A short, efficient, and stereoselective total synthesis of a pyrrolidine alkaloid: (-)-Codonopsinine

Article abstract of DOI:10.1021/jo061940q

An efficient total synthesis of antibiotic (-)-codonopsinine 1 with an overall yield of 44% was achieved from D-alanine as a chiral template. The key steps in our strategy are modified Sharpless asymmetric dihydroxylation reaction and the highly stereosel

Full text of DOI:10.1021/jo061940q

A Short, Efficient, and Stereoselective Total
Synthesis of a Pyrrolidine Alkaloid:
(-)-Codonopsinine†
Jangari Santhosh Reddy and Batchu Venkateswara Rao*
Organic DiVision III, Indian Institute of Chemical Technology,
FIGURE 1. Structures of some important pyrrolidine iminosugar
compounds carrying an aromatic substituent.
Hyderabad 500007, India
SCHEME 1. Retrosynthetic Analysis of (-)-Codonopsinine
Venky@iict.res.in
ReceiVed September 20, 2006
possessing 1,2,3,4,5 penta-substituted pyrrolidine structures
bearing four contiguous stereogenic centers, which are situated
in all trans positions. The absolute configuration of the
natural antibiotic 1 was determined as (2R,3R,4R,5R).6 This was
further confirmed by X-ray crystallographic studies of (-)-
codonopsine 2.7
Because of the interesting pharmacological activity and
unique structural features, these iminosugar compounds have
drawn considerable attention from many synthetic organic
chemists. Although several synthetic approaches have been
reported for (-)-codonopsinine 1,8 many of them involve long
reaction sequences and also show poor stereoselectivity in key
bond-forming reactions. Therefore the need for an efficient
synthesis still remains. Consequently, development of new
strategies and approaches to address the above challenges
continue to be a worthwhile research goal.
An efficient total synthesis of antibiotic (-)-codonopsinine
1 with an overall yield of 44% was achieved from D-alanine
as a chiral template. The key steps in our strategy are
modified Sharpless asymmetric dihydroxylation reaction and
the highly stereoselective intramolecular acid-catalyzed ami-
docyclization.
The chiral polyhydroxy alkaloids (or iminosugars)1 show
remarkable biological properties and have attracted considerable
attention in organic synthesis. Over the past two decades, many
studies aimed at isolation and sterocontrolled syntheses of these
alkaloids have been carried out.1,2 Among these, pyrrolidine
alkaloids carrying an aromatic substituent on the iminosugar
ring are of a rare class found in nature. (-)-Codonopsinine 1
and (-)-codonopsine 2 are the first two examples in this unusual
category (Figure 1), initially isolated in 1969 from Codonopsis
clematidea.3 These two compounds display antibiotic as well
as hypotensive activities without affecting the central nervous
system in animal tests.4 After structural characterization,3b,5 they
were revealed to be a new class of simple pyrrolidine alkaloids
Our interest in the development of new and efficient synthetic
routes to some important chiral pyrrolidine compounds9 prompted
(4) Khanov, M. T.; Sultanov, M. B.; Egorova, M. R. Farmakol.
AlkaloidoV Serdech. GlikoyidoV 1971, 210; Chem. Abstr. 1972, 77, 135091r.
(5) Matkhalikova, S. F.; Malikov, V. M.; Yugadev, M. R.; Yunusov, S.
Y. Khim. Prir. Soedin 1971, 7, 210-211.
(6) (a) Iida, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1986,
27, 5393-5396. (b) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem.
1987, 52, 1956-1962.
(7) (a) Wang, C. L. J.; Calabrese, J. C. J. Org. Chem. 1991, 56, 4341-
4343. (b) Tashkhodzaev, B.; Aripova, S. F.; Turgunov, K. K.; Abdilalimov,
O. Chem. Nat. Compd. 2004, 40, 618-619.
(8) For the synthesis of codonopsinine, see refs 6b, 7, and (a) Yoda, H.;
Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531-5534. (b)
Oliveira, D. F.; Severino, E. A.; Correia, C. R. D. Tetrahedron Lett. 1999,
40, 2083-2086. (c) Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2,
3039-3042. (d) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett
2003, 35-38. (e) Haddad, M.; Larcheveˆque, M. Synlett 2003, 274-276.
(f) Goti, A.; Cicchi, S.; Mannucci, V.; Cardona, F.; Guarna, F.; Merino, P.;
Tejero, T. Org. Lett. 2003, 5, 4235-4238. (g) Chandrasekhar, S.; Jagadesh-
war, V.; Prakash, S. J. Tetrahedron Lett. 2005, 46, 3127-3129. (h)
Chandrasekhar, S.; Saritha, B.; Jagadeshwar, V.; Prakash, S. J. Tetrahe-
don: Asymmetry 2006, 17, 1380-1386. (i) Iida, H.; Yamazaki, N.;
Kibayashi, C. Tetrahedron Lett. 1985, 26, 3255. This last reference actually
marks the first total synthesis of the unnatural (+)-codonopsinine. However,
the stereochemical representation for (+)-codonopsinine made in this work
was later revised; see ref 6a.
* To whom correspondence should be addressed. Tel: + 91-040-27160123,
Ext 2614. Fax: + 91-40-27193108.
† IICT Communication no. 060920.
(1) For a review on iminosugars, see: (a) Stu¨tz, A. E. Iminosugars as
Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH: Weinheim,
1999. (b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedon: Asymmetry 2000, 11, 1645-1680. (c) Watson, A. A.; Fleet,
G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry 2001,
56, 265-295. (d) Martin, O. R.; Compain, P. Symposium-in-print. Curr.
Top. Med. Chem. 2003, 3, 5.
(2) (a) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles 2002, 57,
1539-1553. (b) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.;
Girdhar, A.; Ramsden, N. G.; Peach, J. M.; Hegarty, M. P.; Scofield, A.
M. Phytochemistry 1990, 29, 111-114. (c) Harris, C. M.; Harris, T. M.;
Molyneux, R. J.; Tropea, J. E.; Elbein, A. D. Tetrahedron Lett. 1989, 30,
5685-5688. (d) Nash, R. J.; Fellows, L. E.; Plant, A. C.; Fleet, G. W. J.;
Derome, A. E.; Baird, P. D.; Hegarty, M. P.; Scofield, A. M. Tetrahedon
1988, 44, 5959-5964.
(9) (a) Madhan, A.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5641-5643.
(b) Kumar, A. R.; Reddy, J. S.; Rao, B. V. Tetrahedron Lett. 2003, 44,
5687-5689. (c) Madhan, A.; Rao, B. V. Tetrahedron Lett. 2005, 46, 323-
324. (d) Reddy, J. S.; Kumar, A. R.; Rao, B. V. Tetrahedron: Asymmetry
2005, 16, 3154-3159.
(3) (a) Matkhalikova, S. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir.
Soedin 1969, 5, 30-32; Chem. Abstr. 1969, 71, 13245z. (b) Matkhalikova,
S. F.; Malikov, V. M.; Yunusov, S. Y. Khim. Prir. Soedin 1969, 5, 606-
607; Chem. Abstr. 1970, 73, 25712d.
10.1021/jo061940q CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/23/2007
2224
J. Org. Chem. 2007, 72, 2224-2227

TABLE 1. Stereoselective Dihydroxylation Studies on Compound 5 under Various Conditions
entry
reagents
solvent (ratio)
conditions (time)
yield (%)a
dr
1
2
3
OsO4 (1 mol %), NMO
AD-mix-â (1.4 g/mmol)
AD-mix-â (1.4 g/mmol), OsO4 (0.6 mol %),
CH3SO2NH2 (95 mg/mmol),
NaHCO3 (0.25 g/mmol)
acetone/water (5:1)
tert-butanol/water (1:1)
tert-butanol/water (1:1)
0 °C to rt (1 h)
0 °C (48 h) and 10 °C (48 h)
0 °C (15 h)
92
62
96
54:46b
53:47c
89:11b
4
AD-mix-â (1.4 g/mmol), OsO4 (0.6 mol %),
(DHQD)2PHAL (4 mol %),
tert-butanol/water (1:1)
0 °C (15 h)
99
91:9b
CH3SO2NH2 (95 mg/mmol),
NaHCO3 (0.25 g/mmol)
1
a Yield represents the combined diastereomers after purfication. b Determined from HPLC. c Determined from H NMR data.
SCHEME 2. Synthesis of the Basic Carbon Skelton of (-)-Codonopsinine
us to investigate the total synthesis of (-)-codonopsinine 1,
starting from simple and readily available amino acid D-alanine
as a chiral template. Our retrosynthetic strategy is outlined in
Scheme 1. The key transformations in the proposed strategy
will involve (i) Sharpless asymmetric dihydroxylation reaction
to install the hydroxy groups at C3 and C4 positions stereose-
lectively and (ii) an intramolecular acid-catalyzed amidocy-
clization protocol to construct the pivotal pyrrolidine core of
the target molecule.
Using a literature procedure, D-alanine was readily converted
to N-Cbz-protected alaninol derivative 4 (Scheme 2) in one pot
(94%).10 The alcohol functionality of the compound 4 was
oxidized to aldehyde under Swern conditions. The resultant
aldehyde on Wittig reaction with (4-methoxyphenacyl)triph-
enylphosphorane11 yielded the trans-R,â-unsaturated ketone 5
(86%). Further, the compound 5 was subjected to dihydroxy-
lation under various conditions; the results are summarized in
Table 1. Using OsO4 (entry 1) at room temperature for 1 h, the
corresponding dihydroxylated compound 6 was obtained in 92%
yield. Unfortunately this reaction gave poor stereoselectivity.
Sharpless asymmetric dihydroxylation (SAD) using AD-mix-â
[1.4 g contains (DHQD)2PHAL (7.73 mg, 1.0 mol %), K3Fe-
(CN)6 (980 mg, 3 mmol), K2OsO2(OH)4 (1.46 mg, 0.004 mmol),
K2CO3 (411 mg, 3 mmol)] at 0 °C for 48 h and another 48 h at
10 °C gave 6 in 62% yield also with poor stereoselectivity (entry
2). Treatment of compound 5 under modified SAD12 (entry 3)
condition at 0 °C for 15 h gave the desired diol derivative 6 in
96% yield (dr ) 89:11). Finally, increasing the ligand concen-
tration from 1 mol % to 5 mol % in the above modified SAD
(entry 4) reaction at 0 °C for 15 h resulted in the formation of
diol derivative 6 in 99% yield with increased diastereoselectivity
(dr ) 91:9). The product was carried to the next reaction without
separating the diastereomers.
Reduction of compound 6 with NaBH4 resulted in the
formation of triol as a diastereomeric mixture (Scheme 3), which
was utilized in the next reaction without purification. Treatment
of the triol with the acetic anhydride in dichloromethane afforded
the diastereomeric triacetate derivative 7 (∼1:1) in 90%. For
the synthesis of the 2,5-trans-substituted pyrrolidine core, the
diastereomeric mixture of 713 was treated with trifluoroacetic
acid in dichloromethane at 0 °C for 4 h to give the single isomer
814 in 81% yield.
The stereoselective formation of pyrrolidine compound 8 from
7 can be explained through intramolecular SN1 reaction via
resonance-stabilized benzylic carbocation. The benzylic car-
bocation can be further stabilized by the neighboring acetoxy
group to give a trans dioxolane carbocation (acetoxonium ion)
intermediate, thereby further facilitating the approach of the
N-nucleophile preferentially from the opposite face (Scheme
4) and giving stable 2,5-trans-substituted pyrrolidine 8.15 When
compound 8 was treated with LAH in THF under reflux for 5
h, it smoothly led to the natural product (-)-codonopsinine 1
in 74% yield. In the above reaction concomitant convertion of
N-Cbz to N-Me took place along with the deprotection of the
(13) Only for the sake of characterization, both diastereomers were
separated and spectral data were taken.
(14) Acid-mediated cyclization gave exclusive formation of compound
8. We did not observe any other product, resulting from the minor
diastereomer of compound 6.
(15) Because of the existence of compound 8 in rotamers, we were unable
to determine the isomeric purity at this stage. Therefore compound 8 was
taken to the next reaction and treated with LAH, which gave only (-)-
codonopsinine 1. It denotes that the acid-catalysed cyclization gave
exclusively trans isomer 8.
(10) Schlessinger, R. H.; Iwanowicz, E. J. Tetrahedron Lett. 1987, 28,
2083-2086.
(11) Wittig ylide was prepared from 4-methoxyphenacylbromide ac-
cording to the preparation of phenacyltriphenylphosporane; see: Ramirez,
F.; Dershowitz, S. J. Org. Chem. 1957, 22, 41-45.
(12) Walsh, P. J.; Sharpless, K. B. Synlett 1993, 605-606.
J. Org. Chem, Vol. 72, No. 6, 2007 2225

SCHEME 3. Total Synthesis of (-)-Codonopsinine
SCHEME 4. Proposed Mechanism for the Stereoselective Cyclization
NMR (400 MHz, CDCl3) δ 1.36 (3H, d, J ) 6.8 Hz), 3.86 (3H, s),
4.49-4.58 (1H, br s), 4.85 (1H, d, J ) 8.0 Hz), 5.09 (2H, s), 6.84
(1H, dd, J ) 5.2, 15.2 Hz), 6.87 (2H, d, J ) 8.0 Hz), 6.92 (1H, d,
J ) 15.2 Hz), 7.24-7.36 (5H, m), 7.87 (2H, d, J ) 8.0 Hz); 13C
NMR (75 MHz, CDCl3) δ 20.5, 48.1, 55.4, 66.9, 113.8, 124.2,
128.1, 128.5, 130.5, 130.9, 136.3, 147.5, 155.5, 163.5, 188.7; LC-
MS m/z 340 (M+ + 1); HRMS calcd for C20H21NO4Na 362.1368,
found 362.1380.
acetates. The spectral and analytical data of synthetic (-)-
codonopsinine 1 were in excellent agreement with the reported
values.3a
In summary, a novel, short, and efficient stereoselective
synthesis of natural (-)-codonopsinine 1 was developed in good
overall yield starting from D-alanine, utilizing highly stereose-
lective intramolecular amidocyclization protocol as the key
step. The present synthesis compares well with the reported
methods and offers an attractive alternate approach to the title
compound. Application of the above strategy for the synthesis
of some important pyrrolidine and piperidine molecules is in
progress.
Benzyl (2R,3R,4S)-3,4-Dihydroxy-5-(4-methoxyphenyl)-5-oxo-
pentan-2-ylcarbamate (6). To a stirred solution of AD-mix-â (3.3
g) in 1:1 tert-butanol/water (15 mL each) at room temperature were
added toluene solutions of OsO4 (2.83 mL, 0.05 M, 0.6 mol %),
(DHQD)2PHAL (0.73 g, 4 mol %), NaHCO3 (0.59 g, 7.05 mmol),
and MeSO2NH2 (0.22 g, 2.35 mmol) sequentially. After 15 min,
the clear solution was cooled to 0 °C ,and to it was added compound
5 (0.8 g, 2.35 mmol) at once. After 15 h of stirring at 0 °C, ethyl
acetate (10 mL) was added followed by Na2S2O3 (3.53 g), and the
solution was warmed to room temperature with vigorous stirring
for 1 h. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3 × 50 mL). The combined
organic layers were washed with the brine, dried over Na2SO4, and
concentrated under vacuum. The residue was chromatographed on
silica gel (hexane/ethyl acetate ) 2:1) to afford compound 6 (0.87
Experimental Section
(R,E)-Benzyl 5-(4-Methoxyphenyl)-5-oxopent-3-en-2-ylcar-
bamate (5). To a solution of DMSO (1.36 mL, 19.13 mmol) in
dichloromethane (5 mL) was added oxalyl chloride (0.83 mL, 9.56
mmol) dropwise at -78 °C. After stirring for 30 min, a solution of
the amido alcohol 4 (1 g, 4.78 mmol) in dichloromethane (15 mL)
was added over a period of 10 min. After stirring for 30 min at
-78 °C, the reaction mixture was quenched with diisopropyl
ethylamine (4.16 mL, 23.92 mmol). The reaction mixture was
slowly warmed to 0 °C, diluted with chloroform (30 mL), washed
with water and brine, dried over Na2SO4, and concentrated under
vacuum. The crude residue was dissolved in dichloromethane (20
mL), and (4-methoxyphenacyl)triphenylphosphorane (2.35 g, 5.74
mmol) was added and stirred for 4 h at room temperature. The
reaction mixture was diluted with chloroform (50 mL), washed with
water and brine, dried over Na2SO4, and concentrated under
vacuum. The residue was chromatographed over silica gel (hexane/
ethyl acetate ) 5:1) to afford the trans compound 5 (1.4 g, 86%)
g, 99%) as a white powder: mp 144-146 °C; [R]34 ) -55.7 (c
D
0.11, CHCl3) [dr ) 91:9 was determined from HPLC using C18
column (CH3CN/H2O ) 34:66), flow rate ) 1 mL/min]; IR (KBr)
1
3484, 3302, 1688, 1550, 1459, 1052 cm-1; H NMR (300 MHz,
CDCl3) δ 1.37 (3H, d, J ) 6.4 Hz), 2.43 (1H, d, J ) 9.4 Hz), 3.90
(3H, s), 3.94-4.11 (2H, m), 4.22 (1H, d, J ) 4.9 Hz), 5.08-5.14
(2H, m), 5.16 (1H, d, J ) 4.9 Hz), 5.47 (1H, d, J ) 8.3 Hz), 6.97
(2H, d, J ) 8.7 Hz), 7.30-7.39 (5H, m), 7.87 (2H, d, J ) 8.7 Hz);
13C NMR (75 MHz, CDCl3) δ 17.0, 50.9, 55.6, 66.8, 72.8, 73.9,
114.2, 125.9, 128.1, 128.5, 130.9, 135.4, 136.4, 156.4, 164.3, 199.0;
LC-MS m/z 374 (M+ + 1); HRMS calcd for C20H23NO6Na
396.1423, found 396.1434.
as colorless needles: mp 101-103 °C; [R]34 ) +7.7 (c 0.3,
D
1
CHCl3); IR (KBr) 3301, 1683, 1568, 1535, 1457, 1078 cm-1; H
2226 J. Org. Chem., Vol. 72, No. 6, 2007

(1R/S,2R,3R,4R)-4-(Benzyloxycarbonylamino)-1-(4-methox-
yphenyl)pentane-1,2,3-triyl Triacetate (7). To a solution of keto
diol 6 (0.62 g, 1.62 mmol) in MeOH (5 mL) at 0 °C was added
NaBH4 (0.07 g, 1.99 mmol) in portions over a period of 10 min,
and the mixture was stirred at the same temperature for 90 min.
The mixture was neutralized by adding saturated aqueous NH4Cl,
and volatiles were removed under vacuum. The crude residue was
subjected to flash column chromatography over silica gel (hexane/
ethyl acetate ) 1:1) to obtain a diastereomeric mixture of triol as
a white solid. To the stirred diastereomeric mixture of triol in
dichloromethane (10 mL) were added triethyl amine (1.39 mL, 9.97
mmol), acetic anhydride (0.47 mL, 4.98 mmol), and 4-dimethy-
lamino pyridine (5 mg) at 0 °C. After completion of the addition,
the reaction mixture was allowed to remain at room temperature
and was stirred for 16 h. The reaction mixture was diluted with
chloroform (50 mL), washed with water and brine, dried over Na2-
SO4, and concentrated under vacuum. The residue was chromato-
graphed over silica gel (hexane/ethyl acetate ) 8.5:1.5) to afford
the faster moving isomer of compound 7 (0.39 g, 47%) as a
temperature for 4 h. The reaction mixture was neutralized with
NaHCO3 at 0 °C, filtered through a celite pad, and washed with
chloroform (2 × 20 mL). The chloroform layer was washed with
water and brine, dried over Na2SO4, and concentrated under
vacuum. The crude residue was purified through silica gel column
chromatography (hexane/ethyl acetate ) 6:1) to afford single desired
pyrrolidine diacetate derivative 8 (0.39 g, 81%) as colorless oil:
[R]34D ) +20.2 (c 0.11, CHCl3); IR (neat) 1745, 1705, 1613, 1514,
1454, 1075 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.53 (3H, d, J )
6.8 Hz), 1.81 (3H, s), 2.15 (3H, s), 3.80 (3H, s), 4.28 (1H, m),
4.76-5.2 (5H, m), 6.73-6.83 (3H, m), 7.06-7.39 (6H, m); 13C
NMR (75 MHz, CDCl3) δ 17.2, *18.3, 20.7, 21.0, 55.2, *60.7, 61.4,
66.7, *67.2, 67.6, *68.0, 80.3, *81.3, *81.5, 82.4, 113.5, *113.6,
127.1, 127.3, 127.5, *127.6, 128.1, *128.2, *128.5, 131.6, 136.1,
154.2, 158.8, 169.5, 169.6. *rotamer; LC-MS m/z 442 (M+ + 1);
HRMS calcd for C24H27NO7Na 464.1685, found 464.1699.
(2R,3R,4R,5R)-2-(4-Methoxyphenyl)-1,5-dimethylpyrrolidine-
3,4-diol [(-)-codonopsinine] (1). To a stirred suspension of LiAlH4
(0.07 g, 1.9 mmol) in THF (3 mL) was added pyrrolidine derivative
8 (0.28 g, 0.63 mmol) in THF (5 mL) at 0 °C. After the completion
of addition the reaction mixture was refluxed for 5 h. The reaction
mixture was cooled to 0 °C, and quenched with water (0.07 mL),
15% NaOH (0.07 mL), and water (0.20 mL) successively. After
15 min of stirring at room temperature, the reaction mixture was
filtered through a celite pad, washed with chloroform (3 × 10 mL),
and evaporated under vacuum. The residue was purified through
silica gel column chromatography (CHCl3/MeOH ) 7:1) to afford
the codonopsinine 1 (0.112 g, 74%) as a white powder: mp 168-
colorless oil: [R]33 ) +10.6 (c 1.55, CHCl3); IR (neat) 3349,
D
1747, 1613, 1517, 1035 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.12
(3H, d, J ) 6.8 Hz), 1.83 (3H, s), 1.98 (3H, s), 2.08 (3H, s), 3.76
(3H, s), 3.90-4.07 (1H, m), 4.85 (1H, d, J ) 9.8 Hz), 5.00 (2H,
dd, J ) 12.1, 17.4 Hz), 5.15 (1H, dd, J ) 2.3, 7.6 Hz), 5.53 (1H,
dd, J ) 2.3, 9.1 Hz), 5.63 (1H, d, J ) 9.1 Hz), 6.7 (2H, d, J ) 8.7
Hz), 7.23 (2H, d, J ) 8.7 Hz), 7.26-7.33(5H, m); 13C NMR (75
MHz, CDCl3) δ 17.2, 20.5, 20.6, 20.9, 46.9, 55.1, 66.8, 71.4, 72.2,
72.5, 113.6, 128.0, 128.4, 128.8, 129.0, 129.4, 136.4, 155.4, 159.7,
169.2, 169.4, 170.4; LC-MS m/z 519 (M+ + H2O); HRMS calcd
for C26H31NO9Na 524.1896, found 524.1903. The slower moving
isomer of compound 7 (0.36 g, 43%) was eluted (hexane/ethyl
acetate ) 8.4:1.6) as a colorless oil: [R]32D ) +72.9 (c 0.4, CHCl3);
IR (neat) 3384, 1748, 1613, 1516, 1031 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.04 (3H, d, J ) 6.8 Hz), 2.02 (3H, s), 2.05 (3H, s), 2.1
(3H, s), 3.77 (3H, s), 3.89-4.03 (1H, m), 4.60 (2H, m), 5.03 (2H,
dd, J ) 12.5, 15.5 Hz), 5.48 (1H, dd, J ) 3.2, 8.2 Hz), 5.72 (1H,
d, J ) 8.2 Hz), 6.8 (2H, d, J ) 8.7 Hz), 7.19 (2H, d, J ) 8.7 Hz),
7.23-7.37 (5H, m); 13C NMR (75 MHz, CDCl3) δ 16.5, 20.7, 20.9,
47.2, 55.2, 66.8, 72.5, 73.0, 74.1, 114.3, 127.7, 128.0, 128.1, 128.5,
170 °C, [R]34D ) -8.7 (c 0.3, MeOH) {lit.3a mp 169-170 °C, [R]20
D
) -8.8 (c 0.1, MeOH)}; IR (KBr) 3378, 1580, 1515, 1054 cm-1
;
1H NMR (300 MHz, pyridine-d5) δ 1.31 (3H, d, J ) 6.8 Hz), 2.20
(3H, s), 3.62-3.70 (4H, m), 4.00 (1H, d, J ) 6.4 Hz), 4.36 (1H,
dd, J ) 3.8, 4.2 Hz), 4.60 (1H, dd, J ) 4.2, 6.0 Hz), 6.96 (2H, d,
J ) 8.7 Hz), 7.58 (2H, d, J ) 8.7 Hz); 13C NMR (75 MHz, CDCl3)
δ 14.0, 34.8, 55.2, 65.2, 74.4, 85.0, 87.2, 114.2, 129.9, 134.9, 159.3;
LC-MS m/z 238 (M+ + 1); HRMS calcd for C13H20NO3 238.1443,
found 238.1449.
Acknowledgment. J.S.R. thanks UGC, New Delhi for a
research fellowship. The authors also thank Dr. J. S. Yadav,
Dr. A. C. Kunwar, and Dr. T. K. Chakraborty for their support
and suggestions.
128.9, 136.5, 155.4, 160.1, 169.8, 170.0; LC-MS m/z 519 (M+
+
H2O); HRMS calcd for C26H31NO9Na 524.1896, found 524.1919.
(2R,3R,4R,5R)-Benzyl 3,4-Diacetoxy-2-(4-methoxyphenyl)-5-
methylpyrrolidine-1-carboxylate (8). To a stirred solution of the
mixture of diastereomeric triacetate 7 (0.55 g, 1.09 mmol) in
dichloromethane (3 mL) was added trifluoroacetic acid (1.0 mL)
in dichloromethane (2 mL) dropwise at 0 °C over a period of 5
min. After completion of the addition the reaction mixture was
warmed to room temperature, and stirring was continued at the same
Supporting Information Available: Spectral (1H and 13C
NMR) data for all synthetic intermediates (1, 5-8) and HPLC
diagram of compound 6. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO061940Q
J. Org. Chem, Vol. 72, No. 6, 2007 2227