Highly diastereoselective construction of substituted pyrrolidines: Formal synthesis of (-)-bulgecinine

Article abstract of DOI:10.1055/s-0030-1260546

A highly diastereoselective synthesis of substituted pyrrolidines has been achieved starting from nonchiral molecule, allyl bromide, or cis-but-2-ene-1,4-diol. The method involves the asymmetric epoxidation and endo-mode epoxide opening with azide nucleop

Full text of DOI:10.1055/s-0030-1260546

LETTER
1285
Highly Diastereoselective Construction of Substituted Pyrrolidines: Formal
Synthesis of (–)-Bulgecinine1
F
ormal Synthesis
i
of (–)-
s
Bulgecini
wne anath Das,* Duddukuri Nandan Kumar
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193198; E-mail: biswanathdas@yahoo.com
Received 13 January 2011
epoxide 4. This epoxide 4 in turn can be synthesized from
Abstract: A highly diastereoselective synthesis of substituted pyr-
rolidines has been achieved starting from nonchiral molecule, allyl
bromide, or cis-but-2-ene-1,4-diol. The method involves the asym-
metric epoxidation and endo-mode epoxide opening with azide nu-
the alcohol 5 prepared from allyl bromide (6) or cis-but-2-
ene-1,4-diol (7). Thus this synthetic approach constitutes
the preparation of (–)-bulgecinine (1) starting from non-
cleophile as the key steps. The method has been applied for the chiral molecules. Allyl bromide (6) or cis-but-2-ene-1,4
formal synthesis of (–)-bulgecinine.
diol (7) was initially converted into the allyl alcohol 8 fol-
lowing the reported methods.6 This allyl alcohol 8 was
Key words: substituted pyrrolidine, (–)-bulgecinine, diastereo-
selective synthesis, asymmetric epoxidation, endo-mode epoxide
opening
subjected to Sharpless asymmetric epoxidation7 to pro-
duce the epoxide 9 (Scheme 2). The regioselective reduc-
tion of the epoxide 9 with Red-Al8 afforded the alcohol 5.
The primary hydroxy group of 5 was protected as TBS
Substituted pyrrolidines are important bioactive natural ether and the secondary hydroxy group as PMB ether to
products. Many of these compounds are known to possess form the product 10. The TBS ether group of the latter was
various impressive biological properties including anti- again deprotected to generate the primary alcohol 11. This
fungal, antibacterial, and hypotensive activities.2 (–)- alcohol was subsequently converted into an aldehyde un-
Bulgecinine (1), a tetrasubstitued pyrrolidine, is a core der Swern oxidation conditions, and the resulting alde-
constituent of the glycosides, bulgecinine A, B, and C de- hyde was subjected to two-carbon homologation using
rived from Pseudomonas sp.3 These glycosides exhibit in- ethoxy carboxymethylene triphenylphosphorane in
teresting synergistic antibacterial activity. In continuation CH2Cl2 to furnish the (E)-a,b-unsaturated ester 12 in high
of our work4 on the stereoselective synthesis of natural yield. The ester group of 12 was reduced with DIBAL-H
products we report here a highly diastereoselective con- to generate the allylic alcohol 13 which underwent asym-
struction of substituted pyrrolidines and the application of metric epoxidation to give the epoxide 4. This epoxide
the method for the formal synthesis of (–)-bulgecinine (1). was then purified, and the pure compound was subjected
Previously, some methods have been reported5 for the to a highly efficient C-2 selective azide substitution reac-
synthesis of 1. However, the present method constitutes a tion using NaN3-(MeO)3B system9 to form the diol 3. The
novel approach for the synthesis of this pyrrolidine deriv- reaction proceeded via an intramolecular boron chelate
ative.
through a novel endo-mode epoxide opening.9 The minor
1,2-diol that resulted from C-3 opening was removed by
treatment of the reaction mixture with NaIO4 followed by
purification over chromatography. The 1,3-diol group of
3 was protected as acetonide, and the PMB ether group
The retrosynthetic analysis (Scheme 1) revealed that the
compound 1 can be prepared from the intermediate 25e
which can be obtained from the azide 3 generated from the
OH
O
PMBO
OH
OH
O
BnO
HOOC
OH
N
H
N
N3
OH
Cbz
1
2
3
Br
OH
OPMB
6
O
BnO
BnO
or
OH
OH
5
4
HO
OH
7
Scheme 1
SYNLETT 2011, No. 9, pp 1285–1287
x
x.
x
x.
2
0
1
1
Advanced online publication: 05.05.2011
DOI: 10.1055/s-0030-1260546; Art ID: D01211ST
© Georg Thieme Verlag Stuttgart · New York

1286
B. Das, D. N. Kumar
LETTER
OR1
O
b
e
a
BnO
BnO
BnO
OH
O
OR2
OH
8
9
5 R1 = R2 = H
c
10 R1 = PMB, R2 = TBS
11 R1 = PMB, R2 = H
d
OPMB
BnO
OPMB
OPMB
g
f
O
BnO
BnO
OEt
OH
OH
12
13
4
O
PMBO
OH
R1O
O
O
O
h
i
k
BnO
BnO
OH
N
H
N3
N3
OBn
3
14 R1 = H
16
j
15 R1 = Ms
O
O
OH
O
O
l
m
n
N
N
H
HO2C
N
H
OH
OH
OH
Cbz
17
2
1
Scheme 2 Reagents and conditions: (a) Ti(i-OPr)4 (0.2 equiv), (+)-DIPT (0.3 equiv), TBHP (2.5 equiv), CH2Cl2, –20 °C, 12 h, 82%; (b) Red
Al, THF, 0 °C to r.t., 12 h, 98%; (c) 1. TBSCl, imidazole, r.t., 12 h, 94%; 2. PMBBr, NaH, THF, 0 °C to r.t., 3.5 h, 93%; (d) PTSA, MeOH, r.t.,
94%; (e) 1. IBX, DMSO, CH2Cl2, 0 °C to r.t., 3 h; 2. PPh3CHCOOEt, CH2Cl2, r.t., 2 h, 86% (in two steps); (f) DIBAL-H, CH2Cl2, –78 °C
to –10 °C, 0.5 h, 84%; (g) Ti(i-OPr)4 (0.2 equiv), (+)-DIPT (0.3 equiv), TBHP (2.5 equiv), CH2Cl2, –20 °C, 20 h, 80%; (h) NaN3, (MeO)3B,
DMF, 90 °C, 3.5 h, 85%; (i) 1. 2,2 DMP, PTSA, CH2Cl2, r.t., 4 h, 71%; 2. DDQ, CH2Cl2–H2O, r.t., 5 h, 90%; (j) MeSO2Cl, i-Pr2NH, 0 °C to
r.t., 4.5 h; (k) indium powder, NH4Cl, Et3N, MeOH, reflux, 6 h, 89% (in the last two steps); (l) Pd/C, MeOH, r.t., 5 h, 86%; (m) CbzCl, EtOAc,
NaHCO3, 0 °C, 1 h, 78%; (n) ref. 5e.
was deprotected with DDQ in CH2Cl2–H2O to give the References and Notes
azido alcohol 14. The hydroxy functionality of 14 was
converted into its mesylate using methanesulfonyl chlo-
(1) Part 45 in the series ‘Synthetic Studies on Natural Products
and Bioactive Compounds’.
ride and diisopropylamine to afford 15. The mesylate
compound 15 was directly treated with indium powder
and NH4Cl in MeOH to produce the substituted pyrroli-
dine 16. The latter was hydrogenated using catalytic
amount of Pd/C in MeOH to generate the amino alcohol
17 which was subsequently reacted with benzyl chlorofor-
mate and saturated NaHCO3 in EtOAc to afford the N-Cbz
protected alcohol 2 in good yield. Compound 2 could be
converted into (–)-bulgecinine (1) following the method
reported earlier.5e The structures of all the products of the
present synthesis were confirmed from their spectral (IR,
1H NMR, 13C NMR, and MS) and analytical data.10
(2) (a) Cheng, Y.; Huang, Z. T.; Wang, M. X. Curr. Org. Chem.
2004, 8, 325. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22,
603.
(3) (a) Imada, A.; Kintaka, K.; Nakao, M.; Shinagawa, S.
J. Antibiot. 1982, 35, 1400. (b) Shinagawa, S.; Kashara, F.;
Wada, Y.; Harada, S.; Asai, M. Tetrahedron 1984, 40, 3465.
(c) Shinagawa, S.; Maki, M.; Kintaka, K.; Imada, A.; Asai,
M. J. Antibiot. 1985, 38, 17.
(4) (a) Das, B.; Suneel, K.; Satyalakshmi, G. Tetrahedron:
Asymmetry 2009, 20, 1536. (b) Das, B.; Krishnaiah, M.;
Sudhakar, Ch. Bioorg. Med. Chem. Lett. 2010, 20, 2303.
(c) Das, B.; Kumar, D. N. Tetrahedron Lett. 2010, 51, 6011.
(5) Some earlier syntheses: (a) Wakamiya, T.; Yamauoi, K.;
Nishikawa, M.; Shiba, T. Tetrahedron Lett. 1985, 26, 4739.
(b) Bashyal, B. P.; Chow, H. F.; Fleet, G. W. J. Tetrahedron
Lett. 1986, 27, 3205. (c) Fehn, S.; Burger, K. Tetrahedron:
Asymmetry 1997, 8, 2001. (d) Maeda, M.; Okazaki, F.;
Murayama, M.; Tachibana, Y.; Aoyagi, Y.; Ohta, A. Chem.
Pharm. Bull. 1997, 45, 962. (e) Khalaf, J. K.; Datta, A.
J. Org. Chem. 2004, 69, 387. (f) Chavan, S. P.; Praveen,
Ch.; Sharma, P.; Kalkote, U. R. Tetrahedron Lett. 2005, 46,
439. (g) Toumi, M.; Couty, F.; Evano, G. Tetrahedron Lett.
2008, 49, 1175.
In conclusion, we have developed a highly diastereoselec-
tive synthesis of substituted pyrrolidines starting from
nonchiral molecules involving asymmetric epoxidation
and endo-mode epoxide opening with azide nucleophile
as the key steps. We have also demonstrated the applica-
tion of this method for the synthesis of (–)-bulgecinine.
The major steps of this synthesis included simple protec-
tion–deprotection strategies.
(6) (a) Izzo, I.; Scioscia, M.; Del Gaudio, P.; De Riccardis, F.
Tetrahedron Lett. 2001, 42, 5421. (b) Poulard, C.; Carnet,
J.; Legoupy, S.; Dujardiu, G.; Dhal, R.; Huct, F. Lett. Org.
Chem. 2009, 6, 359.
(7) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko,
S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc.
1987, 109, 5765. (c) Goument, B.; Duchamel, L.; Mauge, R.
Acknowledgment
The authors thank CSIR and UGC, New Delhi for financial assi-
stance.
Synlett 2011, No. 9, 1285–1287 © Thieme Stuttgart · New York

LETTER
Tetrahedron 1994, 50, 171.
(8) (a) Ma, P.; Martin, V. S.; Masumune, S.; Sharpless, K. B.;
Viti, S. M. J. Org. Chem. 1982, 47, 1378. (b) Finan, J. M.;
Kishi, Y. Tetrahedron Lett. 1982, 23, 2719.
(9) Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. T. Org. Lett.
2003, 5, 1789.
(10) Spectral and Analytical Data of Selected Compounds
(3-{3-(Benzyloxy)-2-[(4-methoxybenzyl)oxy]propyl}-
oxiran-2-yl)methanol (4)
Formal Synthesis of (–)-Bulgecinine
1287
127.7, 126.7, 116.0, 73.2, 72.8, 70.1, 66.1, 65.5, 62.6, 55.9,
29.8. ESI-MS: m/z = 401 [M]+. Anal. Calcd (%) for
C21H27N3O5: C, 62.84; H, 6.73. Found: C, 62.80; H, 6.75.
(4aR,6S,7aS)-6-(Benzyloxymethyl)-2,2-dimethyl-
hexahydro[1,3]dioxino[5,4-b]pyrrole (16)
[a]D25 +31.3 (c 1.7, CHCl3). IR (KBr): nmax = 3385, 1600,
1490, 1279 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.37–
7.20 (5 H, m), 4.53 (2 H, s), 4.22 (1 H, m), 4.08 (1 H, m),
3.47 (1 H, m), 3.33 (1 H, m), 2.93–2.74 (3 H, m), 2.30 (1 H,
m), 1.97–1.71 (2 H, m), 1.48 (6 H, s). 13C NMR (75 MHz,
CDCl3): d = 138.8, 129.3, 128.5, 127.8, 100.9, 81.8, 72.6,
72.2, 70.0, 54.0, 36.7, 27.7. ESI-MS: m/z = 277 [M]+. Anal.
Calcd (%) for C16H23NO3: C, 69.31; H, 8.30. Found: C,
69.33; H, 8.27.
[a]D25 –16.8 (c 0.9, CHCl3). IR (KBr): nmax = 3449, 1455,
1375, 1248 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.43–
7.16 (7 H, m), 6.81 (2 H, d, J = 8.0 Hz), 4.65–4.43 (4 H, m),
3.79 (3 H, s), 3.74–3.63 (2 H, m), 3.62–3.42 (3 H, m), 2.99
(1 H, m), 2.82 (1 H, m), 1.92–1.73 (2 H, m). 13C NMR (75
MHz, CDCl3): d = 158.3, 139.2, 13 2.3, 129.3, 128.8, 128.0,
121.9, 116.0, 73.2, 71.4, 70.7, 70.5, 70.3, 61.2, 56.3, 49.3,
30.7. ESI-MS: m/z = 358 [M]+. Anal. Calcd (%) for
C21H26O5: C, 70.39; H, 7.26. Found: C, 70.41; H, 7.21.
2-Azido-6-(benzyloxy)-5-(4-methoxybenzyloxy)hexane-
1,3-diol (3)
(4aR,6S,7aS)-Benzyl 6-Hydroxymethyl)-2,2-dimethyl-
tetrahydro[1,3]dioxino[5,4-b]pyrrole-5(6H)-carboxylate
(2)
[a]D25 –55.4 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 7.32–7.13 (5 H, m), 5.05 (2 H, s), 4.40 (1 H, m), 4.24–
4.00 (2 H, m), 3.96–3.65 (4 H, m), 3.07 (1 H, m), 2.63 (1 H,
br s), 2.25 (1 H, m), 1.47 (6 H, s). 13C NMR (75 MHz,
CDCl3): d = 155.8, 135.5, 129.0, 128.7, 128.5, 127.8, 100.1,
72.0, 68.5, 67.0, 66.2, 61.1, 58.6, 31.4, 29.5, 19.8. ESI-MS:
m/z = 321 [M]+. Anal. Calcd (%) for C17H23NO5: C, 63.55;
H, 7.17. Found: C, 63.51; H, 7.12.
IR (KBr): nmax = 3390, 2103 cm–1. 1H NMR (200 MHz,
CDCl3): d = 7.38–7.16 (7 H, m), 6.81 (2 H, d, J = 8.0 Hz),
4.65–4.44 (4 H, m), 4.07 (1 H, m), 3.85 (1 H, m), 3.78 (3 H,
s), 3.56–3.47 (4 H, m), 2.09 (1 H, m), 1.99–1.78 (1 H, m).
13C NMR (100 MHz, CDCl3): d = 158.0, 137.8, 129.5, 128.5,
Synlett 2011, No. 9, 1285–1287 © Thieme Stuttgart · New York