A new concise synthesis of nectrisine and its facile conversion to phosphonoazasugars

Article abstract of DOI:10.1016/S0040-4039(01)01684-7

The synthesis of new sugar-derived phosphonic acids from protected nectrisine is described. The key step is a highly stereoselective addition of a phosphonate anion to a sugar-derived dihydropyrrole to provide a versatile synthetic intermediate which can be functionalised in multiple ways.

Full text of DOI:10.1016/S0040-4039(01)01684-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7949–7952
A new concise synthesis of nectrisine and its facile conversion to
phosphonoazasugars
Michae¨l Bosco, Philippe Bisseret, Claire Bouix-Peter and Jacques Eustache*
Laboratoire de Chimie Organique et Bioorganique associe´ au CNRS, Universite´ de Haute-Alsace,
Ecole Nationale Supe´rieure de Chimie de Mulhouse 3, Rue Alfred Werner, F-68093 Mulhouse Cedex, France
Received 14 July 2001; revised 7 September 2001; accepted 10 September 2001
Abstract—The synthesis of new sugar-derived phosphonic acids from protected nectrisine is described. The key step is a highly
stereoselective addition of a phosphonate anion to a sugar-derived dihydropyrrole to provide a versatile synthetic intermediate
which can be functionalised in multiple ways. © 2001 Elsevier Science Ltd. All rights reserved.
Glycosyltransferases catalyse the transfer of a mono- or
oligosaccharide unit from a ‘donor’ to an ‘acceptor’
(usually a growing polysaccharide chain). There are
several types of donors but they all feature a common
core: a sugar 1-phosphate linked either to a nucleotide
(NDP sugars) or to a long polyunsaturated alcohol (e.g.
undecaprenol). The reaction mechanism is reminiscent
of that of glycosidases and is believed to involve a
positively charged transition state. For some time, we
have been interested in sugar 1-phosphate analogues as
inhibitors of glycosyltransferases. In our approach, sub-
stitution of the ring oxygen by a nitrogen should
strongly favour binding to the enzyme’s active site, as
observed for glycosidases, while isosteric replacement of
the phosphate leaving group by a stable phosphonate
should prevent the cleavage to take place. The overall
expected result is a strong inhibition of glycosyltrans-
ferases.1,2 In this work, we describe the synthesis of a
range of phosphonoazasugars (2, 3, 4, 5 Fig. 1). In
addition the approach was used for a facile preparation
of nectrisine (1 Fig. 1), a known powerful glycosidase
inhibitor with immunostimulating properties,3 which
remains an attractive synthetic target.4
Hydrazinolysis of phthalimide 65 (Scheme 1) and treat-
ment of the crude amine thus obtained with tri-
fluoroacetic anhydride provided the trifluoroacetamide
7. Dihydroxylation (OsO4/NMO) of the olefinic bond
and oxidative cleavage (NaIO4) of the resulting diol led
to an aldehyde which cyclised to the protected aminal 8
upon standing. Initial attempts to remove the benzyl
groups in 8 by hydrogenolysis, using a variety of condi-
tions, were disappointing as the desired deprotected
product 10 was obtained only in low yield, always
accompanied by substantial amounts of the amino-
alcohol arising from reduction of the latent aldehyde
function in 8. Fortunately, and to our surprise in view
of the expected sensitivity of compounds 8 and 9, the
desired conversion could be effected in high yield by
BCl3 treatment at low temperature.6 Hydrolysis of the
trifluoroacetamide with dilute NaOH and concomitant
dehydration, followed by ion-exchange chromatogra-
phy (Sephadex® CM-C-25 (NH4 ), elution with 2%
+
aqueous ammonia) completed our synthesis of nec-
trisine, thus obtained in nine steps and 18% overall
yield starting from commercially available 2,3,5-tri-O-
Figure 1.
* Corresponding author. Fax: 33 (0)3 89 336860; e-mail: j.eustache@uha-mulhouse.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01684-7

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M. Bosco et al. / Tetrahedron Letters 42 (2001) 7949–7952
Scheme 1. (a) N2H4·H2O, ethanol, reflux, 1.5 h; (b) (CF3CꢀO)2O, NEt3, 0°C–rt, 2 h, 72% (two steps); (c) OsO4 (cat.), NMO,
THF/acetone/H2O 4/4/1, rt, 48 h; (d) NaIO4, THF/acetone/H2O (4/4/1), rt, 1.5 h, 98% (two steps); (e) LiOH (0.5 M) in
THF/MeOH/H2O (4/4/1), rt, 2 h, 86%; (f) BCl3, CH2Cl2, −78°C, 2 h, then −40°C, 16 h, 96%; (g) NaOH (0.5 M), rt, 30 min, then
AcOH to pH 4, 96%.
benzyl-(
D
)-arabinose.5 This synthesis compares well
phosphonic acid to the corresponding triethylammo-
nium salt. Treatment with trichloroacetonitrile then
1-eicosanol afforded the corresponding monophospho-
nate in good yield. Cleavage of the benzyl protecting
groups gave the free N-acetyl phosphonate 4 and N-
deacetylation by acidic treatment gave 3.
with previously published ones.4
The use of protected nectrisine 9 for the synthesis of
2-phosphonylmethylpyrrolidines (Scheme 2) was
explored next. Although additions of alkyl or aryl
lithium or Grignard reagents to simple cyclic imines are
known, the use of the method with more complex,
sugar-derived dihydropyrroles seems to have been
reported only twice.7 Furthermore, addition of phos-
phonate anions even to simple imines was, to the best
of our knowledge, unprecedented. We found that treat-
ment of 9 with lithiated dimethylmethylphosphonate,
under Lewis acid catalysis afforded exclusively the sub-
stituted 2-(S)-pyrrolidine 11 albeit in modest yield.8
Our synthesis was then completed as shown in Scheme
2: selective cleavage of the phosphonate esters with
TMSBr and removal of the benzyl protective groups
with BCl3 afforded cleanly the free phosphonate 2, the
first example of a free azasugar-derived phosphonic
acid. Coupling of this phosphonic acid with long chain
alcohols was then attempted. Among the various meth-
ods tested, only Vasella’s method worked well.9 Thus,
N-acetylation of 11 was followed by cleavage of the
phosphonate esters and conversion of the resulting
We examined whether the highly stereoselective addi-
tion of simple dimethyl methylphosphonate to the imi-
nosugar 9, could be extended to more complex
phosphonates. Our intention was to exploit the result-
ing intermediates for further derivatisation and we
decided to focus on a-selenophosphonates because of
their high synthetic potential. We were pleased to find
that treatment of the cyclic imine 9 with lithiated
dimethylphenylselanylmethylphosphonate 2010 afforded
exclusively 14, having the a-configuration, as a ca. 1:1
mixture of 7(R) and 7(S) isomers, in good yield. The
corresponding Cbz derivatives 7(R) 15 (48%) and 7(S)
15 (46%) could be separated by chromatography. Treat-
ment with triphenyltin hydride effected clean removal
of the phenylselanyl group to afford in both cases 16
quantitatively.11 On the other hand, treatment of 14
with acryloyl chloride provided the acrylamide 17
which, upon treatment with triphenyltin hydride, was
Scheme 2. LiCH2P(O)(OMe)2 (2 equiv.), BF3·OEt2, THF, −78°C, 2 h, rt, 32%; (b) TMSBr, CH2Cl2, 0°C–rt, 16 h; (c) BCl3,
CH2Cl2, −78 to −40°C, 97% (2), 90% (3); (d) Ac2O, pyridine, 20°C, 16 h, 61%; (e) NEt3, MeOH, rt, 10 min; (f) C20H41OH,
CCl3CN, pyridine, 70°C, 16 h, 76%; (g) 8N HCl, 45°C, 16 h, 40%.

M. Bosco et al. / Tetrahedron Letters 42 (2001) 7949–7952
7951
Scheme 3. (a) LiCH(PhSe)P(O)(OMe)2 (2 equiv.), BF3·OEt2, THF, −78°C, 2 h, rt, 69%; (b) CbzCl, Na2CO3, CH2Cl2/H2O, 20°C,
1.5 h, 48%; (c) Ph3SnH, toluene, 110°C, 16 h, 80% (16) or 37% (5); (d) CH2ꢀCH–COCl, NEt3, 20°C, CH2Cl2, 0°C, 2 h, 64%; (e)
mCPBA (2 equiv.), CH2Cl2, 4°C, 16 h, 64% (from 15 (R)), 66% (from 15 (S)); (f) H2 (P=8 bar), Pd/C 10%, MeOH, 16 h.
chemistry briefly examined here, in particular for the
synthesis of rigid analogues of the phosphonosugars
described in this work, is in progress.
converted to the protected cyclic phosphonate 5,
obtained as a single isomer to which we tentatively
attribute the structure indicated in Scheme 3. This
provides a convenient entry toward cyclic, conforma-
tionnaly constrained phosphonoazasugars.
Acknowledgements
Finally, all phosphonoazasugars described so far have
the 2-a configuration, but we are also interested in 2-b
analogues and we were intrigued by the possibility of
inverting the configuration at C-2 in 15 (from a to b),
again using selenium chemistry. Our approach is shown
in Scheme 3. There were no previous reports of sele-
nenic acid eliminations in b-amino-(or b-amido)-
selenoxides to afford enamines. In our case, the method
proved to be highly effective: thus, 7(R) 15 and 7(S) 15
were submitted to a selenide oxidation/selenenic acid
elimination sequence. The faster (presumably 7(S))
migrating isomer gave exclusively Z-18 as evidenced by
the strong NOE between protons 7 and 3 (see Scheme
3 for numbering), while the other (presumably 7(R))
isomer gave 18 as an E/Z mixture.12 To complete the
synthesis, catalytic hydrogenolysis of the Cbz group
and simultaneous hydrogenation of the double bond in
18 was performed. The Z and E isomers of 18 were
separated by chromatography and submitted to the
same catalytic hydrogenation conditions. In both cases,
16 was formed predominantly: the major, Z-18 isomer
afforded a 6:4 mixture of a-(16) and b-(19) anomers in
76% yield, and the minor, E-18 isomer afforded 71% of
an anomeric mixture containing less than 10% of 19.
We thank Drs. Didier Le Nouen and Ste´phane Bourg
for help with NMR recording and spectra interpreta-
tion. We gratefully acknowledge the French Ministry of
Research and the ‘Fondation de l’Ecole Nationale
Supe´rieure de Chimie de Mulhouse’ for fellowships to
M.B and C.B.-P., respectively. This work was done
within the frame of a COST program (action D13 New
Molecules for Human Health).
References
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L.; Russo, G. J. Org. Chem. 1996, 61, 3428–3432; (b)
Cipolla, L.; La Ferla, B.; Nicotra, F.; Panza, L. Tetra-
hedron Lett. 1997, 38, 5567–5568.
2. Vaghefi, M. M.; Bernacki, R. J.; Dalley, N. K.; Wilson,
B. E.; Robins, R. K. J. Med. Chem. 1987, 30, 1383–1391.
3. Shibata, T.; Nakayama, O.; Tsurumi, Y.; Okuhara, M.;
Terano, H.; Kohsaka, M. J. Antibiot. 1988, 51, 297–301.
4. (a) Kayariki, H.; Takase, S.; Setoi, H.; Ucida, I.; Terano,
H.; Hashimoto, M. Tetrahedron Lett. 1988, 29, 1725–
1728; (b) Chen, S.-H.; Danishevsky, S. J. Tetrahedron
Lett. 1990, 31, 2229–2232; (c) Kayariki, H.; Nakamura,
K.; Takase, S.; Setoi, H.; Uchida, I.; Terano, H.; Hashi-
moto, M.; Tada, T.; Koda, S. Chem. Pharm. Bull. 1991,
39, 2807–2812; (d) Kim, Y. J.; Kitahara, T. Tetrahedron
Lett. 1997, 38, 3423–3426; (e) Kim, Y. J.; Takatsuki, A.;
Kogoshi, N.; Kitahara, T. Tetrahedron 1999, 55, 8353–
8364.
Thus, starting from 6, obtained in a few steps from
commercially available 2,3,5-tri-O-benzyl-arabinose, we
have devised a short synthetic route to nectrisine as well
as to a range of 2-phosphonylmethyl-polyhydroxy-
pyrrolidines (phosphonoazasugars). Phosphonoazasug-
ars are analogues of sugar 1-phosphates, a class of
compounds involved in many important biochemical
processes. In particular the new phosphonates 2–4 are
candidates as inhibitors of mycobacterial glycosyltrans-
ferases. Exploration of the potential of the selenium
5. Bouix, C.; Bisseret, P.; Eustache, J. Tetrahedron Lett.
1998, 39, 825–828.

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M. Bosco et al. / Tetrahedron Letters 42 (2001) 7949–7952
6. Congreve, M. S.; Davison, E. C.; Fuhry, M.-A. M.;
dd, J=12.6, 3.9 Hz, H%-6), 3.95–4.05 (2H, m, H-3+H-4).
13C NMR (62.9 MHz, 300 K, D2O) l 29.19 (J=131 Hz,
C-7), 58.84, 59.99 (J=2 Hz, C-2), 63.14, 74.90, 76.02
(J=8.5 Hz, C-3). 31P NMR (101.2 MHz, 300 K, D2O) l
16.66 (s).
Holmes, A. B.; Payne, A. N.; Robinson, R. A.; Ward, S.
E. Synlett 1993, 663.
7. (a) Furneaux, R. H.; Limberg, G.; Tyler, P. C.; Schramm,
V. L. Tetrahedron 1997, 53, 2915–2930; (b) Horenstein, B.
A.; Zabinski, R. F.; Schramm, V. L. Tetrahedron Lett.
1993, 34, 7213–7216.
8. In related examples, using simpler aryllithiums, additions
to cyclic imines appear to proceed in modest to medium
yields: Mutzer, J.; Meier, A.; Buschmann, J.; Luger, P.
Synthesis 1996, 123–132 and Ref. 7.
9. Billault, I.; Vasella, A. Helv. Chim. Acta 1999, 82, 1137–
1149.
10. 20 is best prepared in good yield (64%) from readily
available dimethylmethylphosphonate by lithiation (n-
BuLi), transmetallation using ZnCl2 and treatment by
phenylselenenyl chloride. All experiments were performed
at −78°C. Under these conditions, no bis selenylation was
observed.
1
3: H NMR (250 MHz, 300 K, CD3OD) l 0.89 (3H, t,
J=6.8 Hz, CH3), 1.27 (34H, m, -CH2-), 1.63 (2H, m,
-O-CH2-CH2-), 2.01 (1H, ddd, J=17, 14, 7.8 Hz, H-7),
2.10 (1H, ddd, J=17.6, 14, 6.5 Hz, H%-7), 3.48 (1H, m,
H-5), 3.59 (1H, m, H-2), 3.75 (1H, dd, J=11.7, 7 Hz,
H-6), 3.83–4.0 (4H, m, H-4+H%-6+-O-CH2), 4.0 (1H, m,
H-3). 13C NMR (62.9 MHz, 300 K, CD3OD) l 14.49,
23.78, 26.95, 27.67 (J=132 Hz, C-7), 30.53, 30.82, 32.08
(J=6.5 Hz, -O-CH2-CH2-), 33.12, 60.15, 61.29 (J<1 Hz,
C-2), 65.79 (J=6 Hz, -O-CH2-CH2-), 65.90, 76.96, 80.55
(J=8 Hz, C-3). 31P NMR (101.2 MHz, 300 K, CD3OD)
l 19.72 (s).
1
4: H NMR (400 MHz, 300 K, CD3OD) (ꢀ2:1 mixture
of rotamers. Signals which could be attributed to major
and minor rotamers are listed as ‘M’ and ‘m’, respec-
tively) l 0.88 (M) (3H, t, J=6.9 Hz, CH3), 1.19–1.43
(34H, m, -CH2-), 1.61 (2H, m, -O-CH2-CH2-), 1.80 (M)
(ꢀ0.66H, ddd, J=17.3, 15.2, 1.9 Hz, H-7), 1.93 (m)
(ꢀ0.33H, m, H-7), 2.11(m) (ꢀ1H, s, -C(O)-CH3), 2.13
(M) (ꢀ2H, s, -C(O)-CH3), 2.50 (M) (ꢀ0.66H, dt, J=
15.5, 12.1 Hz, H%-7), 3.67(m) (0.33H, m, H-6), 3.79 (M)
(ꢀ0.66H, dd, J=10.7, 3.9 Hz, H-6), 3.81–3.92 (ꢀ3.3H,
m), 3.96 (M) (ꢀ0.66H, dd, J=5.7, 3.9 Hz, H-5), 4.02–
4.10 (1H, m), 4.11 (M) (ꢀ0.66H, broad s, H-4), 4.19 (m)
(ꢀ0.33H, broad s, H-4), 4.38 (M) (ꢀ0.66H, broad s,
H-3), 4.42 (m) (ꢀ0.33H, broad s, H-3). 31P NMR (101.2
MHz, 300 K, CD3OD) l 19.06 (M) (ꢀ0.66P, s), 22.10
(m) (ꢀ0.33P, s).
11. All new compounds show HRMS data in agreement with
the expected structure. The a configuration in 16 was
deduced from NMR data: protons H-3 and H-4 appear
as singlets, indicating and all trans relationship for pro-
tons H-2, H-3, H-4, H-5. This was further ascertained by
comparing ROESY data for the N-PMB derivatives cor-
responding to 16 and 19 (the presence of rotamers pre-
cludes direct ROESY analysis of 16 and 19). Notable
features include: for the ‘19-derived PMB’, strong
‘through space’ interactions between H-2 and H-3/H-5,
which are absent in the other PMB derivative. The posi-
tive NOE effect between protons 3 and 7 in 5 is indicative
of an exo location for the phosphonate group. NMR
data for selected compounds are listed below:
1
1
16: H NMR (400 MHz, 393 K, C2D2Cl4) l 2.34 (1H, dt,
5: H NMR (500 MHz, 300 K, C6D6) l 1.37 (3H, d, J=7
J=15, 15, 11 Hz, H-7), 2.6 (1H, broad, H%-7), 3.60–3.71
(7H, m, H-6+2×OCH3), 3.96 (1H, broad, H%-6), 4.22 (1H,
dd, J=10, 6 Hz, H-5), 4.25 (1H, s, H-3 or H-4), 4.30 (1H,
ddd, J=10.8, 6, 2.4 Hz, H-2), 4.42 (1H, s, H-4 or H-3),
4.47 (1H, d (ABq), J=12 Hz, -OCHaHbPh), 4.45–4.65
(5H,-overlapping Abq’s, -OCH2Ph), 5.15 (1H, d (ABq),
J=12 Hz, -C(ꢀO)OCHaHbPh), 5.24 (1H, d (ABq), J=12
Hz, -C(ꢀO)OCHaHbPh), 7.3–7.4 (20H, m, Ph).
Hz, CH3), 2.2 (1H, ddd, J=20.5, 11.5, 9 Hz, H-7), 3.02
(1H, ddd, J=17, 11.5, 7 Hz, H-8), 3.27 (3H, d, 10.5 Hz,
-OCH3), 3.29 (3H, d, 10.5 Hz, -OCH3), 3.52 (1H,
dd, J=9.5, 6 Hz, H-6), 3.58 (1H, t, J=9.5 Hz, H%-6),
3.93 (1H, broad s, H-3), 4.18 (1H, Abq, J=11.5 Hz,
-OCH2Ph), 4.23 (1H, ddd, J=15.5, 9, 3.5 Hz, H-2), 4.26
(1H, Abq, J=12 Hz, -OCH2Ph), 4.28 (1H, broad s, H-4),
4.30 (1H, Abq, J=9, 6 Hz, H-5), 7.06–7.33 (15H, m, Ph).
12. Selenoxide elimination is known to be syn indicating a
7(S) starting selenide. The other isomer should then give
rise to E-18. The observed E/Z mixture may result from
equilibration prior or following selenenic acid elimina-
tion. We favour the first possibility, considering the
strong acidic character of proton H-7 in the selenoxide
derived from 15.
1: 1H NMR (250 MHz, 300 K, D2O) l 3.79 (1H, dd,
J=9.4, 3.6 Hz, H-6), 3.90 (1H, m, H-5), 3.97 (1H, dd,
J=9.4, 3.7 Hz, H%-6), 4.12 (1H, t, J=5.3 Hz, H-4), 4.78
(1H, t, J=5.3 Hz, H-3), 7.73 (1H, broad s, H-2).
2: 1H NMR (250 MHz, 300 K, D2O) l 1.98 (2H, dd,
J=17.2, 7.3 Hz, H-1+H%-1), 3.52 (1H, m, H-5), 3.59 (1H,
m, H-2), 3.79 (1H, dd, J=12.6, 6.2 Hz, H-6), 3.90 (1H,