b110035a/ for crystallo-
graphic files in .cif or other electronic format.
1 P. Collins and R. Ferrier, Monosaccharides: their chemistry and their
roles in natural products, Wiley, Chichester, 1995.
2 Iminosugars as glycosidase inhibitors: nojirimycin and beyond, ed. A. E.
Stütz, Wiley-VCH, Weinheim, 1999.
3 For previous work on imino glycals, see J. Désiré, P. J. Dransfield, P. M.
Gore and M. Shipman, Synlett, 2001, 1329; J. Désiré and M. Shipman,
Synlett, 2001, 1332; D. L. Comins and A. B. Fulp, Tetrahedron Lett.,
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4 P. S. Liu, J. Org. Chem., 1987, 52, 4717; S. Moutel and M. Shipman, J.
Chem. Soc., Perkin Trans. 1, 1999, 1403.
5 For the corresponding additions to 3,4,6-tri-O-acetyl D-glucal, see Y.
Scheme 3 Reagents and conditions: (a) BF3·Et2O, Et2Zn, CH2Cl2, 220
°C?rt; 2 h; (b) OsO4 (cat.), N-methylmorpholine N-oxide, acetone–H2O, 5
d; (c) Ac2O, pyridine, 2 h; (d) piperidine, CH2Cl2, 1 h.
Ichikawa, M. Isobe, M. Konobe and T. Goto, Carbohydr. Res., 1987, 171,
193; S. N. Thorn and T. Gallagher, Synlett, 1996, 185; R. D. Dawe and
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6 J. M. Bailey, D. Craig and P. T. Gallagher, Synlett, 1999, 132.
7 For previous syntheses of deoxoprosophylline, see: (a) Y. Saitoh, Y.
Moriyama, H. Hirota, T. Takahashi and Q. Khuong-Huu, Bull. Chem.
Soc. Jpn., 1981, 54, 488; (b) K. Takao, Y. Nigawara, E. Nishino, I.
Takagi, K. Maeda, K. Tadano and S. Ogawa, Tetrahedron, 1994, 50,
5681; (c) T. Luker, H. Hiemstra and W. N. Speckamp, J. Org. Chem.,
1997, 62, 3592; (d) I. Kadota, M. Kawada, Y. Muramatsu and Y.
Yamamoto, Tetrahedron: Asymmetry, 1997, 8, 3887; (e) I. Ojima and E.
S. Vidal, J. Org. Chem., 1998, 63, 7999; (f) C. Herdeis and J. Telser, Eur.
J. Org. Chem., 1999, 1407; (g) C. Yang, L. Liao, Y. Xu, H. Zhang, P. Xia
and W. Zhou, Tetrahedron: Asymmetry, 1999, 10, 2311; (h) A. Jourdant
and J. Zhu, Tetrahedron Lett., 2001, 42, 3431.
8 Q. Khuong-Huu, G. Ratle, X. Monseur and R. Goutarel, Bull. Soc. Chim.
Belg., 1972, 81, 425; Q. Khuong-Huu, G. Ratle, X. Monseur and R.
Goutarel, Bull. Soc. Chim. Belg., 1972, 81, 443.
Fig. 2 X-Ray structure of one of the two independent molecules in 11.
CHEM. COMMUN., 2002, 150–151
151