π-Allyl palladium approach toward the diazabicyclo[3.2.1]octane core of the naphthyridinomycin alkaloids

Article abstract of DOI:10.1016/j.tet.2006.06.114

A novel and efficient protocol for the synthesis of the 3,8-diazabicyclo[3.2.1]octane system found in the naphthyridinomycin, dnacin, and tetrazomine families of alkaloids is described. The key transformation involves an intramolecular palladium-catalyzed

Full text of DOI:10.1016/j.tet.2006.06.114

Tetrahedron 62 (2006) 10507–10517
p-Allyl palladium approach toward the diazabicyclo[3.2.1]octane
core of the naphthyridinomycin alkaloids
*
Grace H. C. Woo, Se-Ho Kim and Peter Wipf
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 14 January 2006; revised 5 May 2006; accepted 12 June 2006
Available online 2 August 2006
Abstract—A novel and efficient protocol for the synthesis of the 3,8-diazabicyclo[3.2.1]octane system found in the naphthyridinomycin,
dnacin, and tetrazomine families of alkaloids is described. The key transformation involves an intramolecular palladium-catalyzed allylic
alkylation. The cyclization proceeds smoothly under mild conditions (20 mol % Pd2dba3, 1.5 equiv DBU, 65 ꢀC, THF, 20 min) to afford
3,8-diazabicyclo[3.2.1]octanes in excellent yields (94–98%).
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
novel inhibitors of Cdc25 phosphatase,5 thereby broadening
their potential for use as chemotherapeutics. Inspired by the
wide range of biological activities and the structural com-
plexity of these alkaloids, several total syntheses and a
number of partial synthesis efforts have been documented.6
Nonetheless, more practical and efficient routes to these nat-
ural products that would allow an improved stereocontrol in
the assembly of the core structure need to be developed.
Over the past three decades, antitumor antibiotics belonging
to the tetrahydroisoquinoline alkaloid family have been
extensively investigated.1 These natural products which
include saframycin, naphthyridinomycin/bioxalomycin, and
quinocarcin/tetrazomine exhibit a wide range of biological
activities, such as antitumor, antifungal, antimicrobial activ-
ities, and others.1–5 Dnacins A1 (1) and B1 (2) are new mem-
bers of the naphthyridinomycin/bioxalomycin class, isolated
from Actinosynnema pretiosum C-14482 in 1980,2 although
their structures were not determined until 1994.3 Interest-
ingly, dnacin B1 (2) is structurally equivalent to naphthyridi-
nomycin (3) with the exception of the amino group at C11 and
the hydrogen atom at C12.3 Akin to naphthyridinomycin, dna-
cin B1 inhibits DNA synthesis as evidenced by its ability to
prevent the incorporation of 3H-thymidine into DNA, and it
has been shown to cleave DNA by the formation of super-
oxide.4 Both dnacins A1 and B1 have been recognized as
As a general strategy toward the synthesis of naphthyridino-
mycins, we envisioned two distinct approaches for the
construction of the 3,8-diazabicyclo[3.2.1]octane core struc-
tures 5 and 6, which are embedded in all targets shown in
Figure 1: the palladium-catalyzed intramolecular Heck
cyclization of vinyl phosphate 7 (Fig. 2, route A) and the
palladium-catalyzed intramolecular allylic alkylation of
malonate 8 (Fig. 2, route B). By employing the intramolecu-
lar processes, the configuration at the stereogenic C1 (*) in
bicycles 5 and 6 should derive from the attachment of the
Me
N
Me
N
Me
N
R
HO
7
O
D
C
N
9
N
B
N
OH
HO
O
4
HO
O
E
MeO
N
N
O
O
A
F
11
H2N
OH HN
1
O
MeO
O
12
Me
O
NH
naphthyridinomycin (3)
dnacin A1 (1): R = CN
dnacin B1 (2): R = OH
tetrazomine (4)
Figure 1. Selected examples of natural products containing the 3,8-diazabicyclo[3.2.1]octane core (C,D-ring system).
* Corresponding author. Tel.: +1 412 624 8606; fax: +1 412 624 0787; e-mail: pwipf@pitt.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.114

10508
G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
reaction parameters were screened, and dppp as a ligand in
Me
N
DME or THF (Table 1, entries 5–7) provided the desired
product 12 in modest yields (45–53%). A similar result was
obtained when the cyclization of 11 was carried out under
microwave heating at 100 ꢀC for 30 min (54%, entry 8).11
R
N
*
A
B
N
O
1. NaBH4, LiCl, EtOH
O
Boc
N
N
O
2. PPh3, DIAD, THF
morpholine-3,5-dione; 82%
Boc
MeO
Boc
N
Boc
N
O
O
X
10
9
1
3 N
7
Ar
N
Y
*
*
CO2Et
N
°
LHMDS, -78 C, THF;
EtO2C
O
Boc
O
ClPO(OEt)2, -78 °C; 60%
N
5
6
OPO(OEt)2
O
11
Intramolecular
Intramolecular
Heck Cyclization
Allylic Alkylation
Scheme 1.
Table 1. Optimization of Heck cyclization of vinyl phosphate 11
OR
X
Boc
O
N
N
*
Ar
Boc
Y
N
N
N
*
20 mol% Pd(OAc)2, 1.1 equiv K2CO3
N
Boc
O
Boc
OPO(OEt)2
O
N
O
N
CO2Et
OPO(OEt)2
40 mol% ligand, solvent
70 °C, 8-10 h
EtO2C
O
O
7
8
11
12
Figure 2. Retrosynthetic analysis of dnacins and related compounds.
Entry
Ligand
Solvent
Product 12
(%)
Starting
material 11 (%)
tether in precursors 7 and 8. Furthermore, both 5 and 6
provide adequate functionalization for the introduction of
the remaining substituents in dnacins and related naphthyri-
dinomycins. In this report, we describe our pursuit of these
new synthetic routes toward the 3,8-diazabicyclo[3.2.1]-
octane ring system.
1
2
3
4
5
6
dppf
THF
THF
THF
DME
THF
DME
DME
DME
—
12
13
36
41
45
53
54
—
—
25
22
7
21
<5
—
BINAP
dppe
dppb
dppp
dppp
dppp
dppp
7a
8a,b
a
Pd(OAc)2 (40 mol %) and dppp (80 mol %) were used.
Reaction mixture was heated in the microwave at 100 ꢀC for 30 min.
2. Results and discussion
b
Our initial strategy for the synthesis of 3,8-diazabicy-
clo[3.2.1]octanes relied upon the intramolecular Heck cycli-
zation (Fig. 2, route A). Although a large number of Heck
reactions have been applied to natural product syntheses,7
only a handful of examples have been documented for the
construction of bridged bicyclic ring systems.8 As outlined
in Scheme 1, starting from the known ester 9 derived from
(S)-pyroglutamic acid,9 vinyl phosphate 11 was prepared
in three steps. The vinyl phosphate was chosen to explore
the key Heck cyclization because vinyl phosphates10a–e
were found to be more reactive than the corresponding trifla-
tes.10f Hence, reduction of 9 with NaBH4/LiCl, followed by
Mitsunobu reaction with morpholine-3,5-dione, afforded 10
in 82% yield (two steps). The desired Heck precursor 11 was
subsequently obtained in 60% yield by treatment of 10
with LHMDS (ꢁ78 ꢀC, THF) followed by slow addition of
diethyl chlorophosphate (Scheme 1). With the desired pre-
cursor in hand, the key intramolecular Heck cyclization
was explored under several different reaction conditions
(Table 1). With Pd(OAc)2 and dppf as a ligand (70 ꢀC,
THF), cyclization failed completely (entry 1). After several
attempts, we found that bidentate ligands and K2CO3 as
a base were most effective. Several bidentate ligands and
To further explore the scope of the Heck cyclization for
the construction of the 3,8-diazabicyclo[3.2.1]octane unit,
we extended this chemistry to a vinyl phosphate substrate
bearing a carbonyl group adjacent to a bridgehead carbon
(Scheme 2). Hydrolysis of 9 followed by EDC-promoted
esterification with pentafluorophenol (PFP-OH) afforded the
activated ester, which was transformed into amide 13 upon
treatment with morpholin-3-one and KHMDS (45%, three
steps). The Heck precursor 14 was then obtained by treating
13 with LDA (ꢁ78 ꢀC, THF) followed by trapping of the
enolate anion with diethyl chlorophosphate. Whereas the
Heck cyclization of 11 led to the desired 3,8-diazabicy-
clo[3.2.1]octane 12 in modest yields, cyclization of deriva-
tive 14 was sluggish and provided the cyclized product 15
in low yield (31%) under optimized conditions (20 mol %
Pd(OAc)2, 40 mol % dppp, 1.1 equiv K2CO3 in DME,
Scheme 2). Presumably, the poor reactivity of 14 can be
attributed to the increased ring strain during the cyclization
due to incorporation of an sp2-hybridized carbon in the
tether. In all cases, the Heck cyclization required high cata-
lyst loadings (up to 40 mol % of Pd) and long reaction times
for complete conversion.

G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
10509
yield (95%). Several allylic substrates were prepared to ex-
amine the palladium-catalyzed allylic alkylation. Desilyla-
tion of 21 with TBAF followed by O-acylations provided
the allylic substrates 22a–c. Initially, the allylic carbonate
22a was examined due to the high reactivity of these deriva-
tives toward allylic alkylation.15 However, the carbonate was
found to be very unstable and decomposed during reaction
workup. Therefore, a more stable allylic benzoate 22b was
prepared and subjected to allylic alkylation conditions.
Treatment of 22b with Pd(OAc)2 and dppe in the presence
of base such as NaH or DBU in THF gave the cycloadduct
23 in 67 and 71% yields, respectively (Table 2, entries 1
and 2). Encouraged by these results, we then screened dif-
ferent allylic substrates and catalysts. Under the same condi-
tions, the pivaloate 22c afforded 23 in higher yields (entries 3
O
N
O
1. LiOH, MeOH, H2O
Boc
N
N
O
2. PFP-OH, EDC, CH2Cl2; 65%
3. KHMDS, morpholin-3-one, THF; 69%
Boc
MeO
O
9
13
O
LDA, -78
°
C, THF;
C; 30%
N
Boc
ClPO(OEt)2, -78
°
N
OPO(OEt)2
O
14
Boc
N
O
N
Pd(OAc)2 (20 mol%), dppp (40 mol%)
°
K2CO3, THF, 80 C, 13 h; 31%
O
15
Scheme 2.
Table 2. Optimization of allylic alkylations of malonates 22b and 22c
OCOR
Boc
Due to these limitations in route A, an alternative strategy
was considered in order to improve the synthesis of the 3,8-
diazabicyclo[3.2.1]octane system, and we turned our atten-
tion to the intramolecular allylic alkylation methodology
(Fig. 2, route B). Although inter- and intramolecular allylic
alkylations have been used extensively in complex natural
product synthesis,7h,12 the application of this chemistry to
the preparation of bridged carbo- and heterocyclic ring sys-
tems is less frequent.13 For our initial investigations, the
key precursors 22a–c were synthesized from the known alde-
hyde 16 in eight steps (Scheme 3).14 Aldehyde 16 underwent
N-Boc protection, NaBH4 reduction, O-TBS protection, and
ester hydrolysis to afford acid 19 in 39% overall yield. Sub-
sequently, acid 19 was coupled with sarcosine ethyl ester to
afford amide 20 using DCC and HOBt (54%). Treatment of
20 with LHMDS, followed by addition of ethyl chloroform-
ate (ꢁ78 ꢀC, THF) furnished the malonate 21 in excellent
N
O
[Pd]
O
N
N
Boc
CO2Et
N
CO2Et
CO2Et
EtO2C
22b; R = Ph
23
22c; R = t-Bu
Entry
R
Catalyst
Base
Time (h)
Yield (%)a
1
2
3
4
5
6
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
Pd(OAc)2/dppe
Pd(OAc)2/dppe
Pd(OAc)2/dppe
Pd(OAc)2/dppe
Pd(PPh3)4
NaH
DBU
NaH
DBU
DBU
DBU
1
4
1
4
4
2
67
71
80
83
95
98
Pd2dba3
a
Standard conditions: 10% palladium catalyst, 20% ligand, 1.5 equiv base,
THF (0.02–0.05 M) at 65 ꢀC.
CHO
CHO
Boc2O, DMAP
1. NaBH4, MeOH, CH2Cl2; 99%
MeO2C
MeO2C
CH2Cl2; 66%
2. TBSCl, Im, DMAP, CH2Cl2; 83%
N
H
N
Boc
17
16
OTBS
OTBS
LiOH, MeOH, H2O; 68%
MeO2C
HO2C
N
N
Boc
Boc
18
19
OTBS
OTBS
DCC, HOBt, CH2Cl2
O
°
O
LHMDS, THF, -78 C;
N
N
Boc
Boc
ClCO2Et, THF, -78 C; 95%
°
sarcosine ethyl ester; 54%
N
N
CO2Et
CO2Et
21
CO2Et
20
OCOR
1. TBAF, THF
2. ClCOR, DMAP
py, CH2Cl2
O
N
22a; R = OEt (unstable)
22b; R = Ph (71%)
Boc
N
CO2Et
22c; R = t-Bu (69%)
CO2Et
Scheme 3.

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G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
and 4). Furthermore, cycloadducts were formed in excellent
yields by employing Pd(PPh3)4 and Pd2dba3 (entries 5 and 6).
standard conditions (ClCOPh, DMAP, pyridine). The benzo-
ates were significantly more stable than the pivaloates and
could be purified by silica gel chromatography immediately
after workup. However, extended storage must be avoided
for intermediates 25–28 due to concomitant decomposition.
With the key precursors in hand, the palladium-catalyzed
allylic alkylations of 28a and 28b were studied (Scheme 5).
To our delight, intramolecular allylic alkylations of 28a
and 28b proceeded smoothly in the presence of 20 mol %
of Pd2dba3 and 1.5 equiv of DBU in THF at 65 ꢀC for
20 min to afford adducts 29a and 29b in excellent yields
(96 and 94%, respectively).
To test the efficacy of this new methodology for the prepara-
tion of the 3,8-diazabicyclo[3.2.1]octane core structure in
our natural product targets, we introduced the aromatic
dnacin A-ring into the malonate moiety (Scheme 4). DEPBT-
promoted16 coupling of 19 and N-benzylglycine ethyl ester
(24a) gave amide 25a in good yield (78%). In a similar man-
ner, amide 25b was prepared from the coupling of 19 and
N-(2,5-dimethoxy)benzylglycine ethyl ester 24b, which is
readily available from 2,5-dimethoxybenzylamine and ethyl
bromoacetate.17 At this stage, the A- and D-rings of the target
molecule are present in the cyclization precursor (Scheme 4).
Treatment of 25a and 25b with LHMDS followed by ethyl
chloroformate provided malonates 26a and 26b (76 and
88%, respectively). It is noteworthy that excess amounts of
LHMDS and ethyl chloroformate (6 equiv each) were neces-
sary in order to drive the reaction to completion. An unde-
sired acylation at C1 of the pyrrolidine was not observed in
either case, presumably due to steric hindrance around this
position. Desilylations of 26a and 26b provided alcohols
27a and 27b in excellent yields of 92 and 89%, respectively.
OBz
Boc
N
O
O
20 mol% Pd2dba3, 1.5 equiv DBU
N
Boc
N
N
°
THF, 65 C, 20 min
CO2Et
CO2Et
CO2Et
R
R
CO2Et
R
R
28a; R = H
28b; R = OMe
29a; R = H; 96%
29b; R = OMe; 94%
Scheme 5.
OTBS
R
O
3. Conclusion
N
1
Boc
NH
CO2Et
DEPBT, TEA
CH2Cl2
N
19
+
We have developed two alternative approaches for the con-
struction of the 3,8-diazabicyclo[3.2.1]octane ring system.
Whereas the initial intramolecular Heck cyclization ap-
proach suffered from poor yields, the palladium-catalyzed
intramolecular allylic alkylation provided an expedient route
to these bridged heterocycles. To the best of our knowledge,
this is the first time that a Pd-based route was used for the
synthesis of the diazabicyclo[3.2.1]octane ring system. In
addition, the functionalization of the 3,8-diazabicyclo-
[3.2.1]octane core obtained from the intramolecular allylic
alkylation protocol provides access to properly functional-
ized A,C,D-rings for the synthesis of dnacins and related
naphthyridinomycin alkaloids. Since the Pd-coupling strat-
egy is highly convergent and the two precursor segments
are readily available in enantiomerically pure form, this strat-
egy should lend itself to an asymmetric synthesis of the target
molecules. Further improvements of this methodology and
its application to natural product synthesis are currently in
progress and will be reported in due course.
R
CO2Et
R
R
24a; R = H
24b; R = OMe
25a; R = H; 78%
25b; R = OMe; 64%
OTBS
O
N
Boc
N
°
LHMDS, Et2O, -78 C;
TBAF, THF
CO2Et
ClCO2Et, Et2O, -78
°
C
R
CO2Et
R
26a; R = H; 76%
26b; R = OMe; 88%
OH
OBz
O
O
N
N
Boc
Boc
CO2Et
4. Experimental
4.1. General
N
N
ClCOPh, DMAP, py, CH2Cl2
CO2Et
R
R
CO2Et
R
CO2Et
R
All moisture-sensitive reactions were performed under an
atmosphere of argon and glassware was flame dried under
vacuum or dried in an oven at 150 ꢀC prior to use. DME,
THF, and Et2O were dried by distillation over Na/Benzophe-
none; Et3N and CH2Cl2 were dried by distillation over CaH2,
and KHMDS and LDA were prepared prior to use. Unless
stated otherwise, solvents or reagents were used without
further purification. Analytical thin layer chromatography
(TLC) was performed on pre-coated silica gel 60 F254
plates (particle size 0.040–0.055 mm, 230–400 mesh) and
27a; R = H; 92%
28a; R = H; 76%
27b; R = OMe; 89%
28b; R = OMe; 70%
Scheme 4.
The allylic pivaloate derivative of 27 was first chosen as
a substrate due to its high reactivity toward Pd-catalyzed
allylic alkylation. However, this pivaloate proved to be too
unstable and decomposed during isolation. Alternatively,
the allylic benzoates 28a and 28b were prepared using

G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
10511
visualization was accomplished with a 254 nm UV light and/
or by staining with KMnO4 reagent (1.5 g of KMnO4, 10 g of
K2CO3, and 1.25 mL of 10% NaOH in 200 mL water). NMR
spectra were recorded in CDCl3 (298 K) at either 300.1 MHz
(1H) or 75.5 MHz (13C) using a Bruker Avance 300 with
XWIN-NMR software. Chemical shifts (d) are reported in
parts per million (ppm) with the residual solvent peak used
as an internal standard. Data are reported as follows: chem-
ical shift, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br s¼broad singlet, br d¼broad
doublet, br t¼broad triplet, app.¼apparent), coupling con-
stants, and integration. Melting points were obtained using
a heating rate of 2 ꢀC minꢁ1 on a MelTemp melting point ap-
paratus with digital temperature reading and were reported
uncorrected. Microwave heating was performed in an Emrys
Optimizer single mode microwave reactor (Biotage) using
5 mL Emrys process vials.
1619, 1402, 1360, 1278, 1226, 1183, 1134 cmꢁ1; 1H NMR
(CDCl3) d 6.55, 6.40 (2br s, 1H), 6.50 (d, J¼2.9 Hz, 1H),
5.01, 4.93 (2br s, 1H), 4.54 (br s, 1H), 4.42–4.17 (m, 6H),
3.89, 3.85 (2d, J¼7.2 Hz, 1H), 3.85–3.65 (m, 1H), 2.78
(dd, J¼16.3, 10.1 Hz, 1H), 2.26 (br d, J¼15.8 Hz, 1H),
1.47 (s, 9H), 1.38 (tt, J¼7.1, 1.2 Hz, 6H); 13C NMR
(CDCl3) d 164.5, 134.1, 134.0, 129.5, 120.1 (2C), 106.1,
80.2, 68.0, 67.7, 65.4 (2C), 65.3, 64.4, 54.9, 42.2, 32.7,
28.3, 16.1, 16.0; EIMS m/z (intensity) 432 (M+, 6), 265
(31), 178 (91), 68 (100); HRMS (EI) m/z calcd for
C18H29N2O8P 432.1662, found 432.1647.
4.1.3. 6-Oxo-4-oxa-7,12-diazatricyclo[7.2.1.00,0]dodeca-
2,10-diene-12-carboxylic acid tert-butyl ester (12). Table
1, entry 7: Pd(OAc)2 (4.4 mg, 0.02 mmol), dppp (16 mg,
0.04 mmol), and K2CO3 (15 mg, 0.11 mmol) were added
to a solution of 11 (21 mg, 0.05 mmol) in DME (490 mL).
This mixture was deoxygenated using freeze thaw cycles un-
der vacuum and the reaction mixture was heated to 70 ꢀC for
8 h. After cooling to rt, the mixture was diluted with brine
(5 mL) and extracted with EtOAc (20 mLꢂ2). The com-
bined organic extracts were dried (MgSO4), concentrated,
and the residue was purified by chromatography on SiO2
(hexanes/EtOAc, 7:3 to 1:1) to afford 12 (7.3 mg, 53%) as
a colorless oily (2.4:1) mixture of rotamers: IR (neat)
4.1.1. 2-(3,5-Dioxomorpholin-4-ylmethyl)-2,3-dihydro-
pyrrole-1-carboxylic acid tert-butyl ester (10). To a mix-
ture of NaBH4 (499 mg, 13.2 mmol) and LiCl (560 mg,
13.2 mmol) in EtOH (18 mL) was added a solution of 2,3-
dihydropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-
methyl ester (9)9 (1 g, 4.4 mmol) in THF (18 mL) at 0 ꢀC.
The reaction mixture was stirred at rt for 10 h, quenched
with water (30 mL), and extracted with Et2O (100 mLꢂ2).
The combined organic extracts were washed with brine
(30 mL), dried (MgSO4), and concentrated to afford crude
alcohol (861 mg).
1
2977, 1693, 1673, 1390 cmꢁ1; H NMR (CDCl3) d 6.21–
6.15 (m, 2H), 6.12 (s, 1H), 4.84–4.64 (m, 2H), 4.39 (d,
J¼14.5 Hz, 1H), 4.22 (d, J¼14.5 Hz, 1H), 3.65 (d,
J¼12.8 Hz, 1H), 3.43 (br s, 1H), 1.43 (s, 9H); 13C NMR
(CDCl3) d 164.1, 152.3, 133.8, 131.9, 125.8, 116.7, 80.7,
67.6, 56.1, 55.2, 40.7, 40.1, 28.2; EIMS m/z (intensity) 278
(M+, 20), 222 (34), 57 (100); HRMS (EI) m/z calcd for
C14H18N2O4 278.1267, found 278.1265.
To a solution of this alcohol (804 mg, 4.04 mmol), morpho-
line-3,5-dione (464 mg, 4.04 mmol), and PPh3 (1.06 g,
4.04 mmol) in THF (20 mL) was added diazadiisopropyl di-
carbonate (801 mL, 4.04 mmol) over 30 min (syringe pump)
at rt. After 1 h, the solvent was removed in vacuo and the
residue was purified by chromatography on SiO2 (hexanes/
EtOAc, 8:2 to 6:4) to afford 10 (980 mg, 82%) as a pale yel-
low oily (6.3:1) mixture of rotamers: IR (neat) 2977, 1742,
Table 1, entry 8: Pd(OAc)2 (5.2 mg, 0.023 mmol), dppp
(19 mg, 0.046 mmol), and K2CO3 (16 mg, 0.108 mmol)
were added to a solution of 11 (21 mg, 0.049 mmol) in
DME (390 mL). The reaction mixture was stirred for 5 min
and heated in the microwave for 30 min (hold time) at
100 ꢀC. After cooling to rt, the mixture was diluted with
brine (5 mL) and extracted with EtOAc (20 mLꢂ2). The
combined organic extracts were dried (MgSO4), concen-
trated, and the residue was purified by chromatography on
SiO2 (hexanes/EtOAc, 7:3 to 1:1) to afford 12 (8.8 mg,
54%) as a colorless oil.
1
1692, 1390, 1366 cmꢁ1; H NMR (CDCl3) d 6.38 (br s,
1H), 4.96 (br s, 1H), 4.66 (br t, J¼10.0 Hz, 1H), 4.41–4.19
(m, 6H), 3.49 (dd, J¼12.1, 2.1 Hz, 1H), 2.87 (dd, J¼16.4,
10.1 Hz, 1H), 2.14 (br d, J¼16.4 Hz, 1H), 1.43 (s, 9H); 13C
NMR (CDCl3) d 169.7 (two peaks), 152.4, 129.4, 106.4,
80.2, 67.7 (two peaks), 53.8, 42.1, 33.6, 28.3; EIMS m/z (in-
tensity) 297 ([M+H]+, 5), 296 (M+, 40), 223 (27), 68 (100);
HRMS (EI) m/z calcd for C14H20N2O5 296.1372, found
296.1369.
4.1.4. tert-Butyl 2-(3-oxomorpholine-4-carbonyl)-2,3-
dihydropyrrole-1-carboxylate (13). To a solution of 2,3-
dihydropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester
2-methyl ester (9)9 (6.5 g, 28.6 mmol) in MeOH (153 mL)
was added LiOH (2.4 g, 57.2 mmol) followed by H2O
(39 mL) at 0 ꢀC and the mixture was stirred at rt for 3 h.
The reaction mixture was concentrated, and partitioned
between water (80 mL) and Et2O (50 mLꢂ2). The aqueous
layer was acidified to pH 2–4 with 3 N HCl and extracted
with Et2O (100 mLꢂ3 and 50 mLꢂ2). The combined ex-
tracts were dried (MgSO4) and concentrated to give the crude
acid. To a solution of the crude acid in CH2Cl2 (143 mL) was
added pentafluorophenol (5.26 g, 28.6 mmol) followed
by EDC (5.48 g, 28.6 mmol) at rt. Reaction mixture was
stirred for 4.5 h, quenched with H2O (100 mL), and extracted
with CH2Cl2. The combined organic layers were dried
(MgSO4), filtered, concentrated, and the residue was purified
4.1.2. 2-[5-(Diethoxyphosphoryloxy)-3-oxo-2,3-di-
hydro[1,4]oxazin-4-ylmethyl]-2,3-dihydropyrrole-1-car-
boxylic acid tert-butyl ester (11). To a solution of 10
(300 mg, 1.01 mmol) in THF (11 mL) was added LHMDS
(1.22 mL, 1.22 mmol) at ꢁ78 ꢀC. After 20 min, the reaction
mixture was allowed to warm to ꢁ30 ꢀC and stirred at this
temperature for 30 min. The mixture was cooled to ꢁ78 ꢀC
and a solution of diethyl chlorophosphate (176 mL,
1.22 mmol) in THF (3 mL) was added. After warming to
0 ꢀC, the reaction mixture was quenched with 5% aqueous
NH4OH (4 mL), extracted with Et2O (15 mLꢂ3), washed
with brine (5 mL), dried (MgSO4), and concentrated. The
residue was purified by chromatography on SiO2 (hexanes/
EtOAc, 7:3, 1% NEt3) to afford 11 (260 mg, 60%) as a pale
yellow oily mixture of rotamers: IR (neat) 2980, 1704,

10512
G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
by chromatography on SiO2 (hexanes/EtOAc, 9:1) to afford
the activated ester (10.89 g, 65%) as a colorless oily (6.3:1)
mixture of rotamers: IR (neat) 3120, 2982, 2936, 1800,
4.1.6. 8-Oxo-4-oxa-7,12-diazatricyclo[7.2.1.000]dodeca-
2,10-diene-12-carboxlic acid tert-butyl ester (15).
Pd(OAc)2 (3.1 mg, 0.014 mmol), dppp (11.4 mg,
0.028 mmol), and K2CO3 (19.2 mg, 0.139 mmol) were
added to a solution of 14 (30 mg, 0.069 mmol) in THF
(360 mL). This mixture was deoxygenated using freeze
thaw cycles under vacuum and heated to 80 ꢀC for 13 h. After
cooling to rt, the mixture was diluted with brine (5 mL) and
extracted with EtOAc (20 mLꢂ2). The combined organic ex-
tracts were dried (MgSO4) and concentrated, and the residue
was purified by chromatography on SiO2 (hexanes/EtOAc,
4:1 to 1:1) to afford 15 (6 mg, 31%) as a colorless oil: IR
(neat) 3400, 2978, 2935, 2975, 1705, 1459, 1379, 1311,
1
1716, 1522, 1458, 1398 cmꢁ1; H NMR (CDCl3) d 6.79,
6.67 (2s, 1H), 5.20–5.00 (m, 2H), 3.46–3.26 (m, 1H), 3.10–
2.92 (m, 1H), 1.58, 1.56 (2s, 9H); 13C NMR (CDCl3)
d 167.8, 167.5, 151.2, 151.0, 142.9 (2C), 142.8, 142.7,
141.4, 139.5 (2C), 139.4, 137.9, 136.2, 130.1, 104.7, 81.8,
81.6, 57.8, 57.6, 35.8, 34.4, 28.2, 28.0; EIMS m/z (intensity)
379 (M+, 20), 324 (60), 279 (75), 278 (65), 112 (62), 57 (100);
HRMS (EI) m/z calcd for C16H14F5NO4 379.0843, found
379.0845.
1
A solution of morpholine-3-one (288 mg, 2.84 mmol) in
THF (15 mL) was treated with KHMDS (5.7 mL,
2.84 mmol, 0.5 M in THF) dropwise at ꢁ78 ꢀC and stirred
for 1 h at this temperature. A solution of activated ester
(863 mg, 2.28 mmol) in THF (10 mL) was then added and
stirred for additional 0.5 h. Reaction mixture was quenched
with a saturated aqueous NH4Cl solution (10 mL), diluted
with CH2Cl2 (10 mL) at ꢁ78 ꢀC, and warmed to rt. Reaction
mixture was extracted with CH2Cl2 (100 mLꢂ2). The com-
bined extracts were dried (MgSO3), filtered, concentrated,
and the residue was purified by chromatography on SiO2
(hexanes/EtOAc, 7:3) to afford 13 (464 mg, 69%) as a color-
less foamy (1.7:1) mixture of rotamers: IR (neat) 2976, 2869,
1284, 1165, 1111, 1044 cmꢁ1; H NMR (CDCl3) d 6.35
(dd, J¼5.6, 2.4 Hz, 1H), 6.25 (dd, J¼5.6, 2.4 Hz, 1H), 5.98
(s, 1H), 4.88 (br s, 1H), 4.81 (d, J¼2.1 Hz, 1H), 4.11–3.96
(m, 2H), 3.90–3.86 (m, 1H), 3.56–3.50 (m, 1H), 1.46 (s,
9H); 13C NMR (CDCl3) d 162.3, 153.6, 132.2, 131.0,
124.5, 114.1, 81.5, 64.8, 64.3, 58.4, 38.9, 28.3; EIMS m/z (in-
tensity) 279 ([M+H]+, 5), 278 (M+, 33), 222 (45), 150 (34), 93
(46), 57 (100); HRMS (EI) m/z calcd for C14H18N2O4
278.1267, found 278.1270.
4.1.7. 4-Formyl-2,3-dihydropyrrole-1,2-dicarboxylic
acid 1-tert-butyl ester 2-methyl ester (17). To a solution of
4-formyl-2,3-dihydropyrrole-2-dicarboxylic acid 2-methyl
ester 1614 (1.04 g, 6.70 mmol) in CH2Cl2 (30 mL) was
added DMAP (82 mg, 0.67 mmol) and Boc2O (1.61 g,
7.37 mmol). The reaction mixture was stirred at rt for 10 h
and concentrated. The residue was purified by chromato-
graphy on SiO2 (hexanes/EtOAc, 7:3) to afford 17 (1.13 g,
66%) as a pale yellow oily (1:1) mixture of rotamers: IR
(neat) 3094, 2981, 2951, 1753, 1727, 1662, 1609,
1704, 1623, 1461, 1401, 1310, 1285, 1250, 1203, 1136 cmꢁ1
;
1H NMR (CDCl3) d 6.71, 6.57 (2 m, 1H), 5.63–5.50 (m, 1H),
4.93–4.87 (m, 1H), 4.38–4.22 (m, 2H), 4.02–3.73 (m, 4H),
3.33–3.20 (m, 1H), 2.62–2.48 (m, 1H), 1.49, 1.41 (2s, 9H);
13C NMR (CDCl3) d 173.6, 173.2, 169.2, 169.1, 151.3,
151.2, 130.3, 104.7, 104.6, 80.8, 80.4, 68.7 (2C), 63.9,
63.8, 61.4, 61.2, 43.7, 43.6, 35.8, 34.8, 28.3, 28.2; EIMS
m/z (intensity) 297 ([M+H]+, 7), 296 (M+, 27), 222 (34), 57
(100); HRMS (EI) m/z calcd for C14H20N2O5 296.1372,
found 296.1368.
1
1415 cmꢁ1; H NMR (CDCl3) d 9.57 (s, 1H), 7.63, 7.46
(2s, 1H), 4.79 (2dd, J¼12.2, 4.6 Hz, 1H), 3.78 (s, 3H),
3.20 (app. t, J¼15.1 Hz, 1H), 2.88 (2br dd, J¼15.1,
4.6 Hz, 1H), 1.53, 1.47 (2s, 9H); 13C NMR (CDCl3)
d 185.0, 170.6, 170.4, 150.0, 146.8, 146.5, 122.3, 122.1,
83.3, 83.0, 59.7, 59.1, 52.4, 31.2, 30.1, 27.8, 27.6, 27.3;
EIMS m/z (intensity) 255 (M+, 25), 155 (40), 96 (40), 57
(100); HRMS (EI) m/z calcd for C12H17NO5 255.1107,
found 255.1118.
4.1.5. tert-Butyl 2-(5-(diethoxyphosphoryloxy)-3,4-di-
hydro-2H-1,4-oxazine-4-carbonyl)-2,3-dihydropyrrole-
1-carboxylate (14). A solution of 13 (213 mg, 0.78 mmol)
in THF (8 mL) was treated with freshly prepared LDA
(1.6 mL, 1.01 mmol, 0.65 M in THF) at ꢁ78 ꢀC. The
resulting mixture was slowly warmed up to ꢁ40 ꢀC over
1 h, quenched with 5% aqueous NH4OH solution (5 mL),
and extracted with Et2O (20 mLꢂ3). The combined
organic layers were washed with brine, dried (MgSO3),
filtered, and concentrated. The crude product was purified
by chromatography on SiO2 (hexanes/EtOAc, 7:3 to 1:1,
1% NEt3) to afford 14 (100 mg, 30%) as a colorless foamy
(1.4:1) mixture of rotamers: IR (neat) 2978, 2933, 1702,
4.1.8. 4-Hydroxymethyl-2,3-dihydropyrrole-1,2-dicar-
boxylic acid 1-tert-butyl ester 2-methyl ester. A solution
of aldehyde 17 (95 mg, 0.370 mmol) in CH2Cl2 (1.5 mL)
was cooled to ꢁ78 ꢀC, treated with solid NaBH4 (30 mg,
0.740 mmol) and then methanol (700 mL) dropwise. The
reaction mixture was warmed to 0 ꢀC over a 2 h period,
quenched with saturated aqueous NH4Cl, and extracted
with CH2Cl2 (5 mLꢂ3). The combined organic layers
were washed with brine, dried (Na2SO4), filtered, and con-
centrated. The residue was purified by chromatography on
SiO2 (hexanes/EtOAc, 4:1 to 1:1) to afford the correspond-
ing alcohol (95 mg, 99%) as a clear oily (1:1) mixture of
rotamers: IR (neat) 3434, 2977, 2866, 1754, 1704, 1479,
1392, 1327, 1275, 1196, 1167, 1116, 1029 cmꢁ1 1H
;
NMR (CDCl3) d 6.71–6.70, 6.55–6.53 (2m, 1H), 6.47
(dd, J¼8.8, 3.5 Hz, 1H), 5.04–4.98 (m, 1H), 4.95–4.87
(m, 1H), 4.31–4.07 (m, 6H), 4.01–3.86 (m, 1H), 3.37–
3.30 (m, 1H), 3.23–3.03 (m, 1H), 2.71–2.63 (m, 1H),
1.46, 1.42 (2s, 9H), 1.37 (t, J¼7.1 Hz, 6H); 13C NMR
(CDCl3) d 171.2, 170.9, 151.2, 151.0, 130.3, 130.1, 126.1,
126.0, 125.1, 125.0, 124.9 (2C), 104.7, 80.3, 65.9, 65.8,
64.9, 64.8 (2C), 58.2, 57.8, 39.9, 39.5, 36.3, 34.8, 28.2,
28.1, 16.1, 16.0, 15.9; EIMS m/z (intensity) 433
([M+H]+, 12), 432 (M+, 50), 359 (30), 239 (100), 155
(69); HRMS (EI) m/z calcd for C18H29N2O8P 432.1662,
found 432.1656.
1
1419 cmꢁ1; H NMR (CDCl3) d 6.63, 6.51 (2br s, 1H),
4.72, 4.64 (2dd, J¼11.9, 5.2 Hz, 1H), 4.18 (app. s, 2H),
3.77 (s, 3H), 3.11 (app. q, J¼14.9 Hz, 1H), 2.69 (dt,
J¼16.8, 4.9 Hz, 1H), 1.49, 1.43 (2s, 9H); 13C NMR
(CDCl3) d 172.2, 172.0, 151.2, 126.0, 125.8, 119.6, 119.4,
80.8, 58.7, 58.5, 58.1, 52.2, 52.0, 35.4, 34.3, 28.0, 27.9;
EIMS m/z (intensity) 258 ([M+H]+, 11), 257 (M+, 75), 198

G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
10513
(50), 157 (62), 53 (100); HRMS (EI) m/z calcd for
C12H19NO5 257.1263, found 257.1275.
NEt3 (1.25 mL, 9.09 mmol) was added. The reaction mix-
ture was warmed to rt and stirred for 12 h, diluted with
EtOAc (40 mL), and filtered. The solid was washed with
EtOAc (5 mL). The combined filtrates were concentrated
and the residue was purified by chromatography on SiO2
(hexanes/EtOAc, 7:3) to afford 20 (734 mg, 54%) as a color-
less glassy mixture of rotamers: IR (neat) 2955, 2930, 2857,
4.1.9. 4-(tert-Butyldimethylsilanyloxymethyl)-2,3-dihy-
dropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-
methyl ester (18). To a solution of the above alcohol
(1.54 g, 5.99 mmol) in CH2Cl2 (25 mL) was added tri-
ethylamine (3.30 mL, 24.0 mmol) and DMAP (1.5 mg,
1.2 mmol) followed by a solution of TBSCl (1.08 g,
7.18 mmol) in CH2Cl2 (5 mL). The reaction mixture was
stirred at rt for 10 h, diluted with CH2Cl2 (30 mL), and
washed with brine. The organic layer was dried (MgSO4),
concentrated, and purified by chromatography on SiO2 (hex-
anes/EtOAc, 8:2) to afford 18 (1.84 g, 83%) as a pale yellow
oily (1:1) mixture of rotamers: IR (neat) 2954, 2931, 2858,
1749, 1705, 1669, 1423, 1366 cmꢁ1 1H NMR (CDCl3)
;
d 6.60, 6.48 (2s, 1H), 5.02, 4.94 (2dd, J¼11.9, 5.3 Hz,
1H), 4.84–4.66 (m, 1H), 4.29–4.11 (m, 4H), 4.01, 3.53
(2d, J¼17.3 Hz, 1H), 3.19–3.01 (m, 4H), 2.62–2.53 (m,
1H), 1.47, 1.43 (2s, 9H), 1.33–1.25 (m, 3H), 0.90, 0.89
(2s, 9H), 0.07, 0.06 (2s, 6H); 13C NMR (CDCl3) d 171.4,
171.0, 168.9, 168.7, 151.2, 126.1, 126.0, 125.7, 119.5,
118.8, 118.6, 80.3, 61.3, 60.8, 59.6, 57.0, 56.2, 51.3, 49.6,
49.5, 35.8, 35.7, 35.4, 35.2, 34.9, 34.0, 28.1, 27.9, 25.7,
18.1, 13.9, ꢁ5.5; EIMS m/z (intensity) 456 (M+, 25), 356
(45), 299 (35), 80 (100); HRMS (EI) m/z calcd for
C22H40N2O6Si 456.2656, found 456.2652.
2887, 1758, 1712, 1419, 1369 cmꢁ1 1H NMR (CDCl3)
;
d 6.55, 6.42 (2s, 1H), 4.70, 4.63 (2dd, J¼11.9, 5.1 Hz, 1H),
4.18 (app. s, 2H), 3.76 (s, 3H), 3.15–3.00 (m, 1H), 2.60 (dt,
J¼18.5, 4.8 Hz, 1H), 1.48, 1.43 (2s, 9H), 0.9, 0.89 (2s,
9H), 0.07, 0.06 (2s, 6H); 13C NMR (CDCl3) d 172.0, 171.7,
151.1, 151.0, 125.4, 125.1, 119.2 (two peaks), 80.5, 80.3,
59.3, 58.6, 58.0, 52.0, 51.8, 35.4, 34.3, 28.0, 27.8, 25.6,
18.0, ꢁ5.6; EIMS m/z (intensity) 371 (M+, 10), 271 (35),
228 (35), 80 (57), 75 (65), 57 (100); HRMS (EI) m/z calcd
for C18H33NO5Si 371.2128, found 371.2136.
4.1.12. 2-{[1-tert-Butoxycarbonyl-4-(tert-butyldimethyl-
silanyloxymethyl)-2,3-dihydro-1H-pyrrole-2-carbonyl]-
methylamino}malonic acid diethyl ester (21). A solution
of 20 (200 mg, 0.438 mmol) in THF (4 mL) was added to
a solution of LHMDS (1.05 mL, 1.05 mmol, 1 M in THF)
in THF (2 mL) at ꢁ78 ꢀC. After 10 min, ethyl chloroformate
(101 mL, 1.05 mmol) was added dropwise. The reaction
mixture was stirred for 2 h at the same temperature and
then quenched with a saturated aqueous NH4Cl solution
(5 mL) at this temperature. The mixture was warmed to rt
and partitioned between water (10 mL) and EtOAc
(50 mL). The aqueous layer was extracted with EtOAc
(10 mL). The combined organic layers were washed with
brine, dried (MgSO4), and concentrated. The residue was
purified by chromatography on SiO2 (hexanes/EtOAc, 7:3)
to afford 21 (221 mg, 95%) as a colorless glassy mixture of
rotamers: IR (neat) 2980, 2962, 2934, 2851, 1740, 1703,
4.1.10. 4-(tert-Butyldimethylsilanyloxymethyl)-2,3-dihy-
dropyrrole-1,2-dicarboxylic acid 1-tert-butyl ester (19).
To a solution of ester 18 (570 mg, 1.53 mmol) in methanol
(8 mL) was added LiOH (78 mg, 1.84 mmol) at 0 ꢀC, fol-
lowed by H2O (1.5 mL). The solution was warmed to rt,
stirred for 10 h, concentrated, redissolved in H2O (10 mL),
acidified to pH 2–4 with 1 N HCl, and extracted with Et2O
(10 mLꢂ3). The combined organic extracts were washed
with brine, dried (Na2SO4), filtered, and concentrated. The
residue was purified by chromatography on SiO2 (hexanes/
EtOAc, 3:1) to afford 19 (350 mg, 68%) as a clear oily mix-
ture of rotamers: IR (neat) 2955, 2931, 2858, 1712, 1421,
1
1670, 1487, 1421, 1367 cmꢁ1; H NMR (CDCl3) d 6.60,
1
1392, 1368, 1251, 1164 cmꢁ1; H NMR (CDCl3) d 6.56,
6.47 (2br s, 1H), 5.98, 5.91 (2s, 1H), 5.03, 4.96 (2d,
J¼11.9, 5.2 Hz, 1H), 4.34–4.10 (m, 6H), 3.23–3.04 (m,
4H), 2.58–2.48 (m, 1H), 1.47, 1.41 (2s, 9H), 1.36–1.24 (m,
3H), 0.89, 0.88 (2s, 9H), 0.06, 0.05 (2s, 6H); 13C NMR
(CDCl3) d 171.7, 171.5, 166.2, 166.2, 166.1, 165.9, 151.1,
151.1, 126.2, 125.9, 118.6, 80.4, 80.3, 61.8, 61.8, 60.2,
60.0, 59.5, 56.9, 56.4, 35.0, 34.1, 32.9, 32.7, 32.1, 31.2,
28.1, 27.8, 25.6, 18.1, 18.0, 13.8, ꢁ5.5; EIMS m/z (intensity)
528 (M+, 7), 428 (45), 212 (66), 154 (83), 80 (100); HRMS
(EI) m/z calcd for C25H44N2O8Si 528.2867, found 528.2866.
6.36 (2s, 1H), 4.76, 4.65 (2dd, J¼11.3, 5.4 Hz, 1H), 4.20
(app. s, 2H), 3.19–2.58 (m, 2H), 1.50, 1.44 (2s, 9H), 0.91,
0.90 (2s, 9H), 0.08, 0.07 (2s, 6H); 13C NMR (CDCl3)
d 176.7, 175.5, 152.1, 151.3, 125.3, 125.0, 120.3, 119.5,
81.5, 81.1, 59.5, 58.5, 58.2, 35.5, 34.0, 28.1, 28.0, 25.7,
25.5, 18.2, ꢁ3.9, ꢁ5.6; EIMS m/z (intensity) 357 (M+,
10), 312 (10), 255 (15), 180 (15), 82 (100); HRMS (EI)
m/z calcd for C17H31NO5Si 357.1972, found 357.1964.
4.1.11. 4-(tert-Butyldimethylsilanyloxymethyl)-2-(ethoxy-
carbonylmethylmethylcarbamoyl)-2,3-dihydropyrrole-1-
carboxylic acid tert-butyl ester (20). To a solution of ester
18 (1 g, 3.01 mmol) in MeOH (15 mL) was added LiOH
(190 mg, 4.52 mmol) followed by H2O (3 mL) at 0 ꢀC. The
reaction mixture was stirred at rt for 10 h, concentrated, and
partitioned between water (15 mL) and Et2O (15 mL). The
aqueous layer was acidified to pH 2–4 with 3 N HCl
(w1.7 mL) and extracted with Et2O (30 mLꢂ2). The com-
bined extracts were dried (MgSO4) and concentrated to
give the crude acid (804 mg). To a solution of this acid
(804 mg, 3.01 mmol), sarcosine ethyl ester hydrochloride
(461 mg, 3.01 mmol) and HOBt (4.05 mg, 3.01 mmol) in
CH2Cl2 (10 mL) was added a solution of DCC (743 mg,
3.6 mmol) in CH2Cl2 (5 mL) at ꢁ10 ꢀC. After 20 min,
4.1.13. 2-{[1-tert-Benzoyloxymethyl-l-tert-butoxy-
carbonyl-2,3-dihydro-1H-pyrrole-2-carbonyl]methyl-
amino}malonic acid diethyl ester (22b). To a solution of 21
(221 mg, 0.420 mmol) in THF (5 mL) was added TBAF
(840 mL, 0.840 mmol, 1.0 M in THF) at 0 ꢀC. The reaction
mixture was slowly warmed to rt, stirred for 10 h, and con-
centrated in vacuo. The residue was purified by chromato-
graphy on SiO2 (hexanes/EtOAc, 2:8 to 1:9) to afford the
alcohol (167 mg, 96%) as a colorless oil.
To a solution of this alcohol (167 mg) in CH2Cl2 (4 mL) was
added DMAP (10 mg, 0.081 mmol), pyridine (130 mL,
1.61 mmol), and benzoyl chloride (94 mL, 0.81 mmol) at
0 ꢀC. The reaction mixture was warmed to rt, stirred for

10514
G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
14 h, and diluted with CH2Cl2. The solution was washed with
saturated aqueous NH4Cl, dried (MgSO4), and concentrated
and the residue was purified by chromatography on SiO2
(hexanes/EtOAc, 8:2 to 6.5:3.5) to afford 22b (154 mg,
74%) as a colorless glassy mixture of rotamers: IR (neat)
2980, 2937, 1740, 1717, 1676, 1422, 1369 cmꢁ1; 1H NMR
(CDCl3) d 8.12–8.09, 8.03–8.00 (2m, 2H), 7.63–7.53 (m,
1H), 7.50–7.40 (m, 2H), 6.86, 6.72 (2s, 1H), 5.96–5.89 (2s,
1H), 5.08, 5.02 (2d, J¼11.9, 5.0 Hz, 1H), 4.94–4.79 (m,
2H), 4.31–4.18 (m, 4H), 3.32–3.02 (m, 4H), 2.68 (dd,
J¼16.0, 5.0 Hz, 1H), 1.48, 1.42 (2s, 9H), 1.33–1.23 (m,
3H); 13C NMR (CDCl3) d 171.7, 171.4, 166.4, 166.3, 166.2
(2C), 151.2 (2C), 133.5, 133.0, 130.5, 130.1, 130.0, 129.6,
128.4, 128.3, 113.2, 113.1, 81.2, 81.1, 62.1, 62.0, 61.2,
60.5, 57.2, 56.8, 35.8, 34.8, 33.1, 33.0, 28.3, 28.2, 28.0,
14.0; ESIMS m/z (intensity) 542 ([M+H]+, 15), 541 (M+,
60), 451 (45), 437 (100), 319 (60), 297 (85); HRMS (ESI)
m/z calcd for C26H34N2O9Na 541.2162, found 541.2180.
concentrated, and purified by chromatography on SiO2 (hex-
anes/EtOAc, 1:1) to afford 23 (18 mg, 67%) as a colorless
glassy solid: IR (neat) 2981, 2936, 1749, 1708, 1682, 1478,
1368 cmꢁ1; 1H NMR (CDCl3) d 5.45 (br s, 1H), 5.15 (br s,
2H), 4.70 (br d, J¼5.8 Hz, 1H), 4.38–4.16 (m, 4H), 2.97 (s,
3H), 2.75–2.60 (m, 2H), 1.44 (s, 9H), 1.33 (t, J¼7.1 Hz,
3H); 13C NMR (CDCl3) d 169.8, 166.0, 165.3, 152.4,
142.1, 112.3, 81.3, 76.3, 62.9, 62.4, 58.9 (br), 36.8, 34.3,
28.1, 13.9; EIMS m/z (intensity) 396 (M+, 10), 296 (41),
190 (85), 57 (100); HRMS (EI) m/z calcd for C19H28N2O7
396.1897, found 396.1895.
Table 2, entry 5: to a solution of 22c (45 mg, 0.09 mmol) in
THF (3 mL) were added DBU (21 mL, 0.14 mmol) and a
solution of Pd(PPh3)4 (10.4 mg, 9.03ꢂ10ꢁ3 mmol) in THF
(1.5 mL). The reaction mixture was heated at 65–75 ꢀC for
4 h, cooled to rt, and concentrated. The residue was purified
by chromatography on SiO2 (hexanes/EtOAc, 7:3) to afford
23 (34 mg, 95%) as a colorless glassy solid.
4.1.14. 2-{[l-tert-Butoxycarbonyl-4-(2,2-dimethylpropio-
nyloxymethyl-2,3-dihydro-1H-pyrrole-2-carbonyl]-
methylamino}malonic acid diethyl ester (22c). To
a solution of 21 (256 mg, 0.484 mmol) in THF (6 mL) was
added TBAF (968 mL, 0.968 mmol, 1.0 M in THF) at 0 ꢀC.
The reaction mixture was slowly warmed to rt, stirred for
10 h, and concentrated in vacuo. The residue was purified
by chromatography on SiO2 (hexanes/EtOAc, 2:8 to EtOAc)
to afford the alcohol (197 mg, 96%) as a colorless oil.
Table 2, entry 6: to a solution of 22c (36 mg, 0.072 mmol) in
THF (3 mL) were added DBU (16 mL, 0.108 mmol) and a so-
lution of Pd2dba3 (6.6 mg, 7.2ꢂ10ꢁ3 mmol) in THF (1 mL).
The reaction mixture was heated at 65–75 ꢀC for 2 h, cooled
to rt, and concentrated. The residue was purified by chroma-
tography on SiO2 (hexanes/EtOAc, 7:3) to afford 23 (29 mg,
98%) as a colorless glassy solid.
4.2. General procedure A for the coupling of acid 19 and
amines (24a and 24b)
To a solution of this alcohol (197 mg) in CH2Cl2 (5 mL) was
added DMAP (5.8 mg, 0.048 mmol), pyridine (95 mL
1.9 mmol), and pivaloyl chloride (117 mL, 0.95 mmol) at
0 ꢀC. The reaction mixture was warmed to rt, stirred for
14 h, and diluted with CH2Cl2. The product portion was
washed with a saturated aqueous NH4Cl solution, dried
(MgSO4), concentrated, and the residue was purified by chro-
matography on SiO2 (hexanes/EtOAc, 8:2 to 7:3) to afford
22c (170 mg, 72%) as a colorless glassy mixture of rotamers:
IR (neat) 2978, 2937, 2974, 1737, 1715, 1675, 1485,
4.2.1. 2-(Benzylethoxycarbonylmethylcarbamoyl)-4-
(tert-butyldimethylsilanyloxymethyl)-2,3-dihydropyr-
role-1-carboxylic acid tert-butyl ester (25a). To a solution
of acid 19 (123 mg, 0.369 mmol), N-benzylglycine ethyl
ester hydrochloride (170 mg, 0.738 mmol), and 3-(diethoxy-
phosphoryloxy)-1,2,3-benzotriazin-4(3H)-one
(170 mg,
0.554 mmol) in CH2Cl2 (3.7 mL) was added triethylamine
(205 mL, 1.48 mmol) dropwise at 0 ꢀC. The solution was
warmed to rt and stirred for 4 h. Saturated aqueous NaCl
(5 mL) was added and the mixture was extracted with EtOAc
(5 mLꢂ3). The combined organic layers were washed with
1 N HCl, 5% Na2CO3, H2O, and brine, dried (Na2SO4), fil-
tered, and concentrated. The residue was purified by chroma-
tography on SiO2 (hexanes/EtOAc, 8:1 to 4:1) to afford 25a
(153 mg, 78%) as a clear oily mixture of rotamers: IR (neat)
2955, 2930, 2857, 1748, 1706, 1674, 1421 cmꢁ1; 1H NMR
(CDCl3) d 7.37–7.28 (m, 5H), 6.62, 6.47 (2s, 1H), 5.13–
4.66 (m, 2H), 4.61–4.29 (m, 2H), 4.24–4.11 (m, 4H), 3.87–
3.54 (m, 1H), 3.13–2.90 (m, 1H), 2.66 (dt, J¼16.6, 4.8 Hz,
1H), 1.48 (s, 9H), 1.28–1.22 (m, 3H), 0.92–0.89 (m, 9H),
0.11–0.05 (m, 6H); 13C NMR (CDCl3) d 171.5, 168.9,
168.7, 151.3, 151.2, 136.2, 135.6, 128.7, 128.4, 128.3, 127.9
(2C), 127.1, 126.9, 118.7, 118.4, 80.6, 80.2, 59.5, 57.2, 56.6,
51.6, 51.3, 47.1, 47.0, 36.2, 35.9, 35.2, 34.6, 28.1 (2C), 25.7,
18.1, 13.9, ꢁ5.54; ESIMS m/z (intensity) 1087 ([2M+Na]+,
15), 555 ([M+Na]+, 100); HRMS (ESI) m/z calcd for
C28H44N2NaO6Si (M+Na) 555.2866, found 555.2826.
1
1414 cmꢁ1; H NMR (CDCl3) d 6.75, 6.62 (2s, 1H), 5.96,
5.89 (2s, 1H), 5.05, 4.98 (2dd, J¼11.9, 4.9 Hz, 1H), 4.67–
4.55 (m, 2H), 4.34–4.19 (m, 4H), 3.17, 3.14 (2s, 3H), 3.07
(d, J¼15.9 Hz, 1H), 2.58 (dd, J¼15.9, 4.7 Hz, 1H), 1.48,
1.45 (2s, 9H), 1.33–1.28 (m, 6H), 1.20, 1.19 (2s, 9H); 13C
NMR (CDCl3) d 178.0, 171.4, 171.2, 166.1, 166.0, 165.9,
165.8, 150.9, 150.8, 129.5, 129.2, 113.4, 113.3, 80.8, 61.9,
60.3, 60.0, 56.9, 56.5, 38.5, 35.4, 34.4, 32.9, 32.7, 28.0,
27.8, 26.9, 13.8; ESIMS m/z (intensity) 522 ([M+H]+, 31),
521 (M+, 100); HRMS (ESI) m/z calcd for C24H38N2O9Na
521.2475, found 521.2476.
4.1.15. 8-(3,3-Dimethylbutyryl)-3-methylene-4-oxo-3,8-
diazabicyclo[3.2.1]octane-2,2-dicarboxylic acid diethyl
ester (23). Table 2, entry 1: to a suspension of NaH (4 mg,
0.1 mmol) in THF (1 mL) was added a solution of 22b
(35 mg, 0.068 mmol) in THF (2.4 mL) at 0 ꢀC. After stirring
for 15 min at rt, the Pd-catalyst, preformed for 1 h at rt from
Pd(OAc)2 (1.5 mg, 6.8ꢂ10ꢁ3 mmol) and dppe (5.4 mg,
1.4ꢂ10ꢁ2 mmol) in THF (1 mL), was added, and the reaction
mixture was heated at 65–70 ꢀC for 1 h. After cooling to
0 ꢀC, the reaction mixture was quenched with a saturated
NH4Cl solution and extracted with EtOAc (20 mLꢂ2).
The combined organic extracts were dried (MgSO4),
4.2.2. 4-(tert-Butyldimethylsilanyloxymethyl)-2-[(2,5-di-
methoxybenzyl)ethoxycarbonylmethylcarbamoyl]-2,3-
dihydropyrrole-1-carboxylic acid tert-butyl ester (25b).
According to general procedure A, acid 19 (70 mg,

G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
10515
0.210 mmol), N-(2,5-dimethoxy)benzylglycine ethyl ester17
24b (59 mg, 0.231 mmol), 3-(diethoxyphosphoryloxy)-
1,2,3-benzotriazin-4(3H)-one (69 mg, 0.231 mmol), and
triethylamine (60 mL, 0.420 mmol) afforded ester 25b
(80 mg, 64%) as a pale yellow oily (2.2:1) mixture of ro-
tamers: IR (neat) 2955, 2931, 2856, 1748, 1705, 1674,
1502, 1463, 1421, 1391, 1366, 1279, 1250, 1224, 1166,
NMR (CDCl3) d 7.28, 7.10 (2s, 1H), 6.81–6.75 (m, 2H),
6.57, 6.43 (2s, 1H), 5.30, 5.23 (2s, 1H), 4.91–4.56 (m, 3H),
4.23–4.03 (m, 5H), 3.86 (s, 2H), 3.80, 3.79 (2s, 3H), 3.75
(s, 2H), 2.98 (app. t, J¼11.9 Hz, 1H), 2.65 (dt, J¼18.1,
4.5 Hz, 1H), 1.50, 1.44 (2s, 9H), 1.28–1.10 (m, 6H), 0.89,
0.88 (2br s, 9H), 0.05, 0.04 (2s, 6H); 13C NMR (CDCl3)
d 172.6, 172.3, 165.9, 165.7, 165.6, 165.5, 153.6, 151.3,
150.8, 150.4, 150.3, 126.2, 125.1, 124.6, 118.4, 118.3,
114.7, 114.2, 112.7, 111.9, 110.8, 110.6, 80.9, 80.0, 62.1,
61.7, 59.5, 56.7, 56.5, 55.6, 55.4, 45.8, 36.2, 34.3, 28.1,
28.0, 25.6, 18.0, 13.7, 13.6, 13.4, ꢁ5.6 (two peaks); ESIMS
m/z (intensity) 1351 ([2M+Na]+, 65), 687 ([M+Na]+, 100);
HRMS (ESI) m/z calcd for C33H52N2NaO10Si (M+Na)
687.3289, found 687.3286.
1
1114 cmꢁ1; H NMR (CDCl3) d 7.03 (s, 1H), 6.83–6.75
(m, 2H), 6.59, 6.47 (2br s, 1H), 5.06, 4.94 (2dd, J¼11.9,
5.5 Hz, 1H), 4.61–4.44 (m, 3H), 4.30–4.10 (m, 5H), 3.95–
3.48 (m, 7H), 3.10–2.86 (m, 1H), 2.73–2.60 (m, 1H), 1.45,
1.43 (2s, 9H), 1.29–1.22 (m, 3H), 0.89, 0.88 (2s, 9H), 0.06,
0.04 (2s, 6H); 13C NMR (CDCl3) d 171.9, 171.4, 169.0,
168.9, 153.7, 153.5, 151.4 (2C), 151.0, 126.3, 126.2, 124.9,
124.3, 119.7, 119.1, 118.5 (2C), 114.0, 113.7, 111.0, 110.8,
80.5, 80.0, 61.2, 60.7, 59.6, 56.8, 56.4, 55.5, 55.4, 49.2,
48.7, 47.2, 46.9, 36.0, 34.6, 28.1, 28.0, 25.7, 18.1, 13.9,
ꢁ5.5; ESIMS m/z (intensity) 1207 ([2M+Na]+, 85), 615
([M+Na]+, 100); HRMS (ESI) m/z calculated for
C30H48N2NaO8Si (M+Na) 615.3078, found 615.3049.
4.4. General procedure C for the TBS-deprotection of
malonates 26a and 26b
4.4.1. 2-[Benzyl-(1-tert-butoxycarbonyl-4-hydroxy-
methyl-2,3-dihydro-1H-pyrrole-2-carbonyl)amino]-
malonic acid diethyl ester (27a). Malonate 26a (100 mg,
0.165 mmol) was dissolved in THF (2 mL), cooled to 0 ꢀC,
and treated with TBAF (330 mL, 0.330 mmol, 1.0 M in
THF). The solution was warmed to rt, stirred for 10 h,
quenched with H2O, and extracted with CH2Cl2 (5 mLꢂ3).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The crude product was purified
by chromatography on SiO2 (hexanes/EtOAc, 2:1) to afford
27a (74 mg, 92%) as a clear oily mixture of rotamers: IR
(neat) 3468, 2980, 2934, 1741, 1702, 1497, 1421 cmꢁ1; 1H
NMR (CDCl3) d 7.44–7.31 (m, 5H), 6.68, 6.53 (2s, 1H),
5.38, 5.34 (2s, 1H), 4.95–4.84 (m, 1H), 4.81–4.61 (m, 2H),
4.27–4.04 (m, 5H), 3.93–3.84 (m, 1H), 3.09–2.68 (m, 2H),
1.53, 1.48 (2s, 9H), 1.27, 1.25 (2t, J¼7.1 Hz, 3H), 1.15 (t,
J¼7.1 Hz, 3H); 13C NMR (CDCl3) d 172.8, 172.5, 166.0,
165.9, 165.8, 151.5, 151.2, 136.0, 135.8, 128.6, 127.9,
127.6, 127.3, 126.9, 126.8, 118.6, 118.3, 81.3, 80.6, 62.0,
61.6, 61.5, 59.0 (2C), 57.4, 56.7, 50.5, 36.1, 34.7, 28.3,
28.2, 13.8 (2C), 13.7; ESIMS m/z (intensity) 1003
([2M+Na]+, 65), 985 (100), 513 ([M+Na]+, 40); HRMS
(ESI) m/z calcd for C25H34N2NaO8 (M+Na) 513.2213, found
513.2228.
4.3. General procedure B for the C-acylations of esters
25a and 25b with ethyl chloroformate
4.3.1. 2-{Benzyl[1-tert-butoxycarbonyl-4-(tert-butyl-
dimethylsilanyloxymethyl)-2,3-dihydro-1H-pyrrole-2-
carbonyl]amino}malonic acid diethyl ester (26a). To
a solution of ester 25a (270 mg, 0.507 mmol) in Et2O
(5 mL) was added freshly prepared LHMDS (3.00 mL,
3.04 mmol, 1 M in THF) dropwise at ꢁ78 ꢀC. After stirring
for 1 h at this temperature, ethyl chloroformate (290 mL,
3.04 mmol) was added dropwise. The reaction mixture was
stirred for 7 h at ꢁ78 ꢀC and then quenched with saturated
aqueous NH4Cl (5 mL) at this temperature. The mixture
was warmed to rt and extracted with CH2Cl2 (5 mLꢂ3).
The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The crude product was purified
by chromatography on SiO2 (hexanes/EtOAc, 8:1 to 4:1) to
afford 26a (233 mg, 76%) as a clear oily mixture of rotamers:
IR (neat) 2956, 2930, 2857, 1742, 1706, 1462, 1421 cmꢁ1
;
1H NMR (CDCl3) d 7.44–7.30 (m, 5H), 6.59, 6.43 (2s, 1H),
5.46, 5.40 (2s, 1H), 4.91–4.61 (m, 3H), 4.29–4.00 (m, 5H),
3.91–3.78 (m, 1H), 2.99, 2.81 (2app. t, J¼13.9 Hz, 1H),
2.68, 2.57 (2dd, J¼15.8, 4.8 Hz, 1H), 1.52, 1.47 (2s, 9H),
1.27, 1.25 (2t, J¼7.1 Hz, 3H), 1.15, 1.13 (2t, J¼7.1 Hz,
3H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) d 172.7,
172.4, 166.1, 166.0, 165.9, 165.8, 151.4, 151.1, 136.2,
135.9, 128.5, 127.8, 127.5, 126.8 (2C), 126.5, 126.3, 118.6,
118.3, 81.1, 80.3, 61.9, 61.8, 61.4, 61.2, 59.6, 57.3, 56.7,
50.5, 50.3, 36.1, 34.8, 28.2, 25.8, 18.2, 13.8 (two peaks),
13.6, ꢁ5.4; ESIMS m/z (intensity) 1232 ([2M+Na]+, 50),
628 ([M+Na]+, 100); HRMS (ESI) m/z calcd for
C31H48N2NaO8Si (M+Na) 627.3078, found 627.3078.
4.4.2. 2-[(1-tert-Butoxycarbonyl-4-hydroxymethyl-2,3-
dihydro-1H-pyrrole-2-carbonyl)-(2,5-dimethoxybenzyl)-
amino]malonic acid diethyl ester (27b). According to
general procedure C, malonate 26b (540 mg, 0.810 mmol)
and TBAF (1.6 mL, 1.62 mmol) afforded alcohol 27b
(396 mg, 89%) as a clear foamy mixture of rotamers: IR
(neat) 3479, 2978, 2837, 1741, 1702, 1501, 1465, 1420,
1391, 1368, 1301, 1282, 1223, 1178, 1115 cmꢁ1; 1H NMR
(CDCl3) d 7.26, 7.11 (2s, 1H), 6.84–6.76 (m, 2H), 6.67,
6.52 (2s, 1H), 5.21, 5.12 (2s, 1H), 4.93–4.54 (m, 3H), 4.32–
4.08 (m, 5H), 3.86 (s, 2H), 3.80 (s, 3H), 3.74 (s, 2H), 3.02
(app. t, J¼13.8 Hz, 1H), 2.88–2.74 (m, 1H), 1.50, 1.45 (2s,
9H), 1.28–1.12 (m, 6H); 13C NMR (CDCl3) d 172.4, 172.3,
165.5, 165.4, 165.3, 153.5, 151.2, 150.7, 150.4, 150.3,
126.7, 126.5, 124.8, 124.3, 118.6, 114.6, 114.2, 112.8,
112.1, 110.7, 110.6, 80.9, 80.0, 62.1, 61.7, 61.6, 58.4, 56.7,
56.5, 55.4, 55.3, 45.9, 35.9, 34.3, 27.9, 27.8, 13.5, 13.4,
13.3; ESIMS m/z (intensity) 1123 ([2M+Na]+, 35), 573
([M+Na]+, 100); HRMS (ESI) m/z calcd for C27H38N2NaO10
(M+Na) 573.2424, found 573.2433.
4.3.2. 2-{[1-tert-Butoxycarbonyl-4-(tert-butyldimethyl-
silanyloxymethyl)-2,3-dihydro-1H-pyrrole-2-carbonyl]-
(2,5-dimethoxybenzyl)amino}malonic acid diethyl ester
(26b). According to general procedure B, ester 25b
(550 mg, 0.927 mmol), LHMDS (6.5 mL, 6.49 mmol), and
ethyl chloroformate (620 mL, 6.49 mmol) afforded 26b
(540 mg, 88%) as a clear foamy mixture of rotamers: IR
(neat) 2955, 2932, 2856, 1742, 1705, 1501, 1464, 1421,
1391, 1301, 1281, 1251, 1266, 1223, 1165, 1114 cmꢁ1; 1H

10516
G. H. C. Woo et al. / Tetrahedron 62 (2006) 10507–10517
4.5. General procedure D for the O-benzylation of
alcohols 27a and 27b
THF (4 mL) was cooled to ꢁ78 ꢀC and treated with DBU
(19 mL, 0.126 mmol). The reaction mixture was warmed to
rt and then heated to 65 ꢀC for 20 min. Upon cooling, the
mixture was transferred to a short Celite column and washed
with CH2Cl2 (10 mL). The eluant was concentrated and
purified by chromatography on SiO2 (hexanes/EtOAc, 5:1
to 1:1) to afford 29a (38 mg, 96%) as a clear oil: IR (neat)
2981, 2935, 1748, 1690, 1392, 1368, 1310, 1254, 1166,
4.5.1. 2-[(4-Benzoyloxymethyl-1-tert-butoxycarbonyl-
2,3-dihydro-1H-pyrrole-2-carbonyl)benzylamino]-
malonic acid diethyl ester (28a). A solution of alcohol 27a
(375 mg, 0.765 mmol) and DMAP (9.3 mg, 0.0765 mmol)
in CH2Cl2 (8 mL) was cooled to 0 ꢀC and treated with pyri-
dine (250 mL, 3.06 mmol) followed by benzoyl chloride
(178 mL, 1.53 mmol). The solution was warmed to rt, stirred
for 3 h, quenched with saturated aqueous NH4Cl, and
extracted with CH2Cl2 (10 mLꢂ3). The combined organic
layers were washed with brine, dried (Na2SO4), and concen-
trated. The crude product was purified by chromatography
on SiO2 (hexanes/EtOAc, 5:1 to 2:1) to afford 28a
(346 mg, 76%) as a clear oily (6.7:1) mixture of rotamers:
IR (neat) 2980, 1713, 1452, 1418, 1368, 1269, 1107,
1
1107 cmꢁ1; H NMR (CDCl3) d 7.25 (dd, J¼7.2, 7.2 Hz,
2H), 7.15 (t, J¼7.2 Hz, 1H), 7.07 (d, J¼7.2 Hz, 2H), 5.48
(br s, 1H), 5.24 (br s, 2H), 4.80–4.65 (m, 3H), 4.23–3.86
(m, 4H), 2.78–2.67 (m, 2H), 1.48 (s, 9H), 1.19 (t,
J¼7.2 Hz, 3H), 1.12 (t, J¼7.1 Hz, 3H); 13C NMR (CDCl3)
d 170.2, 166.0, 165.7, 152.7, 142.2, 137.8, 128.0, 126.3,
125.8, 112.8, 81.3, 75.8, 62.6, 62.3, 59.1, 49.7, 36.6, 28.2,
13.6, 13.5; ESIMS m/z (intensity) 967 ([2M+Na]+, 100),
495 ([M+Na]+, 75); HRMS (ESI) m/z calcd for
C25H32N2NaO7 (M+Na) 495.2107, found 495.2088.
1
1070 cmꢁ1; H NMR (CDCl3) d 8.02 (d, J¼8.1 Hz, 2H),
7.55 (t, J¼7.4 Hz, 1H), 7.45–7.29 (m, 7H), 6.85, 6.69 (2s,
1H), 5.37, 5.35 (2s, 1H), 4.97–4.57 (m, 5H), 4.28–4.00 (m,
3H), 3.90–3.76 (m, 1H), 3.15–2.75 (m, 2H), 1.53, 1.49 (2s,
9H), 1.25, 1.23 (2t, J¼7.1 Hz, 3H), 1.12 (t, J¼7.1 Hz, 3H);
13C NMR (CDCl3) d 172.3, 172.0, 166.4, 166.1, 165.9,
165.8, 151.4, 151.0, 135.9, 135.7, 132.9, 130.5, 130.1,
130.0, 129.6, 128.7, 128.4, 128.3, 127.9, 127.6, 126.8,
126.7, 113.1, 112.8, 81.6, 81.0, 62.1, 62.0, 61.5, 61.4, 61.2
(two peaks), 57.5, 56.9, 50.5, 50.4, 36.5, 35.2, 28.3, 28.2,
13.9, 13.8, 13.7; ESIMS m/z (intensity) 635 ([M+K]+,
100), 617 ([M+Na]+, 65); HRMS (ESI) m/z calcd for
C32H38N2NaO9 (M+Na) 617.2475, found 617.2448.
4.6.2. 2-[(4-Benzoyloxymethyl-1-tert-butoxycarbonyl-
2,3-dihydro-1H-pyrrole-2-carbonyl)-(2,5-dimethoxy-
benzyl)amino]malonic acid diethyl ester (29b). According
to general procedure E, malonate 28b (310 mg, 0.473 mmol),
Pd2dba3 (87 mg, 0.0946 mmol), and DBU (107 mL,
0.709 mmol) afforded 29b (273 mg, 94%) as a clear foam:
IR (neat) 2981, 2939, 1747, 1689, 1499, 1466, 1433, 1391,
1368, 1309, 1277, 1254, 1219, 1164, 1111, 1047 cmꢁ1; 1H
NMR (CDCl3) d 6.67–6.57 (m, 2H), 6.37 (d, J¼2.7 Hz,
1H), 5.44 (br s, 1H), 5.22 (app. d, J¼12.4 Hz, 2H), 4.78 (br
d, J¼5.2 Hz, 1H), 4.63, 4.59 (AB q, J¼17.6 Hz, 2H), 4.15–
3.73 (m, 4H), 3.69 (s, 3H), 3.62 (s, 3H), 2.79–2.62 (m, 2H),
1.48 (s, 9H), 1.11–1.02 (m, 6H); 13C NMR (CDCl3)
d 169.9, 165.7, 165.3, 153.2, 152.4, 150.1, 142.0, 126.7,
112.7, 111.6, 111.5, 110.6, 81.0, 77.2, 75.6, 62.4, 62.1,
59.0, 55.4, 55.1, 44.9, 36.6, 28.0, 27.9, 13.3 (2C), 13.2;
ESIMS m/z (intensity) 1087 ([2M+Na]+, 100), 555
([M+Na]+, 72); HRMS (ESI) m/z calcd for C27H36N2NaO9
(M+Na) 555.2319, found 555.2314.
4.5.2. 2-[(4-Benzoyloxymethyl-1-tert-butoxycarbonyl-
2,3-dihydro-1H-pyrrole-2-carbonyl)-(2,5-dimethoxy-
benzyl)amino]malonic acid diethyl ester (28b). According
to general procedure D, alcohol 27b (390 mg, 0.707 mmol),
DMAP (9 mg, 0.0707 mmol), pyridine (63 mL, 0.778 mmol),
and benzoyl chloride (165 mL, 1.41 mmol) afforded 28b
(320 mg, 70%) as a clear foamy (4.8:1) mixture of rotamers:
IR (neat) 2979, 1712, 1681, 1501, 1451, 1392, 1368, 1318,
1270, 1223, 1163, 1108 cmꢁ1; 1H NMR (CDCl3) d 8.05 (d,
J¼7.5 Hz, 2H), 7.56 (t, J¼6.8 Hz, 1H), 7.43 (app. t, J¼
7.5 Hz, 2H), 7.27 (s, 0.5H), 7.12 (s, 0.5H), 6.84 (s, 0.5H),
6.81–6.74 (m, 2H), 6.69 (s, 0.5H), 5.27, 5.14 (2s, 1H),
4.95–4.57 (m, 5H), 4.23–4.01 (m, 3H), 3.85 (s, 2H), 3.79
(s, 3H), 3.74 (s, 2H), 3.08 (app. t, J¼13.8 Hz, 1H), 2.86 (dt,
J¼18.2, 4.7 Hz, 1H), 1.50, 1.47 (2s, 9H), 1.28–1.09 (m,
6H); 13C NMR (CDCl3) d 172.0, 171.8, 166.0, 165.6,
165.4, 165.3, 151.1, 150.4, 150.4, 150.2, 132.6, 130.1,
130.0, 129.7 (2C), 129.6, 129.2, 127.9, 124.7, 124.2, 114.6,
114.2, 112.8, 112.7, 112.6, 112.0, 110.7, 110.6, 81.1, 80.4,
62.2, 61.7, 61.6, 60.8, 56.9, 56.7, 55.4, 55.3, 45.9, 45.8,
36.4, 34.8, 27.9, 27.8, 13.6, 13.5, 13.3; ESIMS m/z (intensity)
1331 ([2M+Na]+, 20), 677 ([M+Na]+, 100); HRMS (ESI) m/z
calcd for C34H42N2NaO11 (M+Na) 677.2686, found
677.2662.
Acknowledgements
This work was supported by a grant from the National Insti-
tutes of Health (AI-33506). We thank Dr. Corey Hopkins for
the preparation of precursors and preliminary studies on the
Heck cyclization (Hopkins, C. R. PhD Thesis, University of
Pittsburgh, 2002).
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