An efficient stereoselective synthesis of (2S,4S,5R)-(-)-bulgecinine

Article abstract of DOI:10.1016/S0040-4039(01)00071-5

N-Benzyl-N-carbobenzyloxy-O-tert-butyldimethylsilyl-d-serinal (6) was reacted under Barbier conditions with allyl bromide affording diastereoselectively (82:18) the anti-adduct 5, which was subsequently transformed into (2S,4S,5R)-(-)-bulgecinine (1).

Full text of DOI:10.1016/S0040-4039(01)00071-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2019–2021
An efficient stereoselective synthesis of
(2S,4S,5R)-(−)-bulgecinine
Antoni Krasin´skia and Janusz Jurczaka,b,
*
aInstitute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
bDepartment of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
Received 29 November 2000; revised 18 December 2000; accepted 10 January 2001
Abstract—N-Benzyl-N-carbobenzyloxy-O-tert-butyldimethylsilyl-D-serinal (6) was reacted under Barbier conditions with allyl
bromide affording diastereoselectively (82:18) the anti-adduct 5, which was subsequently transformed into (2S,4S,5R)-(−)-
bulgecinine (1). © 2001 Elsevier Science Ltd. All rights reserved.
a-Amino aldehydes are synthetically useful chirons,
readily available from naturally occurring a-amino
acids.1 In our recent studies, involving the synthesis of
antibiotic amino sugars, we have shown that suitably
protected a-amino aldehydes are versatile chirons.2 For
example, addition of allyltrimethylsilane to N-mono-
and N,N-diprotected a-amino aldehydes offers an easy
access to almost enantiomerically pure both syn- and
anti-adducts,3 which are readily transformed into natu-
ral products, such as 3-hydroxyproline,4 1,3-dideoxy-
nojirimycin,5 statine,6 and preussin.7
Now we report a new application of our methodology
to the stereoselective synthesis of (2S,4S,5R)-(−)-bulge-
cinine (1), an amino acid constituent of naturally occur-
ring antibiotic glycopeptides called bulgecins, isolated
from Pseudomonas acidophila and Pseudomonas
mesoacidophila.8 While bulgecins themselves show no
Scheme 1. Retrosynthetic analysis.
Keywords: asymmetric induction; amino aldehydes; allylation; epoxidation; cyclization; pyrrolidines.
* Corresponding author. Tel.: +00 48 22 632 05 78; e-mail: jurczak@icho.edu.pl
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00071-5

2020
A. Krasin´ski, J. Jurczak / Tetrahedron Letters 42 (2001) 2019–2021
biological activity, they are synergists with some b-lac-
tam antibiotics found in the above-mentioned culture
broths. These properties make (−)-bulgecinine an
attractive synthetic target.9
(Scheme 2). Olefin 5, obtained in pure form via column
chromatography, was subjected to the vanadium-
catalysed epoxidation reaction,13 furnishing in 79%
yield a chromatographically inseparable mixture of
diastereoisomeric epoxides 8 (of syn relation between
hydroxy and epoxy groups) and 9 (anti ) in a ratio of
76:24. Protection of the secondary hydroxy group, with
acetic anhydride in pyridine, afforded a still inseparable
mixture of epoxides 4 and 10 in 90% overall yield.
Hydrogenation of this mixture, on palladium-on-char-
coal as a catalyst, caused deprotection of the amino
group and subsequent cyclisation to afford a mixture of
diastereoisomeric pyrrolidines, which after treatment
with benzyl chloroformate (protection of the secondary
amino group) was subjected to chromatographic sepa-
ration giving two pure diastereoisomers 314 and 1115 in
Retrosynthetic analysis, shown in Scheme 1, suggested
that suitably protected
D-serinal could serve as a start-
ing material. On the basis of our earlier investigations
we assumed the use of an N,N-diprotected derivative of
D
-serine.5,10 Among several possible candidates we
selected
methylsilyl-
N-benzyl-N-carbobenzyloxy-O-tert-butyldi-
D
-serinal (6).11
Allyl addition to aldehyde 6, carried out under Barbier
conditions at room temperature, afforded diastereose-
lectively (5:7–82:18) the anti-adduct 5 in 96% yield
Scheme 2. Reagents and conditions: (a) AllBr, Zn, satd aq. NH4Cl, THF, rt; (b) t-C4H9OOH, VO(acac)2 cat., CH2Cl2, rt; (c)
Ac2O, Py, DMAP cat., rt; (d) H2, 5% Pd/C, CH3OH, rt; (e) ClCO2CH2Ph, CH2Cl2, satd aq. NaHCO3, rt; (f) NaIO4, RuCl3 cat.,
CH3CN–CCl4–H2O 2:2:3, 0°C; (g) 3 M aq. HCl, THF, reflux.

A. Krasin´ski, J. Jurczak / Tetrahedron Letters 42 (2001) 2019–2021
2021
the same ratio as their precursors 8 and 9 (Scheme 2).
The major diastereoisomer 3, isolated in 65% yield
(calculated from the mixture of epoxides 8 and 9), was
subjected to ruthenium-catalysed oxidation16 furnishing
protected (−)-bulgecinine (2) in 80% yield. Deprotection
of both hydroxy groups by heating in a mixture of 3 M
aqueous HCl with THF (2:3), followed by Pd/C hydro-
genation of the benzyl carbamate, completed the syn-
thesis of (2S,4S,5R)-(−)-bulgecinine (1) in 24% overall
yield (calculated from 6) with the correct stereochem-
istry. All analytical data, including [h]D −13.5 (c 0.95,
H2O), are in agreement with those previously
reported8,9 (lit. [h]D −13.1 (c 0.95, H2O)).8b
Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem. 1990,
55, 5194; (g) Barrett, A. G. M.; Pilipauskas, D. J. Org.
Chem. 1991, 56, 2787; (h) Hirai, Y.; Terada, T.;
Amemiya, Y.; Momose, T. Tetrahedron Lett. 1992, 33,
7893; (i) Oppolzer, W.; Moretti, R.; Zhou, C. Helv. Chim.
Acta 1994, 77, 2363; (j) Madau, A.; Porzi, G.; Sandri, S.
Tetrahedron: Asymmetry 1996, 7, 825; (k) Graziani, L.;
Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1996, 7,
1341; (l) Panday, S. K.; Langlois, N. Synth. Commun.
1997, 27, 1373; (m) Maeda, M.; Okazaki, F.; Murayama,
M.; Tachibana, Y.; Aoyagi, Y.; Ohta, A. Chem. Pharm.
Bull. 1997, 45, 962; (n) Fehn, S.; Burger, K. Tetrahedron:
Asymmetry 1997, 8, 2001.
10. Gryko, D.; Jurczak, J. Helv. Chim. Acta 2000, 83, 2705.
It is noteworthy that 5 undergoes the Al(Ot-C4H9)3/t-
C4H9OOH epoxidation with anti-selectivity (81:19),
leading to compound 9 as the major diastereoisomer.
This possibility provides selective access to diastereoiso-
mer 11 and, as a consequence, to 2-epi-bulgecinine.
11. The
D
-serine derivative 6 was obtained in 70% overall
-serine methyl ester hydro-
yield via the following route:
D
chloride was treated with 1 equiv. of benzaldehyde and 1
equiv. of triethylamine in methanol, followed by in situ
imine reduction with NaBH4, giving N-benzyl-
methyl ester. Its reaction with benzyl chloroformate
afforded N-Bn-N-Cbz- -serine methyl ester, then the
D-serine
D
Acknowledgements
hydroxy group was protected with TBSCl in DMF, fol-
lowed by reduction of the ester moiety with LiBH4 to
give N-Bn-N-Cbz-O-TBS-D-serinol. Finally, oxidation of
This work was supported by the State Committee for
Scientific Research (Project PBZ 6.05/T09/1999).
this amino alcohol using the TEMPO procedure12
afforded the desired aldehyde 6.
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hedron Lett. 1992, 33, 5029; (b) Jurczak, J.; Gryko, D.;
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1998, 54, 6051.
13. Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am.
Chem. Soc. 1981, 103, 7690.
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