Aza variant of intramolecular nucleophile-catalyzed aldol lactonization (NCAL): Formal synthesis of (3S,4R) and (3R,4S) 4-(hydroxymethyl)pyrrolidin-3-ol

Article abstract of DOI:10.1016/j.tet.2010.10.085

Aza variant of intramolecular catalytic, asymmetric nucleophile-catalyzed, aldol lactonization (NCAL) reaction has been explored to synthesize β-lactone fused nitrogen heterocycles as aza sugars' precursors by employing achiral amino acids. The utility of these bicyclic β-lactones is presented by the formal synthesis of aza sugars, (3S,4R) and (3R,4S) 4-(hydroxymethyl)pyrrolidin-3-ol.

Full text of DOI:10.1016/j.tet.2010.10.085

Tetrahedron 67 (2011) 210e215
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Aza variant of intramolecular nucleophile-catalyzed aldol lactonization (NCAL):
formal synthesis of (3S,4R) and (3R,4S) 4-(hydroxymethyl)pyrrolidin-3-ol
*
Dimpy Sikriwal, Dinesh K. Dikshit
Division of Medicinal and Process Chemistry, Central Drug Research Institute (C.S.I.R.), Lucknow 226 001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2010
Received in revised form 25 October 2010
Accepted 27 October 2010
Available online 2 November 2010
Aza variant of intramolecular catalytic, asymmetric nucleophile-catalyzed, aldol lactonization (NCAL)
reaction has been explored to synthesize
by employing achiral amino acids. The utility of these bicyclic
synthesis of aza sugars, (3S,4R) and (3R,4S) 4-(hydroxymethyl)pyrrolidin-3-ol.
Ó 2010 Elsevier Ltd. All rights reserved.
b
-lactone fused nitrogen heterocycles as aza sugars’ precursors
b
-lactones is presented by the formal
Keywords:
Aza sugars
Aza-NCAL reaction
b-Lactone
O-Acetylquinidine
O-Acetylquinine
1. Introduction
OH
COOH
OH
COOH
OH
OH
Polyhydroxylated pyrrolidines, piperidines (often called amino or
aza sugars), and their synthetic analogs have attracted considerable
interest due to their ability to mimic sugars.1 Their often potent in-
hibitory activity toward glycosidases and glycosyltransferases of var-
ious species makes them useful in a wide range of potential
therapeutic areas, such as viral infections,2 cancer,3 diabetes,4 tuber-
culosis,5 lysosomal storage diseases,6 and parasitic protozoa.7
Hydroxylated-piperidine structural framework is found in a wide
variety of bio-actives, such as cis-3-hydroxypipecolic acid as a
constituent of antibiotic tetrazomine,8 isofebrifugine,9 and 1-de-
oxygalactonojirimycin.6,10 On the other hand, cis-3-hydroxyproline
structural motif is a part of cyclothialidine11 (a potent DNA-gyrase
inhibitor), slaframine,12 castanospermine,13 and detoxinine.14 For
the synthesis of cis-3-hydroxy-2-hydroxymethylpyrrolidines (the
‘azaDNA’ analog) there are only a few syntheses reported in the liter-
ature.15 In recent years, 4-hydroxymethyl-pyrrolidin-3-ol, a precursor
for BCX-4208 and its analogs, has been the target of several synthetic
approaches of which many are multi-steps or selectivity deficient
(Fig. 1).16 It is therefore necessary to develop new short routes to this
class of compounds.
HN
N
H
N
H
3-hydroxypiperidine-
4-carboxylic acid
3-hydroxyproline 3-Hydroxy-
2-hydroxymethyl
pyrrolidines
OH
OH
H
HO
OH
OH
OH
O
N
H
H
N
N
H
N
H
H
H
NH
OMe
1-deoxy
O
galactonojirimycin
tetrazomine
OH
HN
OH
O
O
N
OH
N
O
N
N
N
H
HN
isofebrifugine
BCX-4208
Fig. 1. Structures of aza sugars and related molecules.
Derivatives of cinchona alkaloids have shown great promise as
catalyst for a broad range of asymmetric transformations thereby
providing access to chiral products of high enantiopurity.17 Re-
cently, Romo et al. have reported a high enantioselective synthesis
of a series of bicyclic b
-lactone fused carbocycles,18 pyrrolidinone19a
or tetrahydrofurans19b via intramolecular nucleophile-catalyzed
aldol lactonization (NCAL) of aldehyde/keto acids (Fig. 2). Inspired
* Corresponding author. Fax: þ91 522 262 3405; e-mail address: dk_dikshit@
cdri.res.in (D.K. Dikshit).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.085

D. Sikriwal, D.K. Dikshit / Tetrahedron 67 (2011) 210e215
211
COOH
O
R
reaction
NCAL
R
Romo. et al.
CHO
O
Ref . 18
OH
Aza
NCAL
Cbz
Cbz
N
N
Cbz
achiral
amino
acids
O
OH
OH
Cbz
N
OHC
N
CO2H
( )n
( )m
O
intermediate A
OH
Fig. 2. Retrosynthetic analysis.
Table 1
by this work, we thought it worthwhile to develop the general
synthetic strategy toward the chiral synthesis of several cis-aza
sugars and related molecules as depicted in Fig. 2.
Optimization of the racemic aza-NCAL reactions
4a-c
(3.0 equiv)
TEA (4.0 equiv)
3a-d
O
5,6
N
Cbz
CH3CN, rt, 12 h
O
2. Results and discussion
(+)-5a-d
Achiral amino acids (3aed) required as the starting point for
NCAL reactions were prepared either by N-allylation of Cbz-AlaOH
(1a20/2a) or Cbz-GABA (1b20/2b) followed by ozonolysis (route
A) to afford 3a,b or by a three-step procedure comprising (i)
R=Me; X=Cl; Y=I; 4a
R=Me; X=Br; Y=OTf; 4b
N
R
X
4c
R=Et; X=Br; Y=BF4;
Y
N-u
-alkenylation of glycine methyl ester21 (1c,d), (ii) one pot Cbz
Entry
1
Aldehyde-acid
(ꢁ)-Bicyclic
b
-lactone
Methoda
Yieldb (%)
protection, hydrolysis of ester group (2c,d), and (iii) subsequent
ozonolysis (route B), to give aldehyde-acids 3c,d (Scheme 1). The
5
O
O
A
B
C
53
76
69
Cbz
N
3a
1
O
O
ROUTE B
5a
H
( )m
Br (CH2)m
N
CO2Me
(73.3%)
Cbz
H3N
Cl
CO2Me
1
N
K2CO3, CH3CN, rt
A
B
C
51
71
63
1c
m=2;
m=3;
2
3
3b
3c
1d
(68.1%)
6
5b
Cbz-Cl, TEA, CH2Cl2, 0 oC-rt
then LiOH.H2O, THF:H2O, rt
5
1
O
A
B
C
dc
55
51
ROUTE A
N
allylbromide,
NaH, DMF
Cbz
O
O
H
N
Cbz
5c
N
CO2H
CO2H
( )n
( )n
( )m
Cbz
6
2a
n=2, m=1;
(80.8%)
O
1a
n=2;
n=3, m=1; 2b (68.6%)
n=3; 1b
B
C
53
52
2c
n=1, m=2;
(90.6%)
(78.5%)
4
3d
1
N
2d
n=1, m=3;
Cbz
O3, -78 oC, Me2S
80-82%
CO2H
5d
a
3a
n=2, m=1;
Substrates 3aed were added by syringe pump. Method A: 4a (3.0 equiv), ad-
dition time (10 h). Method B: 4b (3.0 equiv), addition time (3 h). Method C: 4c
(3.0 equiv), addition time (3 h).
Cbz
N
n=3, m=1; 3b
n=1, m=2; 3c
( )m ( )n
O
3d
n=1, m=3;
b
Isolated yields.
c
N-Benzyloxycarbonyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid was isolated
Scheme 1. Synthesis of aldehyde-acids 3aed.
albeit in low yields.
scope of intramolecular aza-NCAL reaction was studied using sub-
strates 3aed and Mukaiyama’s reagent 4a under conditions as
described by Romo et al.18a The reactions were performed by slow
syringe pump addition of aldehyde-acids 3aed over a period of 10 h
to a magnetically stirred solution of pyridinium salt 4a and TEA in
acetonitrile at room temperature (method A). The results are
summarised in Table 1. It was found that the reactions with 3a and
Having optimized the reaction conditions, asymmetric NCAL
reactions of substrates 3aec using chiral amine catalysts were
studied next (Scheme 2). It was observed that slow addition of
aldehyde-acids 3aec to
a
solution of O-acetylquinidine,23
Mukaiyama’s reagent 4b, and DIPEA in CH3CN gave the enantio-
meric bicyclic lactones, (þ)-5a (65%), (þ)-5b (63%), and (ꢀ)-5c
(51%) with an ee of 92, 97, and 91%, respectively, as determined by
chiral HPLC. Likewise the enantiomeric bicyclic lactones (ꢀ)-5a
(66%), (ꢀ)-5b (67%), and (þ)-5c (53%) were synthesized, using
O-acetylquinine24 with an ee of 83, 88, and 95%, respectively
(Scheme 2).
The (1S,5S) configuration of bicyclic lactone (þ)-5a was con-
firmed by its reduction with DIBAl-H to the known Cbz protected
(3S,4R) 4-(hydroxymethyl)pyrrolidin-3-ol [(þ)-6a] in 43% yield,
3b afforded racemic b-lactones, 5a and 5b in 53% and 51% yield,
respectively (Table 1, entries 1 and 2). However, the reaction with
aldehyde-acid 3c gave only the decomposed product (Table 1,
entry 3).22 Use of N-methyl-2-bromopyridinium triflate (4b)18b
(method B) and N-ethyl-2-bromopyridinium tetrafluoroborate
(4c) (method C) greatly improved efficiency of the reaction and
better yields of the cyclised products were obtained (Table 1,
entries 1e4). These results were in conformity with the observa-
tions of Romo et al.18b

212
D. Sikriwal, D.K. Dikshit / Tetrahedron 67 (2011) 210e215
DIPEA (4.0 equiv),
DIPEA (4.0 equiv),
10 mol%O-Ac Quinidine
CH3CN, rt, 30 h
CO2H
10 mol%O-Ac Quinine
Cbz
N
O
O
CH3CN, rt, 30 h
5,6
5,6
N
Cbz
N
Cbz
( )n
( )m
O
method B (Table 1)
method B (Table 1)
O
O
3a-c
(+)-5a
(1S,5S), 65% yield, 92% ee
(1S,6S), 63% yield, 97% ee
(1S,5R), 51% yield, 91% ee
(-)-5a
(-)-5b
(+)-5c
(1R,5R), 66% yield, 83% ee
(1R,6R), 67% yield, 88% ee
(1R,5S), 53% yield, 95% ee
OMe
OMe
(+)-5b
(-)-5c
N
N
N
N
OAc
O-Ac quinidine
OAc
O-Ac quinine
Scheme 2. Catalytic, asymmetric aza-NCAL reactions.
29
which was compared with the authentic sample ([
a]
þ2.01
spectrometers. IR spectra were recorded on a PerkineElmer FT-IR
RXI spectrometer. Microanalytical data were obtained using Vario-
EL-III elemental analyzer. Optical rotations were determined on an
Autopol III polarimeter. Chiral HPLC analyses were performed using
Daicel Chiralpak IA column.
D
25
(c 0.71, MeOH)) [lit.25
[
a
]
D
þ2.6 (c 0.835, MeOH)]. Likewise, diol
(ꢀ)-6a could also be obtained from lactone (ꢀ)-5a with an overall
29
yield of 45%, which has not been reported in literature so far ([a]
D
ꢀ5.00 (c 0.69, MeOH)) (Scheme 3).
4.2. General procedure for N-allylation (2a,b)
5S
5R
1R
O
4.2.1. N-Allyl-N-benzyloxycarbonyl-
b
-alanine (2a). To
a
cooled
O
Cbz
N
Cbz
N
(0 ꢂC) suspended stirred solution of NaH (4.48 g, 112.1 mmol, 60%
NaH in mineral oil) in anhydrous DMF (25 ml) was added a solution
of 1a20 (5.0 g, 22.4 mmol) in DMF (25 ml) dropwise under nitrogen.
Once the hydrogen evolution ceased, allyl bromide (2.9 ml,
33.6 mmol) was added dropwise into the above heterogeneous so-
lution and stirring was continued for additional 2 h at 0 ꢂC. The re-
action mixture was quenched at same temperature by the addition of
1 N HCl to become acidic (pH 2), diluted with water (250 ml),
and extracted with ethyl acetate (3ꢃ80 ml). The combined organic
extracts were washed with brine (2ꢃ40 ml), dried (Na2SO4), and
concentrated in vacuo. The resulting crude oil was purified by
flash chromatography over silica gel using ethyl acetate/hexane (3:7)
to afford 2a as clear oil (4.76 g, 80.81%) [found: C, 63.58; H, 6.39; N,
5.12. C13H15NO4 requires C, 63.87; H, 6.51; N, 5.32%]; Rf (1:1, EtOAc/
hexane) 0.25; nmax (neat) 3069, 2928, 1688, 1474, 1419, 1249, 1135,
1S
O
O
(+)-5a
(-)-5a
DIBAl-H, CH2Cl2, 0 oC-rt, 8 h
43%
45%
3S
3R
OH
OH
OH
Cbz
Cbz N
N
4S
4R
OH
(+)-6a
(-)-6a
Scheme 3. Synthesis of diols (þ)-6a and (ꢀ)-6a.
1104, 1032, 990, 926 cmꢀ1
; dH (300 MHz, CDCl3) 7.33 (5H, br s),
5.75e5.77 (1H, br), 5.13 (4H, br s), 3.93 (2H, br), 3.51e3.56 (2H, t, J
6.9 Hz), 2.59 (2H, br); dC (75 MHz, CDCl3) 176.7, 156.1, 136.6, 133.5,
128.6, 128.1, 127.9, 117.0, 67.4, 50.5, 43.4, 36.8; MS (ESI) m/z: 264
[MþH]þ.
3. Conclusion
In conclusion, we have delineated a formal NCAL strategy for the
chiral synthesis of -lactone fused nitrogen heterocycles where the
reactive -lactone provides a handle for further manipulations. We
b
b
4.2.2. N-Allyl-N-benzyloxycarbonyl-GABA (2b). The acid was pre-
pared from 1b20 (6.0 g, 25.2 mmol), NaH (5.05 g, 126.4 mmol, 60%
NaH in mineral oil), and allyl bromide (3.28 ml, 37.9 mmol) at room
temperature in 10 h. Purification by flash chromatography over
silica gel using ethyl acetate/hexane (1:4) afforded 2b as clear oil
(4.8 g, 68.57%) [found: C, 64.73; H, 6.96; N, 5.00. C15H19NO4 requires
C, 64.97; H, 6.91; N, 5.05%]; Rf (3:2, EtOAc/hexane) 0.3; nmax (neat)
are currently investigating the scope of this methodology for the
synthesis of natural products.
4. Experimental section
4.1. General
3020, 2360, 1692, 1597, 1472, 1422, 1216, 1045 cmꢀ1
; dH (300 MHz,
CDCl3) 7.32e7.34 (5H, br m), 5.76 (1H, br), 5.13 (4H, br s), 3.87 (2H,
br), 3.31 (2H, br), 2.34 (2H, br), 1.86 (2H, br); dC (75 MHz, CDCl3)
178.2, 156.4, 136.7, 133.6, 128.5, 128.1, 127.9, 117.0, 67.4, 49.7, 46.3,
31.2, 23.3; MS (ESI) m/z: 278 [MþH]þ.
All NCAL reactions were done using flame-dried glassware
under nitrogen atmosphere. Acetonitrile (CH3CN), triethylamine
(TEA), N,N-diisopropylethylamine (DIPEA), and dichloromethane
(CH2Cl2) were distilled over calcium hydride. Reactions were
monitored by thin layer chromatography (TLC) using 0.25 mm
E. Merck pre-coated (Merch 60 F254) silica gel plates and using
ninhydrine or KMnO4 as visualizing agent. Purification was per-
formed by flash chromatography using silica gel (230e400 mesh).
NMR spectra were recorded on a Bruker Advance-300 spectro-
4.3. General procedure for mono N-alkenylation (1c,d)
4.3.1. Methyl N-(but-3-enyl)glycinate (1c). K2CO3 (9.39 g, 67.9 mmol)
was added to
a
solution of methyl glycinate$HCl21 (3.15 g,
meter. Chemical shifts are reported as parts per million (
to TMS as internal standard. Mass spectra were recorded on
LCQ Advantage MAX (ESI) and JOEL JMS-600H (EI/HRMS) mass
d
) relative
35.4 mmol) in CH3CN (150 ml) and the mixture was stirred for 1 h.
4-Bromo-1-butene (3.0 ml, 29.5 mmol) was added to the mixture
and the reaction mixture was stirred for 48 h. The insoluble materials

D. Sikriwal, D.K. Dikshit / Tetrahedron 67 (2011) 210e215
213
were filtered off and the filtrate was concentrated under reduced
pressure. To the residue was added water (150 ml) and extracted
with ethyl acetate (3ꢃ60 ml). The combined organic extracts were
washed with brine (2ꢃ25 ml), dried (Na2SO4), and concentrated in
vacuo to afford a clear liquid. Purification by flash chromatography
on silica gel using ethyl acetate/hexane (4:6/10:0) furnished 1c as
clear oil (3.1 g, 73.28%) [found: C, 58.82; H, 9.10; N, 9.81. C7H13NO2
requires C, 58.72; H, 9.15; N, 9.78%]; Rf (EtOAc) 0.3; nmax (neat) 3020,
(rotamers), 30.9/30.8 (rotamers), 27.5/27.1 (rotamers); MS (ESI) m/z:
278 [MþH]þ.
4.5. General procedure for ozonolysis (3aed)
Ozone was bubbled through a cooled (ꢀ78 ꢂC) solution of 2a
(3.2 g, 11.0 mmol) in 75 ml of anhydrous CH2Cl2 for 1 h. After that,
a stream of argon was passed through the cooled solution for
30 min to eliminate the excess of ozone. The cooled reaction
mixture was then quenched with excess of Me2S (3.57 ml,
48.6 mmol), allowed to warm up to room temperature and treated
with cold water (40 ml), extracted with CH2Cl2 (3ꢃ45 ml), dried
(Na2SO4), and concentrated in vacuo to obtain the aldehyde 3a
(2.59 g, 80.4%). Similarly 3bed were obtained from 2bed in
81e82% and were used immediately for NCAL reaction without any
further purification.
1743, 1634,1437, 1215 cmꢀ1
; dH (300 MHz, CDCl3) 5.74e5.88 (1H, m),
5.05e5.15 (2H, m), 3.74 (3H, s), 3.44 (3H, s), 2.67e2.72 (2H, t, J
6.9 Hz,), 2.24e2.31 (2H, q, J 6.9, 13.8 Hz); dC (75 MHz, CDCl3) 172.9,
136.1, 166.6, 51.8, 50.7, 48.5, 34.3; MS (ESI) m/z: 144 [MþH]þ.
4.3.2. Methyl N-(pent-3-enyl)glycinate (1d). Compound 1d was
prepared from methyl glycinate$HCl (3.15 g, 35.4 mmol), K2CO3
(9.39 g, 67.9 mmol), and 5-bromo-1-pentene (3.5 ml, 29.5 mmol).
Purification by flash column chromatography on silica gel using
chloroform as eluant isolated 1d as clear oil (3.16 g, 68.10%) [found:
C, 61.01; H, 9.28; N, 8.93. C8H15NO2 requires C, 61.12; H, 9.62; N,
8.91%]; Rf (CHCl3) 0.3; nmax (neat) 3020, 2933, 1740, 1639, 1439,
4.6. N-Methyl-2-bromopyridinium triflate (4b)18b
Pyridinium salt 4b was prepared from 2-bromopyridine (2.0 ml,
20.9 mmol) and methyl trifluoromethanesulfonate (2.3 ml,
20.9 mmol) in CH2Cl2 (10 ml) according to the literature method as
white crystalline solid (6.46 g, 95.98%); mp 158e160 ꢂC; nmax (KBr)
1217 cmꢀ1
; dH (300 MHz, CDCl3) 5.76e5.89 (1H, m), 4.96e5.07
(2H, m), 3.74 (3H, s), 3.42 (3H, s), 2.60e2.65 (2H, t, J 7.1 Hz),
2.08e2.15 (2H, q, J 7.1, 14.4 Hz), 1.56e1.66 (2H, m); dC (75 MHz,
CDCl3) 173.1, 138.4, 114.8, 51.8, 50.8, 49.1, 31.4, 29.2; MS (ESI) m/z:
158 [MþH]þ.
3087, 1616, 1491, 1443, 1267, 1156, 1032 cmꢀ1
; dH (300 MHz,
CDCl3þCD3OD) 9.10e9.12 (1H, d, J 5.2 Hz), 8.34e8.40 (1H, m),
8.27e8.30 (1H, d, J 7.2 Hz), 8.0e8.05 (1H, m), 4.48 (3H, s); dC (75 MHz,
CDCl3) 149.0, 146.3, 133.9, 127.1, 122.5, 118.2, 50.8.
4.4. General procedure for Cbz introduction and hydrolysis
(2c,d)
4.7. General procedure for the racemic aza-NCAL reaction as
described for ( )-5a
4.4.1. N-(Benzyloxycarbonyl)-N-(but-3-enyl)-glycine (2c). To a cooled
(0 ꢂC) stirred solution of 1c (2.63 g, 18.3 mmol) and TEA (5.63 ml,
40.4 mmol) in anhydrous CH2Cl2 (45 ml) was added Cbz-Cl
(2.97 ml, 21.2 mmol) dropwise under nitrogen. The clear yellow
solution was warmed to room temperature and stirred for 2 h, at
which point the volatiles were removed under reduced pressure to
afford yellow oil. The crude oil was then dissolved in THF/H2O (4:1,
50 ml) with stirring followed by the addition of LiOH$H2O (2.31 g,
55.1 mmol) at room temperature. After stirring for 2 h, the reaction
mixture was diluted with water (30 ml) and extracted with ether
(2ꢃ35 ml). The pH of aqueous layer was adjusted to 2e3 by the
addition of dilute hydrochloric acid (1:1) at 0 ꢂC and extracted the
liberated oil with ethyl acetate (4ꢃ50 ml). The combined organic
extracts were washed with brine (2ꢃ45 ml) and dried (Na2SO4).
Removal of the solvent in vacuo gave the analytically pure product
2c as clear oil (4.38 g, 90.68%) [found: C, 63.76; H, 6.40; N, 5.12.
C14H17NO4 requires C, 63.87; H, 6.51; N, 5.32%]; Rf (7:3, EtOAc/
hexane) 0.35; nmax (neat) 3020, 2361, 1696, 1475, 1431, 1367, 1217,
4.7.1. Benzyl 7-oxo-6-oxa-3-azabicyclo[3.2.0]heptane-3-carboxylate
[(ꢁ)-5a]. Method B: To a stirred solution of Mukaiyama’s reagent
4b (1.65 g, 5.13 mmol, 3.0 equiv) and TEA (0.95 ml, 6.85 mmol,
4.0 equiv) in CH3CN (30 ml) at 25 ꢂC was added via syringe pump
a solution of aldehyde-acid 3a (0.45 g, 1.71 mmol) in CH3CN
(20 ml) over a period of 3 h. Stirring of the resulting dark red
solution was continued for another 12 h. The volatiles were re-
moved under reduced pressure and to the crude reaction mixture
were added ethyl acetate (150 ml) and saturated aqueous NH4Cl
(150 ml). The phases were separated, and the aqueous layer was
extracted with ethyl acetate (2ꢃ50 ml). The combined organic
phases were washed with brine (100 ml), dried (Na2SO4), filtered,
and concentrated to afford a brown residue. Purification of the
crude residue by flash chromatography on SiO2 using ethyl ace-
tate/hexane (13:7) afforded the b-lactone-5a as light yellow oil
(0.7 g, 76.07%) [found: C, 63.23; H, 5.41; N, 5.65. C13H13NO4
1149 cmꢀ1
;
dH (300 MHz, CDCl3) 7.27e7.37 (5H, br m), 5.72e5.78
requires C, 63.15; H, 5.30; N, 5.67%]; Rf (7:3, EtOAc/hexane) 0.35;
(1H, m), 5.15e5.19 (2H, d, J 11.4 Hz), 5.03e5.07 (2H, app t, J 6.9 Hz),
4.04e4.07 (2H, d, J 10.5 Hz), 3.43 (2H, br), 2.32 (2H, br); dC (75 MHz,
CDCl3) 174.5/174.3 (rotamers), 156.8/156.0 (rotamers), 136.4/136.3
(rotamers),135.0/134.8 (rotamers),128.57/128.51 (rotamers),128.1/
128.0 (rotamers), 127.8/127.7 (rotamers), 117.2/117.0 (rotamers),
67.7/67.5 (rotamers), 49.4/48.9 (rotamers), 48.4/48.0 (rotamers),
32.9/32.4 (rotamers); MS (ESI) m/z: 264 [MþH]þ.
nmax (neat) 1836, 1705, 1423, 1356, 1261, 1227, 1187, 1114 cmꢀ1
; dH
(300 MHz, CDCl3) 7.32e7.40 (5H, m, ArH), 5.15 (2H, br s, PhCH2),
5.09e5.12 (1H, dd, J 4.0, 5.9 Hz, H-5), 4.23e4.28 (2H, br m,
H-2þH-4), 4.08e4.12 (1H, m, H-1), 3.29e3.35 (2H, m, H-20þH-40);
dC (75 MHz, CDCl3) 168.6 (C]O, lactone), 155.0 (C]O, carba-
mate), 136.1 (qC), 128.5, 128.2, 128.0 (ArC), 74.9/74.3 (C-5,
rotamers), 67.5 (PhCH2), 56.1/55.4 (C-1, rotamers), 49.6 (C-4), 45.6
(C-2); HRMS (ESI): [MþH]þ found 248.0919. C13H14NO4 requires
248.0922.
4.4.2. N-(Benzyloxycarbonyl)-N-(pent-3-enyl)-glycine (2d). Clear oil
(78.49%) [found: C, 64.73; H, 6.77; N, 4.99. C15H19NO4 requires C,
64.97; H, 6.91; N, 5.05%]; Rf (1:9, MeOH/CHCl3) 0.3; nmax (neat) 2935,
4.7.2. Benzyl 7-oxo-8-oxa-3-azabicyclo[4.2.0]octane-3-carboxylate
[(ꢁ)-5b]. This lactone was prepared from oxo-acid 3b (0.286 g,
1.02 mmol), pyridinium salt 4b (0.989 g, 3.07 mmol), and TEA
(0.49 ml, 3.55 mmol). Purified by flash column chromatography
using ethyl acetate/CH2Cl2 (7:93) as eluant isolated 5b as clear
viscous oil (0.19 g, 71.16%) [found: C, 64.24; H, 5.81; N, 5.34.
C14H15NO4 requires C, 64.36; H, 5.79; N, 5.36%]; Rf (1:9, EtOAc/
CH2Cl2) 0.5; nmax (neat) 1826, 1698, 1421, 1353, 1290, 1224, 1117,
2363, 1699, 1470, 1433, 1221 cmꢀ1
; dH (300 MHz, CDCl3) 7.28e7.37
(5H, m), 5.71e5.83 (1H, m), 5.15e5.19 (2H, d, J 11.9 Hz), 4.96e5.07
(2H, m), 4.02e4.07 (2H, d, J 12.6 Hz), 3.33e3.40 (2H, q, J 7.1 Hz),
2.01e2.12 (2H, m),1.61e1.68 (2H, m); dC (75 MHz, CDCl3) 175.2/174.8
(rotamers), 156.9/156.0 (rotamers), 137.8/137.6 (rotamers), 136.4,
128.6, 128.2/128.1 (rotamers), 127.9/127.8 (rotamers), 115.3/115.2
(rotamers), 67.8/67.6 (rotamers), 49.1/48.7 (rotamers), 48.5/48.0

214
D. Sikriwal, D.K. Dikshit / Tetrahedron 67 (2011) 210e215
1052 cmꢀ1
;
dH (300 MHz, CDCl3) 7.34 (5H, br s, ArH), 5.08e5.21
afforded the
b
-lactone-(þ)-5a as light yellow oil (0.315 g, 64.94%).
29
(2H, m, PhCH2), 4.74e4.80 (1H, br d, J 15.6 Hz, H-1), 4.42e4.47
(0.5H, d, J 15.6 Hz, H-2, rotamers), 4.32e4.37 (0.5H, d, J 15.6 Hz,
H-2, rotamers), 3.82e3.87 (1H, m, H-6), 3.67e3.69 (1H, br, H-4),
3.46e3.56 (1H, td, J 4.5, 12.6 Hz, H-40), 3.36e3.41 (1H, d, J 15.6 Hz,
H-20), 2.09e2.18 (1H, app t, J 15.5 Hz, H-5), 1.89e2.02 (1H, m, H-50);
dC (75 MHz, CDCl3) 169.6 (C]O, lactone), 155.8 (C]O, carbamate),
136.4 (qC), 128.6, 128.2, 127.9 (ArC), 69.1/68.7 (C-1, rotamers), 67.5
(PhCH2), 47.6 (C-6), 42.0/41.5 (C-2, rotamers), 39.9 (C-4),19.7 (C-5);
HRMS (ESI): [MþH]þ found 262.1080. C14H16NO4 requires
262.1079.
[
a
]
þ111.4 (c 0.20, CHCl3). Enantiomeric excess (ee) was de-
D
termined to be 92% by chiral stationary phase HPLC analysis using
Daicel Chiralpak IA column (MtBE/EtOH¼99:1, flow rate 0.6 ml/
min, lmax 213.9 nm), t1S,5S¼20.74 min (major), t1R,5R¼22.66 min
(minor). All other spectroscopic data matched that displayed by
(ꢁ)-5a.
4.8.2. (1S,6S)-Benzyl 7-oxo-8-oxa-3-azabicyclo[4.2.0]octane-3-car-
boxylate [(þ)-5b]. This lactone was prepared from oxo-acid 3b
(0.25 g, 0.89 mmol), pyridinium salt 4b (0.864 g, 2.68 mmol), DIPEA
(0.62 ml, 3.58 mmol), and O-acetylquinidine (32 mg, 0.089 mmol).
Purification by flash column chromatography on silica gel using
ethyl acetate/CH2Cl2 (7:93) as eluant gave (þ)-5b as viscous oil
4.7.3. Benzyl 7-oxo-8-oxa-2-azabicyclo[4.2.0]octane-2-carboxylate
[(ꢁ)-5c]. This lactone was prepared from oxo-acid 3c (0.225 g,
0.84 mmol), pyridinium salt 4b (0.819 g, 2.54 mmol), and TEA
(0.47 ml, 3.39 mmol). Purified by flash column chromatography
using ethyl acetate/CH2Cl2 (1:49) as eluant isolated 5c as viscous oil
(0.115 g, 55.02%) [found: C, 63.05; H, 5.39; N, 5.61. C13H13NO4 re-
quires C, 63.15; H, 5.30; N, 5.67%]; Rf (1:9, EtOAc/CH2Cl2) 0.6; nmax
(0.147 g, 63.09%). [
a
]
29 þ118.7 (c 1.09, MeOH). Enantiomeric excess
D
(ee) was determined to be 97% by chiral stationary phase HPLC
analysis using Daicel Chiralpak IA column (MtBE/EtOH¼99:1, flow
rate 0.6 ml/min, lmax 209 nm), t1S,6S¼20.98 min (major),
t1R,6R¼32.31 min (minor). All other spectroscopic data matched that
displayed by (ꢁ)-5b.
(neat) 1837, 1708, 1422, 1347, 1306, 1266, 1216, 1108, 1059 cmꢀ1
; dH
(300 MHz, CDCl3) 7.32e7.36 (5H, m, ArH), 5.53e5.65 (1H, br, H-1),
5.15e5.17 (3H, m, PhCH2þH-5), 4.12e4.19 (1H, app t, J 9.7 Hz, H-3),
3.37e3.46 (1H, td, J 6.2, 11.5 Hz, H-30), 2.29e2.36 (1H, dd, J 6.2,
14.8 Hz, H-4), 1.87e2.00 (1H, m, H-40); dC (75 MHz, CDCl3) 166.7
(C]O, lactone), 153.3 (C]O, carbamate), 135.9 (qC), 128.7, 128.4,
128.2 (ArC), 77.8 (C-5), 70.2/69.8 (C-1, rotamers), 67.9 (PhCH2),
44.0 (C-3), 29.1 (C-4); HRMS (ESI): [MþNa]þ found 270.0741.
C13H13NNaO4 requires 270.0737.
4.8.3. (1S,5R)-Benzyl 7-oxo-8-oxa-2-azabicyclo[4.2.0]octane-2-car-
boxylate [(ꢀ)-5c]. This lactone was prepared from oxo-acid 3c
(0.29 g, 1.09 mmol), pyridinium salt 4b (1.05 g, 3.27 mmol), DIPEA
(0.76 ml, 4.37 mmol), and O-acetylquinidine (40 mg, 0.109 mmol).
Purification by flash column chromatography on silica using ethyl
acetate/CH2Cl2 (1:49) as eluant gave (ꢀ)-5c as viscous oil (0.137 g,
50.74%). [
a
]
D
27 ꢀ132.4 (c 0.16, MeOH). Enantiomeric excess (ee) was
determined to be 91% by chiral stationary phase HPLC analysis
using Daicel Chiralpak IA column (MtBE/EtOH¼98:2, flow rate
0.8 ml/min, lmax 213 nm), t1R,5S¼8.82 min (minor), t1S,5R¼11.64 min
(major). All other spectroscopic data matched that of the racemic
compound (ꢁ)-5c.
4.7.4. Benzyl 8-oxo-7-oxa-2-azabicyclo[4.2.0]octane-2-carboxylate
[(ꢁ)-5d]. This lactone was prepared from oxo-acid 3d (0.41 g,
1.46 mmol), pyridinium salt 4b (1.418 g, 4.4 mmol), and TEA
(0.81 ml, 5.87 mmol). Purified by flash column chromatography
using ethyl acetate/hexane (3:7) as eluant isolated 5d as viscous
oil (0.202 g, 52.74%) [found: C, 64.29; H, 5.65; N, 5.39. C14H15NO4
requires C, 64.36; H, 5.79; N, 5.36]; Rf (1:1, EtOAc/hexane) 0.45;
4.8.4. (1R,5R)-Benzyl 7-oxo-6-oxa-3-azabicyclo[3.2.0]heptane-3-car-
boxylate [(ꢀ)-5a]. The lactone was prepared from aldehyde-acid 3a
(0.348 g, 1.31 mmol), pyridinium salt 4b (1.268 g, 3.93 mmol),
DIPEA (0.91 ml, 5.25 mmol), and O-acetylquinine24 (48 mg,
0.13 mmol) following the procedure as described for (þ)-5a.
Purification by flash chromatography on SiO2 using ethyl acetate/
nmax (neat) 1832, 1703, 1418, 1310, 1216, 1114, 1037 cmꢀ1
; dH
(300 MHz, CDCl3) 7.35 (5H, br s, ArH), 5.80e5.82 (0.5H, d, J 6.6 Hz,
H-1, rotamers), 5.58e5.60 (0.5H, d, J 6.6 Hz, H-1, rotamers),
5.12e5.22 (2H, m, PhCH2), 4.97 (1H, br s, H-6), 3.68e3.72 (1H, dd,
J 3.6, 11.8 Hz, H-3), 3.36e3.41 (1H, m, H-30), 2.26e2.30 (1H, d,
J 12.6 Hz, H-4), 1.80e1.99 (3H, m, H-5þH-50þH-40); dC (75 MHz,
CDCl3) 170.5/169.9 (C]O, lactone, rotamers), 155.7/154.6 (C]O,
carbamate, rotamers), 136.0 (qC), 128.6, 128.4, 128.1 (ArC),
72.1/71.9 (C-6, rotamers), 68.1/68.0 (PhCH2, rotamers), 59.7/59.5
(C-1, rotamers), 43.0/42.9 (C-3, rotamers), 25.9 (C-4), 16.1/15.8
(C-5, rotamers); HRMS (ESI): [MþH]þ found 262.1094. C14H16NO4
requires 262.1079.
hexane (13:7) gave the (ꢀ)-5a as colorless oil (0.214 g, 66.04%
29
yield). [
a
]
ꢀ39.1ꢂ (c 0.44, CHCl3). Enantiomeric excess (ee) was
D
determined to be 83% by chiral stationary phase HPLC analysis
using Daicel Chiralpak IA column (MtBE/EtOH¼99:1, flow rate
0.6 ml/min, lmax 213.9 nm), t1S,5S¼20.56 min (minor), t1R,5R
¼
22.42 min (major). All other spectroscopic data matched with
(ꢁ)-5a.
4.8.5. (1R,6R)-Benzyl 7-oxo-8-oxa-3-azabicyclo[4.2.0]octane-3-car-
boxylate [(ꢀ)-5b]. This lactone was prepared from oxo-acid 3b
(0.195 g, 0.698 mmol), pyridinium salt 4b (0.674 g, 2.09 mmol),
DIPEA (0.48 ml, 2.79 mmol), and O-acetylquinine (25 mg,
0.069 mmol). Purification by flash column chromatography on sil-
ica gel using ethyl acetate/CH2Cl2 (7:93) as eluant gave (ꢀ)-5b as
4.8. General procedure for asymmetric aza-NCAL reaction
as described for b-lactone-(D)-5a
4.8.1. (1S,5S)-Benzyl 7-oxo-6-oxa-3-azabicyclo[3.2.0]heptane-3-car-
boxylate [(þ)-5a]. To a stirred solution of O-acetylquinidine23
(71 mg, 0.196 mmol), Mukaiyama’s reagent 4b (1.895 g,
5.88 mmol), and DIPEA (1.36 ml, 7.84 mmol) in CH3CN (35 ml)
was added a solution of aldehyde-acid 3a (0.52 g, 1.96 mmol) in
CH3CN (30 ml) via syringe pump over a period of 3 h. After the
addition was completed, the reaction was stirred for additional
30 h at 25 ꢂC. The solvent was removed in vacuo, and the residue
was partitioned between ethyl acetate (150 ml) and saturated
NH4Cl (100 ml). The phases were separated, and the aqueous
layer was extracted with ethyl acetate (2ꢃ50 ml). The combined
organic phases were washed with brine (100 ml), dried (Na2SO4),
and concentrated in vacuo. Purification of the crude residue by
flash chromatography on SiO2 using ethyl acetate/hexane (13:7)
viscous oil (0.12 g, 67.03%). [
a
]
29 ꢀ63.3 (c 1.11, MeOH). Enantiomeric
D
excess (ee) was determined to be 88% by chiral stationary phase
HPLC analysis using Daicel Chiralpak IA column (MtBE/EtOH¼99:1,
flow rate 0.6 ml/min, lmax 209 nm), t1S,6S¼20.05 min (minor),
t1R,6R¼33.36 min (major). All other spectroscopic data matched
with the racemic compound (ꢁ)-5b.
4.8.6. (1R,5S)-Benzyl 7-oxo-8-oxa-2-azabicyclo[4.2.0]octane-2-car-
boxylate [(þ)-5c]. This lactone was prepared from oxo-acid 3c
(0.2 g, 0.753 mmol), pyridinium salt 4b (0.728 g, 2.26 mmol), DIPEA
(0.52 ml, 3.01 mmol), and O-acetylquinine (27 mg, 0.075 mmol).
Purification by flash column chromatography on silica using ethyl

D. Sikriwal, D.K. Dikshit / Tetrahedron 67 (2011) 210e215
215
acetate/CH2Cl2 (1:49) as eluant gave (þ)-5c as viscous oil (0.098 g,
Supplementary data
28
52.68%). [
a
]
þ67.7 (c 0.37, MeOH). Enantiomeric excess (ee) was
D
determined to be 95% by chiral stationary phase HPLC analysis
using Daicel Chiralpak IA column (MtBE/EtOH¼98:2, flow rate
0.8 ml/min, lmax 213 nm), t1R,5S¼8.76 min (major), t1S,5R¼11.63 min
(minor). All other spectroscopic data matched with the racemic
compound (ꢁ)-5c.
1H, 13C, and HSQC spectral data for lactones (ꢁ)-5aed and diol
(þ)-6a, chiral HPLC data for 5aec, and 1H and 13C spectral data for
4b are provided. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2010.10.085.
These data include MOL files and InChIKeys of the most important
compounds described in this article.
4.9. General procedure for reduction as described for diol
(D)-6a
References and notes
1. (a) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199; (b) O’Hagan, D. Nat.
Prod. Rep. 1997, 14, 637; (c) Stutz, A. E. Iminosugars as Glycosidase Inhibitors;
Wiley: Weinheim, 1999; (d) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645.
4.9.1. (3S,4R)-N-Benzyloxycarbonyl-4-(hydroxymethyl)pyrrolidin-
3-ol [(þ)-6a]. To a magnetically stirred solution of (þ)-5a (0.17 g,
0.687 mmol) in CH2Cl2 (5.3 ml) was added dropwise a solution of
DIBAl-H (1.0 M in toluene, 0.738 ml, 0.742 mmol) at 0 ꢂC. After
5 min, the solution was warmed to room temperature and stirred
overnight. The reaction mixture was then cooled to 0 ꢂC, diluted
with ethyl acetate (2.4 ml), and quenched with acetone (1.5 ml)
and Rochelle’s salt (4.0 ml). The mixture was vigorously stirred at
25 ꢂC for 10 h. The layers were separated and the aqueous layer
was extracted with ethyl acetate (2ꢃ4 ml). The combined organic
layers were washed with brine (8 ml), dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatography
on SiO2 using MeOH/ethyl acetate (1:9) gave the diol (þ)-6a as a
colorless oil (74 mg, 43.19% yield) [found: C, 62.23; H, 6.75; N, 5.52.
C13H17NO4 requires C, 62.14; H, 6.82; N, 5.57%]; Rf (1:9, MeOH/
€
2. (a) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.;
Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1988,
85, 9229; (b) Block, T. M.; Xu, X. L.; Platt, F. M.; Foster, G. R.; Gerlich, W. H.;
Blumberg, B. S.; Dwek, R. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2235.
3. Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935.
4. Watson, K. A.; Mitchell, E. P.; Johnson, L. N.; Son, J. C.; Bichard, C. J. F.; Orchard,
M. G.; Fleet, G. W. J.; Oikonomakos, N. G.; Leonidas, D. D.; Kontou, M.;
Papageorgiou, A. C. Biochemistry 1994, 33, 5745.
5. (a) Davis, B. G.; Brandstetter, T. W.; Hackett, L.; Winchester, B. G.; Nash, R. J.;
Watson, A. A.; Griffiths, R. C.; Smith, C.; Fleet, G. W. J. Tetrahedron 1999, 55,
4489; (b) Shilvock, J. P.; Wheatley, J. R.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.;
Butters, T. D.; Muller, M.; Watkin, D. J.; Winkler, D. A.; Fleet, G. W. J. J. Chem. Soc.,
Perkin Trans. 1 1999, 2735.
6. Fan, J. Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nat. Med. 1999, 5, 112.
7. (a) Li, C. M.; Tyler, P. C.; Furneaux, R. H.; Kicska, G.; Xu, Y. M.; Grubmeyer, C.;
Girvin, M. E.; Schramm, V. L. Nat. Struct. Biol. 1999, 6, 582; (b) Miles, R. W.; Tyler,
P. C.; Evans, G. B.; Furneaux, R. H.; Parkin, D. W.; Schramm, V. L. Biochemistry
1999, 38, 13147.
8. Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron Lett. 1998, 39, 3659.
9. (a) Kuehl, F. A., Jr.; Spencer, C. F.; Folkers, K. J. Am. Chem. Soc. 1948, 70, 2091;
(b) Kobayashi, S.; Ueno, M.; Suzuki, R. Tetrahedron Lett. 1999, 40, 2175.
10. Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.;
Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005, 48, 2036.
11. Watanabe, J.; Nakada, N.; Sawairi, S.; Shimada, H.; Ohshima, S.; Kamiyama, T.;
Arisawa, M. J. Antibiot. 1994, 47, 32.
þ2.01 (c 0.71, MeOH) [lit.25
[
a
]
þ2.6 (c 0.835,
29
25
EtOAc) 0.3; [
a
]
D
D
MeOH)]; nmax (neat) 3389, 2920, 1682, 1433, 1358, 1216, 1136,
1097 cmꢀ1
; dH (300 MHz, CDCl3) 7.28e7.32 (5H, m, ArH), 5.04e5.14
(2H, m, PhCH2), 4.41 (1H, br s, H-3), 3.78e3.83 (2H, t, J 7.8 Hz,
CH2OH), 3.44e3.56 (3H, m, H-2þH-20þH-5), 3.32e3.39 (1H, t, J
10.5, H-50), 2.28e2.29 (1H, br, H-4); dC (75 MHz, CDCl3) 155.5
(C]O),136.8 (qC), 128.6, 128.1, 127.9 (ArC), 72.3/71.5 (C-3, rotamers),
67.1 (PhCH2), 60.3 (CH2OH), 55.2/54.9 (C-2, rotamers), 45.9/45.6
(C-5, rotamers), 45.1/44.3 (C-4, rotamers); MS (ESI) m/z: 252
[MþH]þ; HRMS (ESI): [MþH]þ found 252.1216. C13H18NO4 requires
252.1235.
12. Gardiner, R. A.; Rinehart, K. L.; Snyder, J. J.; Broquist, H. P. J. Am. Chem. Soc. 1968,
90, 5639.
13. Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.; Pryce, R. J.; Arnold, E.;
Clardy, J. Phytochemistry 1981, 20, 811.
14. Kakinuma, K.; Otake, N.; Yonehara, H. Tetrahedron Lett. 1972, 2509.
15. (a) Mascavage, L. M.; Lu, Q.; Vey, J.; Dalton, D. R.; Carroll, P. J. J. Org. Chem. 2001,
66, 3621; (b) Yoshitomi, Y.; Makino, K.; Hamada, Y. Org. Lett. 2007, 9, 2457.
16. (a) Godskesen, M.; Lundt, I. Tetrahedron Lett. 1998, 39, 5841; (b) Kotian, P. L.;
Chand, P. Tetrahedron Lett. 2005, 46, 3327; (c) Chen, L.; Jones, E. D.; Ma, D.;
Baylis, D. C.; Li, B.; Coates, J. A. V.; Xie, X.; Rhodes, D. I.; Chen, R.; Deadman, J. J. W. O.
092293A1, 2009.
4.9.2. (3R,4S)-N-Benzyloxycarbonyl-4-(hydroxymethyl)pyrrolidin-
3-ol [(ꢀ)-6a]. The diol was prepared from lactone (ꢀ)-5a (0.142 g,
0.574 mmol) and DIBAl-H (1.0 M in toluene, 0.618 ml, 0.62 mmol).
Purification by flash chromatography on SiO2 using MeOH/ethyl
ꢀ
17. For a review see: Kacprzak, K.; Gawronski, J. Synthesis 2001, 961.
18. (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945;
(b) Oh, S. H.; Cortez, G. S.; Romo, D. J. Org. Chem. 2005, 70, 2835; (c) Henry-
Riyad, H.; Lee, C. S.; Purohit, V. C.; Romo, D. Org. Lett. 2006, 8, 4363.
19. (a) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143; (b) Morris, K. A.;
Arendt, K. M.; Oh, S. H.; Romo, D. Org. Lett. 2010, 12, 3764.
acetate (1:9) gave the diol (ꢀ)-6a as colorless oil (58 mg, 44.16%
29
yield). [
a]
ꢀ5.0 (c 0.69, MeOH). All other spectroscopic data
D
matched with diol (þ)-6a.
20. Schmuck, C.; Rehm, T.; Geiger, L.; Schӓfer, M. J. Org. Chem. 2007, 72, 6162.
21. Almeida, J. F.; Anaya, J.; Martin, N.; Grande, M.; Moran, J. R.; Caballero, M. C.
Tetrahedron: Asymmetry 1992, 3, 1431.
Acknowledgements
22. N-Benzyloxycarbonyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid was isolated
albeit in low yields.
23. Waddell, T. G.; Woods, L. A.; Harrison, W.; Meyer, G. M. J. Tenn. Acad. Sci.1984, 59, 48.
24. Pracejus, H.; Matje, H. J. Prakt. Chem. 1964, 195.
D.S. thanks CSIR-UGC, New Delhi, India, for the financial support
in the form of Senior Research Fellowships. We thank SAIF, CDRI, for
the spectral data.
25. Asahina, Y.; Takei, M.; Kimura, T.; Fukuda, Y. J. Med. Chem. 2008, 51, 3238.