Diastereoselective syntheses of α-amino-β-hydroxyesters precursors of the ribosyl-diazepanone core of the liposidomycins

Article abstract of DOI:10.1016/S0040-4039(03)00460-X

The diastereoselective syntheses of the O-protected ribosyl-β-hydroxy-α-amino esters 3 and 4, precursors of α-ribosyl-diazepanone core analogues of the liposidomycins, respectively, from the β-ketoesters 5 and 6 are described. The anti relationship between the two adjacent aminated and hydroxylated carbons was controlled by sequential hydrogenation of the β-ketoesters in the presence of chiral ruthenium catalysts and electrophilic amination of the resulting β-hydroxyesters.

Full text of DOI:10.1016/S0040-4039(03)00460-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2781–2783
Diastereoselective syntheses of a-amino-b-hydroxyesters
precursors of the ribosyl-diazepanone core of the liposidomycins
Bruno Drouillat, Olivia Poupardin,† Yann Bourdreux and Christine Greck*
Laboratoire SIRCOB, UMR CNRS 8086, Universite´ de Versailles Saint-Quentin-en-Yvelines, 45 avenue des Etats-Unis,
78035 Versailles Ce´dex, France
Received 31 January 2003; revised 18 February 2003; accepted 19 February 2003
Abstract—The diastereoselective syntheses of the O-protected ribosyl-b-hydroxy-a-amino esters 3 and 4, precursors of a-ribosyl-
diazepanone core analogues of the liposidomycins, respectively, from the b-ketoesters 5 and 6 are described. The anti relationship
between the two adjacent aminated and hydroxylated carbons was controlled by sequential hydrogenation of the b-ketoesters in
the presence of chiral ruthenium catalysts and electrophilic amination of the resulting b-hydroxyesters. © 2003 Elsevier Science
Ltd. All rights reserved.
The liposidomycins represent a class of complex
nucleoside antibiotics isolated from Streptomyces
griseosporeus.1 They inhibit the formation of the lipid
intermediate in bacterial peptidoglycan synthesis.2 The
structure of the liposidomycin A, B 1 and C 2 are
identical except for slight variations in the lipid
portion.3
We propose here the diastereoselective syntheses of
O-protected a-amino-b-hydroxyesters 3 and 4 which
could be the key intermediates in a convergent
approach to analogues of the ribosyldiazepanone core.
The compounds 3 and 4 were obtained with complete
anti stereoselectivity at C2ꢀC3 from the corresponding
b-ketoesters 5 and 6 by catalytic hydrogenation fol-
lowed by electrophilic amination of the resulting b-
hydroxyesters. To our knowledge the diastereoselective
catalytic hydrogenation of b-ketoester bearing a glyco-
syl moiety at C3 has never been reported.
However, the relative and absolute configurations at
C-5%, C-6%, C-2%%% and C-3%%% of the ribosyl-diazepanone
core remained unassigned for many years. Very recently
the absolute configurations were proposed by Knapp
and co-workers4 for these four stereocentres as 5%S, 6%S,
2%%%S and 3%%%S. Various approaches to the synthesis of
derivatives of the common a-ribosyl-diazepanone core
of the liposidomycins have been reported.4–7
The synthesis of the O-protected (2S,3R)-methyl 2-
amino-3-t-butyldimethylsilyloxy-4,4-dimethoxybutano-
ate 3 was performed from 5 in five steps. The syn-
thesis of the enantiomer of the compound 7 was
previously described.8 The use of RuCl2[(S)-Binap]–
Et3N9 as catalyst for the hydrogenation step afforded 7
with comparable yield and stereoselectivity. The
* Corresponding author. Tel.: 33(1)39254474; fax: 33(1)39254452;
e-mail: greck@chimie.uvsq.fr
† PhD thesis, 2000; Laboratoire de Synthe`se Organique (UMR 7553),
Ecole Nationale Supe´rieure de Chimie de Paris, 11 rue Pierre et
Marie Curie, 75231 Paris Ce´dex 05, France.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00460-X

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B. Drouillat et al. / Tetrahedron Letters 44 (2003) 2781–2783
hydroxyl function was protected as a t-butyldimethylsil-
yl ether to give 8 in 88% yield because the cleavage of
the NꢀN bond could not be performed in the presence
of an alcohol. The benzylcarbamates were first removed
by hydrogenolysis in the presence of Pd/C. The best
results for the cleavage of the resulting hydrazine were
obtained with H2 in the presence of Raney-Ni and the
O-protected a-amino-b-hydroxyester 310 was isolated in
72% yield from 8 (Scheme 1).
Scheme 2. Reagents and conditions: (a) i. Im2CO 1.3 equiv.,
THF, 16 h, 20°C, ii. Mg(MeOOCCH2COO-)2 1.3 equiv., 16 h,
60%; (b) H2 1 atm, RuBr2L2 0.02 equiv. (for 10a, L2: (S)-
Binap and for 10b, L2: (R)-Binap), MeOH, 16 h, 40°C, quant.
yield; (c) MeZnBr 1.1 equiv., THF, 30 min, 0°C; LDA 2.2
equiv., 1 h, −78°C; CbzNꢁNCbz 2 equiv., −78°C; satd aq.
NH4Cl, 59% (de >95%) for 11a and 56% (de >95%) for 11b.
Scheme 1. Reagents and conditions: (a) H2 1 atm, RuCl2[(S)-
Binap]–Et3N 1%, MeOH, 65°C, 18 h, 91% (ee=90%); (b)
MeZnBr 1.1 equiv., THF, 30 min, 0°C; LDA 2.2 equiv., 1 h,
−78°C; CbzNꢁNCbz 2 equiv., −78°C; satd aq. NH4Cl, 66%
(de >95%); (c) TBDMSOTf 1.5 equiv., 2,6-lutidine 2 equiv.,
DCM, −78°C, 88%; (d) i. H2 1 atm, Pd/C 10%, MeOH, 1.5 h,
20°C, ii. H2 1 atm, Raney-Ni, MeOH, 18 h, 72%.
Raney-Ni. Under these conditions, 11a and 11b
afforded 12a and 12b, respectively, in 75% yield. A
synthesis of 12a based on the aldol condensation of a
chiral glycine enolate has been described with a de of
64%.16 The synthesis of the N-methylated a-amino-b-
hydroxyester 4 was achieved from 12b. The reduction
of its benzophenone Schiff base derivative followed by
reductive N-methylation afforded 13 in 74% yield. The
hydroxyl function was then silylated and the benzhydril
group hydrogenolysed to give 417 in 95% yield from 13
(Scheme 3).
The
steps from
D
-ribose acid derivative 9 was prepared in two
-ribose.11 The b-ketoester 6 was easily
D
obtained by homologation of the carboxylic acid func-
tion of 9 using the Masamune procedure.12 Partial
epimerisation at C4 was noticed, however optically pure
b-ketoester 6 was isolated by recrystallisation from
diisopropyl ether. 6 was first reduced with sodium
borohydride and a mixture of diastereomers 10a:10b in
a 75:25 ratio was obtained. The b-hydroxyesters 10a
and 10b were easily separated by silica gel chromatog-
raphy. Catalytic hydrogenations of 6 were conducted in
methanol at 40°C under atmospheric pressure in the
presence of 2% mol. of chiral ruthenium(II)
complexes13 and afforded the b-hydroxyesters 10 in
quantitative yield. With RuBr2[(R)-Binap], the
diastereomeric ratio was 90:10 in favour of 10a. The use
of RuBr2[(S)-Binap] yielded 10b as the major
diastereomer in
a
10a:10b ratio of 5:95.14 The
diastereoselectivity of the hydrogenation of the opti-
cally pure b-ketoester 6 bearing a ribosyl moiety at C3,
with chiral ruthenium catalysts was completely con-
trolled by the chirality of the diphosphane ligand in the
ruthenium complex. The diastereoselective amination
step was carried out with dibenzylazodicarboxylate as
electrophilic reagent because the conditions of depro-
tection of benzylcarbamates are compatible with the
presence of an acetal function on the ribosyl moiety.
The zinc enolates of the b-hydroxyesters 10 were gener-
ated using methyl zinc bromide and lithium diisopropyl-
amide,15 their reaction with the dibenzylazodicar-
boxylate produced exclusively the anti diastereomers
11a and 11b with 59 and 56% isolated yield respectively
(Scheme 2).
Scheme 3. Reagents and conditions: (a) H2 1 atm, MeOH,
Raney-Ni, 24 h; (b) i. Ph2CꢁNH 1.05 equiv. DCM, MeOH
satd HCl cat., 24 h, ii. NaBH3CN 3 equiv., MeCN, AcOH
cat., 2 h, iii. aq. HCHO 15 equiv., NaBH3CN 13 equiv.,
AcOH cat., 24 h; (c) TBDMSOTf 3 equiv., 2,6-lutidine 4
equiv., DCM, 16 h; (d) H2 1 atm, DCM/MeOH, Pd/C, 16 h.
Hydrogenolyses of the benzylcarbamates and of the
NꢀN bond occurred simultaneously under catalysis of

B. Drouillat et al. / Tetrahedron Letters 44 (2003) 2781–2783
2783
4417; (b) Ubukata, M.; Kimura, K.; Isono, K.; Gregson,
J. M.; McCloskey, J. A. J. Org. Chem. 1992, 57, 6392–
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4. Knapp, S.; Morriello, G. J.; Doss, G. A. Org. Lett. 2002,
4, 603–606 and references cited therein.
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9. Kawano, H.; Ikariya, T.; Ichii, Y.; Saburi, M.;
Yoshikawa, S.; Uchida, Y.; Kumobayashi, A. J. Chem.
Soc., Perkin Trans. 1 1989, 1571–1575.
10. Compound 3 [h]2D5=+23 (c 0.7, CHCl3).
11. Hampton, A.; Perini, F.; Harper, P. J. Carbohydr. Res.
1974, 37, 359–367.
12. Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew.
Chem., Int. Ed. Engl. 1979, 18, 72–74.
13. Geneˆt, J. P.; Ratovelomanana-Vidal, V.; Can˜o de
Andrade, C.; Pfister, X.; Guerreiro, P.; Lenoir, J. Y.
Tetrahedron Lett. 1995, 36, 4801–4804. Review:
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Chem. 1998, 567, 163–171.
14. Compound 10a: oil; Rf: 0.64 (diethyl ether/pentane 75/
25), [h]2D5=−37 (c 1.7, CH2Cl2). Compound 10b: white
solid; mp 31–32°C (iPr2O); Rf: 0.60 (diethyl ether/pentane
75/25), [h]2D5=−45 (c 1.0, CH2Cl2).
15. (a) Greck, C.; Geneˆt, J. P. Synlett 1997, 741–748; (b)
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Scheme 4. X-Ray structure of 14.
Relative and absolute configurations of the stereocen-
tres were confirmed by crystallographic analysis. The
X-ray structure of compound 1418 shows an anti rela-
tionship between the two adjacent aminated and
hydroxylated carbons with C5 (R) and C6 (S) absolute
configurations, respectively, in 75% yield (Scheme 4).
In conclusion, we propose here the syntheses of the
O-protected anti-a-amino-b-hydroxyesters 3 and 4 (or
12a) precursors of 5%-epi (or 6%-epi) analogues of the
ribosyldiazepanone core of the liposidomycins. These
compounds were obtained with high enantio and
diastereoselectivities. Coupling and cyclisation are
under progress in our laboratory. Furthermore, we
described the catalytic hydrogenation of the chiral b-
ketoester bearing a ribosyl moiety 6 and showed the
stereochemistry of the created hydroxyl centre was con-
trolled by the catalyst.
17. Compound 4 [h]2D5=−21 (c 1.0, CH2Cl2).
18. X-Ray quality crystals of 14 were obtained by slow
evaporation from a methanol–water solution. Atomic
coordinates, bond distances and angles, and anisotropic
displacement parameters have been deposited with the
Cambridge Crystallographic Data Centre (CCDC) as
deposition No. CCDC 201717. Colourless crystal; mp
120°C, [h]2D5=−77 (c 1.1, CH2Cl2). IR (KBr) 3058, 2956,
1
2926, 2850, 1734 (CꢁO), 1492, 1471, 1252, 1092, 741. H
References
NMR (300 MHz, CDCl3): 0.03 (s, 3H), 0.10 (s, 3H), 0.79
(s, 9H), 1.41 (s, 3H), 1.64 (s, 3H), 2.33 (s, 1H), 3.46 (s,
3H), 3.56 (s, 3H), 3.60 (d, 1H, J=9 Hz), 4.38 (dd, 1H,
J=3.7 and 7 Hz), 4.42 (dd, 1H, J=2 and 9 Hz), 4.55–
4.57 (m, 1H), 4.59 (s, 1H), 4.74 (dd, 1H, J=3.7 and 7
Hz), 4.92 (d, 1H, J=3.7), 7.18–7.30 (m, 6H), 7.41–7.46
(m, 4H). 13C NMR (75.5 Hz, CDCl3): −5.2, −3.5, 18.2,
25.7, 25.9, 27.2, 35.4, 50.5, 57.0, 65.8, 71.3, 74.6, 77.2,
83.3, 84.4, 109.4, 114.1, 126.8, 127.0, 128.0, 128.1, 128.3,
128.7, 141.6, 142.8, 170.5; Anal. calcd for C32H47NO7Si:
C, 65.61; H, 8.09; N, 2.39. Found: C, 65.54; H, 8.23; N,
2.46.
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