An asymmetric dihydroxylation route to (-)-bulgecinine

Article abstract of DOI:10.1016/j.tetasy.2011.06.018

The stereoselective synthesis of (-)-bulgecinine is reported from L-aspartic acid using Sharpless asymmetric dihydroxylation and intramolecular cyclization via nucleophilic displacement of a-tosylate as key steps.

Full text of DOI:10.1016/j.tetasy.2011.06.018

Tetrahedron: Asymmetry 22 (2011) 1234–1238
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An asymmetric dihydroxylation route to (ꢀ)-bulgecinine
⇑
Krishanu Show, Puspesh K. Upadhyay, Pradeep Kumar
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of (ꢀ)-bulgecinine is reported from
L-aspartic acid using Sharpless asym-
Received 6 June 2011
Accepted 17 June 2011
Available online 23 July 2011
metric dihydroxylation and intramolecular cyclization via nucleophilic displacement of
key steps.
a-tosylate as
Ó 2011 Elsevier Ltd. All rights reserved.
OH
1. Introduction
O
NaO3SO
HO
(ꢀ)-Bulgecinine is a constituent non-proteinogenic amino acid of
the novel glycopeptide bulgecins, potent b-lactam synergists found
in the culture broth of Pseudomonas acidophila and of Pseudomonas
mesoacidophila (Fig. 1).1 Bulgecins A and B induce a characteristic
morphological change called bulge formation in Gram-negative
bacteria in cooperation with b-lactam antibiotics such as sulfazecin
or isosulfazecin which is also produced by P. acidophila and
P. mesoacidophila, respectively. As a result of bulge formation, the
activity of these antibiotics is effectively enhanced.
The structure of the new amino acid in the bulgecins named (ꢀ)
bulgecinine 3,2 has been determined chemically and crystallo-
graphically to be (2S,4S,5R)-4-hydroxy-5-hydroxymethyl proline.
In the last decade, the total synthesis of non-proteinogenic ami-
no acids has attracted considerable attention. This class of amino
acids has not only provided new insights into the secondary struc-
ture of oligopeptides3 but also have been the constituents of sev-
eral bioactive natural products such as echinocandin B,4a
fosinopril,4b prolinalin A and B4c and AG-7352.4d
O
NHAc
HO
CO2R
N
H
1 bulgecin A : R = NH(CH2)2SO3H
2 bulgecin B : R = NH(CH2)2COOH
OH
OH
OH
OH
HO2C
HO2C
N
H
N
H
(-)-bulgecinine 3
(+)-bulgecinine 4
Figure 1. Structures of bulgecin and bulgecinine.
Due to its novel structural features and important biological
activity, bulgecinine has been the subject of synthetic investiga-
tions, and as a result several total syntheses of this molecule have
been reported in the literature.5 However, many of these methods
suffer from lack of efficiency and poor diastereoselectivity in the
key step and consequently, interest in the development of new
strategies to address the above challenges still continues unabated.
As a part of our research program on the enantioselective syn-
thesis of pyrrolidine and piperidine based alkaloids,6 we became
interested to develop a simple and efficient route to the synthesis
2. Results and discussion
Our synthetic approach for the synthesis of (ꢀ)-bulgecinine 3
was envisioned through the retrosynthetic route shown in
Scheme 1. Compound 5 was visualized as a key precursor for the
target molecule 3, which in turn could be obtained from 6 via
nucleophilic displacement of a tosyl group with an amine and
subsequent intramolecular cyclization. The tosylate 6 could be pre-
pared from olefin 7 through asymmetric dihydroxylation, which in
turn could be accessed easily from acetonide alcohol 8 derived
of (ꢀ)-bulgecinine from easily available
L-aspartic acid employing
from L-aspartic acid 9.
Sharpless asymmetric dihydroxylation (AD) and an intramolecular
cyclization reaction as the key steps.
2.1. The synthesis of (ꢀ)-bulgecinine
As outlined in Scheme 2, the synthesis of target molecule 3
commenced from
L-aspartic acid 9, which was converted into
⇑
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
known compound 8 following a literature procedure.7 With a
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.018

K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1234–1238
1235
OH
OH
TBDPSO
HO
OEt
OH
N
H
N
H
O
O
3
5
(-)-bulgecinine
Boc
OH
H
N
O
O
NHBoc
TBDPSO
TBDPSO
OEt
OEt
OTs
6
7
Boc
NH2
N
CO2H
O
HO2C
OH
8
9
L-aspartic acid
Scheme 1. Retrosynthetic analysis of (ꢀ)-bulgecinine 3.
substantial amount of 8 in hand, our next task was to carry out the
two-carbon homologation by means of a Wittig reaction in order to
generate the trans-olefin required for AD reaction. To this end,
compound 8 was oxidized under Swern conditions,8 followed by
subsequent treatment with (ethoxycarbonylmethylene) triphenyl-
phosphorane in anhydrous THF at room temperature to furnish the
trans-Wittig product 109 in 80% yield.
described has significant potential for stereochemical variations
at the C-2, C-4 and C-5 positions and further extension to other
stereoisomers and analogues. Currently studies are in progress in
this direction.
4. Experimental
Cleavage of the acetonide group with camphor sulfonic acid fol-
lowed by hydroxyl group protection with TBDPSCl produced the re-
quired compound 7 in 75% yield. The dihydroxylation of olefin 7
with osmium tetroxide (0.4 mol % OsO4) and potassium ferricyanide
K3Fe(CN)6 as co-oxidant in the presence of (DHQ)2PHAL under the
Sharpless asymmetric dihydroxylation (AD) conditions10 delivered
the diol 11 in 90% yield and with 97% de.11
4.1. General information
All reactions were carried out under argon or nitrogen in oven-
dried glassware using standard gas-light syringes, cannulas and
septa. Solvents and reagents were purified and dried by standard
methods prior to use. Optical rotations were measured at room
temperature. IR spectra were recorded on an FT-IR instrument.
1H NMR spectra were recorded on 200 MHz, 400 MHz and
500 MHz and are reported in parts per million (d) downfield rela-
tive to CDCl3 as an internal standard and 13C NMR spectra were re-
corded at 50 MHz, 100 MHz and 125 MHz and assigned in parts per
million (d) relative to CDCl3. Mass spectra were obtained with TSQ
70, Finningen MAT spectrometer. Column chromatography was
performed on silica gel (100–200 and 230–400 mesh) using a mix-
ture of petroleum ether and ethyl acetate as the eluent. Elemental
analyses were carried out on a Carlo Erba CHNSO analyzer.
Regioselective monotosylation12 of diol 11 at the
a-position to
the ester with p-toluenesulfonyl chloride (p-TsCl) resulted in the
tosylate 6 in 75% yield. Concomitant cleavage of the Boc group with
TFA followed by nucleophilic displacement of the tosyl with a
resultant amine in the presence of diisopropylethyl amine led to
the cyclized product 5 in 65% yield. The ester group reduction13
with NaBH4 (5?12) and subsequent protection of both the hydro-
xyl and amino groups with BnBr produced the fully protected pyr-
rolidine derivative 13 in 83% yield. Cleavage of the TBDPS group
with 1 M TBAF gave the prolinol derivative 14 in 90% yield. Finally,
the hydroxy group was oxidized to the aldehyde under Swern con-
ditions8,14 followed by further oxidation with NaClO2 in the pres-
ence of 2-methyl-2-butene15 to give the required acid.
Subsequent global deprotection under hydrogenation conditions
produced (ꢀ)-bulgecinine 3 in 48% yield over three steps. The spec-
4.1.1. (S,E)-tert-Butyl-4-(4-ethoxy-4-oxobut-2-enyl)-2,2-
dimethyloxazolidine-3-carboxylate 10
A solution of DMSO (3.57 mL, 46.2 mmol) in dry dichlorometh-
ane (13 mL) was added to a solution of oxalyl chloride (1.83 mL,
20.0 mmol) in dry dichloromethane (50 mL) at ꢀ78 °C. The reac-
tion mixture was stirred for 15 min at ꢀ78 °C and a solution of 8
(3.43 g, 14.0 mmol) in dichloromethane (30 mL) was added. The
reaction mixture was stirred for another 45 min at ꢀ60 °C. Next,
Et3N (13.3 mL, 95.2 mmol) was then added at ꢀ78 °C, the cooling
bath removed, and the reaction mixture was stirred for 1 h at room
temperature. The reaction was quenched by the addition of water
and the aqueous phase was extracted with dichloromethane. The
combined organic extracts were washed successively with water,
aqueous NaHCO3 and brine, dried with Na2SO4, filtered through
Celite, and the solvent was removed in vacuo to give the crude
troscopic data including the specific rotation {½a D25
¼ ꢀ13:2 (c 0.92,
ꢁ
H2O); lit.2 ½a 2D4
¼ ꢀ13:1 (c 0.95, H2O)} were in full agreement with
ꢁ
literature precedence. The overall yield of 3 starting from aspartic
acid was found to be 5.2%.
3. Conclusion
In conclusion, we have developed a simple, flexible and efficient
route to (ꢀ)-bulgecinine employing the Sharpless asymmetric
dihydroxylation reaction as the key step. The synthetic strategy

1236
K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1234–1238
(i) (COCl)2, DMSO,
Ba
Boc
iPr2NEt, -78 oC, 2 h
N
NH2
ref. 7
N
O
CO2H
O
O
HO2C
(ii) Ph3P=CHCO2Et,
THF, reflux, 12h, 80%
OH
OEt
8
10
9
L-aspartic acid
(DHQ)2PHAL,
0.4 mol% OsO4,
K2CO3, K3Fe(CN)6
Boc
OH
H
(i) CSA, MeOH, 1h
N
O
NHBoc
O
TBDPSO
TBDPSO
OEt
OEt CH3SO2NH2,
tBuOH:H2O (1:1), 0 oC,
24 h, 90%
(ii) TBDPSCl, imidazole,
dry CH2Cl2, 0 oC-r.t.
4 h, 75%;
OH
7
11
Boc
OH
(i) CF3CO2H, CH2Cl2,
2 h, r.t.
OH
H
N
O
p-TsCl, Et3N,
TBDPSO
TBDPSO
TBDPSO
OEt
CH2Cl2, 5 oC,
72 h, 75%
OEt
N
H
(ii) DIPEA, CH2Cl2,
0 oC, 3 h, 65%;
O
OTs
6
5
OH
OBn
NaBH4, EtOH,
BnBr, NaH,
TBDPSO
OH
OBn
N
DMF, TBAI,
N
r.t, 3h, 70%;
H
Bn
0 oC - r.t. 6 h, 83%;
12
13
(i) (COCl)2, DMSO, Et3N,
-78 oC, dry CH2Cl2, 2 h
OH
OBn
1M TBAF,
dry THF ,r.t.
HO
O
HO
OH
OBn
N
H
N
12 h, 90%;
(ii) NaClO2, KH2PO4,
2-methyl-2-butene,
CH3CN-tBuOH
Bn
3
14
(-)-bulgecinine
(iii) Pd(OH)2/C,
MeOH:H2O (1:1),
48%.
Scheme 2. Asymmetric dihydroxylation route to (ꢀ)-bulgecinine 3.
aldehyde as a pale yellow oil. This aldehyde was used without any
purification for the next step.
[M++Na]. Anal. Calcd for C16H27NO5: C, 61.32; H, 8.68; N, 4.47%.
Found: C, 61.48; H, 8.55; N, 4.51%.
To a solution of (ethoxycarbonylmethylene) triphenylphospho-
rane (6.45 g, 18.51 mmol) in dry THF (30 mL) was added a solution
of the above crude aldehyde (3.0 g, 12.34 mmol) in dry THF
(25 mL). The reaction mixture was refluxed for 12 h. It was then
concentrated and purified by silica gel column chromatography
4.1.2. (S,E)-Ethyl-5-(tert-butoxycarbonylamino)-6-(tert-butyl
diphenylsilyloxy)hex-2-enoate 7
To a solution of the unsaturated ester 10 (480 mg, 1.53 mmol),
catalytic amount of CSA in dry MeOH (3 mL) was added and reac-
tion mixture was stirred at room temperature for 1 h and then
solid NaHCO3 (0.2 g) was added to the reaction mixture. After stir-
ring for another 30 min, the reaction mixture was filtered through
a pad of neutral alumina and filtrate concentrated in vacuo to give
crude amino alcohol which was used for the next step without
purification.
using petroleum ether/EtOAc (8.5:1.5) as eluent to afford the a,b-
unsaturated olefin 10 (3.5 g, 80%, after two steps) as a pale yellow
liquid; ½a 2D5
ꢁ
¼ þ20:0 (c 1.2, CHCl3). IR (neat): mmax 3384, 2931,
1696, 1595, 1298, 982 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 1.22 (t,
J = 7.20 Hz, 3H), 1.40 (s, 9H), 1.48 (s, 3H), 1.54 (s, 3H), 2.35–2.66
(m, 2H), 3.59–3.68 (m, 1H), 3.83–3.90 (m, 2H), 4.12 (q,
J = 7.15 Hz, 2H), 5.79 (d, J = 15.60 Hz, 1H), 6.82 (m, 1H). 13C NMR
(50 MHz, CDCl3): d 14.2, 26.7, 27.3, 28.4, 35.6, 56.1, 60.2, 66.8,
80.3, 94.0, 123.7, 128.9, 144.6, 166.2. ESI[MS](m/z): 336.12
To the above crude amino alcohol (333.0 mg, 1.22 mmol), imid-
azole (125 mg, 1.83 mmol), in dry CH2Cl2 (10 mL), TBDPSCl
(0.4 mL, 1.34 mmol) was added successively at 0 °C. After stirring

K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1234–1238
1237
for 4 h, the reaction mixturewas quenched with water and extracted
with CH2Cl2 (10 ꢂ 3 mL). The solvent was evaporated in vacuo and
the crude residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (9.5:0.5) as eluent to give 7 (587 mg,
4.1.5. (2S,3S,5S)-Ethyl-5-((tert-butyldiphenylsilyloxy)methyl)-3-
hydroxypyrrolidine-2-carboxylate 5
To an ice cold solution of 6 (0.49 g, 0.70 mmol) in dry CH2Cl2
(5 ml) was added TFA (0.1 mL, 1.40 mmol) and the reaction mixture
was stirred for 2 h at room temperature. After completion of the
reaction, the solvent was evaporated in vacuo and the resultant res-
idue was dissolved in dry CH2Cl2 (5 mL) and cooled to 0 °C to which
diisopropylethyl amine (0.14 ml, 0.77 mmol) was added and stirred
for 3 h at 0 °C. Afterward, ice piece was added and the solution was
extracted with EtOAc (3 ꢂ 25 mL). The combined organic extracts
were washed with brine, dried (Na2SO4) and concentrated to yield
the cyclized compound which was purified by silica gel column
chromatography using EtOAc/pet ether (1:9) as a eluent to give pyr-
75% after two steps) as a yellow liquid. ½a D25
ꢁ
¼ ꢀ9:5 (c 1.0, CHCl3).
IR (neat): mmax 3364, 3050, 2931, 1745, 1589, 1428, 979 cmꢀ1
.
1H
NMR (200 MHz, CDCl3): d 1.06 (s, 9H), 1.27 (t, J = 7.20 Hz, 3H), 1.42
(s, 9H), 2.43–2.52 (m, 2H), 3.63–3.71 (m, 3H), 4.17 (q, J = 7. 20 Hz,
2H), 4.70 (br s, 1H), 5.85 (d, J = 15.7 Hz, 1H), 6.80–6.95 (m, 1H),
7.34–7.43 (m, 6H), 7.60–7.65 (m, 4H). 13C NMR (50 MHz, CDCl3): d
14.2, 19.3, 26.8, 28.3, 34.7, 60.2, 65.0, 79.4, 123.8, 127.8, 129.8,
132.9, 135.5. 144.7, 155.2, 166.1. ESI[MS](m/z): 534.27 [M++Na]
Anal. Calcd for C29H41NO5Si: C, 68.07; H, 8.08; N, 2.74%. Found: C,
68.26; H, 8.01; N, 2.68%.
rolidine derivative
¼ þ12:2 (c 0.08, CHCl3). IR (neat): mmax 3498, 3361, 3050,
2858, 1731, 1472, 1209 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.08
5 (194 mg, 65%) as a yellow color oil.
½ ꢁ
a 2D5
.
4.1.3. (2R,3S,5S)-Ethyl-5-(tert-butoxycarbonylamino)-6-(tert-bu
tyldiphenylsilyloxy)-2,3-dihydroxyhexanoate 11
(s, 9H), 1.29 (t, J = 7.20 Hz, 3H), 1.69–1.80 (m, 1H), 2.12–2.26 (m,
1H), 3.04 (br s, 2H), 3.57–3.70 (m, 3H), 3.90 (m, 1H), 4.18 (q,
J = 7.2 Hz, 2H), 4.38–4.44 (m, 1H), 7.35–7.49 (m, 6H), 7.67–7.75
(m, 4H). 13C NMR (100 MHz, CDCl3): d 14.2, 19.1, 26.8, 36.0, 57.7,
61.1, 67.1, 68.9, 74.9, 127.8, 129.9, 132.7, 135.6, 173.3. ESI (MS)
(m/z): 428.13 (M++H), 450.11 [M++Na]. Anal. Calcd for C24H33NO4Si:
C, 67.41; H, 7.78; N, 3.28%. Found: C, 67.27; H, 7.83; N, 3.34%.
To a mixture of K3Fe(CN)6 (10.34 g, 31.43 mmol), K2CO3 (4.34 g,
31.43 mmol) and (DHQ)2PHAL (82 mg, 1 mol %), in t-BuOH–H2O
(1:1, 106 mL) was added OsO4 (0.4 mL, 0.1 M solution in toluene,
0.4 mol %) at 0 °C followed by methanesulfonamide (1.0 g,
10.5 mmol). After being stirred for 5 min at 0 °C, the olefin 7
(5.36 g, 10.5 mmol) was added in one portion. The reaction mix-
ture was stirred at 0 °C for 24 h and then quenched with solid so-
dium sulfite (15.8 g). The stirring was continued for an additional
45 min and then the solution was extracted with EtOAc
(5 ꢂ 100 mL). The combined organic extracts were washed with
brine, dried (Na2SO4) and concentrated. Silica gel column chroma-
tography of the crude product using petroleum ether/EtOAc (3:2)
as eluent gave the diol 11 (7 5.14 g, 90%) as a colorless syrupy li-
4.1.6. (2R,3S,5S)-5-((tert-Butyldiphenylsilyloxy)methyl)-2-(hydr
oxymethyl)pyrrolidin-3-ol 12
To an ice cooled solution of 5 (500 mg, 1.17 mmol) in absolute
EtOH (10 mL) was added sodium borohydride (53 mg, 1.40 mmol)
in one portion. The cooling bath was removed when the reaction
subsided, and the reaction mixture was stirred at room tempera-
ture for 3 h, after this time TLC (EtOAc/EtOH 2:1) analysis indicated
complete consumption of the starting material. After the reaction
was complete, ice piece was added and white precipitate was fil-
tered through a pad of neutral alumina and washed with EtOH
(2 ꢂ 15 mL). The filtrate was concentrated and the residue was
purified by silica gel column chromatography to give 12
quid. ½a 2D5
ꢁ
¼ ꢀ11:0 (c 1.5, CHCl3). IR (neat): mmax . 3413, 2931,
1708, 1501 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 1.09 (s, 9H), 1.29
(t, J = 7.2 Hz, 3H), 1.46 (s, 9H), 1.63–1.76 (m, 1H), 1.83–1.96 (m,
1H), 3.22 (br s, 2H), 3.62–3.69 (m, 1H), 3.79–3.86 (m, 2H), 3.97–
4.02 (m, 1H), 4.07 (d, J = 2.27 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.96
(br s, 1H), 7.37–7.46 (m, 6H), 7.62–7.66 (m, 4H). 13C NMR (50 MHz,
CDCl3): d 14.1, 19.3, 26.9, 28.2, 29.6, 36.5, 48.9, 61.6, 66.4, 68.9,
74.0, 81.1, 127.8, 129.9, 132.8, 133.0, 135.5, 157.3, 173.0.
ESI[MS](m/z): 568.56 [M++Na], 546.53. [M++H]. Anal. Calcd for
(315.6 mg, 70%) as viscous liquid. ½a D25
¼ ꢀ129:8 (c 0.02, CHCl3).
ꢁ
IR (CHCl3): mmax 3354, 2926, 3050, 1681, 1593, 1410, 1297 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 1.06 (s, 9H), 1.65–1.78 (m, 1H),
2.15–2.28 (m, 1H), 3.48 (m, 1H), 3.56–3.65 (m, 2H), 3.75–3.79
(m, 2H), 4.16–4.24 (m, 1H), 6.21 (m, 4H), 7.33–7.42 (m, 6H),
7.63–7.68 (m, 4H). 13C NMR (50 MHz, CDCl3): d 19.1, 26.8, 35.7,
58.4, 59.5, 64.4, 67.3, 71.6, 127.9, 129.9, 132.6, 135.5. ESI[MS](m/
z): 386.37 (M++H). Anal. Calcd for C22H31NO3Si: C, 68.53; H, 8.10;
N, 3.63%. Found: C, 68.63; H, 8.02; N, 3.59%.
C29H43NO7Si: C, 63.82; H, 7.94; N, 2.57%. Found: C, 63.97; H,
7.83; N, 2.51%.
4.1.4. (2R,3S,5S)-Ethyl-5-(tert-butoxycarbonylamino)-6-(tert-
butyldiphenylsilyloxy)-3-hydroxy-2-(tosyloxy) hexanoate 6
To a solution of diol 11 (0.98 g, 1.79 mmol) and Et3N (0.4 mL,
2.68 mmol) in CH2Cl2 (25 mL) at 0 °C was added p-toluenesulfonyl
chloride (0.34 g, 1.79 mmol). The reaction mixture was stirred at
5 °C for 72 h. After the reaction was complete, water (30 mL) was
added and the solution was extracted in CH2Cl2 (3 ꢂ 10 mL). The
combined organic layer was washed with brine, dried (Na2SO4)
and concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (4:1) as eluent gave the tos-
4.1.7. (2R,3S,5S)-1-Benzyl-3-(benzyloxy)-2-(benzyloxymethyl)-
5-((tert-butyldiphenylsilyloxy)methyl)pyrrolidine 13
To an ice cooled solution of compound 12 (30 mg, 0.078 mmol)
in DMF (2 mL) was added NaH (9.3 mg, 0.39 mmol) and TBAI (cat-
alytic amount) followed by benzyl bromide (0.04 mL, 0.35 mmol),
in DMF (2 mL). The reaction mixture was allowed to warm to room
temperature and stirred for 6 h. Progress of the reaction was mon-
itored by TLC analysis. After completion of the reaction, water was
added and diluted with EtOAc. The mixture was extracted with
EtOAc (3 ꢂ 25 mL) and the combined organic phases washed with
brine, dried over Na2SO4, and concentrated in vacuo to afford the
crude benzylated product which was purified by silica gel column
chromatography using pet ether/EtOAc (8:2) which gave com-
ylate 6 (0.942 g, 75%) as a colorless sticky compound. ½a D25
¼ ꢀ5:6
ꢁ
(c 4.0 , CHCl3). IR (neat): mmax 3444, 2931, 1685, 1499, 1428, 1250,
929 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.08 (s, 9H), 1.18 (t,
.
J = 7.2 Hz, 3H), 1.45 (s, 9H), 1.59–1.67 (m, 1H), 1.72–1.87 (m, 1H),
2.42 (s, 3H), 3.57–3.64 (m, 1H), 3.75–3.87 (m, 2H), 4.08–4.18 (m,
3H), 4.88–4.93 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.38–7.47 (m,
6H), 7.62–7.67 (m, 4H), 7.86 (d, J = 8.3 Hz, 2H). 13C NMR (50 MHz,
CDCl3): d 13.7, 19.1, 21.5, 26.7, 28.1, 36.0, 48.7, 61.6, 66.1, 67.9,
80.0, 80.1, 127.8, 128.1, 129.5, 129.8, 132.5, 132.8, 133.1, 135.3,
135.4, 144.8, 157.2, 166.9. ESI[MS](m/z): 722.07 [M++Na], 700.65
[M++H]. Anal. Calcd for C36H49NO9SSi: C, 61.78; H, 7.06; N, 2.00%.
Found: C, 61.67; H, 7.11; N, 2.05%.
pound 13 (42.4 mg, 83%) as a colorless liquid. ½a D25
¼ ꢀ7:2 (c 0.1,
ꢁ
CHCl3). IR (neat): mmax 3385, 3068, 2856, 1676, 1590, 1495, 1298,
823 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.12 (s, 9H), 2.11–2.14
.
(m, 1H), 2.29–2.35 (m, 1H), 3.39 (m, 2H), 3.48–3.49 (m, 2H),
3.82–3.94 (m, 3H), 4.08–4.12 (m, 2H), 4.53–4.62 (m, 4H), 7.29–
7.49 (m, 21H), 7.69–7.75 (m, 4H). 13C NMR (50 MHz, CDCl3): d

1238
K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1234–1238
19.2, 26.8, 34.0, 52.3, 62.3, 65.7, 66.3, 69.9, 70.7, 73.1, 81.5, 126.4,
127.2, 127.5, 127.6, 128.1, 128.3, 129.4, 133.8, 135.5, 135.6, 138.4,
138.9, 140.4 ESI[MS](m/z): 656.36 (M++H), 678.34 (M++Na). Anal.
Calcd for C43H49NO3Si: C, 78.74; H, 7.53; N, 2.14%. Found: C,
78.63; H, 7.58; N, 2.21%.
the reaction was complete, the catalyst was removed by filtration
through Celite and washed with water. The solvent was concen-
trated under reduced pressure to give the target compound 3
(55 mg, 48%) as a white solid. ½a D25
ꢁ
¼ ꢀ13:2 (c 0.92, H2O).{[lit.2
½
a 2D4
ꢁ
¼ ꢀ13:1 (c 0.95, H2O)}. IR (KBr): mmax 3502–2953, 1638,
1453, 1100, 780 cmꢀ1 1H NMR (200 MHz, D2O): d 2.05 (ddd,
.
4.1.8. ((2S,4S,5R)-1-Benzyl-4-(benzyloxy)-5-
(benzyloxymethyl)pyrrolidin-2-yl)methanol 14
J = 14.1, 6.3, 5.0 Hz), 2.59 (ddd, J = 14.1, 9.1, 5.8 Hz), 3.58–3.71
(m, 3H), 4.10 (dd, J = 8.9, 6.5, 1H), 4.33 (m, 1H). 13C NMR
(50 MHz, D2O): d 37.4, 59.7, 60.5, 66.2, 71.7, 174.7. ESI[MS](m/z):
184.06 (M++Na).
To a solution of compound 13 (200 mg, 0.305 mmol) in dry THF
was added 1 M TBAF (in THF) (0.46 ml, 0.457 mmol) at 0 °C and the
reaction mixture was stirred at room temperature for 12 h. After-
ward, the solvent was evaporated in vacuo and crude residue
was purified by silica gel column chromatography using pet
ether/EtOAc (3:7) as eluent to give 14 (114.6 mg, 90%) as an oily
Acknowledgments
K.S. and P.K.U. thank UGC and CSIR, New Delhi for the award of
Junior and Senior Research Fellowship, respectively. The financial
support from DST, New Delhi (Grant No. S1/SR/OC-44/2009) is
gratefully acknowledged.
compound. ½a 2D5
ꢁ
¼ ꢀ37:7 (c 0.76, CHCl3). IR (neat): mmax 3447,
3029, 1604, 1453 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 1.94–1.98
(m, 1H), 2.33–2.40 (m, 1H), 3.23–3.25 (m, 1H), 3.36–3.43 (m,
4H), 3.73–3.77 (m, 1H), 3.83–3.87 (m, 1H), 3.94–4.01 (m, 2H),
4.41–4.49 (m, 2H), 4.52 (s, 2H), 7.19–7.38 (m, 15H). 13C NMR
(100 MHz, CDCl3): d 34.5, 51.6, 61.7, 62.0, 66.3, 69.4, 70.5, 73.2,
81.1, 126.8, 127.4, 127.5, 127.6, 127.7, 128.1, 128.2, 128.3, 134.8,
138.0, 138.2, 138.9, 139.8. Mass (LCMS): 418.02 (M++H), 440.11
(M++Na). Anal. Calcd for C27H31NO3: C, 77.67; H, 7.48; N, 3.35%.
Found: C, 77.73; H, 7.41; N, 3.41%.
References
1. (a) Imada, A.; Kintaka, K.; Nakao, M.; Shinagawa, S. J. Antibiot. 1982, 35, 1400–
1403; (b) Shinagawa, S.; Maki, M.; Kintaka, K.; Imada, A.; Asai, M. J. Antibiot.
1985, 38, 17–23.
2. Shinagawa, S.; Kashara, F.; Wada, Y.; Harada, S.; Asai, M. Tetrahedron 1984, 40,
3465–3470.
3. (a) Chandrasekhar, S.; Reddy, M. S.; Babu, B. N.; Jagadeesh, B.; Prabhakar, A.;
Jagannadh, B. J. Am. Chem. Soc. 2004, 127, 9664–9665; (b) Chandrasekhar, S.;
Reddy, M. S.; Jagadeesh, B.; Prabhakar, A.; Rao, M. H. V. R.; Jagannadh, B. J. Am.
Chem. Soc. 2004, 126, 13586–13587.
4. (a) Raghavan, S.; Reddy, S. R. Tetrahedron Lett. 2003, 44, 7459–7462; (b) Chen,
X.; Du, D. M.; Hua, W. T. Tetrahedron: Asymmetry 2002, 13, 43–46; (c) Hirayama,
C.; Ono, H.; Tamura, Y.; Nakamura, M. Phytochemistry 2006, 67, 579–583; (d)
Tsuzuki, Y.; Tomita, K.; Shibamori, K.; Sato, Y.; Kashimoto, S.; Chuba, K. J. Med.
Chem. 2004, 47, 2097–2109.
5. (a) Krasinski, A.; Jurczak, J. Tetrahedron Lett. 2001, 42, 2019–2021; (b) Holt, K.
A.; Swift, J. P.; Smith, M. E. B.; Taylor, S. J. C.; McCague, R. Tetrahedron Lett. 2002,
43, 1545–1548; (c) Khalaf, J. K.; Dutta, A. J. Org. Chem. 2004, 69, 387–390; (d)
Chavan, S. P.; Praveen, C.; Sharma, P.; Kalkote, U. R. Tetrahedron Lett. 2005, 46,
439–441; (e) Trost, B. M.; Horne, D. B.; Woltering, M. J. Chem. Eur. J. 2006, 12,
6607–6620; (f) Chandrasekhar, S.; Chandrashekar, G.; Vijeendera, K.; Sarma, G.
D. Tetrahedron: Asymmetry 2006, 17, 2864–2869; (g) Das, B.; Kumar, D. N.
Synlett 2011, 1285–1287. and references cited there in.
6. (a) Pandey, S. K.; Kumar, P. Synlett 2007, 2894–2896; (b) Pandey, S. K.; Kumar,
P. Tetrahedron Lett. 2005, 46, 4091–4093; (c) Cherian, S. K.; Kumar, P.
Tetrahedron: Asymmetry 2007, 18, 982–987; (d) Kandula, S. V.; Kumar, P.
Tetrahedron 2006, 62, 9942–9948; (e) Kumar, P.; Bodas, M. S. J. Org. Chem. 2005,
70, 360–363; (f) Bodas, M. S.; Upadhyay, P. K.; Kumar, P. Tetrahedron Lett. 2004,
45, 987–988; (g) Upadhyay, P. K.; Prasad, R.; Pandey, M.; Kumar, P. Tetrahedron
Lett. 2009, 50, 2440–2442; (h) Upadhyay, P. K.; Kumar, P. Synthesis 2010, 3063–
3066.
4.1.9. (2S,4S,5R)-4-Hydroxy-5-(hydroxymethyl)pyrrolidine-2-
carboxylic acid 3
A solution of DMSO (0.152 mL, 2.16 mmol) in dry dichlorometh-
ane (5 mL) was added at ꢀ78 °C to a solution of oxalyl chloride
(0.1 mL, 1.08 mmol) in dry dichloromethane (5 mL) and stirred
for 15 min at ꢀ78 °C. To this a solution of 14 (300 mg, 0.719 mmol)
in dichloromethane (5 mL) was added. The reaction mixture was
stirred for 45 min at ꢀ60 °C. Next, Et3N (13.3 mL, 95.2 mmol)
was then added at ꢀ78 °C, the cooling bath removed and the reac-
tion mixture was stirred for 1 h at room temperature. The reaction
was quenched by addition of water and the aqueous phase was ex-
tracted with dichloromethane. The combined organic extracts
were washed successively with water (2 ꢂ 10 mL), aqueous NaH-
CO3 (1 ꢂ 15 mL) and brine (1 ꢂ 20 mL), dried with Na2SO4, filtered
through Celite, and the solvent was removed in vacuo to give crude
aldehyde as pale yellow oil. This aldehyde was used without any
purification in the next step.
To the above crude solution of aminoaldehyde (280 mg,
0.67 mmol) in 10 mL of t-BuOH–CH3CN (5/3) was added 2-
methyl-2-butene (0.874 mL, 8.07 mmol). To this was added a solu-
tion containing 80% NaClO2 (678 mg, 6 mmol) and NaH2PO4
(484.5 mg.) in H2O (5 mL) dropwise at 0 °C. The resulting solution
was stirred at 0 °C for 3 h and quenched by addition of a small
piece of ice. The solution was adjusted to pH 6 and the mixture
was extracted with ethyl acetate (5 ꢂ 20 mL), the combined organ-
ic phases were washed with brine, dried (Na2SO4) and the solvent
was evaporated to give an amino acid which was used in next step
without purification.
7. Paintner, F. F.; Allmendinger, L.; Bauschke, G.; Klemann, P. Org. Lett. 2005, 7,
1423–1426.
8. (a) Tidwell, T. T. Synthesis 1990, 857–870; (b) Tidwell, T. T. Org. React. 1990, 39,
297.
9. Ma, D.; Zhu, W. Synlett 2006, 1181–1184.
10. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 448–451; (b)
Torri, S.; Liu, P.; Bhuvaneswari, N.; Amatore, C.; Jutand, A. J. Org. Chem. 1996, 61,
3055–3060; For a review on asymmetric dihydroxylation, see: (c) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
11. The diastereoselectivity of diol 11 was confirmed by its 1H and 13C NMR
spectroscopy.
12. Fleming, P. R.; Sharpless, K. B. J. Org. Chem. 1991, 56, 2869–2875.
13. Davies, C. E.; Heightman, T. D.; Hermitage, S. A.; Moloney, M. G. Synth. Commun.
1996, 26, 687–696.
To a solution of the crude acid (150 mg, 0.35 mmol) in a 1:1
mixture of MeOH–H2O (5 mL) was added 40 mg of 20% Pd(OH)2/
C in one portion. The mixture was stirred under a hydrogen
atmosphere and the reaction was monitored by TLC. After 16 h
14. Deur, C. J.; Miller, M. W.; Hegedus, L. S. J. Org. Chem. 1996, 61, 2871–2876.
15. (a) Andrés, J. M.; Elena, N. D.; Pedrosa, R. Tetrahedron 2006, 56, 1523–1531; (b)
Annette Raach, A.; Reiser, O. J. Prakt. Chem. 2000, 342, 605–608.