Stereoselective synthesis of (-)-bulgecinine hydrochloride and its C-2 epimer from l-ascorbic acid

Article abstract of DOI:10.1016/j.tetasy.2006.10.033

An efficient strategy for the stereocontrolled synthesis of (-)-bulgecinine hydrochloride 1 was accomplished by utilizing a Wittig Horner olefination, stereoselective reduction of the double bond and intramolecular N-alkylation to furnish the target.

Full text of DOI:10.1016/j.tetasy.2006.10.033

Tetrahedron: Asymmetry 17 (2006) 2864–2869
Stereoselective synthesis of (ꢀ)-bulgecinine hydrochloride
and its C-2 epimer from L-ascorbic acidI
Srivari Chandrasekhar,a,* Gudise Chandrashekar,a
Kandi Vijeendera and Ganti Dattatreya Sarmab
aOrganic Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bNuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 July 2006; accepted 12 October 2006
Abstract—An efficient strategy for the stereocontrolled synthesis of (ꢀ)-bulgecinine hydrochloride 1 was accomplished by utilizing a
Wittig Horner olefination, stereoselective reduction of the double bond and intramolecular N-alkylation to furnish the target.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
isolated from Pseudomonas acidophilia and Pseudomonas
mesoacidophila.5 Interestingly, even though (ꢀ)-bulgeci-
nines have limited antibacterial activity, these compounds
contribute to cell wall changes in Gram-negative bacteria
in association with b-lactam antibiotics. This cell wall
change (bulge formation) allows the efficient killing of
bacteria even at low concentrations of the antibiotic. This
role of decreased concentration of the actual antibiotic
has attracted the attention of researchers involved in the
design and development of new class of antibiotics.
The total synthesis of non-proteinogenic aminoacids is a
challenging goal. This class of aminoacids has not only
provided new insights into the secondary structures of oligo-
peptides1 but also have been the constituents of several bio-
active natural products viz., Echinocandin B,2a Fosinopril,2b
Prolinalin A & B2c and AG-7352.2d The pyrrolidine ring,
which contains the aminoacids has attracted more atten-
tion due to novel folding patterns.3 Furthermore, proline
and its analogues have proven to be excellent organocata-
lysts in asymmetric synthesis.4
The stereochemical structure of (ꢀ)-bulgecinine 1 has been
unequivocally confirmed by extensive spectroscopic and
crystallographic studies and found to be (2S,4S,5R)-4-hydr-
oxy-5-hydroxymethyl proline.6 Due to its novel biological
properties,7 several groups have embarked onto the total
synthesis of this scaffold and have reported successfully
various strategies.8
Bulgecinine 1 is one such aminoacid, a constituent of
antibiotic glycopeptides called bulgecins 2 and 3 (Fig. 1)
OH
O
NaO3SO
O
NHAc
HO
In our efforts towards the development of new protocols9
for the synthesis of a chiral pyrrolidine scaffold as a tool
in probing biological properties and also for building
‘organocatalysis’,10 we herein report a short and scaleable
synthesis of this synthon. The retrosynthetic strategy is
outlined in Scheme 1.
HO
COOR
N
H
2 Bulgecin A: R = NHCH2CH2SO3H
3 Bulgecin B: R = NHCH2CH2COOH
Figure 1.
2. Results and discussion
q IICT Communication No. 061109.
*
The total synthesis of the (ꢀ)-bulgecinine hydrochloride
Corresponding author. Tel.: +91 4027193434; fax: +91 4027160512;
e-mail: srivaric@iict.res.in
salt began from commercially available L-ascorbic acid.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.033

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 2864–2869
2865
HO
HO
HO
HO
COOH
COOH
N
H
N
H
(-) Bulgecinine 1
C-2 epimer 1a
OBn
OBn NHBoc
O
NHBoc
COOEt
CHO
COOEt
EtO
P
O
O
+
O
O
OEt
7
4
5
OH
O
O
HO
HO
OH
L-ascorbic acid
Scheme 1. Retrosynthesis.
The key compound, a-benzyloxy aldehyde 4 was prepared
from known reactions.11 This was quickly subjected to a
Wittig–Horner reaction12 with the phosphonate salt 5 gen-
erated from Boc-Glycine ethyl ester13 to yield compound 6
as an inseparable mixture (6:4 ratio of Z/E) at ꢀ70 ꢁC to rt
in good yield. We attempted to synthesize the pure geo-
metrical isomer of 6 using various conditions but were
unsuccessful.14 The inseparable mixture of compound 6
was subjected to controlled hydrogenation conditions using
different solvents, such as ethanol (low yield and selectiv-
ity), dichloromethane (2:1 ratio of 7:7a, 60% yield) and
ethyl acetate15 (4:1 ratio of 7:7a, 74% yield). Based on these
results, we carried out the hydrogenation of compound 6 in
ethyl acetate and obtained a mixture, which was easily
BnO
NHBoc
COOEt
OH
O
BnO
BnO
NHBoc
COOEt
O
O
O
7
HO
+
CHO
Ref-11
a
b
O
O
BnO
NHBoc
COOEt
O
O
HO
OH
6
L
-ascorbic acid
4
O
7a
O
7 : 7a = 4 : 1
BnO
NHBoc
BnO
NHBoc
COOEt
d
c
e
COOEt
7
TBDMSO
HO
HO
8
HO
9
BnO
HO
HO
g
TBDMSO
f
HO
TBDMSO
COOEt
N
H
COOH
COOEt
N
H
N
10
H
HCl
11
1
Scheme 2. Reagents and conditions: (a) 5, KOBut, CH2Cl2, ꢀ70 ꢁC, 5 h, 82%; (b) 10% Pd/C, H2, Na2CO3, EtOAc, 3 h, 74%; (c) PPTS, EtOH, 55 ꢁC, 24 h,
80%; (d) TBDMSCl, imidazole, CH2Cl2, 6 h, 96%; (e) (i) MsCl, DIPEA, 2 h; (ii) 15% TFA in CH2Cl2, 3 h then NaHCO3, overnight, 63% (two steps); (f)
10% Pd/C, H2, EtOH, overnight, 90%; (g) 6 M HCl, 100 ꢁC, 5 h, 85%.

2866
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 2864–2869
a
b
i
H2C
d
m
f
H2C
H
O
d
c
e
H
H
e
b
b
H
O
H
O
H
H
d
f
H
a
H
H
g
j
CH3
g
c
O
H3C
Si
H
b
H
N
H
h
H
H
O
j
a
H
H3C
Si
O
H3C
g
h
N
H
CH3
O
j
l
H
H3C
k
CH3
i
O
k
j
b
H3C
H
CH3
H
CH3
k
l
H3C
l
CH3
Figure 2. (a) Characteristic NOE’s observed in compound 10, (b) characteristic NOE’s observed in compound 10a.
separable by silica column chromatography. The diastero-
mers16 were independently carried forward for the syn-
thesis of (2S,4S,5R)- and (2R,4S,5R)-(ꢀ)-bulgecinine
hydrochloride.
4. Experimental
4.1. General
All solvents and reagents were purified by standard tech-
niques. Crude products were purified by column chroma-
tography on silica gel of 60–120 mesh. IR spectra were
recorded on Perkin–Elmer 683 spectrometer. Optical rota-
tions were obtained on Jasco Dip 360 digital polarimeter.
1H and 13C NMR spectra were recorded in CDCl3 or
D2O solution on a Varian Gemini 200, Brucker Avance
300, Varian Unity 400 or Inova Plus 500. Chemical shifts
were reported in parts per million with respect to internal
TMS. Coupling constants (J) are quoted in Hz. Mass spec-
tra were obtained on an Agilent Technologies LC/MSD
Trap SL.
Diastereomer 7 on exposure to pyridinium para toluene-
sulfonate (PPTS) in ethanol furnished diol 8 in 80% yield,
which on selective protection of the primary hydroxyl
group with TBDMSCl and imidazole as base in methylene
chloride afforded 9 in 96% yield. The secondary alcohol in
9 was mesylated, which on deblocking the tert-butyl car-
bonate group using 15% triflouroaceticacid in methylene
chloride followed by basification with NaHCO3 provided
the pyrrolidine scaffold 10 in 63% yield (for two steps)
(Scheme 2).
The structure and stereochemistry of compound 10 was
assigned by one-dimensional 1H, 13C experiments and
two-dimensional DQCOSY, NOESY experiments. The
strong NOE cross peak between Hc–He, Hg–Hc and
Hf–Hd supports the structure. Similarly, for compound
10a, the NOE cross peak between Hc–Hg, and Hf–Hh
supports the derived structure (Fig. 2).
4.1.1.
tert-Butyl-(S)-1-(ethoxycarbonyl)-3-(benzyloxy)-3-
((S)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-enyl carbamate
6. To a stirred solution of potassium tert-butoxide
(0.624 g, 5.57 mmol) in dry CH2Cl2 (20 mL), glycine
phosponate 5 (1.620 g, 4.78 mmol) was added in dry
CH2Cl2 (20 mL) under a nitrogen atmosphere at ꢀ78 ꢁC.
After 30 min, aldehyde 4 (1.000 g, 3.98 mmol) was slowly
added to the reaction mixture in dry CH2Cl2 (10 mL) at
ꢀ78 ꢁC. The reaction mixture was warmed to room tem-
perature and stirred for 5 h. Aqueous saturated NH4Cl
solution (20 mL) was added to the reaction mixture at
0 ꢁC and stirred for 15 min. The reaction mixture was
diluted with water and extracted with CH2Cl2 (100 mL).
The combined organic extracts were washed with water,
brine and dried over anhydrous Na2SO4. The solvent was
removed in vacuo to afford crude alkene 6 (1.421 g, 82%).
Unmasking the hydroxy protecting groups in 10 was
achieved first by exposure to Pd–C/H2 followed by treat-
ment with 6 M HCl at 100 ꢁC to realize (2S,4S,5R)-(ꢀ)-
bulgecinine hydrochloride 1. The spectral data including
optical rotations were in full agreement with the literature
25
25
values {½aꢁD ¼ þ11:6 (c 0.75, 1 M HCl); lit.6 ½aꢁD ¼ þ12:4
(c 0.95, 1 M HCl)}.
The minor isomer 7a under a series of similar reactions
furnished diastereomer (2R,4S,5R)-(ꢀ)-bulgecinine 1a.
4.1.2. tert-Butyl-(1S,3S)-1-(ethoxycarbonyl)-3-(benzyloxy)-
3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]propyl carbamate 7.
A mixture of alkene compound 6 (1.000 g, 2.29 mmol),
Na2CO3 (0.731 g, 6.89 mmol) and 10% Pd/C (0.229 g,
2.29 mmol) in dry ethyl acetate (20 mL) was stirred under
a hydrogen atmosphere pressure for 3 h. The reaction
mixture was filtered through Celite and washed with ethyl
acetate (3 · 10 mL). The filtrate was concentrated under
vacuo and purified by column chromatography (hexane/
3. Conclusion
In conclusion, a practical synthesis of natural (ꢀ)-bulgeci-
nine and its C-2-epimer has been synthesized from com-
mercially available L-ascorbic acid using standard
laboratory chemicals. This route is amenable to both
scale-up and analogue synthesis. Activity testing for the
C-2 epimer is currently underway and will be published
in future.
EtOAc = 4:1) to afford the viscous oily compound 7
25
(0.743 g, 74%). ½aꢁD ¼ ꢀ27:4 (c 1.5, CHCl3); IR (neat):

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 2864–2869
2867
1
3421, 1700, 1637, 772 cmꢀ1; H NMR (200 MHz, CDCl3):
NMR (50 MHz, CDCl3): d 172.7, 155.8, 137.7, 128.7
(2C), 128.4 (2C), 127.6, 80.1, 76.8, 72.6, 72.4, 63.5, 61.7,
51.6, 33.1, 28.5 (3C), 14.1; ESIMS: m/z 420 (M+Na)+;
Anal. Calcd for C20H31NO7: C, 60.44; H, 7.86; N, 3.52.
Found: C, 60.51; H, 7.79; N, 3.58.
d 7.40–7.20 (m, 5H), 5.35–5.27 (m, 1H), 4.70 (d,
J = 11.2 Hz, 1H), 4.54 (d, J = 11.2 Hz, 1H), 4.50–4.30
(m, 1H), 4.24–4.08 (m, 3H), 4.00–3.90 (m, 1H), 3.73–3.49
(m, 2H), 2.05–1.63 (m, 2H), 1.48–1.42 (m, 12H), 1.33–
1.23 (m, 6H); 13C NMR (50 MHz, CDCl3): d 172.6,
155.5, 138.0, 128.4 (3C), 127.8 (2C), 109.5, 79.6, 77.3,
76.6, 73.5, 65.5, 61.3, 51.2, 32.4, 28.3 (3C), 26.4, 25.0,
14.1; ESIMS: m/z 460 (M+Na)+; HRMS calcd for
C23H36NO7: 438.2495; found: 438.2491.
4.1.4. tert-Butyl-(1S,3S,4S)-1-(ethoxycarbonyl)-3-(benzyl-
oxy)-4-hydroxy-5-(tert-butyl dimethyl silyloxy)-pentyl carb-
amate 9. To a stirred solution of diol 8 (1.000 g,
2.51 mmol) in dry CH2Cl2 (20 mL), imidazole (0.428 g,
6.62 mmol) and tert-butyl dimethyl silyl chloride (0.680 g,
4.53 mmol) were added at 0 ꢁC and stirred for 6 h at room
temperature. The reaction mixture was diluted with water
and extracted with CH2Cl2 (40 mL). The combined organic
extracts were washed with water, brine and dried over
anhydrous Na2SO4. Solvent was removed under reduced
pressure and crude product was purified by column chro-
4.1.2.1. tert-Butyl-(1R,3S)-1-(ethoxycarbonyl)-3-(benzyl-
oxy)-3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]propyl carbamate
25
7a. ½aꢁD ¼ ꢀ39:1 (c 1.1, CHCl3); IR (neat): 3425,
1703, 1642, 776 cmꢀ1 1H NMR (200 MHz, CDCl3): d
;
7.32–7.16 (m, 5H), 5.33–5.21 (m, 1H), 4.78 (d,
J = 11.4 Hz, 1H), 4.40 (d, J = 11.4 Hz, 1H), 4.32–4.13
(m, 2H), 4.10–3.80 (m, 3H), 3.70–3.43 (m, 2H), 2.07–1.87
(m, 2H), 1.53–1.28 (m, 15H), 1.14 (t, J = 6.8 Hz, 3H);
13C NMR (50 MHz, CDCl3): d 172.3, 155.2, 138.0, 128.3
(3C), 127.7 (2C), 109.6, 79.8, 77.5, 76.2, 72.8, 65.7, 61.2,
51.3, 32.7, 28.3 (3C), 26.4, 25.1, 14.0; ESIMS: m/z 460
(M+Na)+; HRMS calcd for C23H36NO7: 438.2495; found:
438.2489.
matography (hexane/EtOAc = 7:3) to afford compound 9
25
(1.233 g, 96%). ½aꢁD ¼ ꢀ17:6 (c 1.25, CHCl3); IR (KBr):
1
3500, 3420, 1712, 1637, 1218, 1020, 772 cmꢀ1; H NMR
(200 MHz, CDCl3):
d 7.30–7.28 (m, 5H), 5.34 (d,
J = 6.6 Hz, 1H), 4.57 (s, 2H), 4.43–4.00 (m, 3H), 3.82–
3.67 (m, 4H), 2.48 (s, 1H), 2.35–1.20 (m, 2H), 1.48 (s,
9H), 1.23 (t, J = 7.1 Hz, 3H), 0.95 (s, 9H), 0.10 (s, 6H);
13C NMR (50 MHz, CDCl3): d 172.6, 155.3, 137.9, 128.4
(2C), 128.1 (2C), 127.8, 76.1, 72.8, 72.5, 63.4, 61.2, 51.3,
33.0, 28.3 (3C), 25.9 (3C), 25.8, 18.2, 14.0, ꢀ5.4 (2C);
ESIMS: m/z 534 (M+H+Na)+; Anal. Calcd for
C26H45NO7Si: C, 61.03; H, 8.86; N, 2.74. Found: C,
61.11; H, 8.78; N, 2.86.
4.1.3. tert-Butyl-(1S,3S,4S)-1-(ethoxycarbonyl)-3-(benzyl-
oxy)-4,5-dihydroxy pentyl carbamate 8. To a stirred solu-
tion of compound 7 (1.000 g, 2.28 mmol) in dry ethanol
(20 mL), PPTS (0.250 g, 0.91 mmol) was added under a
nitrogen atmosphere. The reaction mixture was slowly
heated to 50–55 ꢁC. After 12 h, PPTS (0.125 g, 0.41 mmol)
was added to the reaction mixture and stirred at the same
temperature for 12 h. Solid NaHCO3 was added at 0 ꢁC
and stirred for 1 h. The reaction mixture was filtered and
the solvent was removed in vacuo and extracted with
CH2Cl2 (30 mL). The combined organic extracts were
washed with water, brine and dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pres-
sure and the crude product purified by silica gel column
4.1.4.1. tert-Butyl-(1R,3S,4S)-1-(ethoxycarbonyl)-3-(benz-
yloxy)-4-hydroxy-5-(tert-butyl dimethyl silyloxy)-pentyl
25
carbamate 9a. ½aꢁD ¼ ꢀ18:2 (c 1.25, CHCl3); IR (KBr):
1
3502, 3425, 1708, 1639, 1223, 1022, 776 cmꢀ1; H NMR
(200 MHz, CDCl3): d 7.48–7.36 (m, 5H), 5.31 (dd,
J = 7.4 Hz, 1H), 4.57–4.60 (m, 2H), 4.39–3.90 (m, 3H),
3.75–3.61 (m, 4H), 2.52 (s, 1H), 2.38–2.06 (m, 2H), 1.43
(s, 9H), 1.24 (t, J = 7.2 Hz, 3H), 0.89 (s, 9H), 0.24 (s,
6H); 13C NMR (50 MHz, CDCl3): d 172.8, 155.6, 138.0,
128.8, 128.7 (2C), 128.3 (2C), 127.8, 76.5, 73.0, 72.9, 63.6,
61.6, 51.9, 33.4, 28.4 (3C), 26.2 (3C), 27.6, 14.4, ꢀ5.8
(2C); ESIMS: m/z 534 (M+H+Na)+; Anal. Calcd for
C26H45NO7Si: C, 61.03; H, 8.86; N, 2.74. Found: C,
61.06; H, 8.83; N, 2.78.
chromatography (hexane/EtOAc = 1:1) to afford the
25
compound 8 (0.726 g, 80%). ½aꢁD ¼ ꢀ14:6 (c 0.7, CHCl3);
IR (KBr): 3359, 3400, 1702, 1629, 1219, 1032, 771 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.40–7.24 (m, 5H), 5.47
(d, J = 8.7 Hz, 1H, NH), 4.58 (dd, J = 10.8 and 12.4 Hz,
2H), 4.37–4.39 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.66–
3.52 (m, 4H), 3.11 (br s, 1H, OH), 2.70 (br s, 1H, OH),
2.15–1.87 (m, 2H), 1.52 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H);
13C NMR (50 MHz, CDCl3): d 172.5, 155.4, 137.5, 128.3
(2C), 128.0 (2C), 127.8, 79.9, 76.4, 72.4, 72.2, 63.3, 61.3,
51.2, 32.9, 28.1 (3C), 13.9; ESIMS: m/z 420 (M+Na)+;
Anal. Calcd for C20H31NO7: C, 60.44; H, 7.86; N, 3.52.
Found: C, 60.57; H, 7.73; N, 3.64.
4.1.5. (2S,4S,5R)-Ethyl-4-(benzyloxy)-5-(tert-butyl dimethyl
silyloxy methyl)pyrrolidine-2-carboxylate 10. To a stirred
solution of alcohol 9 (1.000 g, 1.96 mmol) and DIPEA
(0.75 mL, 4.31 mmol) in dry CH2Cl2 (20 mL) was slowly
added a solution of methanesulfonyl chloride (0.210 mL,
2.77 mmol) in dry CH2Cl2 (5 mL) at ꢀ10 ꢁC and stirred
for 2 h at room temperature. The reaction mixture was
extracted with CH2Cl2, washed with water, 1 M HCl
(12 mL), brine and dried over anhydrous Na2SO4 and con-
centrated under vacuum to afford a colourless oily residue,
which was used directly for the subsequent reaction.
4.1.3.1. tert-Butyl-(1R,3S,4S)-1-(ethoxycarbonyl)-3-(benz-
25
yloxy)-4,5-dihydroxy pentyl carbamate 8a. ½aꢁD ¼ ꢀ8:8 (c
1.9, CHCl31); IR (KBr): 3362, 3406, 1705, 1626, 1225, 1035,
777 cmꢀ1; H NMR (200 MHz, CDCl3): d 7.37–7.25 (m,
5H), 5.38 (d, J = 6.9 Hz, 1H, NH), 4.51 (dd, J = 11.1 and
14.2 Hz, 2H), 4.34–4.26 (m, 1H), 4.06 (q, J = 7.1 Hz,
2H), 3.78–3.80 (m, 1H), 3.62–3.72 (m, 3H), 3.08 (br s,
1H, OH), 2.76 (br s, 1H, OH), 2.37–2.40 (m, 1H), 2.08–
2.10 (m, 1H), 1.42 (s, 9H), 1.15 (t, J = 7.1 Hz, 3H); 13C
To a stirred solution of the above mesylated product
(0.800 g, 1.36 mmol) in dry CH2Cl2 (20 mL), TFA
(2.4 mL) was added dropwise to the reaction mixture at
0 ꢁC and slowly warmed to room temperature. After

2868
S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 2864–2869
completion of the reaction (by TLC analysis), excess TFA
was removed in high vacuo and 30 mL of dry CH2Cl2 was
added to the reaction mixture at 0 ꢁC under nitrogen atmo-
sphere. Solid NaHCO3 was added to the reaction mixture
and stirred overnight at room temperature. The reaction
mixture was filtered and washed with CH2Cl2 (30 mL),
the solvent was evaporated under reduced pressure and
the crude product was purified by column chromatography
4.1.6.1. (2R,4S,5R)-Ethyl 4-hydroxy-5-(tert-butyl di-
methyl silyloxy methyl)pyrrolidine-2-carboxylate 11a.
25
½aꢁD ¼ þ11:7 (c 0.9, CHCl3); IR (KBr): 3317, 3305, 1728,
1224, 1056, 777 cmꢀ1 1H NMR (200 MHz, CDCl3): d
;
4.23 (q, J = 7.1 Hz, 2H), 4.16–4.05 (m, 1H), 3.85–3.63
(m, 2H), 3.30–3.26 (m, 1H), 2.95–2.87 (m, 3H), 2.26–2.24
(m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.90 (s, 9H), 0.08 (s,
6H); 13C NMR (50 MHz, CDCl3): d 172.7, 73.7, 67.8,
62.6, 61.7, 58.3, 38.5, 25.8 (3C), 18.1, 14.0, ꢀ5.6 (2C);
ESIMS: m/z 304 (M+H)+; HRMS calcd for C14H30NO4Si:
304.1944; found: 304.1950.
(hexane/EtOAc = 4:1) to afford cyclized compound 10
25
(0.485 g, 63% for two steps): ½aꢁD ¼ þ5:4 (c 1.3, CHCl3);
IR (neat): 3415, 1738, 1255, 1099, 773 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d 7.33–7.23 (m, 5H, Ar–H), 4.47 (s,
2H, Hi), 4.15 (q, J = 7.0 Hz, 2H, Hb), 3.93 (dt, J = 2.2
and 4.2 Hz, 1H, He), 3.82 (t, J = 6.2 Hz, 1H, Hc), 3.59
(dt, J = 8.4 and 5.0 Hz, 1H, Hf), 3.43 (m, 2H, Hg), 2.35
(br s, 1H, Hh), 2.27 (dd, J = 4.2, 6.2 Hz, 2H, Hd), 1.22 (t,
J = 7.0 Hz, 3H, Ha), 0.88 (s, 9H, Hk), 0.04 (s, 6H, Hj);
13C NMR (125 MHz, CDCl3): d 174.9, 138.3, 128.2 (2C),
127.3, 127.5 (2C), 79.9, 70.5, 64.8, 64.7, 61.0, 58.9, 34.9,
25.9 (3C), 18.2, 14.1, ꢀ5.4 (2C); ESIMS: m/z 394
(M+H)+; HRMS calcd for C21H36NO4Si (M+H)
394.2413; found: 394.2422.
4.1.7. (2S,4S,5R)-Bulgecinine hydrochloride 1. Compound
11 (0.200 g, 0.66 mmol) was taken up in 6 M HCl (15 mL)
and refluxed for 5 h. The reaction mixture was cooled to
room temperature and extracted once with 20 mL of
CH2Cl2 to remove any organic soluble impurities. The
aqueous layer was then concentrated in a rotary evapora-
tor to remove the volatiles and the excess solvent. The
residual oily product was kept under high vacuum
overnight, to afford bulgecinine hydrochloride 1 as a light
25
yellow viscous solid (0.110 g, 85%): ½aꢁD ¼ þ11:6 (c 0.75,
25
1 M HCl) {lit.6 ½aꢁD ¼ þ12:4 (c 0.95, 1 M HCl)}; 1H
NMR (200 MHz, D2O): d 4.44–4.37 (m, 1H), 4.35–4.27
(m, 1H), 3.81–3.58 (m, 3H), 2.61–2.47 (m, 1H), 2.24–2.13
(m, 1H); 13C NMR (50 MHz, D2O): d 168.9, 67.4, 64.5,
55.3, 54.9, 33.1; ESIMS: m/z 197 (M)+, 162 (M+HꢀHCl)+;
HRMS calcd for C6H12NO4Cl (M)+ 197.6167; found:
197.6143.
4.1.5.1. (2R,4S,5R)-Ethyl-4-(benzyloxy)-5-(tert-butyl di-
methyl silyloxy methyl)pyrrolidine-2-carboxylate 10a.
25
½aꢁD ¼ þ21:6 (c 1.8, CHCl3); IR (neat): 3420, 1744, 1260,
1105, 778 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.35–
;
7.28 (m, 5H, Ar–H), 4.51 (dq, J = 11.7, 9.5 Hz, 2H, Hm),
4.18 (q, J = 7.0 Hz, 2H, Hb), 3.97 (dt, J = 1.9 and 5.0 Hz,
2H, Hc and Hf), 3.68 (dd, J = 4.2 and 10.2 Hz, 1H, Hh),
3.61 (dd, J = 5.4 and 10.2 Hz, 1H, Hi), 3.25 (ddd,
J = 3.8, 5.7 and 9.2 Hz, 1H, Hg), 2.24 (ddd J = 2.9, 7.3
and 10.2 Hz, 1H, Hd), 2.18 (br s, 1H, Hk), 1.94 (ddd,
J = 6.7, 9.2 and 2.9 Hz, 1H, He), 1.27 (t, J = 7.0 Hz, 3H,
Ha), 0.88 (s, 9H, Hl), 0.05 (s, 6H, Hj); 13C NMR
(125 MHz, CDCl3): d 173.9, 138.2, 128.4 (2C), 128.2,
127.6 (2C), 80.6, 71.2, 66.1, 63.2, 60.9, 58.9, 36.6, 25.8
(3C), 18.1, 14.1, ꢀ5.5 (2C); ESIMS: m/z 394 (M+H)+;
HRMS calcd for C21H36NO4Si (M+H) 394.2413; found:
394.2419.
4.1.7.1. (2R,4S,5R)-Bulgecinine hydrochloride 1a.
25
½aꢁD ¼ þ29:8 (c 0.60, 1 M HCl); 1H NMR (300 MHz,
D2O): d 4.60–4.54 (m, 1H), 4.42–4.37 (m, 1H), 3.92–3.83
(m, 1H), 3.76–3.70 (m, 2H), 2.42–2.36 (m, 2H); 13C
NMR (75 MHz, D2O): d 172.9, 71.5, 68.6, 58.7, 36.7,
29.5; ESIMS: m/z 197 (M)+, 162 (M+HꢀHCl)+; HRMS
calcd for C6H12NO4Cl (M)+ 197.6167; found: 197.6032.
Acknowledgement
Three of us (G.C.S.), (K.V.) and (G.D.S.) thank CSIR,
New Delhi, for the financial support in the form of a
fellowship.
4.1.6. (2S,4S,5R)-Ethyl 4-hydroxy-5-(tert-butyl dimethyl
silyloxy methyl)pyrrolidine-2-carboxylate 11. A mixture
of compound 10 (0.400 g, 1.01 mmol) and 10% Pd/C
(0.300 g) in dry ethanol (20 mL) was stirred under a hydro-
gen atmosphere overnight. The reaction mixture was fil-
tered through Celite and washed with ethanol (30 mL).
The solvent was removed under reduced pressure and the
crude product was purified by column chromatography
References
1. (a) Chandrasekhar, S.; Reddy, M. S.; Babu, B. N.; Jagadeesh,
B.; Prabhakar, A.; Jagannadh, B. J. Am. Chem. Soc. 2005,
127, 9664; (b) Chandrasekhar, S.; Reddy, M. S.; Jagadeesh,
B.; Prabhakar, A.; Rao, M. H. V. R.; Jagannadh, B. J. Am.
Chem. Soc. 2004, 126, 13586.
2. (a) Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2003, 44,
7459; (b) Chen, X.; Du, D. M.; Hua, W. T. Tetrahedron:
Asymmetry 2002, 13, 43; (c) Hirayama, C.; Ono, H.; Tamura,
Y.; Nakamura, M. Phytochemistry 2006, 67, 579; (d) Tsuzuki,
Y.; Tomita, K.; Shibamori, K.; Sato, Y.; Kashimoto, S.;
Chiba, K. J. Med. Chem. 2004, 47, 2097.
(hexane/EtOAc = 7:3) to afford the pyrrolidine carboxylate
25
11 as an oily product (0.277 g, 90%): ½aꢁD ¼ ꢀ8:1 (c 0.9,
CHCl3); IR (KBr): 3315, 3300, 1726, 1219, 1054,
1
772 cmꢀ1; H NMR (200 MHz, CDCl3): d 4.25–4.14 (m,
2H), 4.10–4.05 (m, 1H), 3.72 (dd, J = 4.0 and 8.8 Hz,
1H), 3.58 (dd, J = 7.3 and 12.1 Hz, 1H), 3.38 (dd, J = 7.2
and 9.9 Hz, 1H), 3.23–3.14 (m, 1H), 2.35 (s, 1H), 2.30–
2.26 (m, 2H), 1.94–1.85 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H),
0.83 (s, 9H), 0.03 (s, 6H); 13C NMR (50 MHz, CDCl3): d
175.8, 74.3, 67.0, 65.2, 61.2, 58.1, 37.8, 25.8 (3C), 18.2,
14.0, ꢀ5.5 (2C); ESIMS: m/z 304 (M+H)+; HRMS calcd
for C14H30NO4Si: 304.1944. Found: 304.1930.
3. (a) Karle, L. I.; Gopi, N. H.; Balaram, P. Proc. Natl. Acad.
Sci. U.S.A. 2001, 98, 3716; (b) Gopi, N. H.; Roy, S. R.;
Raghothama, R. S.; Karle, L. I.; Balaram, P. Helv. Chim.
Acta 2002, 85, 3313.

S. Chandrasekhar et al. / Tetrahedron: Asymmetry 17 (2006) 2864–2869
2869
4. (a) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem.
Commun. 2002, 3024; (b) List, B.; Lerner, R. A.; Barbas,
C. F., III. J. Am. Chem. Soc. 2000, 122, 2395.
5. (a) Imada, A.; Kintaka, K.; Nakao, M.; Shinagawa, S.
J. Antibiot. 1982, 35, 1400; (b) Shinagawa, S.; Maki, M.;
Kintaka, K.; Imada, A.; Asai, M. J. Antibiot. 1985, 38, 17.
6. Shinagawa, S.; Kashara, F.; Wada, Y.; Harada, S.; Asai, M.
Tetrahedron 1984, 40, 3465.
2787; (s) Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem.
1990, 55, 5194; (t) Ohta, T.; Hosoi, A.; Nozoe, S. Tetrahedron
Lett. 1988, 29, 329; (u) Bashyal, B. P.; Chow, H. F.; Fleet, G.
W. J. Tetrahedron 1987, 43, 423; (v) Ofune, Y.; Hori, K.;
Sakaitani, M. Tetrahedron Lett. 1986, 27, 6079; (w) Bashyal,
B. P.; Chow, H. F.; Fleet, G. W. J. Tetrahedron Lett. 1986,
27, 3205; (x) Wakamiya, T.; Yamanoi, K.; Nishikawa, M.;
Shiba, T. Tetrahedron Lett. 1985, 26, 4759.
7. For biological studies, see: (a) van Asselt, E. J.; Kalk, K. H.;
Dijkstra, B. W. Biochemistry 2000, 39, 1924; (b) Thunnissen,
A. M. W. H.; Rozeboom, H. J.; Kalk, K. H.; Dijkstra, B. W.
Biochemistry 1995, 34, 12729; (c) Templin, M. F.; Edwards,
D. H.; Hoeltje, J. Y. J. Biol. Chem. 1992, 267, 20039, and
references cited therein.
9. (a) Chandrasekhar, S.; Jagadeshwar, V.; Prakash, J. S.
Tetrahedron Lett. 2005, 46, 3127; (b) Chandrasekhar, S.;
Ramachander, T.; Reddy, M. V. Synthesis 2002, 1867.
10. (a) Chandrasekhar, S.; Vijeender, K.; Reddy, K. V. Tetra-
hedron Lett. 2005, 46, 6991; (b) Chandrasekhar, S.; Nars-
ihmulu, Ch.; Reddy, N. R. K.; Sultana, S. S. Tetrahedron
Lett. 2004, 45, 4581; (c) Chandrasekhar, S.; Narsihmulu, Ch.;
Reddy, N. R. K.; Sultana, S. S. Chem. Commun. 2004, 2450.
11. (a) Ermolenko, L.; Sasaki, A. N. J. Org. Chem. 2006, 71, 693,
and references cited therein; (b) Abushanab, E.; Vemishetti,
P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.; Wu,
D. C.-J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53,
2598; (c) Wang, Q.; Sasaki, A. N. J. Org. Chem. 2004, 69,
4767; (d) Wei, C. C.; De Bernardo, S.; Tengi, J. P.; Borgese,
J.; Weigele, M. J. Org. Chem. 1985, 50, 3462; (e) Abushanab,
E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K. J. Org. Chem.
1988, 53, 2598; (f) Andre, C.; Bolte, J.; Demuynck, C.
Tetrahedron: Asymmetry 1998, 9, 1359.
12. (a) Rao, A. V. R. Pure Appl. Chem. 1998, 70, 391; (b) Rao, A.
V. R.; Chakraborty, T. K.; Reddy, K. L.; Rao, A. S.
Tetrahedron Lett. 1992, 33, 4799.
13. (a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53;
(b) Steglish, W.; Kober, R. Liebigs Ann. Chem. 1983, 599.
14. Wittig–Horner reaction of 4 and 5 at ꢀ90 ꢁC gave a 9:1 ratio
(Z/E) of compound 6. However, this inseparable mixture
produced the 7 and 7a in 3:2 ratio upon hydrogenation.
15. Cook, G. R.; Lars, G. B.; Stille, J. R. J. Org. Chem. 1994, 54,
3575.
8. For earlier syntheses of (ꢀ)-bulgecinine, see: (a) Chavan, S.
P.; Praveen, C.; Sharma, P.; Kalkote, U. R. Tetrahedron Lett.
2005, 46, 439; (b) Kharaf, J. K.; Datta, A. J. Org. Chem.
2004, 69, 387; (c) Holt, K. A.; Swift, J. P.; Smith, M. E. B.;
Taylor, S. J. C.; McCague, R. Tetrahedron Lett. 2002, 43,
1545; (d) Krasinski, A.; Jurczak, J. Tetrahedron Lett. 2001,
42, 2019; (e) Burk, M. J.; Allen, J. G.; Kiesman, W. F. J. Am.
Chem. Soc. 1998, 120, 657; (f) Maeda, M.; Okazaki, F.;
Murayama, M.; Tachibana, Y.; Aoyagi, Y.; Ohta, A. Chem.
Pharm. Bull. 1997, 45, 962; (g) Mazon, A.; Najera, C.;
Ezquerra, J.; Pedregal, C. Tetrahedron Lett. 1997, 38, 2167;
(h) Panday, S. K.; Langlois, N. Synth. Commun. 1997, 27,
1373; (i) Fehn, S.; Burger, K. Tetrahedron: Asymmetry 1997,
8, 2001; (j) Graziani, L.; Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 1996, 7, 1341; (k) Yuasa, Y.; Ando, J.; Shibuya,
S. J. Chem. Soc., Perkin Trans. 1 1996, 793; (l) Madau, A.;
Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1996, 7, 825;
(m) Schmeck, C.; Hegedus, L. S. J. Am. Chem. Soc. 1994,
116, 9927; (n) Jackson, R. F. W.; Rettie, A. B.; Wood, A.;
Wythes, M. J. J. Chem. Soc., Perkin Trans. 1 1994, 1719; (o)
Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Chem.
Commun. 1994, 1383; (p) Jackson, R. F. W.; Rettie, A. B.
Tetrahedron Lett. 1993, 34, 2985; (q) Hirai, Y.; Terada, T.;
Amemiya, Y.; Momose, T. Tetrahedron Lett. 1992, 33, 7893;
(r) Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem. 1991, 56,
16. The stereochemistry for the diastereomers 7 and 7a were
assigned and confirmed after NOE studies for compound 10
and 10a.