A solution to the stereochemical problems posed by amaryllidaceae constituents using a highly syn-selective arylcuprate conjugate addition to γ-amino and γ-carbamato-α,β-enoates

Article abstract of DOI:10.1016/j.tetasy.2006.11.029

Various substituted arylcuprates undergo stereocontrolled additions to l-serine-derived γ-amino- and γ-carbamato-α,β-enoates with high syn-selectivities. The stereochemical outcome of these reactions is fully consistent with the reductive elimination-base

Full text of DOI:10.1016/j.tetasy.2006.11.029

Tetrahedron: Asymmetry 17 (2006) 3170–3178
A solution to the stereochemical problems posed by
amaryllidaceae constituents using a highly syn-selective
arylcuprate conjugate addition to c-amino and
c-carbamato-a,b-enoates
Shiva K. Rastogi and Alexander Kornienko*
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA
Received 27 October 2006; accepted 13 November 2006
Abstract—Various substituted arylcuprates undergo stereocontrolled additions to L-serine-derived c-amino- and c-carbamato-a,b-
enoates with high syn-selectivities. The stereochemical outcome of these reactions is fully consistent with the reductive elimination-based
model proposed previously. This method is well suited for the preparation of a broad range of biologically active amaryllidaceae
constituents and their aromatic analogues.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
The major synthetic challenge stems from the dense stereo-
chemistry of the cyclitol ring, in which the creation of the
benzylic stereocenter C10b can be particularly arduous
due to the necessity of stereoselective installation of an aro-
matic group.9 A close inspection of the structures in Figure
1 reveals consistent stereochemical relationships. Thus, the
aromatic moiety is nearly always cis to the adjacent hydro-
xyl substituent (C, O) and trans to the nitrogen-bearing ste-
reocenter on the other side (C, N). It follows that a flexible
synthetic methodology that allows the introduction of an
aromatic moiety with stereocontrol exerted by either oxy-
gen- or nitrogen-containing adjacent stereocenters would
be generally applicable to the synthesis of compounds that
belong to these structural types. Furthermore, if the meth-
odology is not sensitive to the identity and positioning of
the substituents on the aromatic ring, a library of ana-
logues of these natural products could be prepared for
structure–activity studies.
Numerous natural products found in the plants of the ama-
ryllidaceae family have been the focus of intense research
effort. Their diverse biological activities and, therefore,
medicinal utility attract the attention of biochemists and
pharmacologists.1 Meanwhile, the complex structures and
limited natural abundance of many of these plant metabo-
lites continue to fuel the interest of synthetic chemists.2
According to a recent comprehensive review, over 100
small molecule amaryllidaceae constituents that belong to
pancratistatin, lycorine, or lycorenine structural types have
been isolated (Fig. 1).3 Many of these exhibit anticancer,4
antiviral,5 antiparasitic,6 and anti-inflammatory7 activities
amongst others. Pancratistatin has been in preclinical eval-
uation as an anticancer agent for many years, with limited
availability being a major hurdle for its advancement to
clinical trials. Significantly, a number of recent reports
revealed that this agent displays much better activity/toxi-
city ratios than the currently used anticancer drugs etopo-
side and paclitaxel.8 This discovery is expected to further
stimulate the development of efficient synthetic pathways
to this class of structurally complex natural products.
We have recently reported the utilization of a highly, anti-
selective arylcuprate conjugate addition to a c-alkoxy-a,b-
enoate as one such methodology.10 The anti-stereochemical
relationship of the oxygen-bearing and benzylic stereocen-
ters in the addition products corresponds to their cis
positioning in the target cyclic structures (Fig. 2). A com-
plementary strategy would use a syn-selective arylcuprate
conjugate addition to a,b-enoates with stereocontrol
exerted by a c-nitrogen-containing stereocenter. Since the
*
Corresponding author. Tel.: +1 505 835 5884; fax: +1 505 835 5364;
e-mail: akornien@nmt.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.029

S. K. Rastogi, A. Kornienko / Tetrahedron: Asymmetry 17 (2006) 3170–3178
3171
OH
OH
HO
OH
OH
MeN
o
c
HO
10b
N
c
o
c
N
O
O
MeO
MeO
o
N
O
O
NH
O
N
R
O
OH
R = OH pancratistatin
R = H 7-deoxypancratistatin
lycorine
HO
lycorenine
OH
OH
OMe
MeN
N
c
o
c
c
N
o
O
O
O
O
OH
N
OH
MeO
MeO
NH
O
O
N
R
O
O
hippeastrine
incartine
R = OH dihydronarciclasine
R = H dihydrolycoricidine
Figure 1. Selected amaryllidaceae constituents.
"O"
"N"
tBuPh2SiO
O
1. (COCl)2, DMSO
c
c
o
N
CO2R
RO2C
OMe
2. Ph3P=CHCO2Me
90%
NBn2
tBuPh2SiO
1
"ArCu"
"ArCu"
OH
NBn2
"O"
"N"
c
c
4 steps
ref. 12a,b
o
N
CO2R
RO2C
O
O
OMe
6 steps
ref. 12c
O
HO
OH
"O"
NBoc
o
c
NH2
N
2
"N"
Scheme 1.
Figure 2. Correlation of stereochemical relationships in open-chain and
cyclic structures.
Gratifyingly, the reactions of arylcuprates derived from
aromatic Grignard reagents with enoate 1 gave addition
products 3a–f as single diastereomers (Scheme 2). The
NMR analyses of crude and purified reaction mixtures
revealed the presence of the b-epimeric compounds in only
trace quantities. However, the reactions were sluggish and
provided only modest yields of 3a–f, while the addition
product 3g could not be detected at all. The steric conges-
tion arising from the bulky t-butyldiphenylsilyl protection
clearly plays a role in this unsatisfactory outcome.
feasibility of this stereochemical divergence had been
reported previously,11c we explored this alternative
approach and report our results, herein.
2. Results and discussion
syn-Selective conjugate additions of organocuprates have
been reported for both c-amino- and c-carbamato-a,b-eno-
ates and they have been utilized in the syntheses of various
medicinally relevant complex targets.11 Therefore, to eval-
uate this methodology for the introduction of multisubsti-
tuted aromatic rings, particularly those possessing the
multiple alkoxy groups required in the synthesis of amaryl-
lidaceae constituents, we prepared c-amino- and c-carbam-
ato-enoates 1 and 2 (Scheme 1). While the synthesis of
enoate 2 from L-serine had previously been described in
the literature,12 the key to the successful straightforward
preparation of enoate 1 was a one-pot Swern oxidation–
Wittig olefination method that resulted in exclusive forma-
tion of the E-enoate.13
In contrast, the addition products 4a–g, resulting form the
reactions of enoate 2, were formed in excellent yields.
However, the rotational isomerism associated with the
carbamate moiety led to NMR peak broadening and this
prevented any immediate conclusions regarding the diaste-
reomeric purity of 4a–g. Therefore, each addition product
was reacted with methanolic HCl to remove the Boc
and isopropylidene protecting groups to give ammonium
salts 5a–g. These underwent facile lactam formation upon
treatment with MeONa in MeOH to give 6a–g in good
overall yields. The NMR analyses of 6a–g clearly showed
the presence of a single diastereomer in each case.

3172
S. K. Rastogi, A. Kornienko / Tetrahedron: Asymmetry 17 (2006) 3170–3178
tBuPh2SiO
O
OMe
1
2
NBn2
3a-f
Ar2CuMgBr, Me3SiCl
THF, -78 oC to rt
O
O
MeONa
MeCOCl
HO
OMe
HO
OMe
O
MeOH
85-90%
MeOH
70-85%
NH2
HCl
5a-g
HN
NBoc
4a-g
O
6a-g
O
O
MeO
MeO
O
MeO
F
Cl
O
OMe
3a 58%, >20:1
4a 95%, >20:1
3b 50%, >20:1
4b 87%, >20:1
3e 49%, >20:1
4e 70%, >20:1
3c 55%, >20:1
4c 92%, >20:1
3g 0%
3d 58%, >20:1
4d 83%, >20:1
3f 52%, >20:1
4f 92%, >20:1
4g 70%, >20:1
Scheme 2.
To facilitate the NMR-based stereochemistry assignment,
we attempted to acetylate the primary hydroxyl group in
lactams 5b and 5f (Scheme 3). Unexpectedly, the N-acetyl-
ated products 7b and 7f were isolated instead of the
expected esters when the starting lactams were treated with
equimolar amounts of acetic anhydride. Evidently, the
intramolecular oxygen to nitrogen acetyl transfer leads to
the formation of the thermodynamically more stable imi-
des. However, treatment of 5b and 5f with excess of
Ac2O gives diacetylated lactams 8b and 8f, whose 1H
NMR contain well-resolved lactam proton signals allowing
the unequivocal assignment of the cis stereochemical rela-
tionship between Hc and Hd.
NBn2
Bu4NF, THF
55%
tBuPh2SiO
O
O
OMe
NBn2
O
3a
9a
NH2
MeONa
H2, Pd/C
MeOH
80%
O
dioxane-H2O
62%
HO
HN
6a
O
O
10a
To confirm the syn-stereochemistry in addition products
3a–f by chemical correlation, we attempted to convert 3a
to 6a by way of N-debenzylation, lactamization and O-
desilylation. To this end, 3a was treated with hydrogen
over various palladium catalysts and high pressures. Sur-
prisingly, ester 3a is highly resistant to hydrogenolysis, pos-
sibly due to the steric bulk of the silyl protection and,
consequently, an impaired contact with the catalyst sur-
Scheme 4.
face. Reversing the order of the deprotections by perform-
ing the desilylation first, gave lactone 9a (Scheme 4). This
compound underwent facile double debenzylation when
stirred in a mixture of dioxane–water under a hydrogen
balloon. Finally, lactone to lactam isomerization 10a to
6a was brought about with sodium methoxide in methanol.
This transformation conceivably proceeds through the
intermediacy of the ring-opened methyl ester.
Ac2O (excess)
py, DMAP
AcO
HO
HO
70-75%
AcN
8b,f
HN
AcN
7b,f
3. Conclusions
O
O
O
5b,f
Highly stereoselective processes with the participation of
acyclic systems are not commonplace in organic synthesis.
Therefore, we hope that our previously reported highly
anti-selective arylcuprate additions to c-alkoxy-a,b-eno-
ates10 and the present syn-selective additions to c-amino-
and c-carbamato-a,b-enoates will find utility in the intro-
duction of multisubstituted aromatic groups into complex
acyclic structures with high stereocontrol. Work in our
laboratory is currently underway to apply this chemistry
to the development of practical synthetic pathways to
Hc
Hd
AcN
Jb,c
Hb
AcO
Ha
O
Ja,c 15 Hz
~
J
8 Hz
~
~
c,d
Scheme 3.

S. K. Rastogi, A. Kornienko / Tetrahedron: Asymmetry 17 (2006) 3170–3178
3173
polarimeter. H and 13C NMR spectra were recorded on
JEOL 300 MHz spectrometer.
1
CO2Me
H
reductive
elimination
Cu
R
Ar
Ar
O
O
4.2. Preparation of enoate 1
NR'R''
syn
major
R
H
R''R'N
CO2Me
Ar2CuMgBr
Me3SiCl
NR'R''
H
4.2.1.
5-(tert-Butyldiphenylsilanyloxy)-4-dibenzylamino-
pent-2-enoic acid methyl ester, 1. To oxalyl chloride
(5.0 ml of 2 M in CH2Cl2, 9.7 mmol) in dry CH2Cl2
(50 ml) at ꢀ78 ꢁC was added DMSO (1.42 ml, 19.9 mmol)
in CH2Cl2 (15 ml) over 10 min and the mixture was stirred
for an additional 20 min. 3-(tert-Butyl-diphenyl-silanyloxy)-
2-dibenzylamino-1-propanol12a,b (2.208 g, 4.3 mmol) in
CH2Cl2 (15 ml) was added over 10 min and the mixture
was stirred for an additional 10 min. Triethylamine
(3.37 ml, 23.9 mmol) in CH2Cl2 (15 ml) was added over
10 min and the white slurry was stirred for 20 min at
ꢀ78 ꢁC. To the cold reaction mixture was added methyl
(triphenylphosphoranylidene) acetate (3.34 g, 9.7 mmol)
in one portion and the resulting mixture was stirred for
16 h while it was allowed to warm up to rt. Water
(150 ml) was added to the reaction mixture, the two layers
were separated and aqueous layer was extracted with
CH2Cl2 (3 · 75 ml). The combined organic layers were
dried over MgSO4 and the solvent was evaporated under
reduced pressure. The residual oil was presorbed on silica
gel and the product was purified using chromatography
with gradients 1% and 2% EtOAc/hexane to afford enoate
NR'R''
H
CO2Me
R
Ar
CO2Me
H
H
R
modified
Felkin-Anh
NR'R''
anti
R
"ArCu"
minor
Figure 3. Reductive elimination and modified Felkin–Anh stereochemical
models.
biologically active amaryllidaceae constituents to facilitate
their advancement to clinical trials. Furthermore, the inde-
pendence of the stereochemical outcome of the substitution
pattern on the aromatic ring makes these processes partic-
ularly promising for the synthesis of aromatic analogues of
these natural products.14
Recently, we proposed a stereochemical model to predict
the outcomes of organocuprate addition reactions to c-alk-
oxy-a,b-enoates, based on reductive elimination as a rate-
and stereochemistry-determining step.10b We suggested
that the model could be of general utility encompassing
reactions of other a,b-enoates containing a c-stereocenter.
The results of the present investigation with c-amino-
and c-carbamato-a,b-enoates are fully consistent with this
model that predicts syn-selectivities for these processes
(Fig. 3).
1 (2.21 g, 90.6%) as a colorless oil. Rf 0.62 (10% EtOAc/
23
hexane); ½aꢁD ¼ ꢀ21:4 (c 0.14, CHCl3); 1H NMR (CDCl3):
d 7.63–7.19 (m, 20H), 7.03 (dd, 1H, J = 6.8, 15.6 Hz), 6.02
(dd, 1H, J = 1.3, 15.9 Hz), 4.02–3.8 (m, 3H), 3.78 (s, 1H),
3.77 (s, 3H), 3.62 (s, 1H), 3.58 (s, 1H), 3.51 (m, 1H), 1.03
(s, 9H); 13C NMR (CDCl3): d 166.7, 146.1, 139.7, 135.6,
133.2, 129.8, 128.7, 128.5, 128.3, 128.2, 127.8, 127.0, 123,
63.9, 60.5, 54.5, 51.6, 26.8, 19.2; HRMS m/z (ESI) calcd
for C36H41NO3Si (M+H)+ 564.2934, found 564.2921.
In contrast, the modified Felkin–Anh model11c,15 leads to
the prediction of anti-isomers as the favored addition prod-
ucts. Furthermore, the reductive elimination model
explains the low reactivity of c-amino-a,b-enoates with a
sterically demanding group R. Clearly, the hypothetical
transition state would be highly energetic in this case due
to the 1,3-allylic strain (Cc–R and Ca–H in the top pathway
in Fig. 3). The sluggish nature of reactions of enoate 1 are
in agreement with this mechanistic interpretation.
4.3. General procedure for the arylcuprate addition
Ca. 1 ml of a required aryl bromide (10.0 mmol) was added
to crushed Mg turnings (10.0 mmol, 0.242 g) in THF
(10 ml) under a nitrogen atmosphere. Once the reaction
had started, the solution was warmed up and slightly dark-
ened. The rest of the aryl bromide was added dropwise to
allow a gentle reaction. The reaction mixture was allowed
to cool to room temperature and was cannulated to a slur-
ry of CuI (5 mmol, 0.952 g) in THF (10 ml) at ꢀ78 ꢁC. The
mixture was stirred at ꢀ78 ꢁC for 40 min (in the synthesis
of 3e and 4e, the mixture was stirred at 0 ꢁC for 2 h as
no transmetalation occurred at ꢀ78 ꢁC). Me3SiCl
(10.0 mmol, 1.08 g) and enoate 1 or 2 (1 mmol, in 10 ml
of THF) were added sequentially at ꢀ78 ꢁC. The yellow
brown solution was stirred overnight while slowly warming
up to rt. The reaction mixture was quenched with a mixture
of concd NH4OH and satd NH4Cl (1:9, 30 ml) and
extracted with EtOAc (3 · 40 ml). The combined organic
layers were washed with water and brine (2 · 5 ml) and
dried over anhyd MgSO4. The solution was concentrated
under reduced pressure, the residue was absorbed on silica
gel and purified by column chromatography (2–10%
EtOAc/hexanes) to yield 3a–f (49–58%) and 4a–g
(70–95%) as an oil.
4. Experimental
4.1. General methods
Unless otherwise noted, all commercially obtained reagents
were used without purification. THF was distilled from
sodium benzophenone ketyl prior to use. Dichloromethane
was distilled from calcium chloride. Reactions were carried
out under a nitrogen atmosphere in oven-dried glassware
using standard syringe, cannula and septa techniques.
Reactions were monitored by TLC (Silica Gel 60 F254
,
250 lm) and visualized with UV light and ceric ammonium
molybdate solution. Aryl bromides f and g were prepared
as previously described.16 Flash chromatography was per-
formed on silica gel (32–63 lm, 60 A pore size). Optical
rotations were measured with an Autopol III automatic
˚

3174
S. K. Rastogi, A. Kornienko / Tetrahedron: Asymmetry 17 (2006) 3170–3178
4.3.1. 5-(tert-Butyldiphenylsilanyloxy)-4-dibenzylamino-3-
phenylpentanoic acid methyl ester, 3a. 58%; Rf 0.67 (10%
J = 10.2, 15.4 Hz), 1.14 (br s, 9H); 13C NMR (CDCl3): d
172.7, 148.4, 147.5, 140.0, 135.9, 135.8, 134.7, 133.3,
133.1, 130.0, 129.9, 128.8, 128.0, 127.8, 126.7, 121.0,
111.7, 110.6, 61.7, 60.4, 55.9, 55.6, 54.9, 51.3, 41.6, 38.5,
27.2, 19.2; HRMS m/z (ESI) calcd for C44H51NO5Si
(M+H)+ 702.3615, found 702.3609.
23
1
EtOAc/hexane); ½aꢁD ¼ ꢀ12:6 (c 0.15, CHCl3); H NMR
(CDCl3): d 7.9–6.91 (m, 25H), 4.18 (dd, 1H, J = 3.8,
11.2 Hz), 3.92 (dd, 1H, J = 3.8, 11.2 Hz), 3.8 (d, 2H,
J = 13.7 Hz), 3.72 (m, 1H), 3.45 (s, 3H), 3.41 (br d, 2H),
2.99 (m, 1H), 2.7 (dd, 1H, J = 4.4, 15.1 Hz), 2.41 (dd,
1H, J = 10.2, 15.1 Hz), 1.22 (s, 9H); 13C NMR (CDCl3):
d 172.6, 142.1, 139.9, 136.0, 135.9, 133.4, 133.2, 131.0,
130.0, 129.1, 128.0, 126.7, 126.4, 61.3, 60.3, 54.7, 51.3,
41.8, 39.1, 27.1, 19.3; HRMS m/z (ESI) calcd for
C42H47NO3Si (M+H)+ 642.3403, found 642.3383.
4.3.6. 3-Benzo[1,3]dioxol-5-yl-5-(tert-butyldiphenylsilanyl-
oxy)-4-dibenzylamino-pentanoic acid methyl ester, 3f.
24
52%; Rf 0.56 (10% EtOAc/hexane); ½aꢁD ¼ ꢀ9:1 (c 0.01,
1
CHCl3); H NMR (CDCl3): d 7.82–6.21 (m, 23H), 5.90
(s, 2H), 4.09 (dd, 1H, J = 4.1, 11.2 Hz), 3.82 (dd, 1H,
J = 3.8, 11.2 Hz), 3.73 (d, 2H, J = 13.7 Hz), 3.95 (m,
1H), 3.43 (s, 3H), 3.34 (d, 2H, J = 13.7 Hz), 2.84 (m,
1H), 2.57 (dd 1H, J = 4.1, 11.2), 2.27 (dd, 1H, J=10.2,
15.4 Hz), 1.14 (s, 9H); 13C NMR (CDCl3): d 172.5, 147.2,
145.9, 139.8, 135.9, 135.8, 135.7, 133.3, 133.1, 130.0,
129.0, 127.9, 127.7, 126.7, 122.3, 109.0, 107.6, 100.7, 61.4,
60.2, 54.6, 51.4, 41.8, 39.0, 29.7, 27.0, 19.3; HRMS m/z
(ESI) calcd for C43H48NO5Si (M+H)+ 286.3302, found
286.3293.
4.3.2. 5-(tert-Butyldiphenylsilanyloxy)-4-dibenzylamino-3-
(4-methoxyphenyl)-pentanoic acid methyl ester, 3b. 50%;
24
Rf 0.57 (10% EtOAc/hexane); ½aꢁD ¼ ꢀ10:7 (c 0.06,
CHCl3); 1H NMR (CDCl3): d 7.82–6.72 (m, 24H), 4.1
(dd, 1H, J = 3.8, 11.0 Hz), 3.87 (br dd, 1H), 3.83 (s, 3H),
3.79–3.72 (d, 2H, J = 13.7 Hz), 3.64 (m, 1H), 3.42 (s,
3H), 3.35 (d, 2H, J = 13.7 Hz), 2.91 (m, 1H), 2.62 (dd,
1H, J = 4.1, 15.1 Hz), 2.34 (dd, 1H, J = 10.4, 15.1 Hz),
1.17 (s, 9H); 13C NMR (CDCl3): d 172.7, 158.1, 139.9,
135.9, 135.8, 134.2, 133.4, 133.1, 129.9, 129.0, 127.9,
127.8, 126.7, 113.3, 61.4, 60.4, 55.3, 54.7, 51.3, 41.2, 39.1,
27.1, 19.3; HRMS m/z (ESI) calcd for C43H49NO4Si
(M+H)+ 672.3509, found 672.3484.
4.3.7. (R)-tert-Butyl-4-((R)-2-(methoxycarbonyl)-1-phenyl-
ethyl)-2,2-dimethyloxazolidine-3-carboxylate, 4a. 95%; Rf
21
0.47 (20% EtOAc/hexane); ½aꢁD ¼ þ35:7 (c 0.02, CHCl3);
1H NMR (CDCl3): d 7.45–7.1 (m, 5H), 4.21–3.65 (br m,
3H), 3.6–3.46 (br m, 4H), 2.9–2.68 (br d, 2H), 1.55 (br s,
6H), 1.45 (br s, 9H); 13C NMR (CDCl3): d 173.0, 152.8,
140.4, 128.8, 128.5, 128.2, 127.7, 126.1, 94.5, 80.5, 63.8,
61.6, 51.7, 42.8, 32.1, 28.5, 26.5; HRMS m/z (ESI) calcd
for C20H29NO5 (M+Na)+ 386.1943, found 386.1935.
4.3.3. 5-(tert-Butyldiphenylsilanyloxy)-4-dibenzylamino-3-
(4-fluorophenyl)-pentanoic acid methyl ester, 3c. 55%; Rf
24
0.66 (10% EtOAc/hexane); ½aꢁD ¼ ꢀ22:9 (c 0.02, CHCl3);
1H NMR (CDCl3): d 7.79–6.78 (m, 24H), 4.1 (dd, 1H,
J = 3.6, 11.2 Hz), 3.83 (dd, 1H, J = 3.8, 11.3 Hz), 3.73 (d,
2H, J = 13.2 Hz), 3.62 (m, 1H), 3.40 (s, 3H), 3.33 (d, 2H,
J = 13.2 Hz), 2.84 (m, 1H), 2.61 (dd, 1H, J = 4.1,
15.1 Hz), 2.26 (dd, 1H, J = 10.4, 14.8 Hz); 13C NMR
(CDCl3): d 172.1, 139.6, 137.9, 135.9, 135.8, 135.7, 133.3,
133.1, 130.4, 130.3, 130.1, 130.0, 128.9, 128.0, 127.9,
127.8, 126.8, 114.8, 114.5, 361.2, 60.0, 54.5, 51.3, 41.4,
41.1, 27.1, 19.2; HRMS m/z (ESI) calcd for C42H46FNO3Si
(M+H)+ 660.3309, found 660.3304.
4.3.8. (R)-tert-Butyl-4-((R)-2-(methoxycarbonyl)-1-(4-meth-
oxyphenyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate, 4b.
21
87%; Rf 0.43 (20% EtOAc/hexane); ½aꢁD ¼ þ40:0 (c 0.02,
1
CHCl3); H NMR (CDCl3): d 7.2 (br d, 2H), 6.8 (br d,
2H), 4.14–3.65 (br m, 6H), 3.58–3.47 (br m, 4H), 2.86–
2.68 (br d, 2H), 1.55 (br s, 6H), 1.48 (br s, 9H); 13C
NMR (CDCl3): d 165.0, 150.2, 144.4, 124.1, 120.9, 120.5,
106.4, 105.7, 86.5, 72.3, 55.7, 53.7, 47.1, 44.6, 33.9, 24.2,
20.4, 18.3; HRMS m/z (ESI) calcd for C21H31NO6
(M+Na)+ 416.2049, found 416.2053.
4.3.4. 5-(tert-Butyldiphenylsilanyloxy)-3-(4-chlorophenyl)-4-
dibenzylamino-pentanoic acid methyl ester, 3d. 58%; Rf
24
0.67 (10% EtOAc/hexane); ½aꢁD ¼ ꢀ11:8 (c 0.1, CHCl3);
4.3.9. (R)-tert-Butyl-4-((R)-2-(methoxycarbonyl)-1-(4-fluoro-
4c.
1H NMR (CDCl3): d 7.82–6.85 (m, 24H), 4.2 (br dd,
1H), 3.86 (br dd, 1H), 3.77 (d, 2H, J = 13.5 Hz), 3.69 (m,
1H), 3.44 (s, 3H), 3.36 (d, 2H, J = 13.5 Hz), 2.90 (m,
1H), 2.65 (br dd, 1H, J = 3.8, 15.1 Hz), 2.31 (dd, 1H,
J = 10.7, 15.1 Hz); 13C NMR (CDCl3): d 172.3, 140.8,
139.6, 135.9, 135.8, 133.2, 133.0, 131.9, 130.4, 130.1,
130.0, 129.0, 128.0, 127.9, 127.9, 126.8, 61.2, 59.9, 54.6,
51.4, 41.5, 38.9, 27.1, 19.1; HRMS m/z (ESI) calcd for
C42H46ClNO3Si (M+H)+ 676.3014, found 676.2995.
phenyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate,
21
92%; Rf 0.5 (20% EtOAc/hexane); ½aꢁD ¼ þ33:6 (c 0.03,
CHCl3); 1H NMR (CDCl3): d 7.29–6.93 (br m, 5H),
4.14–3.63 (br m, 3H), 3.6–3.48 (br s, m, 4H), 2.9–2.68 (br
d, 2H), 1.55 (br s, 6H), 1.46 (s, 9H); 13C NMR (CDCl3):
d 172.8, 163.4, 160.1, 135.9, 128.4, 115.5, 94.3, 80.4, 63.8,
61.6, 51.7, 42.4, 32.4, 28.4, 26.1; HRMS m/z (ESI) calcd
for C20H28FNO5 (M+Na)+ 404.1849, found 404.1834.
4.3.10. (R)-tert-Butyl-4-((R)-2-(methoxycarbonyl)-1-(4-chloro-
phenyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate,
4.3.5. 5-(tert-Butyldiphenylsilanyloxy)-4-dibenzylamino-3-
(3,4-dimethoxyphenyl)-pentanoic acid methyl ester, 3e.
4d.
21
83%; Rf 0.54 (20% EtOAc/hexane); ½aꢁD ¼ þ26:0 (c 0.03,
CHCl3); 1H NMR (CDCl3): d 7.33–7.12 (br dd, 4H),
4.14–3.68 (br m, 3H), 3.63–3.48 (br m, 4H), 2.9–2.7 (br d,
2H), 1.54 (br s, 6H), 1.46 (br s, 9H); 13C NMR (CDCl3):
d 172.8, 152.4, 138.8, 132.8, 129.7, 128.8, 94.7, 80.6, 63.9,
61.5, 51.8, 42.6, 33.0, 28.4, 26.6; HRMS m/z (ESI) calcd
for C20H28ClNO5 (M+Na)+ 420.1554, found 420.1537.
24
49%; Rf 0.52 (10% EtOAc/hexane); ½aꢁD ¼ ꢀ13:6 (c 0.03,
1
CHCl3); H NMR (CDCl3): d 7.84–6.5 (m, 23H), 4.08 (br
dd, 1H), 3.90 (m, 1H), 3.88 (br s, 3H), 3.74 (br d, 2H,
J = 14.1 Hz), 3.60 (br s, 3H), 3.57 (br dd, 1H), 3.46 (br
dd, 1H), 3.36 (br d, 2H, J = 14.1 Hz), 2.90 (br m, 1H),
2.64 (br dd, 1H, J = 4.7, 15.4 Hz), 2.42 (br dd, 1H,

S. K. Rastogi, A. Kornienko / Tetrahedron: Asymmetry 17 (2006) 3170–3178
3175
4.3.11. (R)-tert-Butyl-4-((R)-2-(methoxycarbonyl)-1-(3,4-
dimethoxyphenyl)ethyl)-2,2-dimethyloxazolidine-3-carboxyl-
4.4.3. Methyl (3R,4R)-4-amino-3-(4-fluorophenyl)-5-hydr-
oxypentanoate, 5c. 88%; 1H NMR (D2O): d 7.31 (m,
1H), 7.11 (m, 1H), 3.91 (dd, 1H, J = 3.0, 12.6 Hz), 3.78
(dd, 1H, J = 5.5, 12.6 Hz), 3.59 (m, 1H), 3.44 (s, 3H),
3.39 (m, 1H), 2.93 (dd, 1H, J = 4.4, 15.4 Hz), 2.76 (dd,
1H, J = 10.7, 15.4 Hz); 13C NMR (D2O): d 174.4, 133.3,
130.3, 130.2, 116.4, 116.1, 59.2, 56.5, 52.4, 40.7, 37.2;
HRMS m/z (ESI) calcd for C12H16FNO3 (M+H)+
242.1192, found 242.1202.
21
ate, 4e. 70%; Rf 0.33 (20% EtOAc/hexane); ½aꢁD ¼ þ38:2
(c 0.01, CHCl3); 1H NMR (CDCl3): d 6.90–6.71 (br m, 3H),
4.14–3.66 (br m, 9H), 3.65–3.48 (br m, 4H), 2.9–2.71 (br s,
2H), 1.56 (br s, 6H), 1.48 (br s, 9H); 13C NMR (CDCl3): d
173.2, 152.4, 149.0, 147.9, 132.8, 118.9, 111.3, 94.6, 80.5,
63.5, 61.8, 55.8, 51.7, 42.3, 32.8, 28.5, 26.6; HRMS m/z
(ESI) calcd for C22H33NO7 (M+Na)+ 446.2155, found
446.2157.
4.4.4. Methyl (3R,4R)-4-amino-3-(4-chlorophenyl)-5-hydr-
1
4.3.12. (R)-tert-Butyl-4-((R)-2-(methoxycarbonyl)-1-(benzo-
[d][1,3]dioxol-6-yl)ethyl)-2,2-dimethyloxazolidine-3-carboxyl-
oxypentanoate, 5d. 85%; H NMR (D2O): d 7.36 (d, 2H,
J = 8.5 Hz), 7.24 (d, 2H, J = 8.5 Hz), 3.89 (dd, 1H,
J = 3.0, 12.6 Hz), 3.74 (dd, 1H, J = 5.5, 12.6 Hz), 3.72
(m, 1H), 3.41 (s, 3H), 3.34 (m, 1H), 2.89 (dd, 1H,
J = 3.8, 15.4 Hz), 2.74 (br dd, 1H); 13C NMR (D2O): d
174.0, 136.1, 133.8, 130.0, 129.5, 59.2, 56.4, 52.4, 40.9,
37.0; HRMS m/z (ESI) calcd for C12H17ClNO3 (M+H)+
258.0897, found 258.0863.
21
ate, 4f. 92%; Rf 0.42 (20% EtOAc/hexane); ½aꢁD ¼ þ29:4
(c 0.02, CHCl3); 1H NMR (CDCl3): d 6.84–6.6 (br m, 3H),
5.95 (br s, 2H), 4.14–3.66 (br m, 3H), 3.65–3.52 (br m, 4H),
2.74 (br d, 2H), 1.54 (br s, 6H), 1.48 (br s, 9H); 13C NMR
(CDCl3): d 173.0, 152.5, 147.8, 146.4, 134.2, 120.8, 108.4,
101.0, 92.6, 80.5, 63.5, 61.9, 51.7, 42.6, 32.5, 28.5, 26.4;
HRMS m/z (ESI) calcd for C21H29NO7 (M+Na)+
430.1842, found 430.1831.
4.4.5. Methyl (3R,4R)-4-amino-5-hydroxy-3-(3,4-dimeth-
oxyphenyl)pentanoate, 5e. 85%; H NMR (D2O): d 6.92
1
4.3.13.
(R)-tert-Butyl-4-((R)-2-(methoxycarbonyl)-1-(4-
(br d, 3H), 4.16–3.66 (br m, 8H), 3.63–3.25 (br m, 5H),
2.90 (br dd, 1H), 2.75 (br dd, 1H); 13C NMR (D2O): d
174.2, 148.7, 148.1, 130.3, 121.4, 112.4, 111.6, 59.3, 55.8,
52.4, 48.9, 41.2, 37.2; HRMS m/z (ESI) calcd for
C14H21NO5 (M+H)+ 284.1498, found 284.1506.
methoxybenzo[d][1,3]dioxol-6-yl)ethyl)-2,2-dimethyloxazol-
idine-3-carboxylate, 4g. 86%; Rf 0.38 (20% EtOAc/hex-
21
1
ane); ½aꢁD ¼ þ73:3 (c 0.01, CHCl3); H NMR (CDCl3): d
6.41 (br d, 2H), 5.93 (br s, 3H), 4.14–3.67 (br m, 6H),
3.58 (br s, 3H), 3.54 (br m, 1H), 2.74 (br d, 2H), 1.50 (br
s, 15H); 13C NMR (CDCl3): d 173.3, 152.9, 152.0, 149.0,
143.7, 134.8, 128.9, 107.6, 101.4, 94.2, 91.3, 80.0, 63.8,
56.5, 42.8, 33.4, 29.9, 28.5, 26.7; HRMS m/z (ESI) calcd
for C22H31NO8 (M+Na)+ 460.1947, found 460.2023.
4.4.6. Methyl (3R,4R)-4-amino-3-(benzo[d][1,3]dioxol-6-yl)-
1
5-hydroxypentanoate, 5f. 90%; H NMR (D2O): d 6.83–
6.70 (m, 3H), 5.87 (s, 2H), 3.88 (dd, 1H, J = 2.3,
12.1 Hz), 3.71 (dd, 1H, J = 5.2, 12.6 Hz), 3.46 (s, 3H),
3.24 (m, 1H), 2.84 (br dd, 1H, J = 3.8, 14.8 Hz), 2.68 (br
dd, 1H); 13C NMR (D2O): d 174.0, 148.0, 147.2, 130.9,
122.0, 109.0, 108.1, 101.0, 59.1, 56.5, 52.3, 41.1, 37.2;
HRMS m/z (ESI) calcd for C13H20NO4 (M+H)+
268.1185, found 268.1105.
4.4. General procedure for the removal of Boc and isoprop-
ylidene protection
A solution of HCl in MeOH was prepared by the careful
addition of acetyl chloride 30 ll in 3 ml methanol at 0 ꢁC.
Compounds 4a–g (ca. 50 mg) were refluxed in this solution
(3 ml) for 2 h at rt. The solvent was evaporated under re-
duced pressure and the residue was triturated with ethyl
acetate and hexane. White to off white solids 5a–g were ob-
tained in 85–90% yield.
4.4.7. Methyl (3R,4R)-4-amino-5-hydroxy-3-(4-methoxy-
benzo[d][1,3]dioxol-6-yl)pentanoate, 5g. 76%; 1H NMR
(D2O): d 6.57 (d, 2H, J = 8.8 Hz), 5.93 (br s, 2H), 3.95–
3.73 (m, 5H), 2.89 (br dd, 1H), 2.76 (br dd, 1H); 13C
NMR (D2O): d 174.1, 149.2, 143.5, 134.9, 132.1, 108.2,
101.8, 59.2, 56.7, 56.6, 52.4, 41.5, 37.3; HRMS m/z (ESI)
calcd for C14H19NO6 (M+H)+ 298.1291, found 298.1281.
4.4.1. Methyl (3R,4R)-4-amino-5-hydroxy-3-phenylpentan-
oate, 5a. 88%; H NMR (D2O): d 7.49–7.31 (m, 5H), 4.0
1
(dd, 1H, J = 2.2, 9.9 Hz), 3.85 (dd, 1H, J = 5.5, 12.4 Hz),
3.67 (m, 1H), 3.58–3.4 (m, 4H), 3.01 (dd, 1H, J = 3.8,
15.1 Hz), 2.87 (dd, 1H, J = 10.7, 14.6 Hz); 13C NMR
(D2O): d 174.1, 137.4, 126.5 128.6, 128.3 59.2, 56.5, 52.3,
41.2, 37.0; HRMS m/z (ESI) calcd for C12H17NO3
(M+H)+ 224.1287, found 224.1242.
4.5. General procedure for lactam formation
Compounds 5a–g (ca. 30 mg) were stirred in a freshly
prepared solution of sodium methoxide in methanol (2 ml;
pH ꢂ 9) for 1 h at rt. The solvent was evaporated under
reduced pressure. The residue was dissolved in CH2Cl2
(15 ml) and washed with water (3·3 ml), organic phase
was dried with brine (3 ml) and over anhydrous MgSO4.
After evaporation of CH2Cl2 under reduced pressure, white
to pale yellow solids 6a–g were obtained in 70–85% yield.
4.4.2. Methyl (3R,4R)-4-amino-5-hydroxy-3-(4-methoxy-
1
phenyl)pentanoate, 5b. 90%; H NMR (D2O): d 7.23 (d,
2H, J = 7.2 Hz), 6.93 (d, 2H, J = 7.2 Hz), 3.89 (dd, 1H,
J = 3.6, 9.4 Hz), 3.84–3.71 (m, 4H), 3.54 (m, 1H), 3.41 (s,
3H), 3.30 (m 1H), 2.88 (dd, 1H, J = 3.8, 14.1 Hz), 2.73
(br dd, 1H); 13C NMR (D2O): d 174.2, 158.9, 129.7,
129.6, 114.9, 59.3, 56.8, 55.5, 52.4, 40.6, 37.3; HRMS m/z
(ESI) calcd for C13H20NO4H (M+H)+ 254.1392, found
254.1339.
4.5.1. (4R,5R)-5-(Hydroxymethyl)-4-phenylpyrrolidin-2-one,
23
6a. 80%; Rf 0.48 (5% MeOH/EtOAc); ½aꢁD ¼ ꢀ63:4 (c
1
0.01, CH3OH); H NMR (D2O): d 7.31 (m, 5H), 4.04 (br
m, 1H), 3.90 (dd, 1H, J = 9.4, 17.0 Hz), 3.27 (m, 1H),
3.16 (m, 1H), 2.82 (dd, 1H, J = 8.8, 17.0 Hz), 2.64 (dd,

3176
S. K. Rastogi, A. Kornienko / Tetrahedron: Asymmetry 17 (2006) 3170–3178
1H, J = 8.9, 16.8 Hz); 13C NMR (D2O): d 181.0, 138.1,
128.7, 128.0, 127.3, 61.7, 59.6, 41.5, 35.3; HRMS m/z
(ESI) calcd for C11H13NO2 (M+H)+ 192.1025, found
192.1018.
1H), 2.79 (dd, 1H, J = 9.1, 16.5 Hz), 2.63 (dd, 1H,
J = 8.8, 1.8 Hz); 13C NMR (D2O): d 180.8, 153.8, 146.1,
142.9, 107.7, 102.3, 101.7, 61.7, 59.6, 56.6, 41.9, 35.5;
HRMS m/z (ESI) calcd for C13H15NO5 (M+H)+
266.1028, found 266.1032.
4.5.2. (4R,5R)-5-(Hydroxymethyl)-4-(4-methoxyphenyl)pyr-
rolidin-2-one, 6b. 85%; Rf 0.4 (10% MeOH/EtOAc);
4.6. Stereochemistry assignment by acetylation of 5b and 5f
23
1
½aꢁD ¼ ꢀ95:7 (c 0.02, CH3OH); H NMR (D2O): d 7.15
(d, 2H, J = 8.5 Hz), 6.85 (d, 2H, J = 8.5 Hz), 3.90 (m,
1H), 3.77–3.65 (m, 4H), 3.16 (m, 1H), 3.06 (dd, 1H,
J = 6.9, 10.4 Hz), 2.68 (dd, 1H, J = 9.3, 17.0 Hz), 2.50
(dd, 1H, J = 8.7, 16.8 Hz); 13C NMR (D2O): d 180.9,
157.9, 130.5, 129.2, 114.0, 61.8, 59.6, 55.4, 41.0, 35.5.
HRMS m/z (ESI) calcd for C12H15NO3 (M+H)+
222.1130, found 222.1122.
Hydroxymethyl pyrrolidine-2-ones 5b and 5f (0.0185 g,
0.08 mmol) were dissolved in pyridine (1.5 ml) and stirred
with Ac2O (0.224 ml, 2.37 mmol) in the presence of DMAP
(0.5 mg) for 16 h at rt. The solution was concentrated
under reduced pressure and the residual oil was presorbed
on silica gel. The two acetylated products were purified by
column chromatography (15% EtOAc/hexane and 70%
EtOAc/hexane).
4.5.3.
(4R,5R)-4-(4-Fluorophenyl)-5-(hydroxymethyl)pyr-
rolidin-2-one, 6c. 82%; Rf 0.49 (5% MeOH/EtOAc);
4.6.1. (4R,5R)-1-Acetyl-4-(benzo[d][1,3]dioxol-6-yl)-5-(hydr-
oxymethyl)pyrrolidin-2-one, 7f. 45%; Rf 0.41 (50%
EtOAc/hexane); H NMR: d 6.64 (m, 3H), 5.91 (s, 2H),
4.14–4.02 (m, 3H), 3.89 (dd, 1H, J = 3.3, 8.3 Hz), 3.79
(dd, 1H J = 8.3, 8.5 Hz), 3.54 (dd, 1H, J = 8.3, 11.3 Hz),
2.01 (s, 3H); 13C NMR (CDCl3): d 176.9, 170.5, 148.2,
147.1, 131.0, 120.8, 108.5, 107.9, 101.3, 65.0, 56.4, 41.9,
35.6, 20.8; HRMS m/z (ESI) calcd for C14H15NO5
(M+H)+ 278.1028, found 278.1024.
23
1
½aꢁD ¼ ꢀ105:7 (c 0.03, CH3OH); H NMR (D2O): d 7.25
(br t, 2H), 7.05 (br t, 2H), 3.97 (m, 1H), 3.7 (br dd, 1H,
J = 8.5, 17.3 Hz), 3.24 (br dd, 1H, J = 3.5, 13.6 Hz), 3.12
(br dd, 1H, J = 6.6, 11.5 Hz), 2.78 (br dd, 1H, J = 9.1,
16.7 Hz), 2.6 (br dd, 1H, J = 8.8, 16.8 Hz); 13C NMR
(D2O): d 180.9, 157.9, 129.2, 114.0, 61.8, 59.6, 55.4, 41.0,
35.5; HRMS m/z (ESI) calcd for C11H12FNO2 (M+H)+
210.0930, found 210.0927.
1
4.5.4. (4R,5R)-4-(4-Chlorophenyl)-5-(hydroxymethyl)pyr-
rolidin-2-one, 6d. 75%; Rf 0.44 (5% MeOH/EtOAc);
4.6.2. ((2R,3R)-1-Acetyl-3-(4-methoxyphenyl)-5-oxopyrrol-
idin-2-yl)methyl acetate, 8b. 55%; Rf 0.56, (60% EtOAc/
hexane); 1H NMR: d 7.13 (d, 2H, J = 8.5 Hz), 6.88 (d,
2H, J = 8.5 Hz), 4.76 (m, 1H), 4.41 (dd, 1H, J = 2.8,
12.1 Hz), 3.8 (m, 4H), 3.62 (dd, 1H, J = 2.8, 12.1 Hz),
3.24 (dd, 1H, J = 15.2, 16.9 Hz), 2.72 (dd, 1H, J = 8.3,
16.9 Hz), 2.40 (s, 3H), 1.96 (s, 3H); 13C NMR (CDCl3): d
174.5, 171.0, 170.0, 159.9, 128.5, 127.2, 114.4, 61.5, 58.7,
55.3, 39.5, 36.8, 25.4, 21.0; HRMS m/z (ESI) calcd for
C16H19NO5 (M+Na)+ 328.1161, found 328.1149.
23
1
½aꢁD ¼ ꢀ113:7 (c 0.01, CH3OH); H NMR (D2O): d 7.35
(br d, 2H, J = 7.9 Hz), 7.24 (br d, 2H, J = 8.2), 3.95 (m,
1H), 3.84 (dd, 1H, J = 7.98, 17.1 Hz), 3.2 (br dd, 1H,
J = 3.0, 12.1 Hz), 3.08 (br dd, 1H, J = 6.0, 12.5 Hz), 2.74
(br dd, 1H, J = 8.8, 16.5 Hz), 2.56 (br dd, 1H, J = 8.8,
17.1 Hz); 13C NMR (D2O): d 180.8, 138.8, 132.4, 129.6,
128.6, 61.5, 59.4, 41.2, 35.3; HRMS m/z (ESI) calcd for
C11H12ClNO2 (M+H)+ 226.05, found 226.0643.
4.5.5. (4R,5R)-5-(Hydroxymethyl)-4-(3,4-dimethoxyphenyl)-
pyrrolidin-2-one, 6e. 70%; Rf 0.47 (20% MeOH/EtOAc);
4.6.3. ((2R,3R)-1-Acetyl-3-(benzo[d][1,3]dioxol-6-yl)-5-oxo-
pyrrolidin-2-yl)methyl acetate, 8f. 25%; Rf 0.58, (50%
EtOAc/hexane); 1H NMR: d 6.79 (d, 1H, J = 8.0 Hz),
6.69–6.66 (m, 2H), 5.97 (s, 2H), 4.73 (ddd, 1H, J = 2.8,
2.8, 8.2 Hz), 4.44 (dd, 1H, J = 2.8, 12.1 Hz), 3.75 (ddd,
1H, J = 8.2, 8.3, 15.2 Hz), 3.67 (dd, 1H, J = 2.8,
12.1 Hz), 3.20 ( dd, 1H, J = 15.2, 16.9 Hz), 2.69 (dd, 1H,
J = 8.3, 16.9 Hz); 13C NMR (CDCl3): d 174.4, 169.9,
148.3, 147.2, 129.1, 120.7, 108.6, 107.7, 101.3, 61.5, 58.7,
39.9, 36.9, 20.9; HRMS m/z (ESI) calcd for C21H29NO7
(M+Na)+ 342.0954, found 342.0946.
21
1
½aꢁD ¼ ꢀ110:0 (c 0.01, CH3OH); H NMR (D2O): d 6.94
(br m, 3H), 3.89 (br s, 8H), 3.31 (br dd, 1H), 3.20 (br dd,
1H), 2.83 (br dd, 1H), 2.64 (br dd, 1H); 13C NMR
(D2O): d 181.0, 148.1, 147.3, 131.3, 120.5, 111.9, 61.8,
59.7, 55.9, 49.0, 41.5, 35.5; HRMS m/z (ESI) calcd for
C13H17NO4 (M+H)+ 252.1236, found 252.1226.
4.5.6. (4R,5R)-4-(Benzo[d][1,3]dioxol-6-yl)-5-(hydroxymethyl)-
pyrrolidin-2-one, 6f. 76%; Rf 0.35 (5% MeOH/EtOAc);
23
½aꢁD ¼ ꢀ104:2 (c 0.003, CH3OH); 1H NMR (D2O): d
6.77–6.67 (m, 3H), 5.85 (s, 2H), 3.91 (m, 1H), 3.75 (dd,
1H, J = 8.5, 17.0 Hz), 3.19 (m, 2H), 2.70 (dd, 1H,
J = 9.1, 16.7 Hz), 2.54 (dd, 1H, J = 8.8, 17.0 Hz); 13C
NMR (D2O): d 178.5, 148.0, 146.8, 131.7, 120.9, 108.3,
108.1, 101.2, 63.1, 59.7, 42.2, 36.2; HRMS m/z (ESI) calcd
for C12H13NO4 (M+H)+ 236.0923, found 236.0921.
4.6.4. (4R,5R)-5-(Dibenzylamino)-tetrahydro-4-phenylpyran-
2-one, 9a. Tetrabutylammonium fluoride (1 M solution in
THF, 0.498 ml, 0.5 mmol) was added dropwise to a solu-
tion of phenyl cuprate adduct 3a (62.5 mg, 0.1 mmol) in
THF (3 ml). The reaction mixture was stirred for 16 h at
rt. After completion of the reaction (monitored by TLC),
EtOAc (10 ml) was added and the solution was washed
with water (2 ml · 2) and with brine (2 ml · 2). This solu-
tion was dried over anhydrous MgSO4 and the solvent
was concentrated under reduced pressure. The residue
was presorbed on silica gel and purified by column chroma-
tography (4% EtOAc/hexane) to afford 9a (19.5 mg, 55%
4.5.7. (4R,5R)-5-(Hydroxymethyl)-4-(4-methoxybenzo[d][1,3]-
dioxol-6-yl)pyrrolidin-2-one, 6g. 70%; Rf 0.41 (10%
24
MeOH/EtOAc); ½aꢁD ¼ ꢀ123:4 (c 0.01, CH3OH); 1H
NMR (D2O): d 6.55 (d, 2H, J = 14.0 Hz), 5.93 (s, 2H),
3.96 (m, 1H), 3.85 (m, 4H), 3.30 (br m, 1H), 3.22 (br dd,

S. K. Rastogi, A. Kornienko / Tetrahedron: Asymmetry 17 (2006) 3170–3178
3177
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1581.
6. Quarzane-Amara, M.; Franetich, J.-F.; Mazier, D.; Pettit, G.
R.; Meijer, L.; Doerig, C.; Desportes-Livage, I. Antimicrob.
Agents Chemother. 2001, 45, 3409–3415.
yield). Rf 0.38 (20% EtOAc/hexane); H NMR (CDCl3): d
7.44–6.99 (m, 15H), 4.47 (m, 2H), 3.75 (d, 2H,
J = 13.8 Hz), 3.52 (d, 2H, J = 13.8 Hz), 3.35 (m, 2H),
2.82 (br dd, 1H), 2.60 (br dd, 1H); 13C NMR (CDCl3): d
171.6, 142.1, 138.7, 128.8, 128.4, 128.3, 127.7, 127.3,
127.2; HRMS m/z (ESI) calcd for C25H25NO2 (M+H)+
372.1964, found 372.1946.
4.6.5.
(4R,5R)-5-Amino-tetrahydro-4-phenylpyran-2-one,
7. (a) Yii, S.; Mikami, S.; Kitahara, M.; Yamazaki, M.
Immunopharmacology 1998, 40, 151–162; (b) Citoglu, G.;
Tanker, M.; Gumusel, B. Phytother. Res. 1998, 12, 205–
206.
8. (a) McLachlan, A.; Kekre, N.; McNulty, J.; Pandey, S.
Apoptosis 2005, 10, 619–630; (b) Pandey, S.; Kekre, N.;
Naderi, J.; McNulty, J. Artif. Cells, Blood Substitutes,
Immobilization Biotechnol. 2005, 33, 279–295; (c) Kekre, N.;
Griffin, C.; McNulty, J.; Pandey, S. Cancer Chemother.
Pharmacol. 2005, 56, 29–38.
9. For illustration of various strategies to install the C10b
stereocenter, see the published total syntheses of pancratist-
atin: (a) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989,
111, 4829–4837; (b) Tian, X.; Ko¨nigsberger, K.; Hudlicky, T.
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Tian, X.; Ko¨nigsberger, K.; Maurya, R.; Rouden, J.; Fan, B.
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Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143–10144; (e)
Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341–
5342; (f) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J.
Am. Chem. Soc. 2000, 122, 6624–6628; (g) Doyle, T. J.;
Hendrix, M.; VanDerveer, D.; Javanmard, S.; Haseltine, J.
Tetrahedron 1997, 53, 11153–11170; (h) Pettit, G. R.; Melody,
N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583–2587; (i) Kim,
S.; Ko, H. J.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343–1345;
(j) Ko, H. J.; Kim, E.; Park, J. E.; Kim, D.; Kim, S. J. Org.
Chem. 2004, 69, 112–121; (k) Li, M.; Wu, A.; Zhou, P.
Tetrahedron Lett. 2006, 47, 3707–3710.
10a. To a solution of lactone 9a (15.2 mg, 0.041 mmol)
in water/dioxane (2:1, 3 ml) were added two drops of
AcOH and 10% Pd/C (10 mg). The solution was stirred
under an H2 atmosphere (1 atm pressure) at rt for 24 h.
The completion of the reaction was monitored by TLC.
The reaction mixture was filtered through a Celite pad
and the filtrate was concentrated to give 4.7 mg of debenz-
1
ylated lactone 10a (62% yield). H NMR (CDCl3): d 7.41
(m, 5H), 3.96 (dd, 1H, J = 3.0, 12.7 Hz), 3.81 (dd, 1H,
J = 5.8, 12.4 Hz), 3.64 (m, 1H), 3.37 (m, 1H), 2.94 (dd,
1H, J = 4.7, 15.4 Hz), 2.75 (dd, 1H, J = 10.5, 15.1 Hz);
13C NMR (CDCl3): d 176.0, 137.8, 129.6, 128.6, 128.5,
59.4, 56.8, 41.5, 37.5; HRMS m/z (ESI) calcd for
C11H13NO2ÆH2O (M+H)+ 210.1130, found 210.1133.
4.6.6. (4R,5R)-5-Hydroxymethyl-4-phenylpyrrolidin-2-one,
6a. Amino lactone 10a was stirred in a solution of freshly
prepared NaOMe in MeOH (2 ml, pH ꢂ 9) at rt for 1 h.
The reaction mixture was stirred with Amberlyst 15 (dry)
ion-exchange resin (200 mg) at rt for 10 min. The solution
was filtered and the filtrate was concentrated under reduced
pressure. This afforded 3.2 mg of 6a (80% yield), whose
NMR spectra were identical to those recorded with the
material obtained from 5a.
10. (a) Manpadi, M.; Kornienko, A. Tetrahedron Lett. 2005, 46,
4433–4437; (b) Kireev, A. S.; Manpadi, M.; Kornienko, A. J.
Org. Chem. 2006, 71, 2630–2640.
Acknowledgements
11. (a) Reetz, M. T.; Rohrig, D. Angew. Chem., Int. Ed. Engl.
1989, 28, 1706–1709; (b) Jako, I.; Uibera, P.; Mann, A.;
Taddei, M.; Wermuth, C. G. Tetrahedron Lett. 1990, 31,
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Otterlo, W. A. L. Tetrahedron Lett. 2000, 41, 4999–5003; (f)
Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin
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We thank Professor Patrick S. Mariano for his help with
the preparation of the manuscript and the University of
New Mexico Mass Spectrometry Facility for MS analyses.
This work is supported by the US National Institutes of
Health (RR-16480 and CA-99957) under the BRIN/IN-
BRE and AREA programs.
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