Enantioselective synthesis of (+)-anatoxin-a via enyne metathesis

Article abstract of DOI:10.1016/j.tet.2004.06.021

A concise synthesis of the potent nAChR agonist (+)-anatoxin-a (1) has been completed by a series of nine chemical operations and in 27% overall yield from commercially available D-methyl pyroglutamate (12). The strategy featured the application of a new protocol for the diastereoselective synthesis of cis-2,5-disubstituted pyrrolidines bearing unsaturated side chains and an intramolecular enyne metathesis to provide the bridged bicyclic framework of 1. Thus, D-methyl pyroglutamate (12) was converted in five steps to 32, which underwent facile enyne metathesis to deliver the bicyclic diene 33. Selective oxidative cleavage of the less substituted carbon-carbon double bond in 33 followed by deprotection furnished (+)-anatoxin-a (1).

Full text of DOI:10.1016/j.tet.2004.06.021

Tetrahedron 60 (2004) 7301–7314
Enantioselective synthesis of (1)-anatoxin-a via enyne metathesis
*
Jehrod B. Brenneman, Rainer Machauer and Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas, 1 University Station A5300, Austin, TX 78712, USA
Received 7 May 2004; revised 28 May 2004; accepted 4 June 2004
Available online 25 June 2004
Dedicated to Professor Robert H. Grubbs in recognition of his many contributions to organic chemistry and his receipt of the Tetrahedron Prize
Abstract—A concise synthesis of the potent nAChR agonist (þ)-anatoxin-a (1) has been completed by a series of nine chemical operations
and in 27% overall yield from commercially available D-methyl pyroglutamate (12). The strategy featured the application of a new protocol
for the diastereoselective synthesis of cis-2,5-disubstituted pyrrolidines bearing unsaturated side chains and an intramolecular enyne
metathesis to provide the bridged bicyclic framework of 1. Thus, D-methyl pyroglutamate (12) was converted in five steps to 32, which
underwent facile enyne metathesis to deliver the bicyclic diene 33. Selective oxidative cleavage of the less substituted carbon–carbon double
bond in 33 followed by deprotection furnished (þ)-anatoxin-a (1).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
(nAChR) agonists known.10 Also referred to as ‘very fast
death factor’ (VFDF), 1 has been shown to resist enzymatic
degradation by acetylcholine esterase, resulting in respirat-
ory paralysis and eventual death.11 Despite its toxicity, 1 has
emerged as a valuable chemical probe for elucidating the
mechanism of acetylcholine-mediated neurotransmission
and the disease states associated with abnormalities in this
important signaling pathway. Consequent to its potent
pharmacological profile and unique 9-azabicylo[4.2.1]-
nonane skeleton, 1 has remained an attractive synthetic
target since its isolation in 1977.12 A variety of nonlethal
analogs that contain the 9-azabicylo[4.2.1]nonane skeleton
have recently been identified as potential therapeutic targets
for treating neurological disorders such as Alzheimer’s and
Parkinson’s diseases, schizophrenia and depression.13 We
now report the details of a highly efficient synthesis of 1
employing a strategy that features a new method for the
diastereoselective synthesis of cis-2,5-disubstituted pyrroli-
dines and an intramolecular enyne metathesis.14–16
The design and development of general and efficient
strategies for alkaloid synthesis has long been a central
objective in our laboratories. In that context, we became
interested in applying ring-closing metathesis (RCM) to
forming nitrogen heterocyclic subunits that are common to
different polycyclic alkaloids since the seminal discovery by
Grubbs and Fu in 19921 that RCM could be applied to the
formation of heterocycles.2,3 We subsequently established
the efficacy of RCM for the facile construction of not only
simple fused nitrogen heterocycles,4 but of more complex
targets such as dihydrocorynantheol5 and the anticancer
alkaloids manzamine A6 and FR900482.7 More recently we
disclosed a general entry to azabicyclo[m.n.1]alkenes
(m¼3–5, n¼2, 3) by the ring-closing metathesis of cis-
2,6-dialkenyl-N-acyl piperidines.8 In a related development,
we exploited the RCM of a dialkenyl pyrrolidine as a key
step in a concise synthesis of the anticancer alkaloid
peduncularine.9
It was a logical extension of the aforementioned studies to
determine the feasibility of a RCM approach to the unusual
azabicyclo[4.2.1]nonene skeleton found in the potent
neurotoxic alkaloid anatoxin-a (1). (þ)-Anatoxin-a (1)
was isolated from the toxic blooms of the blue–green
´
freshwater algae Anabaena flos-aquae (Lyngb.) de Breb and
is one of the most potent nicotinic acetylcholine receptor
2. Results and discussion
Keywords: Enantioselective synthesis; Ring closing metathesis;
Diastereoselective reduction; Pyrrolidine; Iminium ion.
Although we had prepared the five-membered ring of
azabicyclo[3.2.1]octenes by the RCM of cis-2,6-divinyl
piperidines,8 the stereoselective synthesis of a suitable
*
Corresponding author. Tel.: þ1-512-471-3915; fax: þ1-512-471-4180;
e-mail address: sfmartin@mail.utexas.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.021

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cis-2,7-divinylazepane that would lead to 1 seemed rather
daunting. Hence, we were inspired to develop a route to 1
that featured the formation of the seven-membered ring of
the bridged bicyclic ring system of 1 by the RCM of an
appropriate enyne (Scheme 1). Oxidative cleavage of the
pendant olefinic bond would then unveil the a,b-unsatu-
rated ketone moiety of 1. In order to implement this
attractive strategy, it would be necessary to prepare a cis-
2,5-disubstituted-N-acyl pyrrolidine having unsaturated side
chains as the prelude to the pivotal RCM.
into 4. Thus, reaction of 3 with 3-butenylmagnesium
bromide afforded an intermediate alkoxyaminal that was
treated in situ with a variety of Lewis acids and sterically
demanding hydride donors.18 We found that the combi-
nation of BF3·OEt2 and L-Selectride provided the best yields
of the desired cis-pyrrolidine 4 with excellent diastereo-
selectivity (dr¼31:1).
Although this protocol was effective on smaller scales,
attempts to increase the scale of the reaction to prepare gram
quantities of 4 resulted in drastically reduced yields. The
origin of this problem remains unknown, but we speculated
that inefficient cooling during premixing of the BF3·OEt2
and L-Selectride on larger scales may have resulted in the
generation of borane.19 Despite this drawback, these
experiments provided sufficient quantities of 4 to
explore the feasibility of an enyne metathesis to form a
9-azabicylo[4.2.1]nonane skeleton according to Scheme 1.
Optimizing the procedure to prepare cis-2,5-disubstituted
pyrrolidines would wait for another day.
Removal of the silyl ether protecting group from 4 gave the
alcohol 5 (Scheme 3). Oxidation of 5 gave the correspond-
ing aldehyde that was transformed to the terminal acetylene
6 in excellent overall yield using Ohira’s diazophosphonate
(9).20 When the enyne 6 was treated with the Grubbs first-
generation catalyst 10, the desired bicyclic intermediate 7
was obtained in good yield. Exposure of 6 to the more
reactive Grubbs second-generation catalyst 11 resulted in
diminished yields of 7 owing to the formation of increased
amounts of dimeric product. On the other hand, reaction of 6
with 11 under an atmosphere of ethylene resulted in a cross-
metathesis reaction between ethylene and the alkyne to
deliver a C2-butadiene as the major product.21
Scheme 1.
Examination of the literature revealed that the available
methods for the efficient and diastereoselective preparation
of cis-2,5-disubstituted pyrrolidines incorporating
unsaturated moieties was limited.17 Our first task was thus
to develop an efficient entry to such pyrrolidines that would
provide for the incorporation of butenyl and alkynyl side-
chains. We reasoned that a one-pot protocol for preparing
cis-pyrrolidines could be achieved by the reaction of N-acyl
pyroglutamates, which are readily available in both
enantiomeric forms, with an organometallic reagent
followed by the stereoselective hydride reduction of the
transient iminium ion that would be generated by ionization
of the intermediate N,O-acetal. Use of a bulky hydride
reducing agent would then be expected to preferentially
deliver a hydride to the iminium ion from the face opposite
the C2-substituent.
In order to test the feasibility of this approach to cis-2,5-
disubstituted pyrrolidines, a model study was first under-
taken employing commercially available L-pyroglutaminol
(2). In the event, 2 was converted into the imide 3 in
excellent overall yield using standard procedures
(Scheme 2). We then systematically screened suitable
conditions for effecting the one-pot transformation of 3
Scheme 3.
We had envisioned that the dienic moiety of 7 would be
elaborated into an enone via a Wacker oxidation to deliver
Scheme 2.

J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
7303
8. However, we recognized that this plan was not supported
by a literature precedent as there were no examples of the
conversion of conjugated alkenes to enones under Wacker
conditions. Rather, in one instance a stable palladium-diene
species was isolated and characterized,22 and in another an
oxidative cleavage of a carbon–carbon bond was
observed.23 We were unable to oxidize the exocyclic olefin
of 7 to a methyl ketone under a number of different reaction
conditions; rather 7 (41–63%) was recovered in all
instances.24 After conducting these experiments, we con-
cluded that the desired conversion of 7 to 8 via a Wacker
oxidation would likely not be possible.25 This realization in
conjunction with the variable yields obtained during the
one-pot synthesis of the cis-pyrrolidine 4 led us to
investigate alternative tactics leading to 1.
atom of the carbamate moiety.27 Subsequent treatment of 14
with a premixed solution of BF3·OEt2 and Ph3SiH provided
15 in 94% yield and excellent diastereoselectivity
(dr¼30:1). Efforts to stream-line the conversion of 13 to
15 into a one-pot process proved problematic, resulting in
significantly decreased yields. Therefore, 14 was isolated
and purified prior to the cyclization-reduction step.
Stimulated by the successful cyclization/reduction of 14, we
wished to improve the yield of the initial addition step by
examining carbamate-protecting groups that would be less
susceptible to nucleophilic attack by the Grignard reagent.
The series of carbamate derivatives of 16a-f were thus
prepared and treated with 3-butenylmagnesium bromide to
afford the keto carbamates 17a-f (Scheme 5) and the results
are tabulated in Table 1.
Our initial focus was upon developing improved procedures
for the synthesis of cis-2,5-disubstituted pyrrolidines via the
diastereoselective reduction of iminium ions. We were
cognizant of several cases wherein the combination of
BF3·OEt2 and Et3SiH was employed to effect the selective
reduction of D1,2-pyrrolinium ions having a bulky group at
the C3-position that directed the facial selectivity of the
reduction.26 We thus envisioned that use of an even more
sterically demanding hydride donor such as Ph3SiH might
reduce 2,5-disubstituted-D1,2-pyrrolinium ions in a highly
diastereoselective fashion from the face opposite the
substituent at C5. Such a reduction protocol might also
allow for the selective reduction of an N-acyl iminium ion in
the presence of a C2-ester moiety, thereby allowing more
expeditious assembly of a suitable metathesis precursor.
In order to explore the feasibility of the above hypothesis,
we directed our attention to preparing 15 according to
Scheme 4. D-Methyl-pyroglutamate (12) was first converted
to the imide 13, which underwent addition of 3-butenyl-
magnesium bromide to provide the keto carbamate 14 in
modest yield. The remainder of the mass balance was
primarily accounted for by the recovery of 12, which arose
from attack of the Grignard reagent on the carbonyl carbon
Scheme 5.
Table 1. Preparation of keto carbamates 17a-f
Entry
R
Yield (%) 16
Yield (%) 17
a
b
c
d
e
f
Cl3(CH2)2
(Cl3C)CMe2
Bn
Cyclopentyl
i-Pr
t-Bu
91
95
100
59
84
89
16
34
44
59
79
92
As evident by examining Table 1, relatively unhindered or
strongly electron withdrawing carbamates were efficiently
cleaved in the presence of 3-butenylmagnesium bromide.
Only the i-propyl and t-butyl carbamates 16e,f gave the keto
carbamates 17e,f in acceptable yields. When 17e was
treated with BF3·OEt2 and Ph3SiH, the cis-pyrrolidine 18
was isolated in near quantitative yield and .30:1 dia-
stereoselectivity (Scheme 5).
Initial attempts to induce the cyclization/reduction of 17f
using BF3·OEt2 and Ph3SiH under the same conditions that
worked well for transforming 17e into 18 resulted in
extensive loss of the t-butyl carbamate moiety. However, we
Scheme 4.

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J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
very recently discovered that the cleavage of the N-Boc
protecting group can be avoided by a modification of our
original protocol. Thus, exposure of the keto carbamate 17f
to a premixed solution of Ph3SiH and B(C6F5)3 (10 mol%)
afforded 19 in very good diastereoselectivity (dr¼11:1) and
in 98% yield.28 Inasmuch as the putative reducing agent in
this process is the bulky hydridoborate HB(C6F5)23 ion,29 we
reasoned that Et3SiH might be used in place of Ph3SiH as a
less expensive and more atom economical hydride source.
Supporting this intriguing hypothesis, we discovered that
when 17f was treated with a mixture of Et3SiH and B(C6F5)3
(10 mol%), 19 was obtained in 80% (unoptimized) yield
together with a small amount of a lactone that was produced
by reduction/cyclization of 17f (Scheme 6).
dibromide 20 was then converted to the silyl alkyne 21 in
modest yield. Exposure of 21 to 5 mol% of 11 provided an
excellent yield of the bicyclic vinylsilane 22.
Unfortunately, our plan to convert the vinylsilane moiety of
22 to a methyl ketone by selective epoxidation, followed by
an acid-catalyzed hydrolysis and a Peterson elimination was
doomed at the outset. Namely, epoxidation of the pendant
olefin of 22 with m-CPBA furnished the undesired epoxide
23 as the major product contaminated with smaller
quantities of a bis-epoxide in a combined 77% yield
(10.4:1 ratio respectively). Although an alternative pro-
cedure that was developed by Mukaiyama was considered
for the hydrolysis of the vinylsilane to the ketone,32 the
operational complexity of the procedure made this option
less attractive than a more direct route that we had begun to
explore.
During the course of our investigations, Kozmin had
reported that the enyne metathesis of siloxy alkynes could
be used to synthesize cyclic enones.33 Encouraged by these
results, we queried whether a similar tactic might be
employed to provide a silyl enol ether that could be
unmasked to reveal the methyl ketone of 1. We therefore
elaborated 18e to the highly unstable dibromoketone 24
(Scheme 8).
Scheme 6.
Returning to the task at hand, it was necessary to develop an
efficient means of converting 18 into a substrate for an
intramolecular enyne metathesis that would give a product
bearing functionality that could be readily elaborated to
introduce the methyl ketone moiety found in 1. In this
regard, we had found a simple acetylenic group wanting
(vide supra). We thus envisaged that an enyne metathesis
involving a TMS-substituted alkyne would give a vinyl-
silane that could be unmasked to provide the requisite
methyl ketone.30
Toward this end, 18 was converted to the dibromo olefin 20
by reducing the ester to an aldehyde with DIBAL-H,
followed by Corey-Fuchs olefination (Scheme 7).31 The
Scheme 8.
Application of the Kowalski protocol for converting 24 to
the siloxy alkyne 25 was surprisingly inefficient,34 and all
attempts to optimize the procedure were unsuccessful.
Despite the low yields obtained for the conversion of 24 to
25, we opted to proceed with the enyne metathesis. Thus,
when 25 was exposed to 20 mol% of 11 under an ethylene
atmosphere, the desired bicyclic intermediate 26 was
isolated in 55% yield. In the absence of ethylene, the
reactions required longer reaction times (21 h vs. 5 h) and
provided 26 in lower yield (44–46%).
Scheme 7.

J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
7305
Our intention at this stage was to effect the global
deprotection of 26 to arrive at 1. A survey of the literature
revealed but a few examples for removing isopropyl
carbamates. The known conditions included exposure to
AlCl3,35 gaseous HF,36 or to mixtures of H2SO4 in TFA.37 It
seemed reasonable that application of these conditions to 26
might simultaneously cleave both the carbamate and silyl-
protecting group. Although the silyl enol ether was readily
transformed into a methyl ketone under a variety of
conditions, the isopropyl carbamate was stable. Attempts
to force the reaction under acidic conditions led to
decomposition. We explored several other methods used
to deprotect carbamates, including n-BuLi, Super-Hydride,
and basic hydrolysis. We were again unable to remove the
carbamate. Owing to the known stability of tertiary
isopropyl carbamates, we had anticipated difficulties, but
we had optimistically predicted of an eventual success that
was not to be. It was thus evident that a more labile
carbamate would be required for the synthesis of 1.
Furthermore, the poor yield obtained for the conversion of
24 to 25 signaled that an alternative strategy for the
synthesis of a functionalized bicyclic intermediate suitable
for conversion to 1 was essential.
Scheme 9.
The requirement for a hindered carbamate moiety was
dictated by a lack of selectivity in the additions of
organometallic reagents to N-alkoxycarbonyl pyrogluta-
mate derivatives. A practical solution to that vexing
problem was discovered in the context of methodological
studies directed toward developing improved routes to cis-
2,5-disubstituted pyrrolidines. In particular, we discovered
that the yields of the additions of Grignard reagents to
N-alkoxycarbonyl pyroglutamates was significantly
improved by premixi0ng the organometallic reagent with
an excess of N,N,N,0N -TMEDA.38 Under these conditions,
competing nucleophilic attack on the carbonyl carbon atom
of the carbamate moiety was reduced dramatically. It
remained to validate this tactic in our synthesis of (þ)-
anatoxin-a.
Scheme 10.
In the event, treating 16c with a premixed solution of
3-butenylmagnesium bromide and TMEDA afforded the
keto carbamate 17c in 73% yield as contrasted with a yield
of 44% in previous experiments (Scheme 9). The 17c thus
obtained was cyclized and reduced with BF3·OEt2 and
Ph3SiH as before to afford the cis-pyrrolidine 27 in 99%
yield (dr¼11:1). A one-pot reduction–homologation
procedure, which had been developed within our group,8b
was performed to obtain the enyne 28. At this stage the
minor trans-diastereomer (6%) was removed by flash
chromatography to provide pure 28.
the enyne metathesis of 29 in the presence of 11 (20 mol%)
at room temperature failed to provide any of the desired
bicycle 30; rather 29 (73%) was recovered along with a
small amount of the protodesilylated material 31 (4%).
When the reaction was performed at 80 8C (sealed tube), 31
(76%) was isolated along with smaller quantities of 29 (8%)
and 28 (9%), indicating that the silacyclobutane moiety was
labile under these conditions. The mechanistic pathway by
which the desilylation occurs is unclear, but it is possible
that oxidative insertion of the ruthenium alkylidene species
into the silacyclobutane might be responsible.41
It was recently reported that vinyl silacyclobutanes may be
oxidatively converted to ketones.39 We therefore envisioned
a new strategy for the synthesis of 1 that involved the enyne
metathesis of an alkynyl silacyclobutane to give a vinyl
siletane that could be elaborated to a methyl ketone under
mild conditions (Scheme 10). Supporting our idea was an
example of a ruthenium catalyzed RCM involving a
silacyclobutane.40
It was again time to explore other variations of an enyne
metathesis that would lead to (þ)-anatoxin-a (1). The plan
for what was to be our final attempt was predicated on the
hypothesis that it should be possible to induce the selective
oxidative cleavage of a diene such as 33 to generate the
elusive methyl ketone moiety in 1 (Scheme 11). Toward this
end, 29 was first deprotonated with LDA and the resulting
lithium acetylide was trapped with MeI or MeOTf.
However, the yield of 32 was poor owing to competing
Encouraged by these findings, we converted 28 to the enyne
metathesis precursor 29 (Scheme 10). Attempts to induce

7306
J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
rather expensive, we screened several other tertiary amines
and discovered that the complex generated from OsO4 and
Et3N provided 34 (76%) together with 35 (13%). This
mixture of diols was readily separated by flash chromato-
graphy to afford pure 34 that was subsequently cleaved by
periodate ion to deliver Cbz-anatoxin-a 36.44 N-Deprotec-
tion of 36 by the action of TMSI at 210 8C furnished 1 in
nearly quantitative yield. The free base thus obtained was
then converted into its more stable hydrochloride salt to
prevent light-induced decomposition.45 The spectral and
physical data obtained for synthetic 1 and its hydrochloride
salt were consistent with those reported by Rapoport.44,46
3. Conclusions
In summary, we have completed a concise and practical
synthesis of the potent neurotoxic alkaloid (þ)-anatoxin-a
(1) in a sequence of only nine chemical operations and in
27% overall yield from commercially available 12. The
strategy featured the application of a new protocol for the
diastereoselective synthesis of cis-2,5-disubstituted pyrroli-
dines bearing unsaturated side chains and an intramolecular
enyne metathesis to provide the requisite azabicyclo[4.2.1]-
nonane skeleton of 1. We also developed an improvement to
our method for the cyclization/reduction of keto carbamates
derived from pyroglutamic acid in which catalytic amounts
of B(C6F5)3 and silanes are employed to reduce transient
iminium ions. We are currently exploring the scope of this
new reagent combination for the stereoselective reduction
of oxonium and iminium ions. Significantly, the approach is
versatile and may be applied to the facile preparation of
nonlethal analogs of 1 by simply modifying the nature of the
unsaturated side-chains at the 2- and 5-positions of the cis-
pyrrolidine ring prior to metathesis. We are in the process of
developing new applications of intramolecular enyne
metathesis and related processes for the synthesis of
alkaloid natural products, the results of which will be
reported in due course.
Scheme 11.
deprotection of the Cbz-group. This problem was, however,
readily circumvented by alkylation of the corresponding
sodium acetylide with MeOTf to furnish 32 in excellent
yield. When the enyne 32 was exposed to 10 mol% of 11,
the bicyclic diene 33 was obtained in 91% yield.
The critical stage was then set for selectively converting the
pendant isopropenyl group present in 33 to a methyl ketone
moiety via an oxidative cleavage. Previous work in our
laboratories with a related system suggested that a Sharpless
asymmetric dihydroxylation42 followed by diol cleavage
would be superior to ozonolysis for effecting this transfor-
mation.8b However, we found that oxidation of 33 using
AD-mix b gave a mixture of diols 34 and 35 from which the
desired enone 36 was obtained in only 57% yield. Worse
yields arose from the use of AD-mix a, presumably because
of a chiral mismatch.
4. Experimental
4.1. General
Solvents and reagents were reagent-grade and were used
without purification, unle0ss0 otherwise noted. Dichloro-
methane (CH2Cl2), N,N,N N -tetramethylethylene-diamine
(TMEDA), and diisopropylamine were distilled from
calcium hydride and stored under nitrogen. Boron trifluoride
diethyl etherate (BF3·OEt2) was distilled from calcium
hydride. Tetrahydrofuran (THF) and diethyl ether (Et2O)
were passed through two columns of neutral alumina and
stored under argon. Methanol (MeOH) and acetonitrile
(MeCN) was passed through two columns of molecular
sieves and stored under argon. Toluene were first passed
through a column neutral alumina, then through a column of
Q5 reactant and stored under argon. Iodotrimethylsilane
(TMSI) was freshly distilled over flame-dried copper
powder onto the same under argon, in the absence of
light. All reactions were performed in flame-dried glassware
under argon unless otherwise noted. All metatheses were
performed in freshly distilled solvent, degassed with a
We then examined the utility of the complexes generated by
mixing OsO4 with amines. Corey had found that enantio-
selective dihydroxylations could be induced with OsO4 in
the presence of chiral diamines.43 Even though such a tactic
would require use of stoichiometric amounts of OsO4, we
reasoned that the increased steric bulk about osmium in
these complexes would favor dihydroxylating the more
accessible isopropenyl group. Although treating 33 with the
complex generated from OsO4 and TMEDA resulted in
complete recovery of 33, reaction of 33 with the complex of
OsO4 and quinuclidine provided 34 in 74% yield along with
the regioisomeric diol 35 (11%). Because quinuclidine is

J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
7307
continuous stream of argon for a minimum of 15 min. All
reaction temperatures are reported as the temperature of the
surrounding bath. H nuclear magnetic resonance (NMR)
0.87 (s, 9H), 0.03 (d, J¼3.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3) d 154.8, 138.6, 114.6, 79.5, 60.4, 57.1, 40.6, 31.6,
29.4, 26.8, 26.5, 19.2, 24.2; IR (neat) 3446, 2941, 1696,
1460, 1393, 1365, 1258, 1174, 1101, 837, 776; mass
spectrum (CI) m/z 370.2777 [C20H40NO3Si (Mþ1) requires
370.2778], 370, 314, 298, 270 (base), 256.
1
spectra were obtained at 500 or 400 MHz as solutions in
DMSO-d6 or CDCl3 unless otherwise noted. 13C NMR
spectra were obtained at 125 MHz or 100 MHz as solutions
in DMSO-d6 or CDCl3 unless otherwise noted. Chemical
shifts are reported in parts per million (ppm, d) and
referenced to the solvent. Coupling constants are reported in
Hertz (Hz). Spectral splitting patterns are designated as s:
singlet, d: doublet, t: triplet: q: quartet, m: multiplet, comp
m: complex multiplet, br: broad. Infrared (IR) spectra were
obtained using a Perkin–Elmer FTIR 1600 spectropho-
tometer. IR spectra were taken neat on sodium chloride
plates unless otherwise noted and reported in wave numbers
(cm21). Low-resolution chemical ionization (CI) mass
spectra were obtained with a Finnigan TSQ-70 instrument.
High-resolution measurements were made with a VG
Analytical ZAB2-E instrument. Analytical thin layer
chromatography was performed using Merck 250 micron
60F-254 silica gel plates. The plates were visualized with
ultraviolet (UV) light, potassium permanganate (KMnO4),
ammonium molybdate ceric ammonium nitrate (AmCAN),
or ceric ammonium molybdate (CAM/Hanessians stain).
Flash chromatography was performed according to the
method of Still47 using ICN Silitech 32-63 D 60A silica gel,
Aldrich Activated Brockmann I, standard grade, 150 mesh.
D-methylpyroglutamate (12) was prepared according to the
procedure of Pfaltz.48 Compound 16f was prepared from 12
according to the method of Tamm.49 Compound 3 was
prepared from 2 according to the procedure of Konas.50
Compounds 16a-e were prepared from 12 using the method
of Kikugawa.51 (1-Diazo-2-oxo-propyl)phosphonic acid
dimethyl ester (9) was prepared according to the procedure
of Vandewalle.52
4.1.2. (2S)-But-3-enyl-(5S)-hydroxymethylpyrrolidine-1-
carboxylic acid tert-butyl ester (5). A 1 M solution of
TBAF in THF (6.2 mL, 6.20 mmol) was added to a stirred
solution of 4 (521 mg, 1.41 mmol) in THF (8 mL). The
mixture was stirred for 2 h, and then poured into 10%
H3PO4 (50 mL) and EtOAc (10 mL). The layers were
separated and the aqueous phase was extracted with EtOAc
(3£20 mL), and the combined organic extracts were dried
(Na2SO4), filtered, and concentrated under reduced pressure
to give an orange oil that was purified by flash chromato-
graphy (SiO2) eluting with EtOAc/hexanes (2:3) to afford
250 mg (70%) of 5 as a pale-yellow oil. 1H NMR (500 MHz,
CDCl3) d 5.79 (ddt, J¼17.1, 10.2, 6.6 Hz, 1H), 5.00 (dq,
J¼15.5, 1.6 Hz, 1H), 4.94 (br dq, J¼8.4, 1.8 Hz, 1H), 3.96–
3.90 (m, 1H), 3.87–3.81 (m, 1H), 3.65 (br dd, J¼8.6,
2.4 Hz, 1H), 3.49 (dd, J¼11.2, 7.9 Hz, 1H), 2.11–1.93
(comp, 3H), 1.90–1.80 (m, 1H), 1.77–1.50 (comp, 3H),
1.45 (s, 9H), 1.42–1.29 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 138.1, 114.8, 80.4, 68.8, 61.1, 58.8, 34.6, 30.7,
28.9, 28.5, 26.9; IR (neat) 3416, 3074, 2967, 1693, 1661,
1399, 1255, 1170, 1116, 1047, 908, 855, 775, 737 cm21
;
mass spectrum (CI) m/z 256.1919 [C14H26NO3 (Mþ1)
requires 256.1913], 511, 411, 379, 256 (base), 224, 200,
184, 156.
4.1.3. (2S)-But-3-enyl-(5S)-formylpyrrolidine-1-car-
boxylic acid tert-butyl ester. TPAP (33 mg, 0.094 mmol)
was added to a solution of 5 (239 mg, 0.936 mmol), NMO
˚
(165 mg, 1.40 mmol), and powdered 4 A molecular sieves
4.1.1. (2S)-But-3-enyl-(5S)-(tert-butyldimethylsilanoxyl-
methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4).
4-Bromo-1-butene (18 mL, 0.18 mmol) was added to a
stirred mixture of magnesium turnings (26 mg, 1.1 mmol) in
THF (1.1 mL) at room temperature. After 20 min, an
additional portion of 4-bromo-1-butene (40 mL,
0.35 mmol) was added. The resulting solution was stirred
an additional 20 min and then transferred via cannula to a
stirred solution of 3 (89 mg, 0.27 mmol) in THF (1.4 mL) at
278 8C. The mixture was stirred for 1 h at 278 8C, and
then a mixture of BF3·OEt2 (0.22 mL, 1.7 mmol) and 1 M
L-Selectride in THF (0.57 mL, 0.57 mmol) (mixed at room
temperature) was added via syringe. The resulting solution
was stirred at 278 8C for 1 h, and then the solution was
allowed to slowly warm to room temperature before
quenching with MeOH (2.5 mL) and H2O (3 mL). The
reaction mixture was then poured into a mixture of saturated
NaHCO3 (30 mL) and Et2O/pentane (1:1) (10 mL). The
layers were separated, and the aqueous layer was extracted
with Et2O/pentane (1:1) (3£15 mL), dried (Na2SO4),
filtered, and concentrated under reduced pressure to afford
a yellow oil. The crude product was purified by flash
chromatography (SiO2) eluting with Et2O/pentane (1:5) to
provide 79 mg (79%) of 4 as a clear oil. 1H NMR (400 MHz,
CDCl3) d 5.85–5.75 (m, 1H), 5.00 (dq, J¼17.4, 1.7 Hz,
1H), 4.94 (app d, J¼9.9 Hz, 1H), 3.76–3.36 (comp, 4H),
2.14–1.72 (comp, 5H), 1.68–1.52 (m, 1H), 1.44 (s, 9H),
(300 mg) in CH2Cl2 (31 mL) at room temperature. The
reaction was stirred for 2 h, and then the solvent was
removed under reduced pressure to afford a black residue.
The residue was suspended in Et2O (2 mL), and filtered
through a short plug of SiO2 eluting with Et2O/pentane (2:1)
(175 mL). Removal of the solvent under reduced pressure
afforded 216 mg (91%) of the aldehyde as a pale-yellow oil.
1H NMR (500 MHz, PhMe-d8, 100 8C) d 9.35 (d, J¼2.4 Hz,
1H), 5.73 (ddt, J¼16.7, 10.2, 6.3 Hz, 1H), 4.97 (dq, J¼17.1,
1.7 Hz, 1H), 4.91–4.88 (m, 1H), 3.93–3.90 (m, 1H), 3.78–
3.71 (m, 1H), 2.02–1.81 (comp, 3H), 1.60–1.42 (comp,
3H), 1.37 (s, 9H), 1.30–1.19 (comp, 2H); 13C NMR
(125 MHz, PhMe-d8, 100 8C) d 199.1, 154.7, 138.6, 114.8,
80.2, 66.6, 58.8, 35.0, 30.9, 30.0, 28.6, 25.4; IR (neat) 2974,
1739, 1696, 1455, 1382, 1258, 1168, 1112, 910, 776 cm21
;
mass spectrum (CI) m/z 254.1765 [C14H24NO3 (Mþ1)
requires 254.1756], 254, 238, 226, 224, 198 (base), 182,
180, 155, 136, 124.
4.1.4. (2S)-But-3-enyl-(5S)-ethynylpyrrolidine-1-car-
boxylic acid tert-butyl ester (6). A solution of the
proceeding aldehyde (207 mg, 0.817 mmol) in anhydrous
MeOH (1 mL) was added via syringe to a solution of 9
(188 mg, 0.981 mmol) and K2CO3 (226 mg, 1.63 mmol) in
anhydrous MeOH (6 mL) at room temperature. The reaction
was stirred for 3 h, and then diluted with Et2O (6 mL) and
poured into a mixture of saturated NaHCO3 (25 mL) and

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J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
1
Et2O (5 mL). The layers were separated and the aqueous
phase was extracted with Et2O (4£15 mL), and the
combined organic extracts were dried (MgSO4), filtered,
and concentrated under reduced pressure to give an pale-
yellow oil that was purified by flash chromatography (SiO2)
eluting with Et2O/pentane (1:6) to afford 155 mg (76%) of 6
pale-yellow oil. H NMR (400 MHz, CDCl3) d 5.76 (ddt,
J¼16.8, 10.3, 6.5 Hz, 1H), 5.29 (br s, 1H), 5.04–4.93
(comp, 2H), 4.30 (m, 1H), 3.72 (s, 3H), 3.65 (s, 3H), 2.60–
2.40 (comp, 4H), 2.34–2.25 (comp, 2H), 2.33–2.26 (m,
1H), 1.96–1.84 (m, 1H); 13C NMR (100 MHz, CDCl3) d
208.8, 172.5, 156.6, 136.8, 115.2, 53.2, 52.3, 52.2, 41.6,
38.3, 27.5, 26.0; IR (neat) 3345, 2952, 1713, 1640, 1528,
1443, 1359, 1264, 1219, 1062, 1000, 916, 781 cm21; mass
spectrum (CI) m/z 258.1348 [C12H20NO5 (Mþ1) requires
258.1342], 258, 240 (base), 226, 198.
1
as a clear oil. H NMR (500 MHz, DMSO-d6, 100 8C) d
5.84 (ddt, J¼16.8, 10.2, 6.5 Hz, 1H), 5.03 (dq, J¼17.2,
1.7 Hz, 1H), 4.96–4.92 (m, 1H), 4.47–4.43 (m, 1H), 3.77–
3.72 (m, 1H), 2.89 (d, J¼2.1 Hz, 1H), 2.13–1.96 (comp,
4H), 1.93–1.85 (comp, 2H), 1.78–1.71 (m, 1H), 1.57–1.49
(m, 1H), 1.43 (s, 9H); 13C NMR (125 MHz, DMSO-d6,
100 8C) d 152.7, 137.8, 113.8, 84.9, 78.3, 71.0, 57.0, 47.7,
33.4, 31.1, 29.0, 28.9, 27.6; IR (neat) 3302, 3059, 2978,
4.1.7. (2R,5R)-But-3-enylpyrrolidine-1,2-dicarboxylic
acid dimethyl ester (15). BF3·OEt2 (5.50 mL, 43.2 mmol)
was added to a solution of Ph3SiH (5.63 g, 21.6 mmol) in
CH2Cl2 (14 mL) at room temperature. The solution was
stirred for 5 min, and then transferred via cannula to a
stirred solution of 14 (1.85 g, 7.21 mmol) in CH2Cl2
(24 mL) at 278 8C. The reaction mixture was stirred at
278 8C for 0.5 h, whereupon the cooling-bath was removed
and stirring was continued at room temperature for an
additional 2 h. The reaction mixture was recooled to 278 8C
and poured into a mixture of sat. aqueous NaHCO3 (40 mL)
and CH2Cl2 (10 mL). The layers were separated, and the
aqueous phase was extracted with Et2O (3£20 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure
to afford a clear oil. The crude product was purified by flash
chromatography (SiO2) eluting with Et2O/pentane (3:1) to
1685, 1639, 1390, 1263, 1170, 1107, 916, 737, 650 cm21
;
mass spectrum (CI) m/z 250.1807 [C15H24NO2 (Mþ1)
requires 250.1807], 499, 444, 399, 343, 250 (base), 194.
4.1.5. 2-Vinyl-9-azabicyclo[4.2.1]non-2-ene-9-carboxylic
acid tert-butyl ester (7). To a solution of 6 (18 mg,
72 mmol) in dry degassed CH2Cl2 (8 mL) was added 10
(7 mg, 0.008 mmol) in one portion. The mixture was stirred
at room temperature for 22 h, and then DMSO (1 mL) was
added to decompose the catalyst, and stirring was continued
for an additional 2 h. The solvent was removed under
reduced pressure, and the residue was purified by flash
chromatography (SiO2) using gradient elution Et2O/pentane
(1:5!1:3) to afford 14 mg (78%) of 7 as a pale-yellow oil.
1H NMR (500 MHz, CDCl3) (2 rotamers) d 6.23 (dd,
J¼17.6, 6.6 Hz, 1H), 5.65–5.60 (m, 1H), 5.14 (t,
J¼17.1 Hz, 1H), 4.98–4.90 (comp, 1.4H), 4.80–4.77 (m,
0.6H), 4.40–4.37 (m, 0.6H), 4.28–4.24 (m, 0.4H), 2.32–
2.02 (comp, 5H), 1.77–1.65 (comp, 2H), 1.62–1.51 (comp,
2H), 1.44 (s, 4H), 1.39 (s, 5H); 13C NMR (125 MHz,
CDCl3) (2 rotamers) d 153.5, 153.3, 145.9, 143.8, 139.0,
138.8, 131.2, 130.8, 111.3, 110.5 79.1, 79.0, 55.2, 54.8,
54.3, 33.9, 31.9, 31.4, 31.0, 30.4, 30.3, 29.6, 28.6, 28.5,
23.8, 23.6; IR (neat) 3437, 2978, 2252, 1683, 1420, 1405,
1367, 1250, 1170, 1116, 994, 908, 737, 652 cm21; mass
spectrum (CI) m/z 250.1803 [C15H24NO2 (Mþ1) requires
250.1807], 250 (base), 222, 200, 195, 152.
provide 1.62 g (93%) of 15 as a clear oil (dr¼16:1)53. H
1
NMR (500 MHz, CDCl3) (2 rotamers) d 5.90–5.78 (m, 1H),
5.05 (app dd, J¼17.3, 1.8 Hz, 1H), 4.96 (br d, J¼9.8 Hz,
1H), 4.42–4.30 (m, 1H), 4.01–8.85 (m, 1H), 3.77–3.63
(comp, 6H), 2.26–2.16 (m, 1H), 2.14–1.90 (comp, 5H),
1.78–1.68 (m, 1H), 1.58–1.46 (m, 1H); 13C NMR
(125 MHz, CDCl3) (2 rotamers) d 173.4, 155.6, 155.0,
138.1, 137.9, 114.7, 114.6, 60.0, 59.6, 58.8, 58.1, 52.4, 52.1,
33.5, 33.1, 30.5, 30.0, 29.3, 29.1, 28.1; IR (neat) 2955, 1754,
1704, 1450, 1385, 1202, 1175, 1112, 1000, 912, 773 cm21
;
mass spectrum (CI) m/z 242.1388 [C12H20NO4 (Mþ1)
requires 242.1392], 242 (base), 210, 186, 168.
4.1.8. (2R)-Isopropoxycarbonylamino-5-oxonon-8-enoic
acid methyl ester (17e). 4-Bromo-1-butene (0.70 mL,
6.9 mmol) was added to a stirred mixture of magnesium
turnings (1.3 g, 52 mmol) in THF (55 mL) at room
temperature. The mixture was stirred for 10 min, and an
additional portion of 4-bromo-1-butene was added (2.0 mL,
20 mmol). The resulting mixture was stirred for an
additional 1 h, whereupon the solution was transferred via
cannula to a solution of 16e (2.0 g, 8.7 mmol) in THF
(65 mL) at 278 8C over a 1 h period. Stirring was continued
for an additional 1 h at 278 8C, whereupon a solution of sat.
NH4Cl (10 mL) was added. The reaction mixture was then
poured into a mixture of brine (100 mL) and EtOAc
(50 mL). The layers were separated, and the aqueous layer
was extracted with EtOAc (3£50 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure to afford a
yellow oil. The crude product was purified by flash
chromatography (SiO2) eluting with EtOAc/hexanes (1:2)
to provide 1.9 g (77%) of 17e as a pale-yellow oil. 1H NMR
(500 MHz, CDCl3) d 5.83–5.75 (ddt, J¼16.9, 10.2, 6.6 Hz,
1H), 5.22 (br d, J¼6.6 Hz, 1H), 5.02 (ddd, J¼17.1, 3.4,
1.6 Hz, 1H), 4.97 (ddd, J¼10.2, 3.0, 1.4 Hz, 1H), 4.89 (hept,
J¼6.0 Hz, 1H), 4.32 (br d, J¼5.0 Hz, 1H), 3.74 (s, 3H),
4.1.6. (2R)-Methoxycarbonylamino-5-oxonon-8-enoic
acid methyl ester (14). 4-Bromo-1-butene (72 mL,
0.71 mmol) was added to a stirred mixture of magnesium
turnings (202 mg, 8.32 mmol) in THF (8.3 mL) at room
temperature. The mixture was stirred for 10 min, and an
additional portion of 4-bromo-1-butene (350 mL,
3.45 mmol) was added. The resulting mixture was stirred
for an additional 15 min and then transferred via syringe to a
flask containing TMEDA (3.8 mL, 25 mmol). The initially
cloudy suspension was stirred until all precipitate had
disappeared (5 min), whereupon the solution was trans-
ferred via syringe to a solution of 13 (558 mg, 2.77 mmol) in
THF (14 mL) at 278 8C. The reaction mixture was stirred
for 1.5 h at 278 8C, and MeOH (5 mL) was added. The
reaction mixture was then poured into a mixture of 10%
H3PO4 (50 mL) and Et2O (10 mL). The layers were
separated, and the aqueous layer was extracted with Et2O
(3£20 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure to afford a yellow oil. The crude product
was purified by flash chromatography (SiO2) eluting with
EtOAc/hexanes (2:1) to provide 465 mg (65%) of 14 as a

J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
7309
2.59–2.46 (comp, 4H), 2.35–2.30 (comp, 2H), 2.20–2.11
(m, 1H), 1.96–1.88 (m, 1H), 1.23 (d, J¼6.3 Hz, 3H), 1.21
(d, J¼6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3);
208.7, 172.7, 155.8, 136.9, 115.3, 68.6, 53.1, 52.4, 41.8,
38.4, 27.6, 26.4, 22.1, 22.0; IR (neat) 3349, 3077, 2981,
1714, 1642, 1524, 1438, 1375, 1209, 1180, 1112,
spectrum (CI) m/z 300.1805 [C15H26NO5 (Mþ1) requires
300.1811], 300, 282, 244 (base), 200, 182.
4.1.11. (2R,5R)-1-tert-Butyl-2-methyl-5-(but-3-enyl)-pyr-
rolidine-1,2-dicarboxylate (19). B(C6F5)3 (8.2 mg,
0.02 mmol) was added to a solution of Ph3SiH (92 mg,
0.35 mmol) in CH2Cl2 (1 mL) at room temperature. The
solution was stirred for 10 min, and then added via cannula
to a stirred solution of 17f (48 mg, 0.16 mmol) in CH2Cl2
(0.5 mL) at 278 8C. The mixture was maintained in a
278 8C bath for 0.5 h, whereupon the cooling-bath was
removed, and stirring was continued at room temperature
for an additional 2 h. The mixture was then recooled to
278 8C and an additional 1 mL of a pre-mixed solution of
B(C6F5)3 (8.2 mg, 0.02 mmol) and Ph3SiH (92 mg,
0.35 mmol) was added via cannula. The solution was stirred
at 278 8C for 10 min, and then the cooling bath was
removed and stirring was continued at room temperature for
11 h. Et3N (0.1 mL) was added and stirring was continued
for 20 min. The mixture was poured into a solution of 10%
H3PO4 (20 mL) and Et2O (5 mL). The layers were separated
and the aqueous phase was extracted with Et2O (3£8 mL).
The combined organic layers were dried (MgSO4), filtered
through a 2 cm plug of SiO2 with Et2O (40 mL), and
concentrated under reduced pressure to afford a pale-yellow
oil. The crude product was purified by flash chromatography
(SiO2) eluting with Et2O/pentane (1:1) to provide 44 mg
(97%) of 19 (dr¼11:1, by 1H NMR) as a clear oil. 1H NMR
(500 MHz, DMSO-d6, 100 8C) d 5.84 (ddt, J¼17.0, 10.2,
6.6 Hz, 1H), 4.98 (app dq, J¼17.2, 1.7 Hz, 1H), 4.96–4.93
(m, 1H), 4.21 (t, J¼7.5 Hz, 1H), 3.82–3.77 (m, 1H), 3.65 (s,
2.76H, major diast.), 3.64 (s, 0.24H, minor diast.) 2.20–1.83
(comp, 6H), 1.70–1.65 (m, 1H), 1.52–1.44 (m, 1H), 1.38 (s,
9H); 13C NMR (125 MHz, DMSO-d6, 100 8C) d 172.6,
152.7, 138.0, 113.8, 78.4, 59.1, 57.3, 50.9, 32.7, 29.4, 28.7,
27.6; IR(neat) 2974, 1754, 1697, 1390, 1172, 1115, 710,
513; mass spectrum (CI) m/z 284.1860 [C15H26NO4 (Mþ1)
requires 284.1862], 284 (base), 228, 184.
1043 cm21
;
mass spectrum (CI) m/z 286.1652
[C14H24NO5 (Mþ1) requires 286.1654], 286 (base), 268,
244, 226, 200, 182, 144.
4.1.9. (2R,5R)-1-Isopropyl-2-methyl-5-(but-3-enyl)-pyr-
rolidine-1,2-dicarboxylate (18). A solution of BF3·OEt2
(2.7 mL, 21 mmol) and Ph3SiH (2.7 g, 11 mmol) in CH2Cl2
(5 mL) was added via syringe to a stirred solution of 17e
(1.0 g, 3.5 mmol) in CH2Cl2 (25 mL) at 278 8C. The
reaction mixture was stirred at 278 8C for 0.5 h, whereupon
the cooling-bath was removed and stirring was continued at
room temperature for an additional 2 h. The reaction
mixture was recooled to 278 8C and poured into a mixture
of sat. aqueous NaHCO3 (20 mL) and CH2Cl2 (10 mL). The
layers were separated, and the aqueous phase was extracted
with CH2Cl2 (3£10 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure to afford a clear oil.
The crude product was purified by flash chromatography
(SiO2) eluting with EtOAc/hexanes (1:4) to provide 941 mg
(99%) of 18 (dr .30:1)53 as a clear oil. 1H NMR (500 MHz,
CDCl3) (2 rotamers) d 5.86–5.79 (m, 1H), 5.05–5.02 (m,
1H), 5.00–4.85 (comp, 2H), 4.40–4.24 (m, 1H), 3.98–3.83
(m, 1H), 3.72 (s, 3H), 2.27–1.89 (comp, 6H), 1.79–1.72 (m,
1H), 1.59–1.44 (m, 1H), 1.27–1.12 (comp, 6H); 13C NMR
(125 MHz, CDCl3) (2 rotamers) d 173.7, 173.6, 154.8,
154.1, 138.2, 114.5, 68.7, 68.4, 59.8, 59.7, 59.4, 58.5, 57.8,
52.0, 33.7, 33.0, 30.7, 30.5, 30.1, 29.2, 28.9, 28.1, 22.3,
22.2, 22.1, 21.9; IR (neat) 2978, 2952, 1753, 1699, 1640,
1436, 1404, 1385, 1315, 1202, 1175, 1113, 998 cm21; mass
spectrum (CI) m/z 270.1709 [C14H24NO4 (Mþ1) requires
270.1705], 270 (base), 228, 210, 184, 168, 128.
4.1.10. (2R)-1-tert-Butoxycarbonylamino-5-oxonon-8-
enoic acid methyl ester (17f). A two-neck flask was
charged with magnesium turnings (200 mg, 8.26 mmol) and
THF (8 mL). To this stirred mixture was added a portion of
4-bromo-1-butene (0.10 mL, 0.99 mmol) at room tempera-
ture. After 15 min, an additional portion of 4-bromo-1-
butene (0.32 mL, 3.15 mmol) was added. The resulting
yellow solution was stirred for 10 min and then transferred
via cannula to a stirred solution of 16f (502 mg, 2.06 mmol)
in THF (14 mL) at 278 8C. The mixture was stirred for 3 h
at 278 8C, and then saturated NH4Cl (5 mL) was added and
the reaction mixture was poured into a mixture of H2O
(60 mL) and Et2O (10 mL). The layers were separated, and
the aqueous layer was extracted with Et2O (3£20 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure
to afford a yellow oil. The crude product was purified by
flash chromatography (SiO2) eluting with EtOAc/hexanes
4.1.12. (2R,5S)-5-But-3-enyl-2-(2,2-dibromovinyl)-pyr-
rolidine-1-carboxylic acid isopropyl ester (20). A 1.0 M
solution of DIBAL-H in toluene (1.6 mL, 1.6 mmol) was
added dropwise to a solution of 18 (393 mg, 1.46 mmol) in
toluene (4 mL) at 278 8C. After 1 h at 278 8C, an
additional portion of DIBAL-H (1.6 mL, 1.6 mmol) was
added, and the mixture was stirred at 278 8C for 15 min.
MeOH (0.5 mL) was added, and the mixture was poured
into a solution of saturated Rochelle’s salt (11 mL) and
EtOAc (10 mL), The mixture was stirred at room tempera-
ture until the layers separated (1.5 h). The mixture was then
poured into brine (20 mL), and the layers were separated.
The aqueous layer was extracted with EtOAc (3£15 mL),
dried (Na2SO4), filtered, and concentrated under reduced
pressure to give a yellow oil. The crude product was purified
by flash chromatography (neutral Al2O3) eluting with
EtOAc/hexanes (1:4) to provide 277 mg (79%) of the
aldehyde as a pale-yellow oil that was used immediately in
the next reaction.
1
(1:2) to provide 570 mg (92%) of 17f as a yellow oil. H
NMR (300 MHz, CDCl3) d 5.83–5.68 (m, 1H), 5.12–4.75
(comp, 3H), 4.28–4.17 (m, 1H), 3.70–3.67 (comp, 3H),
2.57–2.37 (comp, 4H), 2.31–2.24 (comp, 2H), 2.14–2.03
(m, 1H), 1.99–1.78 (m, 1H), 1.40–1.37 (comp, 9H); 13C
NMR (75 MHz, CDCl3) d 209.0, 173.1, 155.7, 137.2, 115.6,
80.2, 53.1, 52.6, 42.1, 38.7, 28.5, 27.9, 26.7; IR (neat) 3465,
3064, 2984, 1741, 1707, 1392, 1363, 1169, 733 cm21; mass
A solution of CBr4 (420 mg, 1.26 mmol) and PPh3 (662 mg,
2.52 mmol) in CH2Cl2 (3 mL) was cooled to 0 8C. After
20 min, a solution of the proceeding aldehyde (151 mg,
0.631 mmol) in CH2Cl2 (1 mL) was added. The reaction

7310
J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
mixture was stirred with warming to room temperature for
29 h in the dark. The resulting slurry was concentrated in
vacuo, diluted in a minimal amount of CH2Cl2 (1 mL), and
purified by flash chromatography (neutral Al2O3) eluting
with Et2O/pentane (1:4) to provide 217 mg (87%) of 20 as a
5 min, then transferred dropwise via cannula to a solution of
18 (201 mg, 0.746 mmol) and dibromomethane (0.13 mL,
1.9 mmol) in THF (3.3 mL) at 278 8C. The reaction
mixture was stirred at 278 8C for 3 h, whereupon 10%
citric acid (1 mL) was added. The reaction was immediately
poured into H2O (15 mL) and Et2O (5 mL). The layers were
separated, and the aqueous layer was extracted with Et2O
(3£10 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure
to give a crude yellow oil that was purified by flash
chromatography (SiO2) eluting with Et2O/hexanes (1:3) to
afford 220 mg (72%) of 24 as an unstable pale-yellow oil. A
portion of the product was immediately dissolved in THF
under Ar to avoid decomposition and used in the next
reaction.
1
yellow oil. H NMR (300 MHz, CDCl3) d 6.44–6.20 (m,
1H), 5.88–5.72 (m, 1H), 5.07–4.82 (comp, 3H), 4.52–4.31
(m, 1H), 3.96–3.76 (m, 1H), 2.25–1.29 (comp, 8H), 1.27–
1.18 (comp, 6H); 13C NMR (75 MHz, CDCl3) d 143.3,
140.9, 138.3, 115.0, 83.3, 68.7, 60.6, 32.3, 30.8, 30.6, 29.4,
22.6, 22.4; mass spectrum (CI) m/z 396 (Mþ1) (base), 382,
354, 340, 294, 210.
4.1.13. (2R,5S)-5-But-3-enyl-2-trimethylsilanylethynyl-
pyrrolidine-1-carboxylic acid isopropyl ester (21). A
2.0 M solution of n-BuLi (0.44 mL, 8.8 mmol) in hexanes
was added to a solution of 20 (165 mg, 0.418 mmol) in THF
(5 mL) at 278 8C. The mixture was stirred for 1.5 h at
278 8C, and then TMSCl (60 mL, 0.46 mmol) was added.
The solution was stirred at 278 8C for 4.5 h, and then
phosphate buffer (pH 7.4) (1 mL) was added and the
reaction was poured into a mixture of brine (10 mL) and
Et2O (5 mL). The layers were separated, and the aqueous
layer was extracted with Et2O (3£15 mL). The combined
organic extracts were dried (Na2SO4), filtered, and con-
centrated under reduced pressure to give a dark-yellow oil.
The crude product was purified by flash chromatography
(SiO2) eluting with Et2O/pentane (1:6) to provide 59 mg
(46%) of 21 as a yellow oil. 1H NMR (300 MHz, CDCl3) d
5.88–5.74 (m, 1H), 5.06–4.85 (comp, 3H), 4.61–4.42 (m,
1H), 3.89–3.76 (m, 1H), 2.16–1.50 (comp, 8H), 1.25–1.20
(comp, 6H), 0.13–0.09 (comp, 9H); 13C NMR (75 MHz,
CDCl3) d 154.4, 138.4, 114.4, 86.1, 68.3, 57.8, 49.2, 34.1,
32.2, 30.1, 22.3, 20.01; mass spectrum (CI) m/z 308 (Mþ1)
(base), 292, 266.
A solution of 2.2 M n-BuLi in hexanes (136 mL,
0.294 mmol) was added to solution of 1,1,1,3,3,3-hexa-
methyldisilazane (68 mL, 0.321 mmol) in THF (1.6 mL) at
0 8C. The resulting yellow LiHMDS solution was stirred for
10 min at 0 8C, and then transferred via cannula to a solution
of 24 (110 mg, 0.268 mmol) in THF (1.4 mL) at 278 8C.
The reaction mixture was stirred at 278 8C for 10 min,
whereupon a solution of 1.6 M t-BuLi in pentane (0.36 mL,
0.56 mmol) was added. The resulting yellow solution was
stirred at 278 8C for 1 h, and then freshly distilled TIPSOTf
(0.16 mL, 0.59 mmol) was added. After stirring for an
additional 10 min, the reaction mixture was diluted with
pentane (5 mL) and quenched with saturated NaHCO3
(1 mL) at 278 8C. After warming to ambient temperature,
the reaction mixture was poured into H2O (15 mL) and Et2O
(5 mL). The layers were separated, and the aqueous layer
was extracted with Et2O (3£15 mL). The combined organic
extracts were dried (MgSO4), filtered, and concentrated
under reduced pressure to give a yellow oil that was purified
by flash chromatography (SiO2) eluting with Et2O/pentane
1
4.1.14. 2-(1-Trimethylsilanylvinyl)-9-azabicyclo[4.2.1]-
non-2-ene-9-caboxylic acid isopropyl ester (22). A
solution of 21 (26 mg, 0.085 mmol) in degassed PhMe
(0.85 mL) was treated with one portion of solid 11 (4 mg,
4 mmol), and then the solution was sparged for an additional
10 min. The mixture was then heated to 65 8C for 14 h.
After cooling to room temperature, the solution was allowed
to stir for 2 h exposed to the atmosphere, and then the
solvent was removed under reduced pressure to afford a
crude brown oil that was purified by flash chromatography
(SiO2) using gradient elution with hexanes and then EtOAc/
hexanes (1:5) to afford 24 mg (91%) of 22 as a pale-yellow
(1:6) to afford 26 mg (24%) of 25 as a pale-yellow oil. H
NMR (500 MHz, PhMe-d8, 100 8C) d 5.87–5.79 (m, 1H),
5.05–4.89 (comp, 3H), 4.68–4.66 (m, 1H), 3.80–3.78 (m,
1H), 2.19–2.01 (comp, 2H), 1.79–1.60 (comp, 4H), 1.37–
1.25 (comp, 2H), 1.22–1.05 (comp, 27H); 13C NMR
(125 MHz, PhMe-d8, 100 8C) d 154.5, 139.2, 114.4, 89.2,
68.0, 58.4, 49.4, 35.5, 34.0, 33.7, 30.9, 30.8, 22.5, 20.9,
20.7, 20.6, 20.4, 20.2, 20.1, 19.9, 18.1, 17.7, 12.6; IR (neat)
3058, 2944, 2865, 2262, 1688, 1262, 739 cm21; mass
spectrum (CI) m/z 408.2935 [C23H41NO3Si (Mþ1) requires
408.2934], 408 (base), 366, 279.
1
oil. H NMR (300 MHz, CDCl3) d 5.60–5.31 (comp, 2H),
4.1.16. 2-(1-Triisopropylsilanyloxyvinyl)-9-azabicyclo-
[4.2.1]non-2-ene-9-carboxylic acid isopropyl ester (26).
A screw-capped vial containing 25 (20 mg, 0.049 mmol)
and 11 (8 mg, 10 mmol) in PhMe was sparged with ethylene
for 10 min. The vial was then heated with stirring under an
atmosphere of ethylene (balloon) at 70 8C for 5 h. The
mixture was cooled to room temperature, and then DMSO
(1 mL) was added. The solution was stirred for 16 h at room
temperature, and then concentrated under reduced pressure.
The remaining residue was purified by flash chromato-
graphy (neutral Al2O3) eluting with Et2O/pentane (1:3) to
4.97–4.84 (m, 1H), 4.62–4.38 (br m, 1H), 3.92–3.72 (br m,
1H), 2.68–2.45 (m, 1H), 2.34–2.13 (m, 1H), 2.12–1.75
(comp, 4H), 1.66–1.59 (dd, J¼6.3, 2.1 Hz, 3H), 1.26–1.19
(app dd, J¼6.4, 3.6 Hz, 9H); 13C NMR (75 MHz, CDCl3) d
154.8, 154.4, 148.2, 127.6, 126.5, 68.2, 57.3, 49.5, 36.4,
31.3, 29.7, 22.3, 22.2, 18.0, 20.1; mass spectrum (CI) m/z
308 (Mþ1), 292, 264 (base), 238, 179.
4.1.15. (2R,5S)-5-But-3-enyl-2-(triisopropylsilanyl-oxy-
ethynyl)pyrrolidine-1-carboxylic acid isopropyl ester
(25). A 2.2 M solution of n-BuLi in hexanes (0.83 mL,
1.8 mmol) was added to a solution of 2,2,6,6-tetramethyl-
piperidine (0.34 mL, 2.0 mmol) in THF (3.4 mL) at 0 8C.
The resulting light yellow solution was stirred at 0 8C for
1
afford 11 mg (55%) of 26 as a pale-yellow oil. H NMR
(500 MHz, PhMe-d8, 2 rotamers) d 6.37–6.29 (dt, J¼16.3,
6.0 Hz, 1H), 5.16–5.15 (d, J¼8.0 Hz, 0.3H), 5.08–4.98
(m, 1H), 4.90–4.88 (d, J¼7.6 Hz, 0.7H), 4.66 (s, 0.3H),

J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
7311
4.52–4.46 (comp, 1.3H), 4.36 (s, 0.3H), 4.27–4.22 (comp,
1.2H), 2.27–2.12 (comp, 1.3H), 2.11–1.69 (comp, 4H),
1.69–1.62 (m, 1H), 1.42–1.04 (comp, 29H); 13C NMR
(125 MHz, PhMe-d8) d 156.9, 153.5, 144.2, 127.2, 126.4,
91.0, 89.8, 67.8, 67.5, 57.3, 56.4, 55.7, 55.1, 34.0, 32.5,
32.3, 31.3, 31.1, 29.8, 23.8, 23.6, 22.4, 22.3, 18.4, 13.3;
mass spectrum (CI) m/z 408.2933 [C23H41NO3Si (Mþ1)
requires 408.2934], 448, 436, 408 (base), 394, 364, 348,
322.
6.5 Hz, 1H), 5.15–4.98 (comp, 3H), 4.94–4.91 (m, 1H),
4.36–4.33 (m, 1H), 3.93–3.87 (m, 1H), 3.61 (s, 2.75H,
major diast.), 3.57 (s, 0.25H, minor diast.), 2.24–2.17 (m,
1H), 2.14–1.86 (comp, 5H), 1.74–1.66 (m, 1H), 1.56–1.47
(m, 1H); 13C NMR (125 MHz, DMSO-d6, 100 8C) d 172.2,
153.4, 137.8, 136.3, 127.6, 127.1, 126.7, 113.8, 65.6, 59.1,
57.8, 51.0, 32.6, 29.2, 28.8, 27.6; IR (neat) 2954, 1752,
1707, 1410, 1204, 1176, 1107, 1005, 913, 748, 696 cm21
;
mass spectrum (CI) m/z 318.1695 [C18H24NO4 (Mþ1)
requires 318.1705], 318 (base), 274, 182.
4.1.17. (2R)-Benzyloxycarbonylamino-5-oxonon-8-enoic
acid methyl ester (17c). 4-Bromo-1-butene (1.0 mL,
9.9 mmol) was added to a stirred mixture of magnesium
turnings (3.8 g, 160 mmol) in THF (160 mL) at room
temperature. The mixture was stirred for 20 min, and an
additional portion of 4-bromo-1-butene (7.0 mL, 69 mmol)
was added. The resulting mixture was stirred for an
additional 30 min, and transferred via cannula to a flask
containing TMEDA (24 mL, 160 mmol). The initially
cloudy suspension was stirred until all precipitate had
disappeared (5 min), whereupon the solution was trans-
ferred via cannula to a solution of 16c (14.6 g, 52.7 mmol)
in THF (260 mL) at 278 8C. The mixture was stirred for
1.5 h at 278 8C, and i-PrOH (35 mL) was added, and the
reaction mixture was warmed to room temperature before
pouring into a mixture of 10% H3PO4 (300 mL) and Et2O
(100 mL). The layers were separated, and the aqueous layer
was extracted with Et2O (2£100 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure to afford a
yellow oil. The crude product was purified by flash
chromatography (SiO2) eluting with Et2O/pentane (2:1) to
provide 11.9 g (73%) of 17c as a pale-yellow oil. 1H NMR
(500 MHz, DMSO-d6) d 7.69 (br d, J¼7.9 Hz, 0.9H), 7.38–
7.24 (comp, 5H), 5.76 (ddt, J¼16.8, 10.3, 6.5 Hz, 1H), 5.02
(s, 2H), 4.97 (app dq, J¼17.2, 1.8 Hz, 1H), 4.94–4.90 (m,
1H), 4.01 (m, 1H), 3.62 (s, 2.6H), 3.55 (s, 0.4H), 2.56–2.43
(comp, 4H), 2.20–2.15 (comp, 2H), 1.95–1.88 (m, 1H),
1.76–1.68 (m, 1H); 13C NMR (125 MHz, DMSO-d6) d
208.7, 172.5, 156.0, 137.5, 136.9, 128.3, 127.8, 127.7,
115.0, 65.5, 53.1, 51.8, 40.8, 37.9, 27.2, 24.7; IR (neat)
3342, 2954, 2258, 1712, 1518, 1050, 913, 736 cm21; mass
spectrum (CI) m/z 334.1642 [C18H24NO5 (Mþ1) requires
334.1655], 334, 316, 290 (base), 272, 182, 119.
4.1.19. (2R,5R)-But-3-enyl-2-ethynylpyrrolidine-1-car-
boxylic acid benzyl ester (28). A solution of 1.0 M
DIBAL-H in PhMe (7.4 mL) was added to a solution of
27 (1.4 g, 4.4 mmol) in PhMe (22 mL) at 278 8C. The
resulting solution was stirred at 278 8C for 3 h, whereupon
i-PrOH (22 mL) was slowly added via cannula. The cooling
bath was removed, and the reaction mixture was warmed to
room temperature. To the resulting cloudy-white solution
was added solid Cs2CO3 (8.6 g, 26 mmol) in one portion.
After approximately 1 min, a solution of 9 (1.7 g, 8.8 mmol)
in i-PrOH (13 mL) was added via cannula. The resulting
yellow solution was stirred at room temperature for 17 h,
whereupon a mixture of sat. aqueous Rochelle’s salt
solution (50 mL) and EtOAc (30 mL) were added. The
reaction mixture was vigorously stirred for 2 h, and then
poured into H2O (50 mL). The resulting layers were
separated, and the aqueous layer was extracted with Et2O
(3£30 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure to afford a yellow oil. The crude product
was purified by flash chromatography (SiO2) eluting with
Et2O/pentane (1:2) to provide 826 mg (67%) of 28 as a pale-
yellow oil, and 74 mg (6%) of the corresponding trans-
1
product. H NMR (500 MHz, DMSO-d6, 100 8C) d 7.40–
7.27 (comp, 5H,), 5.80 (ddt, J¼17.0, 10.2, 6.5 Hz, 1H), 5.11
(s, 2H), 5.01 (app dq, J¼17.2, 1.7 Hz, 1H), 4.95–4.91 (m,
1H), 4.58–4.55 (m, 1H), 3.88–3.81 (m, 1H), 2.95 (app d,
J¼2.2 Hz, 1H), 2.17–1.87 (comp, 6H), 1.82–1.75 (m, 1H),
1.60–1.51 (m, 1H); 13C NMR (125 MHz, DMSO-d6,
100 8C) d 153.3, 137.6, 136.5, 127.7, 127.0, 126.7, 113.9,
84.5, 71.6, 65.6, 57.4, 48.0, 33.2, 31.2, 28.9; IR (neat) 3307,
2955, 2355, 2250, 1696, 1408, 1355, 1185, 1102 cm21
;
mass spectrum (CI) m/z 284.1639 [C18H22NO2 (Mþ1)
requires 284.1651], 284 (base), 240.
4.1.18. (2R,5R)-But-3-enylpyrrolidine-1,2-dicarboxylic
acid 1-benzyl ester 2-methyl ester (27). BF3·OEt2
(15.2 mL, 120 mmol) was added to a solution of Ph3SiH
(15.7 g, 60.1 mmol) in CH2Cl2 (40 mL) at room tempera-
ture. The solution was stirred for 10 min, and then added via
cannula to a stirred solution of 17c (10.0 g, 30.0 mmol) in
CH2Cl2 (100 mL) at 278 8C. The reaction mixture was kept
with stirring at 278 8C for 0.5 h, whereupon the cooling-
bath was removed and stirring was continued at room
temperature for an additional 2 h. The reaction mixture was
then recooled to 278 8C and poured into a solution of sat.
aqueous NaHCO3 (350 mL). The layers were separated and
the aqueous phase was extracted with Et2O (3£75 mL),
dried (MgSO4), filtered, and concentrated under reduced
pressure to afford a pale-yellow oil. The crude product was
purified by flash chromatography (SiO2) eluting with Et2O/
pentane (1:1) to provide 9.37 g (98%) of 27 (dr¼11:1, by 1H
NMR) as a clear oil. 1H NMR (500 MHz, DMSO-d6,
100 8C) d 7.38–7.27 (comp, 5H), 5.81 (ddt, J¼16.9, 10.3,
4.1.20. (2R)-But-3-enyl-(5R)-2-(1-methylsiletan-1-
ylethynyl)pyrrolidine-1-carboxylic acid benzyl ester
(29). A solution of 28 (302 mg, 1.07 mmol) in THF
(11 mL) was added via cannula to a solution of KHMDS
(4.3 mL, 2.1 mmol, 0.5 M in PhMe) in THF (4.3 mL) at
278 8C. The mixture was stirred at 278 8C for 10 min, and
then 1-chloro-1-methylsilacyclobutane (0.52 mL, 514 mg,
4.3 mmol) was added via syringe. Stirring was continued at
278 8C for 5 h, whereupon the reaction was poured into a
mixture of 1 N HCl (40 mL) and Et2O (10 mL). The
resulting layers were separated, and the aqueous phase was
extracted with Et2O (2£15 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated under
reduced pressure to provide a crude oil that was purified by
flash chromatography (SiO2) eluting with Et2O/pentane
(1:3) to afford 309 mg (79%) of 29 as a colorless oil along
1
with 15% recovered 28. H NMR (400 MHz, CDCl3) d
7.42–7.25 (comp, 5H), 5.80 (br s, 1H), 5.27–4.88 (comp,

7312
J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
4H), 4.64 (br s, 1H), 3.96–3.80 (m, 1H), 2.18–1.80 (comp,
9H), 1.68–1.56 (m, 1H), 1.24–1.10 (comp, 2H), 1.07–0.96
(comp, 2H), 0.38 (s, 3H); 13C NMR (125 MHz, CDCl3) d
153.3, 138.2, 136.9, 128.4, 127.8, 127.7, 127.5, 114.6, 85.1,
76.1, 66.8, 58.3, 49.4, 32.3, 30.3, 30.1, 29.7, 18.3, 15.3,
20.2.; IR(neat) 3067, 3034, 2931, 2711, 1705, 1641, 1496,
1449, 1406, 1355, 1308, 1252, 1184, 1107, 996, 911,
872 cm21; mass spectrum (CI) m/z 368.2053 [C22H30NOSi
(Mþ1) requires 368.2046], 368 (base), 324, 284.
ture. The resulting brown solution was stirred for 5 min and
then cooled to 278 8C. To this mixture was added a solution
33 (87 mg, 0.29 mmol) in THF (2 mL). The resulting
mixture was allowed to warm slowly to room temperature
over 2 h, and stirring was continued for 20 h at room
temperature. A solution of sat. aqueous NaHSO3 (5 mL)
was added, and the mixture was heated to reflux for 2.5 h.
The resulting black mixture was cooled to room tempera-
ture, diluted with EtOAc (10 mL), and then filtered through
a plug of SiO2, eluting with EtOAc. The filtrate was
concentrated under reduced pressure to provide a crude oil
that was purified by flash chromatography (SiO2) eluting
with EtOAc/hexanes (3:1) to afford 89 mg (76%) of 34 as a
pale-yellow oil and 15 mg (13%) of the undesired cyclic
4.1.21. (2R)-But-3-enyl-(5R)-prop-1-ynylpyrrolidine-1-
carboxylic acid benzyl ester (32). A solution of 28
(765 mg, 2.69 mmol) in THF (13 mL) was added to a
solution of 1.0 M NaHMDS in THF (8.0 mL, 8.0 mmol) at
278 8C. The resulting solution was stirred for 5 min at
278 8C, and then MeOTf (1.53 mL, 13.5 mmol) was added.
After stirring for 2 h at 278 8C, the reaction mixture was
poured into a mixture of sat. aqueous NaHCO3 (90 mL) and
Et2O (20 mL), and the layers were separated. The aqueous
phase was extracted with Et2O (3£50 mL) and the
combined organic extracts were washed with 1 N HCl
(2£70 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure to provide a pale-yellow oil that was
purified by flash chromatography (SiO2) eluting with Et2O/
pentane (1:2) to afford 781 mg (97%) of 32 as a pale-yellow
1
diol 35 (mp 94–95 8C). H NMR (34) (500 MHz, DMSO-
d6, 100 8C) d 7.36–7.27 (comp, 5H), 5.64–5.61 (m, 1H),
5.06 (app q, J¼12.6 Hz, 2H), 4.68–4.66 (m, 1H), 4.41–4.37
(m, 1H), 4.02–3.93 (comp, 2H), 3.39–3.25 (comp, 2H),
2.28–2.12 (comp, 3H), 2.03–1.95 (m, 1H), 1.86–1.80
(comp, 2H), 1.73–1.67 (m, 1H), 1.61–1.55 (m, 1H), 1.26–
1.15 (comp, 3H); 13C NMR (100 MHz, CDCl3) d 152.2,
151.4, 136.7, 127.7, 127.1, 127.0, 122.1, 73.9, 68.0, 65.3,
55.5, 54.9, 31.1, 28.0, 24.2, 22.6; IR (neat) 3401, 2931,
1672, 1426, 1326, 1114, 914, 732 cm21; mass spectrum (CI)
m/z 332.1854 [C19H26NO4 (Mþ1) requires 332.1862], 332,
314 (base).
1
oil. H NMR (500 MHz, DMSO-d6, 100 8C) d 7.39–7.33
(comp, 4H), 7.32–7.27 (m, 1H), 5.80 (ddt, J¼16.9, 10.2,
6.5 Hz, 1H), 5.10 (dd, J¼24.0, 12.9 Hz, 1H), 5.03–4.98 (m,
1H), 4.94–4.90 (m, 1H), 4.55–4.51 (m, 1H), 3.85–3.79 (m,
1H), 2.15–1.96 (comp, 4H), 1.95–1.84 (comp, 2H), 1.82–
1.72 (comp, 4H), 1.58–1.51 (m, 1H); 13C NMR (125 MHz,
DMSO-d6, 100 8C) d 153.3, 137.7, 136.6, 127.6, 127.0,
126.7, 113.8, 79.8, 77.2, 65.4, 57.3, 48.3, 33.3, 31.5, 29.0,
28.9, 2.3; IR (neat) 2955, 1702, 1402, 1343, 1208,
4.1.24. (1)-(1R)-2-Acetyl-9-benzyloxycarbonyl-9-azabi-
cyclo[4.2.1]-2-nonene (36). Solid NaIO4 (140 mg,
0.655 mmol) was added to a solution of 34 (70 mg,
0.21 mmol) in 50% aqueous THF (4 mL) at room
temperature. The reaction mixture was stirred for 1.5 h,
and then diluted with H2O (2 mL). The solution was poured
into a mixture of H2O (15 mL) and Et2O (5 mL), and the
layers were separated. The aqueous phase was extracted
with Et2O (3£10 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated under reduced
pressure to afford a pale-yellow oil. The crude product was
purified by flash chromatography (SiO2) eluting with Et2O/
pentane (8:1) to afford 60 mg (95%) of 36 as a pale-yellow
oil. All data in accordance with the literature.44 [a]D26 236.1
1097 cm21
;
mass spectrum (CI) m/z 298.1800
[C19H24NO2 (Mþ1) requires 298.1807], 298 (base).
4.1.22. (1)-(1R)-2-Isopropenyl-9-benzyloxycarbonyl-9-
azabicyclo[4.2.1]-2-nonene (33). To a degassed solution
of 32 (212 mg, 0.250 mmol) in CH2Cl2 (500 mL) was added
a solution 11 (744 mg, 2.50 mmol) in degassed CH2Cl2
(30 mL). The mixture was stirred under a blanket of argon
for 16 h, and then DMSO (0.89 mL) was added to
decompose the catalyst. The mixture was stirred for an
additional 23 h, whereupon the solvent was removed under
reduced pressure and the resulting residue was purified by
flash chromatography (SiO2) eluting with Et2O/pentane
(1:2) to afford 623 mg (84%) of 33 as a yellow oil. 1H NMR
(500 MHz, DMSO-d6, 100 8C) d 7.36–7.25 (comp, 5H),
5.74–5.71 (m, 1H), 5.10–4.96 (comp, 3H), 4.91–4.84
(comp, 2H), 4.39–4.34 (m, 1H), 2.29–2.16 (comp, 3H),
2.13–1.97 (comp, 2H), 1.82 (s, 3H), 1.77–1.68 (comp, 2H),
1.64–1.57 (m, 1H); 13C NMR (125 MHz, DMSO-d6,
100 8C) d 152.3, 146.3, 142.4, 136.8, 127.6, 127.0, 126.7,
125.2, 110.5, 65.2, 56.5, 54.7, 31.8, 30.6, 29.2, 22.7, 20.7;
IR (neat) 2931, 1701, 1421, 1330, 1107, 1005 cm21; mass
spectrum (CI) m/z 298.1799 [C19H24NO2 (Mþ1) requires
298.1807], 298 (base), 254.
1
(c 1.42, CH3OH) (lit.44 [a]D22 237.5 (c 1.12, CH3OH). H
NMR (400 MHz, CDCl3) d 7.38–7.22 (comp, 5H), 6.83–
6.75 (m, 1H), 5.27 (d, J¼8.9 Hz, 1H), 5.16–4.98 (comp,
2H), 4.52–4.38 (m, 1H), 2.47–2.00 (comp, 8H), 1.74–1.61
(comp, 3H); 13C NMR (100 MHz, CDCl3) d 197.8, 153.4,
149.3, 142.3, 136.8, 128.4, 127.9, 127.7, 66.3, 56.0, 53.0,
31.6, 30.4, 28.5, 25.3, 24.1; IR (neat) 3538, 2951, 1700,
1665, 1418, 1106 cm21; mass spectrum (CI) m/z 300.1587
[C18H22NO3 (Mþ1) requires 300.1600], 300 (base), 256,
192.
4.1.25. (1)-(1R)-2-Acetyl-9-azabicyclo[4.2.1]-2-nonene
(1). Freshly distilled TMSI (122 mL, 0.856 mmol) was
added to a solution of 36 (122 mg, 0.408 mmol) in MeCN
(1.4 mL) at 210 8C. The resulting solution was stirred for
20 min in the absence of light. A solution of 1.25 M
methanolic HCl (1 mL) was added and the resulting solution
was maintained in the dark while warming to room
temperature. The solution was concentrated under reduced
pressure, and the resulting solid was dissolved in H2O
(10 mL). The aqueous solution was extracted with CH2Cl2
(2£4 mL). The aqueous phase was then basified to pH¼12
4.1.23. (1)-(1R)-2-(1,2-Dihydroxy-1-methylethyl)-9-ben-
zyloxycarbonyl-9-azabicyclo[4.2.1]-2-nonene (34). Et3N
(74 mL, 0.53 mmol) was added to a solution of OsO4
(108 mg, 0.424 mmol) in THF (2.1 mL) at room tempera-

J. B. Brenneman et al. / Tetrahedron 60 (2004) 7301–7314
7313
5426–5427. (b) Grubbs, R. H.; Fu, G. C. J. Am. Chem. Soc.
1992, 114, 7324–7325.
with NH4OH and extracted first with CH2Cl2 (2£4 mL) and
then with 3:1 CH2Cl2/i-PrOH (2£5 mL). The combined
organics were rapidly dried (MgSO4), filtered, and con-
centrated under reduced pressure to afford a pale-yellow oil.
The light sensitive free-base was dried at 0.1 mm Hg for 1 h
to afford 67 mg (99%) of 1 as a pale-yellow oil. The 1H and
13C NMR data were consistent with those reported in the
literature.44,46 1H NMR (400 MHz, CDCl3) d 6.89–6.84 (m,
1H), 4.66 (app d, J¼8.9 Hz, 1H), 3.82–3.75 (m, 1H), 3.13
(br s, 1H), 2.52–2.34 (comp, 2H), 2.25 (s, 3H), 2.21–2.09
(m, 1H), 2.01–1.92 (m, 1H), 1.82–1.57 (comp, 4H); 13C
NMR (100 MHz, CDCl3) d 198.9, 152.4, 143.6, 58.1, 54.3,
33.5, 33.1, 30.5, 25.8, 25.2; IR (neat) 3392, 2933, 1663,
1433, 1397, 1361, 1258, 1228, 847 cm21; mass spectrum
(CI) m/z 166.1234 [C10H16NO (Mþ1) requires 166.1232],
166 (base), 149.
2. For a review, see: Martin, S. F. Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley–VCH: New York, 2003; Vol. 2,
pp 338–352.
3. For a recent review of applications of RCM to the synthesis of
oxygen and nitrogen heterocycles, see: Deiters, A.; Martin,
S. F. Chem. Rev. 2004, 104, 2199–2238.
4. (a) Martin, S. F.; Liao, Y.; Chen, H.-J.; Paetzel, M.; Ramser,
M. N. Tetrahedron Lett. 1994, 35, 6005–6008. (b) Martin,
S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Patzel, M.;
Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52,
7251–7264.
5. Deiters, A.; Martin, S. F. Org. Lett. 2002, 4, 3243–3245.
6. (a) Martin, S. F.; Liao, Y.; Wong, Y.-L.; Rein, T. Tetrahedron
Lett. 1994, 35, 691–694. (b) Martin, S. F.; Humphrey, J. M.;
Ali, A.; Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866–867.
(c) Martin, S. F.; Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.;
Wong, Y.-L.; Chen, H.-J.; Courtney, A. K. J. Am. Chem. Soc.
2002, 124, 8584–8592.
4.1.26. (1)-(1R)-2-Acetyl-9-azabicyclo[4.2.1]-2-nonene
hydrochloride (1·HCl). A solution of 1.25 M HCl in
MeOH (1 mL) was added to a solution of 1 (48 mg,
0.16 mmol) in dry MeOH (1 mL) at 0 8C. The solvent was
removed under reduced pressure, and the crude oil was dried
under vacuum (0.3 mm Hg) for 15 h. The resulting off-
white foam was azeotropically dried with PhH (2£0.3 mL)
and then under vacuum (0.3 mm Hg) for 2 h. The resulting
foam was dissolved in a solution of 6% MeOH/Et2O (2 mL),
at 50 8C. The solution was cooled to room temperature and
placed in a 4 8C refrigerator for 5 d. The resulting colorless
prisms were collected by vacuum filtration, rinsing with
cold Et2O (5 mL), and dried at 0.3 mm Hg for 2 d to afford
32 mg (100%) of 1·HCl. All spectra in accordance with the
literature.46 [a]D27 þ37.3 (c 2.08, abs. EtOH) [(lit.46 [a]2D4
þ43.2 (c 0.676, abs. EtOH), (lit.54 [a]D24 þ36 (c 0.85,
7. (a) Martin, S. F.; Wagman, A. S. Tetrahedron Lett. 1995, 36,
1169–1170. (b) Martin, S. F.; Fellows, I. M.; Kaelin, D. E., Jr.
J. Am. Chem. Soc. 2000, 10781, 10787.
8. (a) Martin, S. F.; Neipp, C. E. Tetrahedron Lett. 2002, 43,
1779–1782. (b) Martin, S. F.; Neipp, C. E. J. Org. Chem.
2003, 68, 8867–8878.
9. Washburn, D. G.; Heidebrecht, R. W., Jr.; Martin, S. F. Org.
Lett. 2003, 5, 3523–3525.
10. Devlin, J. P.; Edwards, O. E.; Gorham, P. R.; Hunter, N. R.;
Pike, R. K.; Stavric, B. Can. J. Chem. 1977, 55, 1367–1371.
11. (a) Carmichael, W. W.; Biggs, D. F.; Gorham, P. R. Science
1975, 187, 542–544. (b) Spivak, C. E.; Witkop, B.;
Albuquerque, E. X. Mol. Pharmacol. 1980, 18, 384–394.
12. For a review of earlier syntheses of 1 see: (a) Mansell, H. L.
Tetrahedron 1996, 52, 6025–6061. For recent syntheses of 1,
see: (b) Oh, C.-Y.; Kim, K.-S.; Ham, W.-H. Tetrahedron Lett.
1998, 39, 2133–2136. (c) Trost, B. M.; Oslob, J. D. J. Am.
Chem. Soc. 1999, 121, 3057–3064. (d) Aggarwal, V. K.;
Humphries, P. S.; Fenwick, A. Angew. Chem., Int. Ed. 1999,
38, 1985–1986. (e) Parsons, P. J.; Camp, N. P.; Edwards, N.;
Sumoreeah, L. R. Tetrahedron 2000, 56, 309–315. (f) Wegge,
T.; Schwarz, S.; Seitz, G. Tetrahedron: Asymmetry 2000, 11,
1405–1410, See also Refs. 14,15.
1
EtOH)]; mp 151–153 8C (lit.46 mp 152–153 8C). H NMR
(500 MHz, CDCl3) d 10.02 (br s, 1H), 9.42 (br s, ), 7.11 (dd,
J¼8.2, 3.4 Hz, 1H), 5.23–5.19 (m, 1H), 4.37–4.29 (m, 1H),
2.65–2.58 (m, 1H), 2.56–2.47 (comp, 2H), 2.42–2.30
(comp, 5H), 1.94–1.78 (comp, 3H); 13C NMR (125 MHz,
CDCl3) d 196.4, 145.4, 143.9, 58.3, 52.1, 30.2, 27.7, 27.5,
25.2, 23.6; IR (neat) 3417, 2924, 1661, 1471, 1432, 1403,
1364, 1269, 1230, 911, 743 cm21; mass spectrum (CI) m/z
200.0835 [C10H15NOCl (M21) requires 200.0842], 216,
202, 200 (base), 179.
13. (a) Williams, M.; Arneric, S. P. Exp. Opin. Invest. Drugs 1996,
5, 1035–1045. (b) Arneric, S. P.; Holladay, M. W.; Sullivan,
J. P. Exp. Opin. Invest. Drugs 1996, 5, 79–100. (c) Sutherland,
A.; Gallagher, T.; Sharples, C. G. V.; Wonnacott, S. J. Org.
Chem. 2003, 68, 2475–2478.
Acknowledgements
We thank the National Institutes of Health, the Robert
A. Welch Foundation, Pfizer, Inc., Merck Research
Laboratories, and the Alexander von Humboldt Stiftung
for their generous support of this research. R. M. gratefully
acknowledges a Feodor-Lynen postdoctoral fellowship
from the Alexander von Humboldt Foundation. We
additionally thank Mr. Alexander Rudolph and Dr.
Christopher Straub for helpful discussions. We are also
grateful to Dr. Richard Fisher (Materia, Inc.) for catalyst
support and helpful discussions.
14. For a preliminary account of some of this work, see:
Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6,
1329–1331.
15. Subsequent to publication of our synthesis of 1 (Ref. 14),
another synthesis has been published in which an enyne RCM
was used to construct the bicyclic ring system. See: Mori, M.;
Tomita, T.; Kita, Y.; Kitamura, T. Tetrahedron Lett. 2004, 45,
4397–4399.
16. The synthesis of the closely related alkaloid (2)-ferruginine
using an enyne RCM to construct the requisite aza-
bicyclo[3.2.1]octane skeleton was recently reported. See:
Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett.
2004, 6, 1469–1471.
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