Enantioselective synthesis of 1-deoxy-D-gulonojirimycin from a phenylglycinol-derived lactam

Article abstract of DOI:10.1016/j.tetlet.2004.05.089

Cyclocondensation of (R)-phenylglycinol with appropriately γ-substituted δ-oxo acid derivatives provides bicyclic lactams from which the enantioselective synthesis of 1-deoxy-D-gulonojirimycin has been reported.

Full text of DOI:10.1016/j.tetlet.2004.05.089

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5355–5358
Enantioselective synthesis of 1-deoxy- -gulonojirimycin from a
phenylglycinol-derived lactam
D
a
a
a
a
Mercedes Amat,a, Marta Huguet, Nuria Llor, Oriol Bassas, Antonia M. Gomez,
*
ꢀ
ꢀ
Joan Bosch,a,* Josefa Badia,b Laura Baldomab and Juan Aguilarb
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
bDepartment of Biochemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 1 March 2004; revised 17 May 2004; accepted 18 May 2004
ꢀ
Dedicated to Professor Dr. Jose Luis Soto on the occasion of his retirement
Abstract—Cyclocondensation of (R)-phenylglycinol with appropriately c-substituted d-oxo acid derivatives provides bicyclic lac-
tams from which the enantioselective synthesis of 1-deoxy-
Ó 2004 Elsevier Ltd. All rights reserved.
D
-gulonojirimycin has been reported.
Azasugars (also called iminosugars) are compounds in
which the ring O-atom of a carbohydrate is replaced by
nitrogen.1 They constitute an important class of glyco-
sidase inhibitors that are receiving a great deal of atten-
tion because of their therapeutic potential in the
treatment of viral infections including HIV,2 cancer,3
diabetes,4 and other metabolic disorders.5 In particular,
inhibitory activities have been reported for many natu-
rally occurring polyhydroxylated piperidines (deoxynoj-
irimycin, isofagomine),6 whereas miglitol,7 a synthetic
glucose-mimic piperidine, is commercially available in
several countries for the treatment of diabetes (Fig. 1).
increasingly focused on the synthesis of this class of
compounds from non-carbohydrate sources.8
In the context of our studies on the enantioselective
synthesis of piperidine derivatives from phenylglycinol-
derived bicyclic lactams,9 we have recently reported a
synthetic route to 3,4,5-trihydroxypiperidines, in which
the key step was an unprecedented stereoselective oxi-
dative hydroxylation of N-(1-phenyl-2-hydroxyethyl)-2-
pyridone.10 We present here a different approach to
enantiopure 3,4,5-trihydroxypiperidines that addition-
ally bear a hydroxymethyl substituent at the 2-position,
which is a structural feature characteristic of most
piperidine containing azasugars.
Although traditionally enantiopure azasugars have been
synthesized through multistep transformations of read-
ily available carbohydrate precursors, recent interest has
Our approach consists of two well-differentiated phases:
(i) the assembling of an enantiopure bicyclic d-lactam B
by cyclocondensation of (R)-phenylglycinol with an
appropriately functionalized (and protected) d-oxo acid
derivative (A), and (ii) functional group transforma-
tions, with removal of the chiral auxiliary (Scheme 1).
To illustrate the usefulness of the methodology we
OH
H
N
H
N
N
HO
HO
HO
HO
OH
OH
OH
OH
HO
OH
OH
Miglitol
Isofagomine
Deoxynojirimycin
present here the synthesis of 1-deoxy-
(1;
D
-gulonojirimycin
1,5-dideoxy-1,5-
1-deoxy-3,4-diepi-nojirimycin;
Figure 1. Natural and synthetic azasugars.
imino-D
-gulitol),11 a piperidine-derived azasugar, whose
isolation from the bark of Anglylocalyx pynaertii
(Leguminosae) has recently been reported.12
Keywords: Azasugars; Phenylglycinol; Chiral bicyclic lactams; Poly-
hydroxypiperidines; Enantioselective synthesis.
For the generation of the required enantiopure bicyclic
d-lactam we initially planned to operate from a racemic
* Corresponding authors. Tel.: +34-93-4024538; fax: +34-93-4024539;
e-mail addresses: amat@ub.edu; joanbosch@ub.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.089

5356
M. Amat et al. / Tetrahedron Letters 45 (2004) 5355–5358
C6H5
O
O
C6H5
O
C6H5
O
H
N
H
C6H5
MeOOC
O
OH
O
O
X
OH
OH
O
RO2C
OProt
N
N
N
NH2
OProt
OR
+
8
toluene, reflux
8
HO
X
OR
OR
10 racemic
OH
11a
11b
1
A
R=TBDMS
B
Deoxy-D-gulonojirimycin
Scheme 3.
Scheme 1. Synthetic strategy.
the above epimeric mixture of lactams 5 was satisfac-
torily converted to alcohol 7 by deprotection of the
hydroxy function, followed by Jones oxidation and
subsequent stereoselective Luche reduction of the
resulting ketone 6. Then, treatment of 7 with BH3–THF
brought about both the reduction of the lactam car-
bonyl group and the stereoselective reductive opening of
the oxazolidine ring, with retention of configuration,17
to give the cis piperidine 8. Finally, removal of the chiral
auxiliary by chemoselective hydrogenolysis of the N-
benzylic substituent in the presence of di-tert-butyl di-
carbonate led to the protected 3-hydroxypiperidine 9.18
OMe
O
O
O
HOOC
OBn
OBn
OBn
ii
iii
i
OMEM
OMEM
2
4
3
C6H5
O
R
N
O
N
OBn
OBn
vi
5 X= H, OMEM
6 X= O
7 X= α OH, β H
8
iv
OH
X
v
8 R= (R)-CH(C6H5)CH2OH
9 R=Boc
vii
Scheme 2. Reagents and conditions: (i) m-CPBA, MeOH, 0 °C, 2 h
then DIPEA, ClMEM, rt, 20 h, 77%; (ii) Jones reagent, acetone, rt, 5 h,
40%; (iii) (R)-phenylglycinol, toluene, reflux, 12 h, 72%; (iv) NaI,
CeCl3Æ7H2O, MeCN, reflux, 6 h, then Jones reagent, acetone, rt, 1 h,
66%; (v) CeCl3Æ7H2O, NaBH4, EtOH, THF, rt, 1.5 h, 87%; (vi) BH3–
THF, THF, rt, 24 h, 57%; (vii) H2, (t-BuOCO)2O, Pd(OH)2/C, AcOEt,
25 °C, 72%.
An alternative synthetic route to the key enantiopure
intermediate 6, also based on a cyclocondensation reac-
tion, is depicted in Scheme 4. The required d-oxo acid 14,
incorporating a dithioacetal function at the ketone a
position, was prepared from the Weinreb amide 12,19 by
reaction with the lithium salt of 1,3-dithiane followed by
alkylation of the resulting dithioacetal 13 with ethyl 3-
bromopropionate and subsequent hydrolysis of the ester
group. Cyclocondensation of 14 with (R)-phenylglycinol
took place in satisfactory yield to give lactam 15,15 which
was then desulfurized to ketone 6 by treatment with NBS
in acetone–water.
d-oxo acid 4, which bears two differently protected hy-
droxy groups at the ketone a and a0 positions. Our hope
was that, by analogy with related cyclocondensation
reactions from racemic c-aryl (or alkyl) d-oxo acids,13
a
dynamic kinetic resolution of the stereocenter a to the
ketone carbonyl group would occur during cycloconden-
sation with (R)-phenylglycinol, stereoselectively leading to
a bicyclic lactam with a well-defined configuration at the
piperidine a- and b-positions. The required d-oxo acid 4
was readily prepared from the dihydropyran derivative
2,14 by m-CPBA oxidation followed by protection of the
resulting a-hydroxy ketal and finally Jones oxidation
(Scheme 2). However, cyclocondensation of 4 with (R)-
phenylglycinol led to a C-8 epimeric mixture (3:2 ratio) of
lactams 515 in 74% yield, thus revealing that dynamic ki-
netic resolution had only occurred to a small extent.
The synthesis of the target azasugar 1 from bicyclic
lactam 7 simply required the introduction of two addi-
tional hydroxy groups by stereoselective syn dihydr-
oxylation, after generation of a conjugated carbon–
carbon double bond. The synthetic sequence is illus-
trated in Scheme 5. Debenzylation of 7 followed by
protection of the resulting diol with dimethoxypropane
under acidic conditions gave acetal 16, which was then
converted to a,b-unsaturated lactam 17 via a sulfoxide.
As expected, dihydroxylation of 17 with catalytic OsO4
and NMO occurred on the most accessible endo face, in
contrast with other related exo dihydroxylations,10;17 to
give diol 18 as a single stereoisomer.
To investigate if the above result could be attributed to
the presence of the benzyloxymethyl substituent on the
ketone carbonyl, we studied the cyclocondensation
reaction from racemic O-protected hydroxy-aldehyde
10,16 from which the imine ꢀ enamine equilibrium re-
quired for deracemization would necessarily involve the
epimerizable stereocenter at the aldehyde a-position
(Scheme 3). A C-8 epimeric mixture of bicyclic lactams
11a and 11b (50%, 3:2 ratio)15 was again obtained, thus
indicating that cyclocondensation reactions take place
with low stereoselectivity when there is an oxygenated
substituent on the epimerizable stereocenter a to the
aldehyde or ketone carbonyl group.
Although borane reduction of 18, as in the above model
series, provided a 3:2 mixture of the expected piperidine
C6H5
O
O
HO2C
OBn
O
X
O
N
S
ii, iii
iv
OBn
OBn
X
S
12 X= N(Me)OMe
14
i
S
15 X= S(CH2)3S
6 X= O
v
13 X=
CH
S
Scheme 4. Reagents and conditions: (i) 1,3-dithiane, BuLi, )78 °C, 1 h,
then 0 °C, 2 h, 64%; (ii) LDA, THF, )78 °C, 1 h, then ethyl 3-bromo-
propionate, rt, 24 h, 61%; (iii) 20% aq KOH, MeOH, 0 °C, 1 h, 2 N
HCl, 60%; (iv) (R)-phenylglycinol, toluene, reflux, 36 h, 57%; (v) NBS,
acetone-H2O, )30 °C, 15 min, 68%.
In spite of the above results, the approach depicted in
Scheme 2 proved to be synthetically useful for the
preparation of enantiopure 3-hydroxypiperidines bear-
ing a hydroxymethyl substituent at the 2-position. Thus,

M. Amat et al. / Tetrahedron Letters 45 (2004) 5355–5358
5357
C6H5
C6H5
O
C6H5
O
2001SGR-0084) is gratefully acknowledged. Thanks are
also due to the Ministry of Education, Culture and
Sport for a fellowship to M.H. and to the Ministry of
Science and Technology for a fellowship to O.B. We
O
O
O
N
O
N
N
OBn
O
O
i, ii
iii
iv
OH
O
O
7
16
17
ꢀ
thank DSM Deretil (Almerıa, Spain) for the generous
gift of (R)-phenylglycinol.
C6H5
O
C6H5
HCl
OH
H
N
O
O
N
N
OH
OH
O
O
v
vi
References and notes
HO
HO
HO
O
OH
OH
18
OH
19
1
1. (a) Bols, M. Acc. Chem. Res. 1998, 31, 1; (b) Iminosugars
1-Deoxy-D-gulonojirimycin
€
as Glycosidase Inhibitors. Nojirimicin and Beyond; Stutz, A.
E., Ed.; Wiley-VCH: Weinheim, 1999.
Scheme 5. Reagents and conditions: (i) BF3Et2O, SMe2, rt, 12 h, 81%;
(ii) MeC(OMe)2Me, p-TsOH, CH2Cl2, rt, 3 h, 75%; (iii) KH, THF,
PhSO2Me, rt, then toluene, reflux, 15 h, 76%; (iv) 2.5% OsO4 t-BuOH,
NMO, MeCN, 72 h, 82%; (v) LiAlH4, THF, rt, 15 h, 90%; (vi) H2,
Pd(OH)2/C, MeOH, HCl, 72 h, 40%.
2. (a) Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L.
E.; Tyms, A. S.; Petursson, S.; Namgoong, S. K.;
Ramsden, N. G.; Smith, P. W.; Son, J. C.; Wilson, F.;
Witty, D. R.; Jacob, G. S.; Rademacher, T. W. FEBS Lett.
1988, 237, 128; (b) Taylor, D. L.; Sunkara, P.; Liu, P. S.;
Kang, M. S.; Bowlin, T. L.; Tyms, A. S. AIDS 1991, 5,
693.
19 and its C-2 epimer, reduction with LiAlH4 took place
with retention of configuration at C-2, stereoselectively
affording piperidine 19 in excellent yield. Finally,
hydrogenolysis under acidic conditions with simulta-
neous hydrolysis of the acetonide ring, led to poly-
hydroxylated piperidine 1 as the hydrochloride.20
3. (a) Nishimura, Y. In Studies in Natural Products Chem-
istry; Atta-ur-Rahman, Ed.; Elsevier Science: B.V.
Amsterdam, 1995; Vol. 16, pp 75–121; (b) Gross, P. E.;
Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer.
Res. 1995, 1, 935.
4. (a) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano,
N.; Matsui, K. J. Med. Chem. 1986, 29, 1038; (b)
Robinson, K. M.; Begovic, M. E.; Reinhart, B. L.;
Heineke, E. W.; Ducep, J.-B.; Kastner, P. R.; Marshall,
F. N.; Danzin, C. Diabetes 1991, 40, 825.
5. For a review, see: Asano, N. Glycobiology 2003, 13, 93R.
6. (a) Nash, R. J.; Watson, A. A.; Asano, N. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Elsevier: Oxford, 1996; Vol. 11, pp 345–376; (b) Elbein, A.
D.; Molyneux, R. J. In Comprehensive Natural Products;
Barton, D., Nakanishi, K., Eds.; Elsevier: New York,
1999; Vol. 3, pp 129–160.
7. Drugs Future 1986, 11, 1039; Drugs Future 1987, 12, 1157.
8. Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J.
Chem. Rev. 1996, 96, 1195.
Both the 1H and 13C NMR data of 1 hydrochloride
coincided with those previously reported20d;e for 1-
deoxy-gulonojirimycin hydrochloride, whereas the spe-
cific rotation of our synthetic product, [a]2D2 +2.0 (c 0.2,
MeOH), agreed with that reported20d for the hydro-
chloride of this azasugar, [a]589 +2.6 (c 1.6, MeOH).
Kinetic measurements with 1 were performed on b-
galactosidase, a-amylase and a-glucosidase. In our
conditions only a-glucosidase was significantly inhibited
with an IC50 of 0.25 mM. The assay was performed with
Saccharomyces cerevisiae a-glucosidase acting on p-
ꢀ
ꢀ
9. (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto, M.; Perez, M.;
Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque,
J. J. Org. Chem. 2000, 65, 3074; (b) Amat, M.; Llor, N.;
Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003,
68, 1919; (c) Amat, M.; Escolano, C.; Lozano, O.; Llor,
N.; Bosch, J. Org. Lett. 2003, 5, 3139; For a review, see:
(d) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56,
9843.
nitrophenyl-a-D-glucopyranoside, a synthetic substrate
analogous for a-glucosidases, which was routinely used
at 1.5 mM concentration for the IC50 standard assays.
Reactions were carried out at pH 6.8 and 37 °C. Under
these conditions the KM for p-nitrophenyl-a-D-gluco-
pyranoside was 0.6 mM, and the Ki for 1, assayed in a
range of concentrations of inhibitor going from 0.025 to
0.25 mM in front of different amounts of substrate
ranging from 0.4 to 1.5 mM, was 0.15 mM. Finally it has
to be underscored that in our conditions the inhibition
of this enzyme by deoxynojirimycin displayed a 5 fold
higher IC50 of 1.25 mM and hence this natural product is
a weaker inhibitor than 1.
10. Amat, M.; Llor, N.; Huguet, M.; Molins, E.; Espinosa, E.;
Bosch, J. Org. Lett. 2001, 3, 3257.
11. 1-Deoxy-L-gulonojirimycin is a potent and selective inhib-
€
itor of L-fucosidases. (a) Legler, G.; Sutz, A. E.; Immich,
H. Carbohydr. Res. 1995, 272, 17; (b) Le Merrer, Y.;
Poitout, L.; Depezay, J.-C.; Dosbaa, I.; Gcoffroy, S.;
Foglietti, M.-J. Bioorg. Med. Chem. 1997, 5, 519.
12. (a) Asano, N.; Ishii, S.; Kizu, H.; Ikeda, K.; Yasuda, K.;
Kato, A.; Martin, O. R.; Fan, J.-Q. Eur. J. Biochem. 2000,
267, 4179; (b) Asano, N.; Yasuda, K.; Kizu, H.; Kato, A.;
Fan, J.-Q.; Nash, R. J.; Fleet, G. W. J.; Molyneux, R. J.
Eur. J. Biochem. 2001, 268, 35; (c) However, the sign and
absolute value of specific rotation of this natural product
are in agreement with the data reported in the literature11b
for the enantiomer.
Taking into account that (S)-phenylglycinol is also
commercially available, the methodology here
reported provides access to azasugars in both enantio-
meric series.
Acknowledgements
ꢀ
13. (a) Amat, M.; Canto, M.; Llor, N.; Ponzo, V.; Perez, M.;
Bosch, J. Angew. Chem., Int. Ed. 2002, 41, 65; (b) Amat,
ꢀ
ꢀ
Financial support from the ‘La Marato de TV3’ foun-
ꢀ
M.; Canto, M.; Llor, N.; Escolano, C.; Molins, E.;
dation, the DGICYT, Spain (project BQU2003-00505),
and the CUR, Generalitat de Catalunya (grant
Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343.
14. Oishi, T.; Nagumo, Y.; Hirama, M. Synlett 1997, 980.

5358
M. Amat et al. / Tetrahedron Letters 45 (2004) 5355–5358
15. Minor amounts of the C-8a epimer were also formed. For a
discussion of the stereochemistry at the angular C-8a
position in bicyclic lactams obtained by related cyclocon-
densation reactions using aldehyde-esters or ketoacids, see
Ref. 13.
16. Aldehyde-ester 10 was prepared in 50% overall yield from
methyl 4-oxobutanoate, by reaction with vinylmagnesium
bromide, followed by silylation of the resulting alcohol
and ozonolysis of the vinyl group.
(a) Knight, D. W.; Lewis, N.; Share, A. C.; Haigh, D.
J. Chem. Soc., Perkin Trans. 1 1998, 3673; (b) Takahata,
H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.; Adachi,
I. J. Org. Chem. 2003, 68, 3603.
19. Williams, R. M.; Ehrlich, P. P.; Zhai, W.; Hendrix, J.
J. Org. Chem. 1987, 52, 2615.
20. For previous syntheses of 1-deoxy-D-gulonojirimycin, see:
(a) Liao, L.-X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W.-S.
Tetrahedron: Asymmetry 1999, 1, 3649; (b) Haukaas, M.
H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401; (c) Ruiz, M.;
Ojea, V.; Ruanova, T. M.; Quintela, J. M. Tetrahedron:
Asymmetry 2002, 13, 795; (d) Singh, O. V.; Han, H.
Tetrahedron Lett. 2003, 44, 2387; (e) Takahata, H.; Banba,
Y.; Ouchi, H.; Nemoto, H. Org. Lett. 2003, 5, 2527; For
17. Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.;
McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron
1999, 55, 8931.
18. Compound (9): 1H NMR (CDCl3, 400 MHz) d 1.44 (s, 9H),
1.45–1.60 (m, 2H, H-4 and H-5), 1.67 (dm, J ¼12.8 Hz, 1H,
H-5), 1.90 (dm, J ¼12.4 Hz, 1H, H-4), 2.66 (td, J ¼13.2
and 2.8 Hz, 1H, H-6ax), 2.93 (d, J ¼ 6:4 Hz, 1H, OH), 3.65
(dd, J ¼ 9:6 and 6.0 Hz, 1H, H-10), 3.83 (m, 1H, H-3), 3.90
(masked, 1H, H-6eq), 3.90 (dd, J ¼9.6 and 8.0 Hz, 1H, H-
10), 4.53 (d, J ¼12.0 Hz, 1H, OCH2), 4.56 (d, J ¼12.0 Hz,
1H, OCH2), 4.63 (m, 1H, H-2), 7.33 (m, 5H, C6 H5); 13C
NMR (CDCl3) d 24.0 (C-5), 28.4 (CH3), 28.9 (C-4), 39.0
(C-6), 53.0 (C-2), 66.7 (C-10), 69.6 (C-3), 73.3 (OCH2), 79.8
(C), 127.6 (2 CH), 127.7 (p-C), 128.4 (2 CH), 137.6 (ipso-C),
154.9 (CO). For spectroscopic data of related enantiopure
syntheses of the
€
515; (g) Legler, G.; Julich, E. Carbohydr. Res. 1984, 128,
L enantiomer, see: (f) Leontein, K.;
Lindberg, B.; Lonngren, J. Acta Chem. Scand. 1982, B36,
ꢀ
61; (h) Davis, B. G.; Hull, A.; Smith, C.; Nash, R. J.;
Watson, A. A.; Winkler, D. A.; Griffiths, R. C.; Fleet, G.
W. J. Tetrahedron: Asymmetry 1998, 9, 2947; (i) Joseph, C.
C.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F.
Carbohydr. Res. 2002, 337, 1083, See also Ref. 11b. For a
synthesis in the racemic series, see: (j) Ostrowski, J.;
Altenbach, H.-J.; Wischnat, R.; Brauer, D. J. Eur. J. Org.
Chem. 2003, 1104.
N-Boc-3-hydroxy-2-(hydroxy-methyl)piperidines,
see: