Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids

Article abstract of DOI:10.1016/j.tet.2008.02.008

An intramolecular non-stabilized azomethine ylide dipolar cycloaddition was applied toward the first non-racemic synthesis of the fully oxygenated bridged pyrrolizidine core (45) of (+)-stemofoline (1) in 11 steps from a commercially available starting material.

Full text of DOI:10.1016/j.tet.2008.02.008

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3629e3641
www.elsevier.com/locate/tet
Application of an intramolecular dipolar cycloaddition
to an asymmetric synthesis of the fully oxygenated
tricyclic core of the stemofoline alkaloids
Ryan J. Carra a, Matthew T. Epperson b, David Y. Gin a,
*
a Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
b Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
Received 7 December 2007; received in revised form 1 February 2008; accepted 4 February 2008
Available online 7 February 2008
Abstract
An intramolecular non-stabilized azomethine ylide dipolar cycloaddition was applied toward the first non-racemic synthesis of the fully
oxygenated bridged pyrrolizidine core (45) of (þ)-stemofoline (1) in 11 steps from a commercially available starting material.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
16
Me
15
O
14
13
Me
O
6
Stemofoline (1, Fig. 1) was first isolated from the stems and
leaves of Stemona japonica by Irie and co-workers in 1970.1
X-ray crystallographic analysis of the hydrobromide salt of
1 revealed a pyrrolizidine ring system containing a two-carbon
bridge connecting C7 and C9a and an angular butyl side chain
at C3. Stemofoline also contains a spiroketal functionality at
C8 and a (Z)-olefin bridge from a tetrahydrofuran ring to a
conjugated butenolide moiety. The rigid pentacyclic core of
1 possesses three heteroatoms and seven contiguous stereo-
genic centers.2,3
5
11
12
O
O
OMe
OMe
8
18
7
20
21
Me
Me
Me
22
9
N
4
N
10
17
Me
Me
9a
3
O
O
19
1
2
Stemofoline (1)
Didehydrostemofoline (2)
(formerly Asparagamine A)
O
Me
Me
MeO
O
O
O
O
O
OMe
Me
Me
N
N
Me
O
O
OH
Of the 11 members of the stemofoline alkaloids which have
been reported to date,4e8 most differ only in the oxidation
state of the C3 chain (cf. 1 vs 2 or 3) or the (E)-configuration
versus (Z)-configuration of the C11eC12 alkene (1 vs 4).
Notably, Sekine and co-workers reported isolation of 2, which
they named asparagamine A, from the roots of Asparagus
racemosus.4 Later studies suggested that Sekine and co-
workers had actually isolated 2 from Stemona collinsae, which
19-(S)-Hydroxystemofoline (3)
Isostemofoline (4)
Figure 1. Selected stemofoline alkaloids.
is commonly confused with A. racemosus.5 Parallel studies
found 2 to be a major component of the ethanolic extracts of
S. collinsae,6 along with 19-(S)-hydroxystemofoline (3).5 Since
it appears to have no connection to the Asparagus plant genus, 2
is now commonly referred to as didehydrostemofoline.
The Thai plant from which Sekine and co-workers isolated
didehydrostemofoline (2) had traditionally been administered
to pregnant women to arrest premature uterine contractions,
and it was hypothesized that 2 was the active agent. Indeed,
* Corresponding author. Tel.: þ1 646 888 2555; fax: þ1 646 422 0416.
E-mail address: gind@mskcc.org (D.Y. Gin).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.008

3630
R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
(A)
2 was found not only to inhibit oxytocin-induced labor in
pregnant rats but also to exhibit dose-dependent in vivo activ-
ity against Kato-III human gastric carcinoma cells.9 More
recent explorations have focused on the potential of Stemona
alkaloids as natural insecticides, as 1e3 were found to exhibit
insecticidal and growth-inhibitory activity against the neonate
larvae of Spodoptera littoralis.5,10 Additionally, 1 and 2 have
shown insecticidal and antifeedant activity against the larvae
of the diamondback moth, a vegetable crop pest.6
Me
8
MeO2C
Me
O
OR
H
6
7
Tf2O;
F
OTf
OR
TMS
N
N
2
2
7
CO2Me
9
8
9
H
6
CO2Me
CO2Me
10
Dieckmann
6
O
9
8
N
7
2
CO2Me
Owing to their complex molecular architecture and intrigu-
ing biological activity, the stemofoline alkaloids have attracted
considerable synthetic attention,11e14 culminating in two race-
mic total syntheses.15,16 The studies reported herein comprise
the first non-racemic synthesis of the fully oxygenated tricy-
clic core of the stemofoline alkaloids.
10
Me
Me
OTf
TBSO
10
(B)
6
X
O
OR
H
O
8
Tf2O;
F
7
9
N
TMS
N
Me
2
9a
2. Results and discussion
OTf
RO
9
11
H
12
7
X
O
8
6
The utility of azomethine ylide [3þ2] cycloadditions for the
construction of highly substituted pyrrolidine rings has been
demonstrated by its implementation in the total synthesis of
numerous alkaloid natural products.17e21 Non-stabilized azo-
methine ylides are often generated by desilylation of iminium
salts derived from the O-activation of amides17,22 or the
N-alkylation of vinylogous imidates.23 In a related strategy,
we recently reported the use of N-(trimethylsilyl)methyl vinyl-
ogous amides as precursors to azomethine ylides suitable for the
preparation of substituted pyrrolizidines and indolizidines.13
This method proceeded by O-activation of (trimethylsilyl)-
methyl vinylogous amides such as 5 with trifluoromethanesul-
fonic (triflic) anhydride, followed by desilylation with the
anhydrous fluoride source tetrabutylammonium triphenyl-
difluorosilicate (TBAT) to generate azomethine ylides such as
6, which underwent [3þ2] cycloadditions with a variety of
electron-poor olefins (Scheme 1). Extension of the method to
an intramolecular mode led to a synthesis of the C2-deoxy
bridged pyrrolizidine core of the stemofoline alkaloids. Herein,
we disclose the synthesis of the fully oxygenated core of this
family of alkaloids, overcoming notable stereochemical imped-
ances in installing the C2 oxygen functionality.
Scheme 2. Proposed synthesis of C2 oxygenated bridged pyrrolizidine core of
the stemofoline alkaloids via inter- or intramolecular dipolar azomethine ylide
cycloaddition.
could then effect formation of the C8eC9 bond to provide
bridged pyrrolizidine 10, which directly maps onto the aza-
polycyclic substructure within stemofoline (1). Alternatively,
in an intramolecular cycloaddition approach to the target
(Scheme 2B), the more elaborate vinylogous amide 11, incor-
porating both the C2eOR group and the C6eC7 dipolarophile,
could be used to generate the azomethine ylide to trap the pen-
dant electron-poor olefin, providing the suitably functionalized
bridged pyrrolizidine 12 directly.
The intermolecular cycloadditioneDieckmann approach
began with ArndteEistert homologation of the readily avail-
able N-benzyloxycarbonyl-L-glutamic acid-5-methyl ester
(13),24 which provided bis(methyl ester) 14 (79%, Scheme
3). Selective a-hydroxylation of the ester distal to the N-func-
tionality with Davis oxaziridine 15 allowed for introduction
of the C2-oxygen group, providing the secondary alcohol 16
as a single diastereomer (52%). Hydrogenolysis of the benzyl
carbamate to the corresponding primary amine was followed
by lactamization in hot pyridine. Verification of stereochemis-
try was not conducted until silylation of the secondary alcohol
in 16 to provide the lactam 17 (95%, three steps), whose cis-
stereochemical relationship was established by an NOE signal
between the C9a and C2 methine proton resonances. However,
alkylation of 17 with (chloromethyl)trimethylsilane proceeded
with epimerization of the C2 stereocenter to yield its C2-R
configuration (60%).25 Nevertheless, this was anticipated to
be a welcome occurrence given that this C2 substituent can
be envisioned to serve as a favorable stereochemical determi-
nant in the key cycloaddition. Lactam 18 was converted to
the corresponding (E)-vinylogous amide 19 via a two-pot se-
quence involving thionation with Lawesson’s reagent (95%)
followed by condensation of the resulting thiolactam with
1-bromo-2-butanone and phosphine-mediated Eschenmoser
sulfide contraction (71%).
R
R
Z
Tf2O;
F
OTf
Z
R
O
H2C
N
OTf
TMS
N
N
5
6
7
Scheme 1. Dipolar cycloadditions of azomethine ylides derived from vinylo-
gous amides.
Two synthetic routes were explored (Scheme 2), one involv-
ing an intermolecular mode of the azomethine ylide cycloaddi-
tion and the other focusing on an intramolecular variant. In the
former (Scheme 2A), vinylogous amide 8, incorporating the
requisite C2eOR group, was envisioned to be a suitable precur-
sor to azomethine ylide formation, followed by endo-selective
[3þ2] cycloaddition with methyl acrylate to provide pyrrolizi-
dine 9. Subsequent transannular Dieckmann condensation

R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
3631
MeO2C
CO2H
MeO2C
MeO2C
azomethine ylide corresponding to 21, from the face opposite
to the C9a and C2 substituents in a sterically governed cyclo-
addition, led to the formation of pyrrolizidine 22.
a, b
d-f
CO2Me
NHCbz
NHCbz
13
14
O
NTs
c
15
Support for the rationale of C2-epimerization at the iminium
stage of the reaction was obtained by in situ NMR monitoring
of the O-triflation process of the trans-substituted vinylogous
amide 19 (Scheme 5) in CDCl3. Clean formation of the corre-
sponding vinylogous iminium triflate was observed within 1 h,
providing a 4:1 mixture of the trans- and cis-iminium triflates
20 and 21, respectively. After extending the NMR reaction
time to 4.5 h, further C2-epimerization occurred to provide
a 1:2 ratio of 20/21, signaling the thermodynamic preference
for the cis-iminium triflate 21. Unfortunately, all attempts to
modify the reaction conditions to avoid C2-epimerization, or
to effect C9a- or C3-epimerization via reversible b-elimination,
were unsuccessful.26 Notably, the non-epimerizeable C9a and
C3 substituents in the observed cycloadduct 22 occupied the
same face of the pyrrolizidine ring system; thus, it was not
possible to execute the transannular Dieckmann condensation
for the advancement of the synthesis to stemofoline (1).
O
Ph
OTBS
HN
2
9a
H
CO2Me
17
OH NHCbz
H
16
4.7%
MeO2C
g
Me
O
O
H
H
h, i
TMS
N
2
9a
OTBS
TMS
N
OTBS
18
H
19
H
MeO2C
MeO2C
Scheme 3. (a) EtOCOCl, Et3N, THF, 0 ꢀC; CH2N2, Et2O, ꢁ10 to 23 ꢀC, 87%;
(b) AgOAc, MeOH, 23 ꢀC, 91%; (c) LHMDS, THF, ꢁ78 ꢀC, 52%; (d) H2
(1 atm), 10% Pd/C, MeOH, 23 ꢀC; (e) pyridine, 100 ꢀC; (f) TBSCl, imidazole,
pyridine, 23 ꢀC, 95% (three steps); (g) NaH, TMSCH2Cl, DMF, 23 ꢀC, 60%;
(h) Lawesson’s reagent, PhMe, 65 ꢀC, 95%; (i) 1-bromo-2-butanone, 60 ꢀC;
Ph3P, Et3N, CH2Cl2, 23 ꢀC, 71%.
3.2%
3.5%
In accordance with the cycloaddition method previously
developed in our laboratories, vinylogous amide 19 was treated
sequentially with Tf2O and TBATin the presence of the dipolaro-
phile methyl acrylate (Scheme 4). It was anticipated that the
a-oriented C2eOTBS ether would bias approach of the
dipolarophile onto the b-face of the transient azomethine ylide
in an endo-transition state to provide the cycloadduct 9, origi-
nally depicted in Scheme 2A. Although a regio- and endo-selec-
tive cycloaddition ensued, it proceeded with an unexpected
stereochemical outcome with the isolation of the pyrrolizidine
22 (55%, Scheme 4). The structure of 22, a result consistent
with in situ C2-epimerization leading to a-approach of the dipo-
larophile, was verified by a battery of NMR techniques, most
notably NOE signals between the C9a and C2 methine protons,
as well as between the vinyl and C7 methine protons. It is likely
that the initially formed iminium triflate 20 underwent epimeri-
zation to the more thermodynamically stable cis-stereoisomer
21, in which both C9a and C2 substituents occupied pseudo-
equatorial orientations in an envelope conformation. Subse-
quent approach of the dipolarophile to the cis-substituted
Me
Me
Me
Tf2O, 23 °C,
CDCl3
H
H
O
OTBS
OTf
OTBS
OTf
OTBS
TMS
N
TMS
TfO
N
TMS
N
H
H
H
TfO
MeO2C
H
H
H
MeO2C
MeO2C
4.9%
19
20
21
4 : 1 (@ 1.0 hr)
1 : 2 (@ 4.5 hr)
Scheme 5. C2 epimerization of iminium triflate.
Given the stereochemical impasse in the intermolecular
cycloaddition approach, efforts then focused on the intramole-
cular cycloaddition strategy utilizing the novel vinylogous amide
11 (Scheme 2B). In this route, face-selective approach of the
pendant dipolarophile in the substrate 11 would be dictated
solely by the C9a-configuration irrespective of the stereoconfi-
guration at C2. Indeed, the success of a related intramolecular
cycloaddition in our earlier model study with a simplified sub-
strate devoid of C2-oxygenation boded well for this strategy.13
This approach began with N-methoxymethyl amide 23, avail-
able in three steps from N-benzyloxycarbonyl-L-glutamic
acid-5-methyl ester.13 Hydroxylation of the lithium enolate of
23 (Scheme 6) with Davis oxaziridine 15 provided the second-
ary alcohol 24 as a single diastereomer (57%). Hydrogenolysis
of the benzyl carbamate (Pd/C, H2) preceded spontaneous
lactamization to provide 25 (94%). Selective protection of the
secondary alcohol as a TBS ether (91%) was followed by
N-alkylation of the lactam with (chloromethyl)trimethylsilane,
which proceeded with C2 epimerization, providing a 7:1 mix-
ture (70% overall) favoring the trans-lactam isomer 27 over
its cis-counterpart 26, whose structure was verified by the pres-
ence of a C9aeC2 methine NOE. Lactam 27 was elaborated to
the (E)-vinylogous amide 29 by thionation with Lawesson’s
reagent (86%) and subsequent Eschenmoser sulfide contraction
(52%, Scheme 7). The dipolarophile was installed by treatment
of 29 with ethynylmagnesium chloride and trapping the
5.0%
Me
Me
H
MeO2C
H
O
Tf2O;
TBAT
OTf
OTBS
7
OTBS
TMS
N
2
3
9a
N
2
H
H
CO2Me
55%
22
19
H
H
MeO2C
5.4%
MeO2C
OTf
Me
Me
OTf
TMS
TBSO
H
2
2
N
TMS
CO2Me
9a
N
TBSO
20
CO2Me
9a
H
H
H
21
Scheme 4. Intermolecular dipolar azomethine ylide cycloaddition proceeds
with C2 epimerization.

3632
R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
Me
N
Me
N
EtS
EtS
Me
TfO
H2C
O
O
O
15
NTs
O
O
H
OMe
OMe
N
Ph
Me
2
2
a
X
MeO2C
23
MeO2C
OTBS
32
OTf
TBSO
N
9a
NHCbz
OH NHCbz
24
H
33
Path A X
b
Me
O
O
O
Et
2
OTBS
H
OTBS
H
OH
2
H
2
TMS
Me
N
TMS
N
HN
OTf
TMS
N
9a
9a
9a
OTf
OTBS
H
OTf
c, d
Me
F
OTf
OTBS
H
2
fast
+
2
H
O
H
O
H
O
TMS
N
9a
4.7%
Me
3.5%
N
N
N
H
O
OMe
OMe
26
OMe
31
H
O
34
25
EtS
27
(7 : 1 dr)
EtS
Scheme 6. (a) LHMDS, THF, ꢁ78 ꢀC, 57%; (b) 1 atm H2, 10% Pd/C, MeOH,
23 ꢀC, 94%; (c) TBSCl, imidazole, DMF, 23 ꢀC, 91%; (d) NaH, TMSCH2Cl,
DMF, 23 ꢀC, 70%.
Path B
X
EtS
Me
TfO
H2C
O
EtS
O
O
S
OTBS
N
2
Me
OTBS
H
OTBS
H
X
H
TMS
Me
N
TMS
Me
N
OTf
TBSO
N
a
9a
H
H
O
H
28
27
35
36
N
N
O
Scheme 8. C2 epimerization of iminium triflate.
OMe
OMe
b
Me
Given the likelihood of C2-epimerization in 31 imparting
a detrimental effect on the intramolecular cycloaddition strat-
egy, a modification of this approach was explored, employing
a cycloaddition substrate incapable of C2-epimerization. In this
context, iminium triflate 37 (Scheme 9), in which the C1 and
C2 oxygen substituents are tethered as part of a cis-fused
isopropylidene ketal, was pursued. In this intermediate, C2
epimerization would be prohibited as a result of formation
of a high-energy trans-fused [3.3.0]-bicyclo system.
Me
O
OTBS
H
O
OTBS
H
TMS
N
TMS
Me
N
c, d
H
O
H
O
EtS
N
30
OMe
29
Scheme 7. (a) Lawesson’s reagent, PhMe, 23 ꢀC, 86%; (b) 1-bromo-2-buta-
none, 60 ꢀC; Ph3P, Et3N, CH2Cl2, 23 ꢀC, 52%; (c) HCCMgCl, THF, 23 ꢀC;
(d) EtSH, Et3N, CH2Cl2, 23 ꢀC, 57% (two steps).
Me
EtS
Me
TfO
H2C
O
OTf
H
OTf
O
resulting reactive ynone with ethane thiol, providing the trans-
vinylogous thioester 30 (57%, two steps), thereby setting the
stage for an intramolecular azomethine ylide cycloaddition.
In this key reaction, clean formation of iminium triflate 31
was observed by 1H NMR upon treatment of vinylogous amide
30 with Tf2O; however, only an intractable mixture of prod-
ucts was obtained after addition of TBAT. Based on analogy
to the C2 epimerization of iminium triflate 20 (cf. Scheme
4), it is likely that fluoride anion, prior to desilylating iminium
triflate 31, acted as a general base to effect C2 epimerization,
resulting in a rapid equilibrium favoring iminium 34, in which
the C9a and C2 substituents would both occupy pseudo-equa-
torial positions in the envelope conformation. The observed
lack of productive cycloaddition might arise from the absence
of any appreciable quantity of ylide 32 that could react to form
the desired cycloadduct 33 (Scheme 8, path A). Rather, the
reaction was dominated by the cis-iminium 34, kinetically
favoring decomposition pathways over cycloaddition. This
outcome could be rationalized by an energetically disfavored
cycloaddition transition state 35 (Scheme 8, path B), incorpo-
rating severe C9aeC2 1,3-diaxial interactions, giving way to
other, as yet unidentified, unproductive reaction manifolds.
H
2
F
TMS
N
O
N
1
Me
Me
Me
Me
H
O
H
H
38
O
37
EtS
O
Scheme 9. Proposed dipolar azomethine ylide cycloaddition.
Synthesis of the newly designed cycloaddition substrate
began with the treatment of the commercially available (ꢁ)-2,3-
O-isopropylidine-D-erythronolactone (39) with (trimethylsilyl)-
methyl amine (97%, Scheme 10). ParikheDoering oxidation
of the resulting primary alcohol furnished a hemiaminal, which
was acetylated to afford aminal 40 (69%, two steps). Lewis
acid-promoted Mannich reaction between aminal 40 and the
trimethylsilylketene acetal of ethyl acetate (41, 72%) was fol-
lowed by hydrolysis of the resulting ester to provide carboxylic
acid 42 (96%). Thionation of the lactam functionality within
42 was accomplished by heating in the presence of Lawesson’s
reagent (95%), and the C8-carboxyl group in the resulting
product was then converted to the corresponding N-methoxy-
N-methyl amide 43 (62%). Eschenmoser sulfide contraction
(81%) and then treatment with ethynylmagnesium bromide

R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
3633
O
hydrogen atmosphere in the presence of Pd/C to provide pyrro-
lizidine 46 (89%), which contains the saturated butyl side chain
present in (þ)-stemofoline (1). Installation of a two-carbon
functionality at the equatorial position of C9 was accomplished
by enolate alkylation of ketone 46 with ethyl iodoacetate, fol-
lowed by C9 equilibration (DBU, heat), to afford the ethyl ester
47 (58%, two steps). Treatment of 47 with aqueous hydro-
chloric acid effected deprotection of the isopropylidene group
and hydrolysis of the ester (96%), providing a versatile interme-
diate 48 to explore strategies for butenolide construction and C8
ketal closure en route to the stemofoline alkaloids.
O
H
H
TMS
N
O
O
O
a-c
Me
Me
Me
Me
O
O
AcO
H
H
40
39
OTMS
d, e
EtO
CH2
41
S
O
H
H
TMS
N
O
f, g
TMS
N
O
Me
Me
Me
Me
O
O
H
H
O
H
H
Me
3. Conclusion
N
8
HO
O
43
42
OMe
A key observation regarding the dependence of a-stereo-
chemistry in the azomethine ylide generation and intramole-
cular dipolar cycloaddition of vinylogous amide 44 led to the
development of a successful non-racemic synthesis of the
bridged pyrrolizidine core of the stemofoline alkaloids.
h-j
Me
EtS
O
O
O
H
N
TMS
N
Me
k
Me
Me
OTf
O
4. Experimental section
H
H
O
O
EtS
O
Me Me
45
44
4.1. General
Scheme 10. (a) TMSCH2NH3Cl, Et3N, THF, 70 ꢀC, 97%; (b) SO3$Py, Et3N,
DMSO, 23 ꢀC; (c) Ac2O, pyridine, 23 ꢀC, 69% (two steps); (d) TMSOTf,
CH2Cl2, 23 ꢀC, 72%; (e) LiOH, THF, H2O, 23 ꢀC, 96%; (f) Lawesson’s
reagent, PhMe, 65 ꢀC, 95%; (g) MeONHMe$HCl, EDC, Et3N, CH2Cl2,
23 ꢀC, 62%; (h) 1-bromo-2-butanone; Ph3P, Et3N, CH3CN, 23 ꢀC, 81%; (i)
HCCMgBr, THF, 23 ꢀC; (j) EtSH, Et3N, CH2Cl2, 23 ꢀC, 58% (two steps);
(k) Tf2O, TBAT, CHCl3, ꢁ45 to 23 ꢀC, 71%.
All reactions were performed in flame-dried modified
Schlenk (Kjeldahl shape) flasks fitted with a glass stopper
under a positive pressure of argon, unless otherwise noted.
Air- and moisture-sensitive liquids and solutions were trans-
ferred via syringe. Organic solutions were concentrated by
rotary evaporation below 30 ꢀC. Flash column chromatography
was performed employing 230e400 mesh silica gel. Thin-layer
chromatography (analytical and preparative) was performed us-
ing glass plates pre-coated to a depth of 0.25 mm with 230e400
mesh silica gel impregnated with a fluorescent indicator
(254 nm). Infrared (IR) spectra were obtained using a Perkin
Elmer Spectrum BX spectrophotometer or a Bruker Tensor 27
referenced to a polystyrene standard. Data are presented as
the frequency of absorption (cmꢁ1). Proton and carbon-13
nuclear magnetic resonance (1H NMR or 13C NMR) spectra
were recorded on a Varian 400, a Varian 500, Varian Inova
500 NMR, or a Bruker Avance III spectrometer; chemical shifts
are expressed in parts per million (d scale) downfield from tet-
ramethylsilane and are referenced to the residual protium in
and ethane thiol (58%, two steps) installed the required func-
tionality for the proposed intramolecular [3þ2] azomethine
ylide cycloaddition. In this event, sequential treatment of 44
with triflic anhydride and TBAT provided the desired polycyclic
alkaloid 45 in 71% yield. This result comprises the first non-
racemic synthesis of the fully oxygenated bridged pyrrolizidine
core of the stemofoline alkaloids.
Further advancement of the cycloadduct 45 (Scheme 11) in-
volved reduction of its enol triflate functionality under a
EtS
EtS
O
O
9
N
a
N
Me
Me
the NMR solvent (CHCl3: d 7.26 for 1H NMR, d 77.16 for 13
C
OTf
NMR; CD3OD: d 3.30 for H NMR, d 49.00 for 13C NMR).
Data are presented as follows: chemical shift, multiplicity
(s¼singlet, br s¼broad singlet, d¼doublet, br d¼broad doublet,
t¼triplet, m¼multiplet and/or multiple resonances), coupling
constant in hertz (Hz), integration, assignment.
1
O
O
O
O
46
Me Me
Me Me
45
b, c
EtS
EtS
O
8
O
9
CO2H
d
CO2Et
N
4.2. Dimethyl 3-(benzyloxycarbonylamino)hexanedioate (14)
N
Me
Me
OH OH
To a stirred solution of 2-benzyloxycarbonylamino-pentane-
dioic acid-5-methyl ester (13) (4.45 g, 15.1 mmol, 1.0 equiv)
and triethylamine (2.31 mL, 16.5 mmol, 1.1 equiv) in tetra-
hydrofuran (80 mL) at ꢁ10 ꢀC was added via syringe ethyl
chloroformate (1.60 mL, 16.5 mmol, 1.1 equiv). The white
47
O
O
48
Me Me
Scheme 11. (a) 1 atm H2, 10% Pd/C, MeOH, 23 ꢀC, 89%; (b) LDA,
ICH2CO2Et, THF, HMPA, 0 ꢀC; (c) DBU, PhMe, 80 ꢀC, 58% (two steps);
(d) 2.5 M HCl, THF, 60 ꢀC, 96%.

3634
R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
suspension was stirred at ꢁ10 ꢀC for 1 h before the addition of
diazomethane (0.58 M solution in diethyl ether, 80 mL,
47 mmol, 3.1 equiv). The bright yellow suspension was stirred
at ꢁ10 ꢀC for 1 h and then 23 ꢀC for 3 h. The reaction mixture
was then diluted with diethyl ether (600 mL) and washed with
water (1ꢂ150 mL). The organic layer was separated, dried
over magnesium sulfate, filtered, and concentrated. Purification
by silica gel flash chromatography (50% hexanes in ethyl
acetate) provided 4-benzyloxycarbonylamino-6-diazo-5-oxo-
hexanoic acid methyl ester (4.21 g, 87%) as a yellow solid.
d 7.39e7.29 (m, 5H, Ph), 5.69 (br d, 1H, J¼9.3 Hz, NH), 5.10
(br s, 2H, CH2Ph), 4.28 (br m, 2H, CHOH and CHNHCbz),
3.77 (s, 3H, CO2CH3), 3.68 (s, 3H, CO2CH3), 3.54 (br d, 1H,
J¼4.7 Hz, OH), 2.66 (t, 2H, J¼5.7 Hz, CH2CO2CH3), 2.12
(ddd, 1H, J¼14.0, 10.2, 2.6 Hz, CH2CHNHCbz), 1.77 (ddd,
1H, J¼14.2, 10.9, 3.7 Hz, CH2CHNHCbz); 13C NMR
(126 MHz, CDCl3) d 174.7, 172.1, 156.8, 136.6, 128.8, 128.5,
128.4, 68.1, 67.3, 52.8, 52.1, 45.3, 38.8, 38.7; FTIR (neat film,
NaCl) 3368, 2954, 1734, 1732, 1692, 1531, 1439, 1251, 1217,
1111, 1056, 741 cmꢁ1
; HRMS (FAB) m/z: calcd for
C16H22N1O7 (MHþ) 340.1396, found 340.1395.
1
Rf¼0.43 (50% hexanes in ethyl acetate); H NMR (CDCl3)
d 7.37e7.30 (m, 5H, Ph), 5.60 (d, 1H, J¼9.2 Hz, NH), 5.50 (br
s, 1H, CHN2), 5.09 (s, 2H, CH2Ph), 4.31 (m, 1H, CH2CH2CH-
C(O)CHN2), 3.67 (s, 3H, CO2CH3), 2.46 (m, 1H, CH2CO2CH3),
2.39 (m, 1H, CH2CO2CH3), 2.16 (m, 1H, CH2CH2CHC-
(O)CHN2), 1.85 (m, 1H, CH2CH2CHC(O)CHN2); FTIR (neat
film, NaCl) 3327, 2953, 2110, 1731, 1640, 1525, 1440,
1336 cmꢁ1; HRMS (FAB) m/z: calcd for C15H18N3O5 (MHþ)
320.1246, found 320.1247. Silver acetate (320 mg, 1.92 mmol,
0.20 equiv) was added to a stirred solution of 4-benzyloxycar-
bonyl-amino-6-diazo-5-oxo-hexanoic acid methyl ester (3.07 g,
9.61 mmol, 1.0 equiv) in dry methanol (50 mL). The resulting
brown suspension was stirred at room temperature for 12 h.
The reaction mixture was then filtered through Celite and the
filtrate concentrated. Purification by silica gel flash chromatog-
raphy (40% ethyl acetate in hexanes) afforded 14 (2.83 g, 91%)
as a white powder. Rf¼0.48 (50% ethyl acetate in hexanes); 1H
NMR (500 MHz, CDCl3) d 7.39e7.29 (m, 5H, Ph), 5.32 (d, 1H,
J¼9.2 Hz, NH), 5.09 (m, 2H, CH2Ph), 4.01 (m, 1H, CH2-
CHNHCbz), 3.67 (s, 3H, CO2CH3), 3.66 (s, 3H, CO2CH3),
2.58 (t, 2H, J¼4.6 Hz, CH2CO2CH3), 2.41 (t, 2H, J¼7.2 Hz,
CH2CO2CH3), 1.89 (m, 2H, CH2CH2CO2CH3); 13C NMR
(126 MHz, CDCl3) d 173.8, 172.0, 156.1, 136.6, 128.7, 128.4,
128.3, 67.4, 66.9, 52.0, 47.9, 39.1, 31.0, 29.5; FTIR (neat film,
NaCl) 3350, 2953, 1737, 1691, 1530, 1438, 1245, 1056, 740,
699 cmꢁ1; HRMS (FAB): m/z calcd for C16H22N1O6 (MHþ)
324.1447, found 324.1446.
4.4. [4-(tert-Butyl-dimethyl-silanyloxy)-5-oxo-pyrrolidin-2-yl]-
acetic acid methyl ester (17)
A 100-mL round bottom flask containing 16 (419 mg,
1.23 mmol) and 10% palladium on carbon (ca. 20 mg) in
methanol (20 mL) was charged with hydrogen via balloon,
and the mixture was stirred at room temperature under the
hydrogen atmosphere for 2 h. The reaction mixture was then
filtered through Celite and concentrated. The crude amino al-
cohol was then dissolved in pyridine (20 mL) and heated to
100 ꢀC to effect lactamization. After 24 h, the solution was
cooled to room temperature, and tert-butyldimethylsilyl chlo-
ride (445 mg, 2.96 mmol, 2.4 equiv) and imidazole (419 mg,
6.15 mmol, 5.0 equiv) were added. The solution was stirred
at room temperature for 4 h and concentrated in vacuo. Purifi-
cation by silica gel flash chromatography (33% hexanes
in ethyl acetate) provided 17 (336 mg, 95%) as a white solid.
1
Rf¼0.40 (40% hexanes in ethyl acetate); H NMR (500 MHz,
CDCl3) d 6.44 (br s, 1H, NH), 4.25 (t, 1H, J¼7.5 Hz,
CH2CHOTBS), 3.84 (m, 1H, CH2CHN), 3.71 (s, 3H,
CO2CH3), 2.58 (m, 3H, CH2CO2CH3 and CH2CHOTBS),
1.66 (dt, 1H, J¼12.9, 7.3 Hz, CH2CHOTBS), 0.91 (s, 9H,
TBS tert-butyl), 0.16 (s, 3H, TBS methyl), 0.14 (s, 3H, TBS
methyl); 13C NMR (126 MHz, CDCl3) d 175.9, 172.1, 70.3,
52.2, 46.9, 41.2, 37.6, 26.0, 18.3, ꢁ4.34, ꢁ5.06; FTIR (neat
film, NaCl) 3234, 2949, 1738, 1694, 1473, 1391, 1296,
1252, 1162, 1056, 840, 777 cmꢁ1; HRMS (FAB) m/z: calcd
for C13H26N1O4Si1 (MHþ) 288.1631, found 288.1632.
4.3. 4-Benzyloxycarbonylamino-2-hydroxy-hexanedioic acid
dimethyl ester (16)
A stirred solution of 14 (776 mg, 2.40 mmol, 1.0 equiv) and
3-phenyl-2-(toluene-4-sulfonyl)oxaziridine (15) (990 mg,
3.60 mmol, 1.5 equiv) in dry tetrahydrofuran (30 mL) at
ꢁ78 ꢀC was added dropwise via cannula to a ꢁ78 ꢀC solution
of lithium bis(trimethylsilyl)amide (1.20 g, 7.20 mmol,
3.0 equiv) in tetrahydrofuran (20 mL). The bright yellow solu-
tion was then stirred at ꢁ78 ꢀC for 30 min and then quenched
by the addition of dry methanol (10 mL). The resulting solution
was then warmed to room temperature, diluted with diethyl
ether (500 mL), and washed with 1.0 N aqueous hydrochloric
acid (1ꢂ100 mL) and saturated aqueous sodium bicarbonate
(1ꢂ100 mL). The organic layer was then separated, dried over
magnesium sulfate, filtered, and concentrated. Purification by
silica gel flash chromatography (33% hexanes in ethyl acetate)
provided 16 (419 mg, 52%) as a colorless oil. Rf¼0.49 (33%
hexanes in ethyl acetate); 1H NMR (500 MHz, CDCl3)
4.5. [4-(tert-Butyl-dimethyl-silanyloxy)-5-oxo-1-
trimethylsilanylmethyl-pyrrolidin-2-yl]-acetic acid
methyl ester (18)
To a stirred solution of 17 (853 mg, 2.97 mmol, 1.0 equiv) in
dry dimethylformamide (8 mL) was added sodium hydride
(60% suspension in mineral oil, 131 mg, 3.26 mmol, 1.1 equiv)
and the resulting suspension was stirred at room temperature
for 1 h. Chloromethyltrimethylsilane (1.20 mL, 8.91 mmol,
3.0 equiv) was added and the resulting suspension was stirred
for an additional 3 h at room temperature. The reaction mixture
was diluted with deionized water (40 mL) and extracted with
diethyl ether (1ꢂ200 mL). The organic extracts were dried
over magnesium sulfate, filtered, and concentrated. Purification
by silica gel flash chromatography (20% ethyl acetate in
hexanes) provided 18 (666 mg, trans-isomer only, 60%) as a

R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
3635
colorless oil. Rf¼0.60 (33% ethyl acetate in hexanes); 1H NMR
d 6.01 (d, 1H, J¼5.2 Hz, CH2CHOTBS), 4.83 (s, 1H, vinyl
H), 3.67 (ddt, 1H, J¼9.4, 7.4, 4.4 Hz, CH2CHN), 3.34 (s, 3H,
CO2CH3), 2.88 (dd, 1H, J¼15.7, 9.4 Hz, CH2CO2CH3), 2.68
(dd, 1H, J¼15.8, 4.4 Hz, CH2CO2CH3), 2.45 (d, 1H,
J¼15.7 Hz, TMSCH2N), 2.41 (q, 2H, J¼7.4 Hz, CH2CH3),
2.28 (d, 1H, J¼15.7 Hz, TMSCH2N), 1.75 (m, 2H,
CH2CHOTBS), 1.27 (t, 3H, J¼7.4 Hz, CH2CH3), 1.01 (s, 9H,
TBS tert-butyl), 0.51 (s, 3H, TBS methyl), 0.40 (s, 3H, TBS
methyl), ꢁ0.078 (s, 9H, TMS); 13C NMR (126 MHz, C6D6)
d 195.2, 172.1, 163.3, 89.9, 72.4, 61.6, 51.5, 39.2, 37.8, 37.2,
36.1, 26.6, 18.8, 10.4, ꢁ0.79, ꢁ3.69, ꢁ5.00; FTIR (neat film,
NaCl) 2929, 2856, 1739, 1651, 1564, 1437, 1371, 1314, 1251,
1209, 1126, 1098, 853, 780 cmꢁ1; HRMS (FAB) m/z: calcd
for C21H42N1O4Si2 (MHþ) 428.2652, found 428.2651.
(400 MHz, CDCl3)
d
4.21 (dd, 1H, J¼7.4, 4.7 Hz,
CH2CHOTBS), 3.80 (ddt, 1H, J¼9.9, 7.3, 4.5 Hz, CH2CHN),
3.72 (s, 3H, CO2CH3), 3.20 (d, 1H, J¼15.4 Hz, TMSCH2N),
2.86 (dd, 1H, J¼15.8, 4.4 Hz, CH2CO2CH3), 2.49 (dd, 1H,
J¼15.7, 9.9 Hz, CH2CO2CH3), 2.46 (dt, 1H, J¼13.4, 7.3 Hz,
CH2CHOTBS), 2.33 (d, 1H, J¼15.3 Hz, TMSCH2N), 1.68
(dt, 1H, J¼13.4, 4.6 Hz, CH2CHOTBS), 0.90 (s, 9H, TBS
tert-butyl), 0.15 (s, 3H, TBS methyl), 0.14 (s, 3H, TBS methyl),
0.086 (s, 9H, TMS); 13C NMR (126 MHz, CDCl3) d 172.6,
171.6, 70.5, 54.4, 52.1, 38.9, 35.8, 32.3, 25.9, 18.4, ꢁ1.28,
ꢁ4.31, ꢁ5.05; FTIR (neat film, NaCl) 2954, 1740, 1699,
1437, 1363, 1324, 1251, 1199, 1152, 1127, 983, 840,
780 cmꢁ1; HRMS (FAB) m/z: calcd for C17H36N1O4Si2
(MHþ) 374.2183, found 374.2184.
4.7. 7-(tert-Butyl-dimethyl-silanyloxy)-5-methoxycarbonyl-
methyl-7a-(2-trifluoro-methanesulfonyloxy-but-1-enyl)-
hexahydro-pyrrolizine-1-carboxylic acid methyl
ester (22)
4.6. [4-(tert-Butyl-dimethyl-silanyloxy)-5-(2-oxo-butylidene)-
1-trimethylsilanyl-methyl-pyrrolidin-2-yl]-acetic acid methyl
ester (19)
To a stirred solution of 18 (666 mg, 1.78 mmol, 1.0 equiv) in
dry toluene (10 mL) at room temperaturewas added Lawesson’s
reagent (397 mg, 0.981 mmol, 0.55 equiv). The resulting yellow
suspension was stirred at 65 ꢀC for 1 h. The reaction mixture
was then concentrated in vacuo. Purification by silica gel
flash chromatography (16% ethyl acetate in hexanes) provided
[4-(tert-butyl-dimethyl-silanyloxy)-5-thioxo-1-trimethylsilanyl-
methyl-pyrrolidin-2-yl]-acetic acid methyl ester (657 mg, 95%)
To a stirred solution of 19 (9.2 mg, 0.022 mmol, 1.0 equiv)
in dichloromethane (500 mL) at room temperature was
added via syringe trifluoromethanesulfonic anhydride (4.0 mL,
0.024 mmol, 1.1 equiv). The resulting yellow solution was
stirred for 15 min at room temperature before the addition of
methyl acrylate (20 mL, 0.22 mmol, 10.0 equiv) and tetrabutyl-
ammonium triphenyldifluorosilicate (12.8 mg, 0.0237 mmol,
1.1 equiv). The resulting dark red solution was stirred at room
temperature for 1 h. The reaction mixture was then concentrated
in vacuo. Purification by silica gel flash chromatography (17%
ethyl acetate in hexanes) provided 22 (6.8 mg, 55%, (Z)-isomer
only) as a colorless oil. Rf¼0.50 (17% ethyl acetate in hexanes);
1H NMR (500 MHz, C6D6) d 6.08 (br s, 1H, vinyl H), 4.17 (dd,
1H, J¼11.2, 6.0 Hz, CH2CHOTBS), 3.39 (s, 3H, CO2CH3),
3.36 (s, 3H, CO2CH3), 3.19 (td, 1H, J¼12.1, 5.1 Hz, CH2N),
3.10 (m, 1H, CH2CHN), 2.90 (dd, 1H, J¼16.5, 5.3 Hz,
CH2CO2CH3), 2.80 (dd, 1H, J¼12.2, 6.1 Hz, CHCO2CH3),
2.66 (ddd, 1H, J¼12.1, 7.2, 1.0 Hz, CH2N), 2.62 (dd, 1H,
J¼16.5, 8.5 Hz, CH2CO2CH3), 2.24 (m, 1H, CH2CHOTBS),
2.13 (m, 1H, CH2CH3), 2.00 (m, 1H, CH2CH3), 1.92 (m,
1H, CH2CHN), 1.50 (m, 1H, CH2CHOTBS), 1.48 (m, 1H,
CH2CHN), 0.91 (s, 9H, TBS tert-butyl), 0.86 (t, 3H,
J¼7.3 Hz, CH2CH3), 0.066 (s, 3H, TBS methyl), ꢁ0.028 (s,
3H, TBS methyl); FTIR (neat film, NaCl) 2957, 1736, 1438,
1413, 1260, 1202, 1144, 1033, 978, 884, 779 cmꢁ1; HRMS
(FAB) m/z: calcd for C23H39N1O8F3S1Si1 (MHþ) 574.2118,
found 574.2119.
1
as a colorless oil. Rf¼0.59 (20% ethyl acetate in hexanes); H
NMR (500 MHz, CDCl3) d 4.53 (dd, 1H, J¼6.6, 2.9 Hz,
CH2CHOTBS), 4.10 (dddd, 1H, J¼9.8, 6.9, 4.1, 2.9 Hz,
CH2CHN), 3.94 (d, 1H, J¼14.7 Hz, TMSCH2N), 3.73 (s, 3H,
CO2CH3), 2.90 (dd, 1H, J¼15.9, 4.1 Hz, CH2CO2CH3),
2.83 (d, 1H, J¼14.7 Hz, TMSCH2N), 2.71 (dd, 1H, J¼15.9,
9.8 Hz, CH2CO2CH3), 2.43 (dt, 1H, J¼13.5, 6.9 Hz,
CH2CHOTBS), 1.79 (dt, 1H, J¼13.5, 2.9 Hz, CH2CHOTBS),
0.90 (s, 9H, TBS tert-butyl), 0.20 (s, 3H, TBS methyl), 0.18
(s, 3H, TBS methyl), 0.14 (s, 9H, TMS); 13C NMR (126 MHz,
CDCl3) d 198.8, 171.3, 80.0, 62.8, 52.3, 38.7, 38.4, 36.7, 25.9,
18.3, ꢁ0.63, ꢁ3.95, ꢁ5.03; FTIR (neat film, NaCl) 2953,
1740, 1492, 1437, 1363, 1319, 1251, 1199, 1153, 1129, 1091,
842, 780 cmꢁ1; HRMS (FAB) m/z: calcd for C17H36N1O3S1Si2
(MHþ) 390.1954, found 390.1955. To a stirred solution of
[4-(tert-butyl-dimethyl-silanyloxy)-5-thioxo-1-trimethylsila-
nylmethyl-pyrrolidin-2-yl]-acetic acid methyl ester (96.2 mg,
0.247 mmol, 1.0 equiv) in dichloromethane (2 mL) was added
1-bromo-2-butanone (30 mL, 0.27 mmol, 1.1 equiv). The color-
less solution was then concentrated invacuo and the resulting oil
was heated at 60 ꢀC for 20 min. The resulting white solid was
dissolved in dichloromethane (2 mL), and triphenylphosphine
(71.1 mg, 0.271 mmol, 1.1 equiv) and triethylamine (40 mL,
0.27 mmol, 1.1 equiv) were added at room temperature. The re-
sulting yellow solution was then stirred for 1 h at room temper-
ature and concentrated. Purification by silica gel flash
chromatography (13% ethyl acetate in benzene) provided 19
(75.3 mg, 71%, (E)-isomer only) as a white solid. Rf¼0.32
4.8. Iminium triflates 20 and 21
To a stirred solution of 19 (19.3 mg, 0.0450 mmol, 1.0 equiv)
in CDCl3 (1 mL, freshly distilled from CaH2 under N2 at atmo-
spheric pressure) at room temperature was added via syringe
trifluoromethanesulfonic anhydride (9.0 mL, 0.050 mmol,
1.1 equiv). The resulting pale orange solution was stirred for
1 h at room temperature. Examination of the reaction mixture
1
1
(15% ethyl acetate in hexanes); H NMR (500 MHz, C6D6)
by H NMR revealed both 20 and 21 (>95% conversion, as

3636
R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
a 4:1 mixture of 20/21), each formed as the (Z)-isomer
with respect to the enol triflate double bond. The solution was
then stirred at room temperature for an additional 4.5 h. Exam-
1390, 1254, 1111, 1053, 996, 741 cmꢁ1; HRMS (FAB) m/z:
calcd for C17H25N2O7 (MHþ) 369.1662, found 369.1663.
1
ination of the reaction mixture by H NMR revealed both 20
4.10. 2-(4-Hydroxy-5-oxo-pyrrolidin-2-yl)-N-methoxy-N-
methyl-acetamide (25)
and 21 (>95% conversion, as a 1:2 mixture of 20/21). Iminium
triflate 20: 1H NMR (500 MHz, CDCl3) d 7.12 (br s, 1H, vinyl
H), 5.55 (dd, 1H, J¼6.9, 3.2 Hz, CH2CHOTBS), 4.61 (ddt,
1H, J¼9.1, 7.5, 3.8 Hz, CH2CHN), 4.29 (d, 1H, J¼14.5 Hz,
TMSCH2N), 3.78 (s, 3H, CO2CH3), 3.40 (d, 1H, J¼14.5 Hz,
TMSCH2N), 3.23 (dd, 1H, J¼16.9, 4.2 Hz, CH2CO2CH3),
2.91 (dd, 1H, J¼17.0, 9.1 Hz, CH2CO2CH3), 2.86 (dt, 1H,
J¼13.9, 7.5 Hz, CH2CHOTBS), 2.73 (m, 1H, CH2CH3), 2.61
(m, 1H, CH2CH3), 2.05 (dt, 1H, J¼13.8, 3.3 Hz,
CH2CHOTBS), 1.32 (t, 3H, J¼7.3 Hz, CH2CH3), 0.89 (s, 3H,
TBS methyl), 0.88 (s, 9H, TBS tert-butyl), 0.86 (s, 3H, TBS
A suspension of 24 (1.25 g, 3.39 mmol) and 10% palladium
on carbon (ca. 200 mg) in methanol (50 mL) was charged with
hydrogen via balloon, and the mixture was stirred at room tem-
perature under the hydrogen atmosphere for 1 h. The reaction
mixture was then filtered through Celite and concentrated at
35 ꢀC using a rotary evaporator. Purification by silica gel flash
chromatography (10% methanol in ethyl acetate) provided 25
(642 mg, 94%) as a white solid. Rf¼0.21 (10% methanol in ethyl
1
acetate); [a]2D4 þ4.3 (c 1.24, CHCl3); H NMR (500 MHz,
1
methyl), 0.26 (s, 9H, TMS). Iminium triflate 21: H NMR
CDCl3) d 6.80 (br s, 1H, NH), 4.33 (t, 1H, J¼8.6 Hz,
CH2CHOH), 4.15 (br s, 1H, OH), 3.89 (br m, 1H, CH2CHN),
3.69 (s, 3H, NOCH3), 3.18 (s, 3H, NCH3), 2.86 (br d, 1H, J¼
16.1 Hz, CH2C(O)N(CH3)OCH3), 2.66 (br m, 1H, CH2CHOH),
2.54 (dd, 1H, J¼16.8, 9.7 Hz, CH2C(O)N(CH3)OCH3), 1.70
(dt, 1H, J¼12.9, 8.3 Hz, CH2CHOH); 13C NMR (126 MHz,
CDCl3) d 177.9, 172.2, 89.3, 61.2, 52.7, 38.5, 36.1, 31.4;
FTIR (neat film, NaCl) 3391, 2930, 1698, 1643, 1434, 1393,
1304, 1181, 1118, 993 cmꢁ1; HRMS (FAB) m/z: calcd for
C8H15N2O4 (MHþ) 203.1032, found 203.1033.
(500 MHz, CDCl3) d 6.50 (br s, 1H, vinyl H), 5.41 (t, 1H,
J¼7.6 Hz, CH2CHOTBS), 4.89 (dtd, 1H, J¼8.9, 7.5, 4.8 Hz,
CH2CHN), 4.18 (d, 1H, J¼14.7 Hz, TMSCH2N), 3.77 (s,
3H, CO2CH3), 3.39 (d, 1H, J¼14.7 Hz, TMSCH2N), 3.11 (dd,
1H, J¼16.5, 4.8 Hz, CH2CO2CH3), 2.86 (dt, 1H, J¼12.9,
7.5 Hz, CH2CHOTBS), 2.78 (dd, 1H, J¼16.5, 8.9 Hz,
CH2CO2CH3), 2.77 (m, 1H, CH2CH3), 2.62 (m, 1H,
CH2CH3), 1.89 (dt, 1H, J¼12.9, 7.8 Hz, CH2CHOTBS), 1.30
(t, 3H, J¼7.4 Hz, CH2CH3), 1.01 (s, 3H, TBS methyl), 0.89
(s, 9H, TBS tert-butyl), 0.85 (s, 3H, TBS methyl), 0.31 (s, 9H,
TMS).
4.11. Lactams 26 and 27
4.9. 4-Benzyloxycarbonylamino-2-hydroxy-5-(methoxy-
methyl-carbamoyl) pentanoic acid methyl ester (24)
To a stirred solution of 25 (642 mg, 3.17 mmol, 1.0 equiv)
and imidazole (1.08 g, 15.9 mmol, 5.0 equiv) in anhydrous di-
methylformamide (30 mL) at room temperature was added
tert-butyldimethylsilyl chloride (957 mg, 6.35 mmol, 2.0
equiv). The resulting solution was stirred at room temperature
for 24 h. The reaction mixture was then diluted with deionized
water (250 mL) and extracted with diethyl ether (2ꢂ300 mL).
The organic extracts were then combined, dried over magne-
sium sulfate, filtered, and concentrated. Purification by silica
gel flash chromatography (ethyl acetate) provided 2-[4-(tert-
butyl-dimethylsilanyloxy)-5-oxo-pyrrolidin-2-yl]-N-methoxy-
N-methyl acetamide (913 mg, 91%) as a colorless oil. Rf¼
0.43 (ethyl acetate); [a]2D4 þ15.3 (c 0.50, CHCl3); 1H
NMR (500 MHz, CDCl3) d 6.45 (br d, 1H, J¼8.6 Hz, NH),
4.23 (t, 1H, J¼7.6 Hz, CH2CHOTBS), 3.83 (br m, 1H,
CH2CHN), 3.65 (s, 3H, NOCH3), 3.15 (s, 3H, NCH3), 2.76
(dd, 1H, J¼16.9, 2.6 Hz, CH2C(O)N(CH3)OCH3), 2.56 (m,
2H, CH2C(O)N(CH3)OCH3 and CH2CHOTBS), 1.66 (dt, 1H,
J¼13.0, 7.2 Hz, CH2CHOTBS), 0.88 (s, 9H, TBS tert-butyl),
0.13 (s, 3H, TBS methyl), 0.11 (s, 3H, TBS methyl); 13C
NMR (126 MHz, CDCl3) d 175.7, 172.1, 70.3, 61.4, 46.9,
39.4, 37.6, 32.1, 25.9, 18.4, ꢁ4.4, ꢁ5.1; FTIR (neat film,
NaCl) 3293, 2954, 1715, 1660, 1472, 1390, 1300, 1252, 1151,
1054, 997, 861, 839 cmꢁ1; HRMS (FAB) m/z: calcd for
C14H29N2O4Si1 (MHþ) 317.1897, found 317.1898. To a stirred
solution of 2-[4-(tert-butyl-dimethylsilanyloxy)-5-oxo-pyrroli-
din-2-yl]-N-methoxy-N-methyl acetamide (215 mg, 0.679 mmol,
1.0 equiv) in dry dimethylformamide (6 mL) was added sodium
hydride (60% suspension in mineral oil, 30.0 mg, 0.747 mmol,
To a stirred solution of 23 (2.51 g, 7.36 mmol, 1.0 equiv)
and 3-phenyl-2-(toluene-4-sulfonyl)-oxaziridine (15) (3.04 g,
11.0 mmol, 1.5 equiv) in dry tetrahydrofuran (80 mL) at
ꢁ78 ꢀC was added dropwise via cannula a cold (ꢁ78 ꢀC) solu-
tion of lithium bis(trimethylsilyl)amide (2.71 g, 16.2 mmol,
2.2 equiv) in tetrahydrofuran (80 mL). The bright yellow solu-
tion was then stirred at ꢁ78 ꢀC for 20 min and then quenched
by the cannula addition of a solution of camphor sulfonic acid
(6.67 g, 29.4 mmol, 4.0 equiv) in tetrahydrofuran (40 mL).
The resulting solution was then warmed to room temperature,
diluted with diethyl ether (500 mL), and washed with 1.0 N
aqueous hydrochloric acid (1ꢂ100 mL) and saturated aqueous
sodium bicarbonate (1ꢂ100 mL). The organic layer was then
separated, dried over magnesium sulfate, filtered, and concen-
trated. Purificationbysilicagelflashchromatography(ethylace-
tate) provided 24 (1.50 g, 57%) as a white solid. Rf¼0.45 (ethyl
acetate); [a]2D4 ꢁ16.5 (c 1.08, CHCl3); 1H NMR (CDCl3)
d 7.41e7.30 (m, 5H, Ph), 6.13 (br d, 1H, J¼8.6 Hz, NH), 5.10
(br s, 2H, CH2Ph), 4.28 (br m, 2H, CH2CHOH and
CH2CHNHCbz), 3.76 (s, 3H, NOCH3), 3.66 (s, 3H, CO2CH3),
3.16 (s, 3H, NCH3), 2.87 (br d, 1H, J¼15.3 Hz, CH2CHNHCbz),
2.69 (br dd, 1H, J¼16.3, 4.4 Hz, CH2CHNHCbz), 2.21 (t, 1H,
J¼11.8 Hz, CH2CHOH), 1.75 (br m, 1H, CH2CHOH); 13C
NMR (CDCl3) d 174.7, 172.3, 157.0, 136.6, 128.7, 128.3,
128.2, 68.2, 67.1, 61.5, 52.6, 45.3, 39.1, 35.8, 32.0; FTIR
(neat film, NaCl) 3340, 2953, 1736, 1719, 1642, 1528, 1438,

R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
3637
1.1 equiv) and the resulting suspension was stirred at room
temperature for 1.5 h. Chloromethyltrimethylsilane (290 mL,
2.04 mmol, 3.0 equiv) was added and the resulting suspension
was stirred for an additional 18 h at room temperature. The re-
action mixture was diluted with deionized water (50 mL) and
extracted with diethyl ether (1ꢂ500 mL). The organic extracts
were dried over magnesium sulfate, filtered, and concentrated.
Purification by silica gel flash chromatography (40% ethyl ac-
etate in hexanes) provided 26 and 27 (191 mg as a separable
7:1 mixture favoring 27, 70% total) as colorless oils. Lactam
26: Rf¼0.52 (50% hexanes in ethyl acetate); [a]2D4 þ28.2 (c
1.18, CHCl3); 1H NMR (500 MHz, CDCl3) d 4.32 (t, 1H,
J¼7.2 Hz, CH2CHOTBS), 4.00 (ddt, 1H, J¼9.9, 6.9, 3.6 Hz,
CH2CHN), 3.69 (s, 3H, NOCH3), 3.21 (d, 1H, J¼15.2 Hz,
TMSCH2N), 3.19 (s, 3H, NCH3), 2.82 (dd, 1H, J¼15.4,
3.5 Hz, CH2C(O)N(CH3)OCH3), 2.36 (dd, 1H, J¼15.4,
9.9 Hz, CH2C(O)N(CH3)OCH3), 2.29 (d, 1H, J¼15.2 Hz,
TMSCH2N), 2.14 (dt, 1H, J¼13.1, 6.9 Hz, CH2CHOTBS),
2.07 (ddd, 1H, J¼13.2, 7.5, 3.5 Hz, CH2CHOTBS), 0.89 (s,
9H, TBS tert-butyl), 0.14 (s, 3H, TBS methyl), 0.13 (s, 3H,
TBS methyl), 0.10 (s, 9H, TMS); 13C NMR (126 MHz,
CDCl3) d 172.8, 171.4, 69.9, 61.5, 53.8, 41.8, 36.2, 35.6,
32.3, 26.0, 18.5, ꢁ1.32, ꢁ4.23, ꢁ4.91; FTIR (neat film,
NaCl) 2954, 1697 (C]O), 1664 (C]O), 1462, 1418, 1388,
1362, 1250, 1172, 1114, 1002, 856, 840, 779 cmꢁ1; HRMS
(FAB) m/z: calcd for C18H39N2O4Si2 (MHþ) 403.2448, found
403.2449. Lactam 27: Rf¼0.67 (50% hexanes in ethyl acetate);
[a]2D4 ꢁ8.1 (c 3.03, CHCl3); 1H NMR (400 MHz, CDCl3) d 4.21
(dd, 1H, J¼7.4, 4.4 Hz, CH2CHOTBS), 3.91 (ddt, 1H, J¼9.8,
7.0, 4.0 Hz, CH2CHN), 3.68 (s, 3H, NOCH3), 3.20 (d, 1H,
J¼15.3 Hz, TMSCH2N), 3.19 (s, 3H, NCH3), 2.95 (dd, 1H,
J¼16.2, 3.8 Hz, CH2C(O)N(CH3)OCH3), 2.63, (dd, 1H, J¼
16.2, 9.8 Hz, CH2C(O)N(CH3)OCH3), 2.49 (dt, 1H, J¼14.3,
7.5 Hz, CH2CHOTBS), 2.35 (d, 1H, J¼15.3 Hz, TMSCH2N),
1.65 (dt, 1H, J¼13.5, 4.1 Hz, CH2CHOTBS), 0.89 (s, 9H,
TBS tert-butyl), 0.14 (s, 3H, TBS methyl), 0.13 (s, 3H, TBS
methyl), 0.081 (s, 9H, TMS); 13C NMR (126 MHz, CDCl3)
d 172.6, 171.9, 70.7, 61.5, 54.4, 42.0, 36.7, 36.1, 32.4, 25.9,
18.4, ꢁ1.28, ꢁ4.35, ꢁ4.99; FTIR (neat film, NaCl) 2954,
1698, 1667, 1464, 1417, 1388, 1361, 1250, 1173, 1116, 1004,
841, 780 cmꢁ1; HRMS (FAB) m/z: calcd for C18H39N2O4Si2
(MHþ) 403.2448, found 403.2449.
J¼14.5 Hz, TMSCH2N), 3.67 (s, 3H, NOCH3), 3.20 (s, 3H,
NCH3), 3.02 (dd, 1H, J¼16.4, 3.8 Hz, CH2C(O)N(CH3)OCH3),
2.85, (d, 1H, J¼14.5 Hz, TMSCH2N), 2.83 (dd, 1H, J¼
16.4, 8.7 Hz, CH2C(O)N(CH3)OCH3), 2.47 (dt, 1H, J¼
13.5, 7.1 Hz, CH2CHOTBS), 1.78 (dt, 1H, J¼13.3, 2.8 Hz,
CH2CHOTBS), 0.89 (s, 9H, TBS tert-butyl), 0.20 (s, 3H, TBS
methyl), 0.19 (s, 3H, TBS methyl), 0.14 (s, 9H, TMS); FTIR
(neat film, NaCl) 2953, 1666, 1472, 1416, 1388, 1360, 1250,
1153, 1128, 1082, 1005, 908, 884, 842, 779 cmꢁ1; HRMS
(FAB) m/z: calcd for C18H39N2O3S1Si2 (MHþ) 419.2220, found
419.2219.
4.13. 2-[4-(tert-Butyl-dimethyl-silanyloxy)-5-(2-oxo-
butylidene)-1-trimethylsilanyl-methyl-pyrrolidin-2-yl]-
N-methoxy-N-methyl acetamide (29)
To a stirred solution of 28 (24.7 mg, 0.0589 mmol,
1.0 equiv) in dichloromethane (1 mL) was added 1-bromo-2-
butanone (7.0 mL, 0.065 mmol, 1.1 equiv). The colorless solu-
tion was then concentrated in vacuo. The colorless oil was
heated neat at 60 ꢀC for 10 min. The resulting white solid
was dissolved in dichloromethane (1 mL), and triphenylphos-
phine (17.0 mg, 0.0648 mmol, 1.1 equiv) and triethylamine
(9.0 mL, 0.065 mmol, 1.1 equiv) were added. The resulting yel-
low solution was then stirred for 21 h at room temperature and
concentrated. Purification by silica gel flash chromatography
(33% ethyl acetate in hexanes) provided 29 (14.1 mg, 52%,
(E)-isomer only) as a colorless oil. Rf¼0.31 (33% ethyl acetate
in hexanes); 1H NMR (500 MHz, CDCl3) d 5.82 (d, 1H,
J¼5.5 Hz, CH2CHOTBS), 4.78 (s, 1H, vinyl H), 3.92 (m, 1H,
CH2CHN), 3.65 (s, 3H, NOCH3), 3.19 (s, 3H, NCH3), 2.94
(m, 2H, CH2C(O)N(CH3)OCH3), 2.84 (d, 1H, J¼15.6 Hz,
TMSCH2N), 2.68 (d, 1H, J¼15.6 Hz, TMSCH2N), 2.27 (q,
2H, J¼7.3 Hz, CH2CH3), 2.13 (ddd, 1H, J¼13.2, 8.8, 5.1 Hz,
CH2CHOTBS), 1.83 (d, 1H, J¼13.2 Hz, CH2CHOTBS), 1.10
(t, 3H, J¼7.4 Hz, CH2CH3), 0.83 (s, 9H, TBS tert-butyl),
0.26 (s, 3H, TBS methyl), 0.12 (s, 9H, TMS), 0.10 (s, 3H,
TBS methyl); FTIR (neat film, NaCl) 2954, 1664, 1558,
1462, 1412, 1386, 1305, 1250, 1117, 853, 779 cmꢁ1; HRMS
(FAB) m/z: calcd for C22H45N2O4Si2 (MHþ) 457.2918, found
457.2918.
4.14. 1-[4-(tert-Butyl-dimethyl-silanyloxy)-5-(2-oxo-
butylidene)-1-trimethylsilanyl-methyl-pyrrolidin-2-yl]-
4-ethylsulfanyl-but-3-en-2-one (30)
4.12. 2-[4-(tert-Butyl-dimethylsilanyloxy)-5-thioxo-1-
trimethylsilanylmethyl-pyrrolidin-2-yl]-N-methoxy-
N-methyl acetamide (28)
To a stirred solution of 29 (15.2 mg, 0.0333 mmol, 1.0 equiv)
in dry tetrahydrofuran (1 mL) at room temperature was added
ethynylmagnesium chloride (0.5 M solution in tetrahydrofuran,
400 mL, 0.200 mmol, 6.0 equiv) and the resulting yellow
solution was stirred for 1 h. The reaction mixture was then
filtered through a short pad of silica gel (ethyl acetate) and
the filtrate concentrated. The resulting bright yellow oil
was then dissolved in dichloromethane (1 mL). Ethane thiol
(3.0 mL, 0.036 mmol, 1.1 equiv) and triethylamine (10 mL,
0.073 mmol, 2.2 equiv) were then added at room temperature.
The resulting solution was stirred at room temperature for 8 h
To a stirred solution of 27 (37.1 mg, 0.0921 mmol,
1.0 equiv) in dry toluene (1 mL) at room temperature was added
Lawesson’s reagent (18.6 mg, 0.0460 mmol, 0.51 equiv). The
resulting yellow suspension was stirred at room temperature
for 21 h. The reaction mixture was then concentrated in vacuo.
Purification by silica gel flash chromatography (33% ethyl ace-
tate in hexanes) provided 28 (33 mg, 86%) as a colorless oil.
1
Rf¼0.47 (33% ethyl acetate in hexanes); H NMR (400 MHz,
CDCl3) d 4.54 (dd, 1H, J¼6.5, 2.5 Hz, CH2CHOTBS), 4.21
(ddt, 1H, J¼8.7, 6.6, 3.4 Hz, CH2CHN), 3.95 (d, 1H,

3638
R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
and then concentrated in vacuo. Purification by silica gel
flash chromatography (25% ethyl acetate in hexanes) provided
30 (9.2 mg, 57%, (E)-isomer only) as a pale yellow oil.
Rf¼0.52 (33% ethyl acetate in hexanes); H NMR (500 MHz,
a volume of 500 mL and washed sequentially with a 1:1 solution
of 1 N aqueous hydrochloric acid and brine (1ꢂ100 mL) and
a 4:1 solution of brine and saturated aqueous sodium bicarbon-
ate (1ꢂ100 mL). The organic layer was dried over sodium sul-
fate, filtered, and concentrated in vacuo, affording the desired
hemiaminal, which was carried forward without further purifi-
cation. Hemiaminal was dissolved in pyridine (30 mL) and
acetic anhydride (7.3 mL, 77 mmol, 5.0 equiv) was added to
the solution. After stirring for 42 h at room temperature, the
resulting clear brown solution was transferred to a separatory
funnel containing ethyl acetate (500 mL). The organic layer
was washed sequentially with 0.5 M aqueous hydrochloric
acid (2ꢂ200 mL) and a 9:1 solution of brine and saturated aque-
ous sodium bicarbonate (1ꢂ200 mL). The organic layer was
dried over magnesium sulfate, filtered, concentrated in vacuo,
and purified by silica gel column chromatography (33% ethyl
acetate in hexanes) affording aminal 40 (3.2 g, 69%) as a pale
1
CDCl3) d 7.66 (d, 1H, J¼16.0 Hz, CH3CH2SCH]CHeC]O),
6.11 (d, 1H, J¼16.0 Hz, CH3CH2SCH]CHeC]O), 5.81 (d,
1H, J¼5.4 Hz, CH2CHOTBS), 4.79 (s, 1H, vinyl H), 3.96 (br
m, 1H, CH2CHN), 3.10(dd, 1H, J¼16.9, 7.8 Hz, CH2C(O)CH]
CHSCH2CH3), 2.98 (dd, 1H, J¼16.9, 4.6 Hz, CH2C(O)CH]
CHSCH2CH3), 2.84 (d, 1H, J¼15.6 Hz, TMSCH2N), 2.80
(q, 2H, J¼7.3 Hz, SCH2CH3), 2.57 (d, 1H, J¼15.6 Hz,
TMSCH2N), 2.29 (q, 2H, J¼7.4 Hz, CH2CH3), 2.04 (m, 1H,
CH2CHOTBS), 1.69 (m, 1H, CH2CHOTBS), 1.38 (t, 3H,
J¼7.3 Hz, SCH2CH3), 1.14 (t, 3H, J¼7.4 Hz, CH2CH3), 0.86
(s, 9H, TBS tert-butyl), 0.26 (s, 3H, TBS methyl), 0.12 (s, 9H,
TMS), 0.078 (s, 3H, TBS methyl); FTIR (neat film, NaCl)
2928, 1653, 1557, 1458, 1366, 1250, 1207, 1082, 839 cmꢁ1
;
HRMS (FAB) m/z: calcd for C24H46N1O3S1Si2 (MHþ)
484.2737, found 484.2735.
yellow oil. Rf¼0.51 (50% ethyl acetate in hexanes); H NMR
1
(500 MHz, CDCl3) d 6.01 (s, 1H, NCHCHCH), 4.74 (d, 1H,
J¼6.0 Hz, NCHCHCH), 4.49 (d, 1H, J¼5.6 Hz, NCHCHCH),
3.12 (d, 1H, J¼15.3, NCH2), 2.46 (dd, 1H, J¼15.3, 0.7 Hz,
NCH2), 2.11 (s, 3H, COCH3), 1.44 (s, 3H, C(CH3)2), 1.36 (s,
3H, C(CH3)2), 0.11 (s, 9H, Si(CH3)3); 13C NMR (126 MHz,
CDCl3) d 185.1, 153.3, 113.8, 86.9, 76.2, 32.5, 27.0, 25.7,
21.1, 8.7, ꢁ1.6; FTIR (neat film, NaCl) 2954, 1746,
1719 cmꢁ1; HRMS (ESI) m/z: calcd for C13H23NNaO5Si
(MNaþ) 324.1243, observed 324.1247.
4.15. Acetic acid 2,2-dimethyl-6-oxo-5-trimethyl-
silanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-
4-yl ester (40)
To a solution of lactone 39 (4.9 g, 31 mmol, 1.0 equiv) in tet-
rahydrofuran (30 mL) were added triethylamine (5.6 mL,
40 mmol, 1.3 equiv) and C-trimethylsilanyl-methylammonium
hydrochloride (5.6 g, 40 mmol, 1.3 equiv). The flask was sealed
under argon and heated to 70 ꢀC for 18 h. After cooling to room
temperature, the resulting orange suspension was transferred to
a separatory funnel containing deionized water (300 mL) and
extracted with dichloromethane (3ꢂ300 mL). The combined
organic extracts were dried over sodium sulfate, filtered,
and concentrated in vacuo providing 5-hydroxymethyl-2,2-
dimethyl-[1,3]dioxolane-4-carboxylic acid trimethylsilanyl-
methyl-amide (7.8 g, 97%) as a brown solid, which was used
without further purification. Rf¼0.16 (33% ethyl acetate in hex-
4.16. (2,2-Dimethyl-6-oxo-5-trimethylsilanylmethyl-
tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-4-yl)-acetic acid (42)
To a solution of aminal 40 (154 mg, 0.511 mmol, 1.0 equiv)
in dichloromethane (5 mL) was added silyl ketene acetal 41
(207 mg, 1.02 mmol, 2.0 equiv) followed by trimethylsilyl
trifluoromethanesulfonate (18 mL, 0.102 mmol, 0.20 equiv).
After stirring at room temperature for 26 h, the reaction was
quenched with saturated aqueous sodium bicarbonate (1 mL)
and the mixture transferred to a separatory funnel containing
deionized water (50 mL). Following extraction with dichloro-
methane (3ꢂ100 mL), the combined organic extracts were
dried over sodium sulfate, filtered, concentrated in vacuo, and
purified by silica gel column chromatography (20% ethyl
acetate in dichloromethane) affording (2,2-dimethyl-6-oxo-5-
trimethylsilanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-
4-yl)-acetic acid ethyl ester (121 mg, 72%) as a colorless oil.
1
anes); H NMR (500 MHz, CDCl3) d 6.66 (br s, 1H, CONH),
4.62 (d, 1H, J¼7.6 Hz, COCHCHCH2), 4.54 (ddd, 1H, J¼8.6,
7.7, 4.6 Hz, COCHCHCH2), 3.81 (dd, 1H, J¼11.8, 4.6 Hz,
COCHCHCH2), 3.55 (dd, 1H, J¼11.8, 8.7 Hz, COCHCHCH2),
2.96 (dd, 1H, J¼15.4, 7.0 Hz, NCH2), 2.66 (dd, 1H, J¼15.0,
5.0 Hz, NCH2), 1.54 (s, 3H, C(CH3)2), 1.40 (s, 3H, C(CH3)2),
0.10 (s, 9H, Si(CH3)3); 13C NMR (126 MHz, CDCl3) d 170.6,
110.1, 77.7, 77.4, 61.9, 29.4, 27.2, 24.6, ꢁ2.6; FTIR (neat
film, NaCl) 3272, 2987, 2956, 1644 cmꢁ1; HRMS (ESI) m/z:
calcd for C11H24NO4Si (MHþ) 262.1474, observed 262.1471.
To a solution of 5-hydroxymethyl-2,2-dimethyl-[1,3]dioxol-
ane-4-carboxylic acid trimethylsilanylmethyl-amide (4.0 g,
15.3 mmol, 1.0 equiv) in dimethylsulfoxide (30 mL) was added
triethylamine (15 mL, 107 mmol, 7.0 equiv). Sulfur trioxidee
pyridine complex (9.7 g, 61 mmol, 4.0 equiv) was added via
cannula in a solution in dimethylsulfoxide (30 mL). After stir-
ring at room temperature for 6 h, the resulting clear orange solu-
tion was transferred to a separatory funnel containing ice water
(500 mL) and extracted with dichloromethane (3ꢂ700 mL).
The combined organic extracts were concentrated in vacuo to
1
Rf¼0.37 (50% ethyl acetate in hexanes); H NMR (500 MHz,
CDCl3) d 4.72 (d, 1H, J¼6.0 Hz, COCHCHCHCH2), 4.60 (d,
1H, J¼5.9 Hz, COCHCHCHCH2), 4.14 (q, 2H, J¼7.1 Hz,
OCH2CH3), 3.86 (dd, 1H, J¼7.5, 3.2 Hz, COCHCHCHCH2),
3.33 (d, 1H, J¼15.4 Hz, NCH2), 2.70 (dd, 1H, J¼16.2,
3.3 Hz, COCHCHCHCH2), 2.55 (dd, 1H, J¼16.2, 7.6 Hz,
COCHCHCHCH2), 2.21 (dd, 1H, J¼15.4, 0.7 Hz), 1.45 (s,
3H, C(CH3)2), 1.36 (s, 3H, C(CH3)2), 1.25 (t, 3H, OCH2CH3),
0.12 (s, 9H, Si(CH3)3); 13C NMR (126 MHz, CDCl3) d 170.4,
170.0, 112.4, 77.4, 77.3, 61.4, 60.7, 35.1, 32.0, 27.1, 25.5,
14.3, ꢁ1.4; FTIR (neat film, NaCl) 2986, 1734, 1696 cmꢁ1
;
HRMS (ESI) m/z: calcd for C15H28NO5Si (MHþ) 330.1737,

R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
3639
observed 330.1724. To a solution of (2,2-dimethyl-6-oxo-5-tri-
methylsilanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-4-
yl)-acetic acid ethyl ester (2.38 g, 7.22 mmol, 1.0 equiv) in THF
(130 mL) was added 1.0 M aqueous lithium hydroxide
(21.7 mL, 21.7 mmol, 3.0 equiv). After stirring at room temper-
ature for 3 h, the resulting pale yellow suspension was trans-
ferred into a separatory funnel containing 500 mL 0.5 M
aqueous hydrochloric acid. The aqueous layer was extracted
with dichloromethane (3ꢂ600 mL). The combined organic ex-
tracts were dried over sodium sulfate, filtered, and concentrated,
providing 42 (2.09 g, 96%) as a pale yellow foam. Rf¼0.20
(3ꢂ500 mL). Thecombined organic fractionswere dried overso-
dium sulfate, filtered, concentrated in vacuo, and filtered through
a plug of silica gel with ethyl acetate. Concentration afforded 43
(1.24 g, 62%) as a pale yellow oil. Rf¼0.66 (ethyl acetate); H
1
NMR (500 MHz, CDCl3) d 4.96 (dd, 1H, J¼5.5, 1.1 Hz,
NCHCHCH), 4.59 (d, 1H, J¼5.4 Hz, NCHCHCH), 4.28 (dd,
1H, J¼8.9, 3.7 Hz, NCHCHCH), 4.12 (d, 1H, J¼14.7 Hz,
NCH2TMS), 3.68 (s, 3H, NOCH3), 3.17 (s, 3H, NCH3), 2.84
(dd, 1H, J¼16.7, 3.5 Hz, (MeO)NMeC]OCH2), 2.63 (dd, 1H,
J¼16.5, 8.9 Hz, (MeO)NMeC]OCH2), 2.59 (dd, 1H, J¼14.6,
1.2 Hz, NCH2TMS), 1.44 (s, 3H, C(CH3)2), 1.34 (s, 3H,
C(CH3)2), 0.15 (s, 9H, Si(CH3)3); 13C NMR (126 MHz, CDCl3)
d 196.6, 169.8, 112.6, 86.5, 78.5, 67.6, 61.7, 38.2, 32.3, 27.3,
25.7, 14.6, ꢁ0.7; FTIR (neat film, NaCl) 2953, 1655,
1491 cmꢁ1; HRMS (ESI) m/z: calcd for C15H28N2O4SSi
(MHþ) 361.1617, observed 361.1620.
1
(ethyl acetate); H NMR (500 MHz, CDCl3) d 4.85 (d, 1H,
J¼5.8 Hz, COCHCH), 4.65 (d, 1H, J¼5.9 Hz, COCHCH),
3.84 (dd, 1H, J¼6.6, 3.3 Hz, NCHCH2), 3.74 (app t, 1H,
J¼6.5 Hz, CO2H), 3.31 (d, 1H, J¼15.3 Hz, NCH2), 2.71 (dd,
1H, J¼16.5, 3.3 Hz, NCHCH2), 2.64 (dd, 1H, J¼16.5, 6.6 Hz,
NCHCH2), 2.24 (d, 1H, J¼15.3 Hz, NCH2), 1.42 (s, 3H,
C(CH3)2), 1.34 (s, 3H, C(CH3)2), 0.10 (s, 9H, Si(CH3)3); 13C
NMR (126 MHz, CDCl3) d 172.3, 171.8, 112.3, 77.6, 68.1,
61.2, 34.4, 32.2, 27.0, 25.5, ꢁ1.4; FTIR (neat film, NaCl)
3448, 2989, 1729, 1659 cmꢁ1; HRMS (ESI) m/z: calcd for
C13H23NO5SSi (Mþ) 302.1424, observed 302.1425.
4.18. 1-[2,2-Dimethyl-6-(2-oxo-butylidene)-5-trimethyl-
silanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-4-yl]-
4-ethylsulfanyl-but-3-en-2-one (44)
To a solution of 43 (607 mg, 1.68 mmol, 1.0 equiv) in aceto-
nitrile (34 mL) was added 1-bromo-2-butanone (180 mL,
1.77 mmol, 1.05 equiv) at room temperature. After 22 h,
triphenylphosphine (485 mg, 1.85 mmol, 1.1 equiv) was added
followed by triethylamine (260 mL, 1.85 mmol, 1.1 equiv). The
resulting pale orange solution was stirred for 90 min at room
temperature before being concentrated in vacuo to 5 mL. The
crude reaction solutionwas purified directly by silica gel column
chromatography (50% hexane in ethyl acetate ramped to 100%
ethyl acetate) affording 2-[2,2-dimethyl-6-(2-oxo-butylidene)-
5-trimethylsilanylmethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-
4-yl]-N-methoxy-N-methyl-acetamide (545 mg, 81%) as a pale
yellow oil. Rf¼0.09 (ethyl acetate); 1H NMR (500 MHz, C6D6)
d 6.22 (d, 1H, J¼6.0 Hz, NCHCHCH), 4.96 (s, 1H, vinyl H),
4.39 (d, 1H, J¼6.0 Hz, NCHCHCH), 4.17 (dd, 1H, J¼8.4,
4.2 Hz, NCHCHCH), 2.85 (s, 3H, NOCH3), 2.71 (s, 3H,
NCH3), 2.55 (d, 1H, J¼15.3 Hz, NCH2TMS), 2.41 (q, 1H,
J¼7.5 Hz, CH3CH2C]O), 2.39 (q, 1H, J¼7.6 Hz,
CH3CH2C]O), 2.34 (m, 1H, (MeO)NMeC]OCH2), 2.23 (d,
1H, J¼15.5 Hz, NCH2TMS), 2.10 (dd, 1H, J¼16.1, 8.3 Hz,
(MeO)NMeC]OCH2), 1.39 (s, 3H, C(CH3)2), 1.23 (s, 3H,
C(CH3)2), 1.21 (t, 3H, J¼7.3 Hz, CH3CH2C]O), 0.04 (s, 9H,
Si(CH3)3); 13C NMR (126 MHz, C6D6) d 194.7, 170.6, 160.2,
110.9, 91.3, 81.0, 80.2, 66.0, 60.6, 36.6, 35.1, 33.1, 31.6, 27.2,
4.17. 2-(2,2-Dimethyl-6-thioxo-5-trimethylsilanylmethyl-
tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-4-yl)-N-methoxy-
N-methyl-acetamide (43)
A solution of lactam 42 (1.68 g, 5.57 mmol, 1.0 equiv) in
toluene (56 mL) was charged with Lawesson’s reagent
(1.24 g, 3.07 mmol, 0.55 equiv), sealed, and heated to 65 ꢀC
for 16 h. The resulting pale yellow solution was concentrated
in vacuo and purified directly by silica gel column chromatog-
raphy (dichloromethane followed by 3% acetic acid in ethyl
acetate) to afford (2,2-dimethyl-6-thioxo-5-trimethylsilanyl-
methyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-4-yl)-acetic acid
(1.68 g, 95%) as a pale yellow oil. Rf¼0.44 (3% acetic acid in
1
ethyl acetate); H NMR (500 MHz, CDCl3) d 4.96 (dd, 1H,
J¼5.4, 1.3 Hz, NCHCHCH), 4.58 (d, 1H, J¼5.4 Hz,
NCHCHCH), 4.23 (dd, 1H, J¼8.1, 3.8 Hz, NCHCHCH), 4.20
(d, 1H, J¼14.8 Hz, NCH2TMS), 3.08 (dd, 1H, J¼16.8, 3.8 Hz,
HOC]OCH2), 2.88 (dd, 1H, J¼16.8, 8.1 Hz, HOC]OCH2),
2.56 (dd, 1H, J¼14.8, 1.4 Hz, NCH2TMS), 2.11 (s, 1H, HOC]
OCH2), 1.46 (s, 3H, C(CH3)2), 1.37 (s, 3H, C(CH3)2), 0.18
(s, 9H, Si(CH3)3); 13C NMR (126 MHz, CDCl3) d 197.0, 193.6,
113.0, 86.4, 78.0, 67.4, 44.8, 38.3, 27.2, 25.8, ꢁ0.7; FTIR (neat
film, NaCl) 2954, 1693, 1491 cmꢁ1; HRMS (ESI) m/z: calcd
for C13H24NO4SSi (MHþ) 318.1195, observed 318.1180. To a
solution of (2,2-dimethyl-6-thioxo-5-trimethylsilanylmethyl-
tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-4-yl)-acetic acid (1.75 g,
5.51 mmol, 1.0 equiv)indichloromethane(28 mL)wasaddedse-
quentially N,O-dimethylhydroxylamine hydrochloride (1.07 g,
11.0 mmol, 2.0 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcar-
bodiimide hydrochloride (2.11 g, 11.0 mmol, 2.0 equiv), and tri-
ethylamine (3.85 mL, 27.6 mmol, 5.0 equiv). After stirring 15 h
at room temperature, the resulting brown suspension was trans-
ferred to a separatory funnel containing 300 mL saturated aque-
ous ammonium chloride and extracted with dichloromethane
25.3, 9.7, ꢁ1.4; FTIR (neat film, NaCl) 2937, 1656, 1556 cmꢁ1
;
HRMS (ESI) m/z: calcd for C19H35N2O5Si (MHþ) 399.2315,
observed 399.2327. To a solution of 2-[2,2-dimethyl-6-(2-oxo-
butylidene)-5-trimethylsilanylmethyl-tetrahydro-[1,3]dioxolo-
[4,5-c]pyrrol-4-yl]-N-methoxy-N-methyl-acetamide (545 mg,
1.37 mmol, 1.0 equiv) in tetrahydrofuran (23 mL) at room tem-
perature was added ethynylmagnesium bromide (0.5 M solution
in tetrahydrofuran, 6.6 mL, 3.28 mmol, 2.4 equiv). After stir-
ring for 2 h, the reaction solution was filtered through a plug
of silica gel with ethyl acetate. Concentration of the solution
via rotary evaporation to about 10 mL volume was followed
by dilution with dichloromethane to about 30 mL total volume.

3640
R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
After repeating this procedure four times, ethane thiol (111 mL,
1.50 mmol, 1.1 equiv) was added at room temperature followed
by triethylamine (360 mL, 2.60 mmol, 1.9 equiv). The reaction
solution was stirred for 19 h at room temperature, and then
poured into a separatory funnel containing 150 mL dichlorome-
thane and partitioned with 100 mL deionized water. The aque-
ous layer was extracted with dichloromethane (2ꢂ150 mL)
and the combined organic fractions were dried over sodium
sulfate, filtered, and concentrated in vacuo affording 44
(337 mg, 58%) as a pale yellow oil. Rf¼0.24 (diethyl ether);
1H NMR (500 MHz, C6D6) d 7.50 (d, 1H, J¼15.3 Hz,
CH3CH2SCH]CHC]OCH2), 6.16 (d, 1H, J¼5.8 Hz,
NCHCHCH), 5.86 (d, 1H, J¼15.3 Hz, CH3CH2SCH]
CHC]OCH2), 4.95 (s, 1H, CH3CH2C]OCH]C), 4.22 (d,
1H, J¼6.0 Hz, NCHCHCH), 4.17 (dd, 1H, J¼8.2, 4.2 Hz,
NCHCHCH), 2.50 (d, 1H, J¼15.8 Hz, NCH2TMS), 2.41 (q,
2H, J¼7.9 Hz, CH3CH2SCH]CHC]OCH2), 2.40 (q, 2H,
J¼7.8 Hz, CH3CH2SCH]CHC]OCH2), 2.19 (dd, 1H, J¼
17.1, 4.1 Hz, CH3CH2SCH]CHC]OCH2), 2.15 (q, 2H, J¼
7.2 Hz, CH3CH2C]OCH]C), 2.14 (d, 1H, J¼15.4 Hz,
NCH2TMS), 1.92 (dd, 1H, J¼17.1, 8.4 Hz, CH3CH2SCH]
CHC]OCH2), 1.39 (s, 3H, C(CH3)2), 1.22 (s, 3H, C(CH3)2),
1.21 (t, 3H, J¼7.5 Hz, CH2CH3), 0.82 (t, 3H, J¼7.5 Hz,
CH2CH3), 0.04 (s, 9H, Si(CH3)3); 13C NMR (126 MHz, C6D6)
d 194.8, 192.2, 160.3, 147.3, 122.5, 111.0, 91.0, 81.0, 80.2,
65.5, 40.8, 36.6, 35.1, 27.2, 26.0, 25.3, 13.5, 9.7, ꢁ1.4;
FTIR (neat film, NaCl) 2963, 1648, 1553 cmꢁ1; HRMS (ESI)
m/z: calcd for C21H35NO4SSi (MHþ) 426.2134, observed
426.2143.
2965, 1712, 1560, 1430, 1260 cmꢁ1; [a]D24 ꢁ213.0 (c 0.034,
CHCl3); HRMS (ESI) m/z: calcd for C19H27F3NO6S2 (MHþ)
486.1232, observed 486.1234.
4.20. Bridged pyrrolizidine 46
To a solution of 45 (350 mg, 0.721 mmol) in methanol
(300 mL) was added 10% palladium on carbon (1.00 g) and
the resulting black suspension was charged with hydrogen gas
via balloon and stirred under an atmosphere of hydrogen for
18 h. Filtration through Celite, concentration in vacuo, and
purification of the residue by silica gel column chromato-
graphy (50% ethyl acetate in hexanes) provided 46 (214 mg,
1
89%) as a colorless oil. Rf¼0.46 (ethyl acetate); H NMR
(500 MHz, C6D6) d 4.37 (d, 1H, J¼6.0 Hz, COCH2CHCHCH),
4.04 (d, 1H, J¼6.0 Hz, COCH2CHCHCH), 3.27 (d, 1H,
J¼6.0 Hz, COCH2CHCHCH), 3.13 (dd, 1H, J¼14.0, 5.1 Hz,
COCHCHCH2), 3.03 (s, 1H, COCHCHCH2), 2.97 (dd, 1H,
J¼14.0, 8.3 Hz, COCHCHCH2), 2.63 (dd, 1H, J¼8.3, 5.1 Hz,
COCHCHCH2), 2.12 (q, 2H, J¼7.4 Hz, SCH2CH3), 2.05
(m, 2H, CH2(CH2)2CH3), 1.81 (dd, 1H, J¼15.8, 6.2 Hz,
COCH2CHCHCH), 1.56 (d, 1H, J¼15.8 Hz, COCH2CHCHCH),
1.50 (s, 3H, C(CH3)2), 1.49e1.33 (m, 4H, CH2(CH2)2CH3),
1.09 (s, 3H, C(CH3)2), 0.93 (t, 3H, J¼7.4 Hz, CH2CH3), 0.90
(t, 3H, J¼7.2 Hz, CH2CH3); 13C NMR (126 MHz, CDCl3)
d 207.7, 111.5, 82.7, 81.0, 79.5, 79.2, 65.0, 64.7, 56.8, 40.5,
29.9, 28.3, 26.3, 26.0, 24.9, 23.1, 15.1, 14.0; FTIR (neat film,
NaCl) 2958, 2927, 1712, 1459, 1379 cmꢁ1; HRMS (ESI) m/z:
calcd for C18H30NO3S (MHþ) 339.1868, observed 339.1868.
4.19. Bridged pyrrolizidine 45
4.21. Bridged pyrrolizidine 47
To a solution of 44 (1.32 g, 3.10 mmol, 1.0 equiv) in chloro-
form (220 mL) at ꢁ45 ꢀC was added trifluoromethanesulfonic
anhydride (570 mL, 3.41 mmol, 1.1 equiv). The resulting color-
less solution was stirred at ꢁ45 ꢀC for 15 min, warmed to 0 ꢀC,
and stirred for 20 min and then recooled to ꢁ45 ꢀC. Tetra-
butylammonium triphenyldifluorosilicate (1.84 g, 3.41 mmol,
1.1 equiv) was added and the solution was allowed to warm to
room temperature slowly over 15 h. The resulting clear, purple
solution was concentrated invacuo and purified by silica gel col-
umn chromatography (1% methanol in dichloromethane,
ramped to 2% methanol in dichloromethane), providing 45
A solution of 46 (13 mg, 0.038 mmol, 1.0 equiv) in tetra-
hydrofuran (600 mL) was cooled to 0 ꢀC and charged with a so-
lution of 0.2 M LDA in tetrahydrofuran (260 mL, 1.2 equiv).
After stirring for 1 h, ethyl iodoacetate (5.4 mL, 0.046 mmol,
1.2 equiv) was added and the solution was stirred for a further
30 min at 0 ꢀC and then quenched with saturated aqueous so-
dium bicarbonate. The product was extracted from deionized
water (5 mL) with ethyl acetate (3ꢂ10 mL), and the combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (29% ethyl acetate in hexanes, ramped
to 50% ethyl acetate in hexanes), providing 47 (9.5 mg) as a 1:1
mixture of C-12 epimers. This mixture was dissolved in toluene
(500 mL) and charged with DBU (13.3 mL, 0.089 mmol,
4.0 equiv), and the resulting solution was stirred at 80 ꢀC for
16 h. Elution of the solution through a plug of silica gel with
ethyl acetate provided, upon concentration, 46 (9.5 mg, 58%
over two steps) as a colorless oil. Rf¼0.32 (50% ethyl acetate
in hexanes); 1H NMR (500 MHz, C6D6) d 4.32 (d, 1H,
J¼6.1 Hz, COCHCHCHCH), 4.09 (d, 1H, J¼6.1 Hz,
COCHCHCHCH), 3.95 (q, 1H, J¼7.2 Hz, OCH2CH3), 3.93
(q, 1H, J¼7.2 Hz, OCH2CH3), 3.39 (d, 1H, J¼5.7 Hz,
COCHCHCH2), 3.20 (d, 2H, J¼6.6 Hz, CH2CO2Et), 3.15 (s,
1H, COCHCHCHCH), 3.09 (ddd, 1H, J¼8.8, 5.5, 4.1 Hz,
COCHCHCH2), 3.03 (t, 1H, J¼6.6 Hz, COCHCHCHCH),
1
(1.07 g, 71%) as a colorless oil. Rf¼0.30 (diethyl ether); H
NMR (500 MHz, C6D6) d 5.21 (s, 1H, vinyl H), 4.99 (d, 1H,
J¼3.4 Hz, COCH2CHCHCH), 4.06 (d, 1H, J¼5.8 Hz,
COCH2CHCHCH), 3.49 (s, 1H, COCHCHCH2), 3.24 (d,
1H, J¼5.5 Hz, COCH2CHCHCH), 3.02 (d, 2H, J¼6.1 Hz,
COCHCHCH2), 2.73 (t, 1H, J¼6.3 Hz, COCHCHCH2), 2.32
(quartet, 2H, J¼7.4 Hz, C(OTf)CH2CH3), 2.25 (quartet,
2H, J¼7.4 Hz, SCH2CH3), 1.79 (dd, 1H, J¼16.0, 6.3 Hz,
COCH2(ax)CHCHCH), 1.60 (d, 1H, J¼16.0 Hz, COCH2(eq)
-
CHCHCH), 1.54 (s, 3H, C(CH3)2), 1.19 (s, 3H, C(CH3)2),
1.03 (t, 3H, J¼7.4 Hz, SCH2CH3), 0.98 (t, 3H, J¼7.4 Hz,
C(OTf)CH2CH3); 13C NMR (126 MHz, C6D6) d 203.9, 150.4,
120.0, 118.9, 112.0, 83.4, 80.2, 79.3, 66.9, 64.3, 56.1, 48.6,
39.8, 27.6, 26.6, 26.3, 25.3, 14.6, 10.7; FTIR (neat film, NaCl)

R.J. Carra et al. / Tetrahedron 64 (2008) 3629e3641
3641
2.74 (dd, 1H, J¼16.9, 8.8 Hz, COCHCHCH2), 2.16e2.02 (m,
References and notes
4H, SCH2CH3, CH2(CH2)2CH3), 1.70 (dd, 1H, J¼16.9,
4.1 Hz, COCHCHCH2), 1.52 (t, 3H, C(CH3)2), 1.51e1.34 (m,
4H, CH2(CH2)2CH3), 1.11 (s, 3H, C(CH3)2), 0.96 (t, 3H, J¼
7.1 Hz, CH2CH3), 0.93 (t, 3H, J¼7.3 Hz, CH2CH3), 0.91 (t,
3H, J¼7.4 Hz, CH2CH3); 13C NMR (126 MHz, CDCl3)
d 207.1, 171.8, 111.4, 81.3, 79.2, 79.0, 69.6, 63.7, 61.2, 57.0,
49.3, 44.2, 30.0, 29.8, 28.5, 26.5, 26.1, 24.9, 23.1, 15.2, 14.3,
14.1; FTIR (neat film, NaCl) 2960, 2927, 1732, 1708, 1560,
1412 cmꢁ1; HRMS (ESI) m/z: calcd for C22H36NO5S (MHþ)
425.2236, observed 425.2233.
1. Irie, H.; Masaki, N.; Ohno, K.; Osaki, K.; Taga, T.; Uyeo, S. J. Chem.
Soc., Chem. Commun. 1970, 1066.
2. Numbering scheme of 1 follows that of Seger and co-workers (Ref. 3).
3. Seger, C.; Mereiter, K.; Kaltenegger, E.; Pacher, T.; Greger, H.; Hofer, O.
Chem. Biodivers. 2004, 1, 265e279.
4. Sekine, T.; Fukasawa, N.; Kashiwagi, Y.; Ruangrungsi, N.; Murakoshi, I.
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5. Brem, B.; Seger, C.; Pacher, T.; Hofer, O.; Vajrodaya, S.; Greger, H.
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6. Jiwajinda, S.; Hirai, N.; Watanabe, K.; Santisopasri, V.; Chuengsamarnyart,
N.; Koshimizu, K.; Ohigashi, H. Phytochemistry 2001, 56, 693e695.
7. Mungkornasawakul, P.; Pyne, S. G.; Jatisatienr, A.; Lie, W.; Ung, A. T.;
Issakul, K.; Sawatwanich, A.; Supyen, D.; Jatisatienr, C. J. Nat. Prod.
2004, 67, 1740e1743.
4.22. Bridged pyrrolizidine 48
8. Sastraruji, T.; Jatisatienr, A.; Pyne, S. G.; Ung, A. T.; Lie, W.; Williams,
M. C. J. Nat. Prod. 2005, 68, 1763e1767.
A solution of 47 (2.6 mg, 0.0061 mmol) was charged with
2.5 M aqueous hydrochloric acid (750 mL), sealed under
argon, and heated to 60 ꢀC for 3.5 h. Concentration in vacuo
provided 48 (2.1 mg, 96%) as a colorless film. 1H NMR
(500 MHz, CD3OD) d 4.54 (dd, 1H, J¼14.1, 8.6 Hz,
COCHCHCH2), 4.39 (d, 1H, J¼5.3 Hz, COCHCHCHCH),
4.23 (d, 1H, J¼6.0 Hz, COCHCHCHCH), 4.05 (d, 1H,
J¼5.3 Hz, COCHCHCHCH), 3.78 (dd, 1H, J¼8.6, 5.2 Hz,
COCHCHCH2), 3.68(m, 2H, COCHCHCH2, COCHCHCHCH),
2.88 (dd, 1H, J¼17.4, 7.4 Hz, CH2CO2H), 2.78 (q, 2H,
J¼7.4 Hz, SCH2CH3), 2.43 (dd, 1H, J¼17.4, 5.6 Hz,
CH2CO2H), 2.08 (m, 2H, CH2(CH2)2CH3), 1.47 (m, 4H,
CH2(CH2)2CH3), 1.33 (t, 3H, J¼7.4 Hz, SCH2CH3), 1.01 (t,
3H, J¼7.2 Hz, CH2(CH2)2CH3); FTIR (neat film, NaCl) 3411,
3137, 2960, 2925, 2868, 1727, 1711, 1158 cmꢁ1; HRMS
(ESI) m/z: calcd for C17H28NO5S (MHþ) 358.1688, observed
358.1690.
9. Sekine, T.; Ikegami, F.; Fukasawa, N.; Kashiwagi, Y.; Aizawa, T.; Fujii,
Y.; Ruangrungsi, N.; Murakoshi, I. J. Chem. Soc., Perkin Trans. 1 1995,
391e393.
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Hofer, O.; Vajrodaya, S.; Greger, H. Phytochemistry 2003, 63, 803e816.
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7431e7432.
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Acknowledgements
This research was supported by the NIH-NIGMS
(GM67659) and Merck. MTE thanks NSF and AstraZeneca
for predoctoral fellowships.
24. Feng, X. Q.; Edstrom, E. D. Tetrahedron: Asymmetry 1999, 10, 99e105.
25. The trans-configuration was inferred from comparison of coupling con-
stant values to that of 27 (vide infra), as well as the lack of NOE signal
between the C9a and C2 methine protons. No positive diagnostic NOE
signals were observed.
Supplementary data
26. Cycloaddition conditions involving chloroform, dichloromethane, aceto-
nitrile, and benzene as solvent, TBAT and CsF as fluoride sources and
desilylation temperatures ranging from ꢁ78 to 23 ꢀC failed to prevent
C2 epimerization.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.02.008.