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

Article abstract of DOI:10.1016/j.tetlet.2004.11.101

A short synthetic route to (-)-and (+)-bulgecinine, the amino acid moiety of the bulgecins was achieved from the readily available nonchiral pool starting material cis-2-butene-1,4-diol employing a Claisen orthoester rearrangement and Sharpless asymmetric

Full text of DOI:10.1016/j.tetlet.2004.11.101

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 439–441
An efficient stereoselective synthesis of (2S,4S,5R)-(ꢀ)-
and (2R,4R,5S)-(+)-bulgecinine
Subhash P. Chavan,* Cherukupally Praveen, Pallavi Sharma and U. R. Kalkote
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 17 August 2004; revised 12 November 2004; accepted 17 November 2004
Abstract—A short synthetic route to (ꢀ)-and (+)-bulgecinine, the amino acid moiety of the bulgecins was achieved from the readily
available nonchiral pool starting material cis-2-butene-1,4-diol in which a Claisen orthoester rearrangement and a Sharpless asym-
metric dihydroxylation were used as the key steps.
Ó 2004 Elsevier Ltd. All rights reserved.
Bulgecinine 1 is an amino acid constituent of naturally
occurring antibiotic glycopeptides called bulgecins (2,
3), isolated from Pseudomonas acidophila and Pseudo-
monas mesoacidophila1 bulgecins although devoid of
antibacterial activity, induce characteristic morphologi-
cal changes, called bulge formation, in the cell wall of
Gram-negative bacteria in co-operation with b-lactam
antibiotics. As a result of bulge formation, the activity
of these antibiotics is effectively enhanced and the bacte-
ria are killed at lower b-lactam concentrations. The
structure of (ꢀ)-bulgecinine 1 has been determined
chemically and crystallographically to be (2S,4S,5R)-4-
hydroxy-5-hydroxymethyl proline.2
OH
O
NaO3SO
HO
O
NHAc
HO
COOR
N
H
2 Bulgecin A :R = NHCH2CH2SO3H
3 Bulgecin B :
R = NHCH2CH2COOH
HO
HO
HO
HO
COOH
COOH
N
H
N
H
(+)-Bulgecinine 4
(-)-Bulgecinine 1
As a consequence of their biological effects3 and struc-
tural novelty, several total syntheses of (ꢀ)-bulgecinine
have been reported in the literature.4 Herein we describe
our strategy involving a Sharpless asymmetric dihydr-
oxylation approach for the synthesis of (ꢀ)- and (+)-
bulgecinine. In connection with our current studies di-
rected towards the construction of biologically active
compounds from the versatile intermediate 6,5 we fo-
cused our attention on the stereoselective synthesis of
(ꢀ)- and (+)-bulgecinine starting from the readily avail-
able nonchiral pool starting material cis-2-butene-1,4-
diol.
Br
O
O
O
HO
O
BocNH
BnO
BnO
OH
BnO
5
6
7
Scheme 1. Retrosynthetic analysis of 1.
from the hydroxylactone 6, which in turn was obtained
from the allyl alcohol 7.
The retrosynthetic analysis for our planned synthesis of
(ꢀ)-bulgecinine is shown in Scheme 1. The bromolac-
tone 5, the precursor to bulgecinine, could be obtained
As outlined in Scheme 2, the enantiomerically pure
hydroxylactone 6, was obtained in four steps from cis-
2-butene-1,4-diol 8, in which a Claisen orthoester rear-
rangement and a Sharpless asymmetric dihydroxylation
were used as the key steps to install the requisite chiral-
ity. Mesylation of the hydroxylactone 6 using MsCl and
*
Corresponding author. Tel./fax: +91 20 5893614; e-mail: spchavan@
dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.101

440
S. P. Chavan et al. / Tetrahedron Letters 46 (2005) 439–441
O
O
O
OH
OH
O
d
O
O
c
b
ref 5a
a
MsO
BnO
N3
HO
COOC2H5
BnO
BnO
BnO
10
11
9
8
6
Br
O
HO
HO
HO
O
e
O
g
h
f
O
BocNH
HO
BocNH
BnO
HO
BnO
COOH
N
COOR
COOH
N
H
N
.HCl
H
H
BnO
R = CH3
1
14
15
12
13
5
R = H
Scheme 2. Reagents and conditions: (a) AD-mix-a, CH3SO2NH2, t-BuOH–H2O (1/1), 24 h, 0 °C, 95%, 93% ee; (b) CH3SO2Cl, Et3N, DMAP, DCM,
0 °C, 4 h, 92%; (c) NaN3, DMF, 90 °C, 24 h, 89%; (d) H2, 10% Pd–C, Et3N, Boc2O, EtOAc, rt, 2 h, 88%; (e) LiHMDS, TMSCl, Et3N, NBS, THF,
ꢀ78 °C, 2 h, 65%; (f) (i) CF3COOH, DCM, 60 °C, 3 h, (ii) 0.1 N Ba(OH)2, pH = 9, 3 h, (iii) dil HCl, Amberlite-IR-120, 24 h, (iv) 6 N NH4OH (aq),
3 h; (g) 10% Pd–C, methanolic HCl, rt, 24 h; (h) 1 M NaOH, rt, 92% (over three steps).
Et3N in the presence of a catalytic amount of DMAP
gave the mesylated lactone 10. Displacement of the mes-
ylate with NaN3 at 90 °C in DMF gave the azidolactone
11. Catalytic hydrogenation of the azido lactone over
10% Pd–C in ethyl acetate in the presence of Boc2O gave
the Boc protected lactone 12.
hydroxylactone 6, which in turn was obtained from the
readily available cis-2-butene-1,4-diol, as the common
achiral precursor. The syntheses of other biologically
active compounds from the versatile intermediate 6 are
being investigated in our laboratory.
The challenging task in our synthesis was to introduce
the bromine stereoselectively at C-2 of the lactone 12.
This was achieved using LiHMDS, Et3N and NBS at
ꢀ78 °C for 2 h. The major isomer 5 along with its diaste-
reomer (9:1 ratio) was separated by silica gel column
chromatography. The conditions developed by Oppol-
zer6 were adapted to convert the major isomer
(2R,4S,5R)-5 into the (2S,4S,5R)-13 using the following
sequence of reactions. The lactone 5 was refluxed in
DCM with 10 molequiv of CF3COOH for 3 h followed
by evaporation of the solvent. The residue was then dis-
solved in 0.1 N Ba(OH)2 and the mixture maintained at
pH 9 for 3 h. Acidification to pH 1, stirring the aqueous
solution with Amberlite-IR-120 ion-exchange resin for
24 h, filtration, washing the resin with distilled water
(until it showed clear solution with AgNO3 to test the
complete removal of Clꢀ), stirring the resin with 6 N
aqueous NH4OH solution for 3 h and filtration gave
the benzyl protected (2S,4S,5R)-(ꢀ)-bulgecinine 13. Re-
moval of the benzyl protection was performed using Pd/
C in methanolic HCl under normal hydrogen pressure
and at room temperature to deliver a mixture of (ꢀ)-
bulgecinine hydrochloride 15 and its methyl ester 14.
This mixture was subjected to basic hydrolysis using
1 M NaOH to deliver (ꢀ)-bulgecinine 1.
Acknowledgements
C.P. and P.S. thank CSIR (New Delhi) for research
fellowships. Funding from DST to S.P.C. is gratefully
acknowledged.
References and notes
1. (a) Imada, A.; Kintaka, K.; Nakao, M.; Shinagawa, S. J.
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3. For biological studies see (a) van Asselt, E. J.; Kalk, K. H.;
Dijkstra, B. W. Biochemistry 2000, 39, 1924–1934; (b)
Thunnissen, A. M. W. H.; Rozeboom, H. J.; Kalk, K. H.;
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Templin, M. F.; Edwards, D. H.; Hoeltje, J. Y. J. Biol.
Chem. 1992, 267, 20039–20043, and references therein.
4. For earlier syntheses of (ꢀ)-bulgecinine, see (a) Kharaf, J.
K.; Datta, A. J. Org. Chem. 2004, 69, 387–390; (b) Holt, K.
A.; Swift, J. P.; Smith, M. E. B.; Taylor, S. J. C.; McCague,
R. Tetrahedron Lett. 2002, 43, 1545–1548; (c) Krasinski, A.;
Jurczak, J. Tetrahedron Lett. 2001, 42, 2019–2021; (d) Burk,
M. J.; Allen, J. G.; Kiesman, W. F. J. Am. Chem. Soc. 1998,
120, 657–663; (e) Maeda, M.; Okazaki, F.; Murayama, M.;
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try 1997, 8, 2001–2005; (i) Graziani, L.; Porzi, G.; Sandri, S.
Tetrahedron: Asymmetry 1996, 7, 1341–1346; (j) Yuasa, Y.;
Ando, J.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1996,
793–802; (k) Madau, A.; Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 1996, 7, 825–830; (l) Schmeck, C.; Hegedus, L.
S. J. Am. Chem. Soc. 1994, 116, 9927–9934; (m) Jackson,
Accordingly we also prepared (+)-bulgecinine 4 follow-
ing the same sequence of reactions from the opposite
enantiomer of hydroxylactone 6, which was prepared
from the c,d-unsaturated ester 9 using AD-mix-b. The
physical and spectroscopic data of all the synthetic inter-
mediates were in good agreement with the proposed
structures and those of 1 and 4 are in good agreement
with the literature data.7
In summary (+)-and (ꢀ)-bulgecinine were synthesized in
an efficient overall yield of 43% in seven steps from the

S. P. Chavan et al. / Tetrahedron Letters 46 (2005) 439–441
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4760.
C14H18O6S; C, 53.49; H, 5.77; S, 10.2%. Found: C, 53.62;
24
H, 5.86; S, 10.38%. Compound 11: ½aꢁD ꢀ 15:83 (c 1,
CHCl3). 1H NMR (500 MHz, CDCl3) d, ppm: 2.12 (1H, m),
2.23 (1H, m), 2.44–2.59 (2H, m), 3.62 (1H, dd, J = 10.1,
6.4 Hz), 3.66 (1H, dd, J = 10.1, 4.6 Hz), 3.79 (1H, m), 4.55
(3H, m), 7.32 (5H, m). 13C NMR (125 MHz) d: 23.1, 27.6,
63.0, 68.9, 73.1, 77.6, 127.3, 128.2, 137.1, 175.7 ppm. Anal.
Calcd for C13H15NO3: C, 59.77; H, 5.76; N, 16.08%. Found:
24
C, 59.57; H, 5.84; N, 16.19%. Compound 12: ½aꢁD þ 1:87 (c
1
1, CHCl3). H NMR (200 MHz, CDCl3) d, ppm: 1.39 (9H,
s), 2.15 (2H, m), 2.43 (2H, m), 3.50 (1H, dd, J = 9.4,
3.5 Hz), 3.68–3.80 (2H, m), 4.45–4.56 (3H, m), 5.10 (1H, d,
J = 9.3 Hz), 7.28 (5H, m). 13C NMR (125 MHz) d: 24.4,
27.8, 28.1, 52.9, 68.8, 73.3, 78.5, 79.6, 127.5, 128.2, 137.5,
155.3, 176.2 ppm. Anal. Calcd for C18H25NO5: C, 64.46; H,
7.51; N, 4.17%. Found: C, 64.38; H, 7.32; N, 4.08%.
24
Compound 5: ½aꢁD þ 10:50 (c 1, CHCl3). 1H NMR
5. (a) Chavan, S. P.; Praveen, C. Tetrahedron Lett. 2004, 45,
421–423; (b) Chavan, S. P.; Praveen, C.; Ramakrishna, G.;
Kalkote, U. R. Tetrahedron Lett. 2004, 45, 6028–6077.
6. Oppolzer, W.; Moretti, R.; Zhou, C. Helv. Chim. Acta
1994, 77, 2363–2380.
(200 MHz, CDCl3) d, ppm: 1.36 (9H, s), 2.42 (1H, ddd,
J = 8.2, 5.9, 2.3 Hz), 2.68 (1H, m), 3.52 (1H, dd, J = 9.8, 3.5
Hz), 3.80 (2H, m), 4.42 (1H, dd, J = 6.6, 2.3 Hz), 4.51 (2H,
m), 4.78 (1H, m), 5.10 (1H, d, J = 9 Hz), 7.26 (5H, m). 13C
NMR (125 MHz) d: 28.3, 36.8, 38.3, 52.8, 68.7, 73.5, 77.5,
80.0, 127.7, 128.4, 137.4, 155.3, 171.6 ppm. Anal. Calcd for
C18H24NO5Br; C, 52.18; H, 5.83; N, 3.37; Br, 19.28%.
Found: C, 52.07; H, 5.97; N, 3.36; Br, 19.06%. Compound
7. All new compounds were characterized and gave satisfac-
24
tory spectral data. Compound 6: ½aꢁD þ 40:59 (c 1, CHCl3).
1H NMR (200 MHz, CDCl3) d, ppm: 2.25 (2H, m), 2.48
(2H, m), 2.69 (1H, m), 3.59 (2H, m), 3.84 (1H, m), 4.57 (3H,
m), 7.33 (5H, m). 13C NMR (50 MHz) d: 23.3, 28.1, 70.5,
71.6, 73.1, 79.9, 127.5, 128.1, 137.5, 177.7 ppm. Anal. Calcd
for C13H16O4: C, 66.09; H, 6.83%. Found: C, 65.99; H,
24
1
13: ½aꢁD ꢀ 8:09 (c 1, H2O). H NMR (500 MHz, D2O) d,
ppm: 2.11 (1H, ddd, J = 14.1, 6.2, 4.3 Hz), 2.51 (1H, ddd,
J = 14.1, 9.0, 5.8 Hz), 3.56–3.71 (3H, m), 4.06 (1H, dd,
J = 9.0, 6.6 Hz), 4.23 (1H, m), 4.49 (2H, m), 7.32 (5H, m).
13C NMR (125 MHz) d: 36.2, 59.1, 64.8, 65.7, 70.6, 72.8,
128.0, 128.4, 136.7, 173.6 ppm. Anal. Calcd for C13H17NO4:
C, 62.14; H, 6.81; N, 5.57%. Found: C, 62.02; H, 6.92; N,
24
1
6.77%. Compound 10: ½aꢁD þ 8:31 (c 1, CHCl3). H NMR
(500 MHz, CDCl3) d, ppm: 2.26 (1H, m), 2.36 (1H, m),
2.46 (1H, ddd, J = 16.9, 10.1, 6.4 Hz), 2.67 (1H, ddd,
J = 16.9, 9.6, 6.4 Hz), 3.06 (3H, s), 3.71 (1H, dd, J = 10.5,
3.6 Hz), 3.83 (1H, dd, J = 10.5, 7.3 Hz), 4.55 (2H, m), 4.68
(1H, ddd, J = 8.2, 5.5, 3.2 Hz), 4.80 (1H, m), 7.32 (5H, m).
13C NMR (125 MHz) d: 23.5, 27.3, 38.6, 66.9, 73.3, 77.5,
81.7, 127.7, 128.3, 136.9, 176.0 ppm. Anal. Calcd for
24
1
5.49%. Compound 1: ½aꢁD ꢀ 13:3 (c 0.9, H2O). H NMR
(200 MHz, D2O) d, ppm: 2.11 (1H, ddd, J = 14.5, 6.3,
4.6 Hz), 2.58 (1H, ddd, J = 14.5, 9.0, 5.9 Hz), 3.56–3.71
(3H, m), 4.06 (1H, dd, J = 9.0, 6.6 Hz), 4.34 (1H, m), 13C
NMR (75 MHz) d: 37.2, 59.2, 60.5, 66.2, 71.7, 174.7 ppm.