Studies towards the total synthesis of palau'amine. Formation of 4,5-dihydropyrrole-2-carboxylate intermediates by alkene-enamide ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2004.06.140

A highly functionalized 4,5-dihydropyrrole-2-carboxylate is assembled by alkene-enamide ring-closing metathesis. Subsequent intramolecular azomethine imine dipolar cycloaddition provides a triazacyclopenta[cd]pentalene intermediate of potential use in a t

Full text of DOI:10.1016/j.tet.2004.06.140

Tetrahedron 60 (2004) 9559–9568
Studies towards the total synthesis of palau’amine. Formation of
4
,5-dihydropyrrole-2-carboxylate intermediates by
alkene–enamide ring-closing metathesis
†
Jason D. Katz and Larry E. Overman
*
Department of Chemistry, 516 Rowland Hall, University of California at Irvine, Irvine, CA 92697-2025, USA
Received 9 April 2004; revised 7 June 2004; accepted 9 June 2004
Available online 27 August 2004
Dedicated to Professor Alois F u¨ rstner on receipt of the 2004 Tetrahedron Chair in Organic Synthesis
Abstract—A highly functionalized 4,5-dihydropyrrole-2-carboxylate is assembled by alkene–enamide ring-closing metathesis. Subsequent
intramolecular azomethine imine dipolar cycloaddition provides a triazacyclopenta[cd]pentalene intermediate of potential use in a total
synthesis of palau’amine.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
system, a central fragment that contains six contiguous
stereocenters. Five of these stereogenic carbons comprise
the cyclopentane ring, which is substituted on the concave a
face at every carbon. This density of functionality,
combined with the two proximal spiroguanidine fragments,
make palau’amine an unusually challenging synthetic
A diverse array of secondary metabolites displaying a broad
range of biological activities have been isolated from
sponges. A number of these metabolites contain one or
more guanidine functional groups embedded in novel
polycyclic ring systems. The palau’amines, styloguanidines
and konbu’acidin, exemplified by palau’amine (1) and
styloguanidine (2), are some of the most structurally intricate
members of this group of marine guanidine alkaloids.
1
2
6
target. Published reports from other groups have focused
largely on installing the functionality of the cyclopentane
7
–10
ring.
In contrast, previous work from our laboratories
3
–5
has addressed the issue of relating the configuration of the
two spiroguanidine units to that of the central 3-azabicyclo-
1
1,12
[
3.3.0]octane unit.
been to employ an intramolecular azomethine imine
,3-dipolar cycloaddition to construct triazacyclopenta-
cd]pentalenes that encode these structural features of
Our approach to this objective has
1
[
palau’amine: 3/4/5 (Scheme 1).
We recently described the preparation of cycloaddition
precursor 6 having a siloxy substituent on the side chain and
demonstrated that it, and its siloxy epimer, successfully
condensed with thiosemicarbazide to form the desired
triazacyclopenta[cd]pentalene (azatriquinane) products.
However, the Dieckmann cyclization strategy we employed
to assemble the 4,5-dihydropyrrole-2-carboxylate moiety of
The diverse biological activities of palau’amine, in
particular its substantial immunosupressive activity and
apparent low toxicity, make this alkaloid an important target
for total synthesis. Much of the structural complexity of
palau’amine resides in its 3-azabicyclo[3.3.0]octane ring
12
3
6 was inefficient, and would not be useful in a total synthesis
endeavor directed at palau’amine.
Keywords: Palau’amine; Enamide; Ring-closing metathesis; 4,5-Dihydro-
Only a few methods have been described for the synthesis of
4,5-dihydropyrrole-2-carboxylates. Most involve function-
alization of proline analogs by either elimination of a
pyrrole-2-carboxylate; Azomethine imine cycloaddition.
*
Corresponding author. Tel.: C1-949-824-7156; fax: C1-949-824-3866;
e-mail: leoverma@uci.edu
1
3,14
12,15
†
Current address: Department of Medicinal Chemistry, Merck & Co., Inc.;
P.O. Box 2000; Rahway, NJ 07065, USA.
heteroatom from the a-
or by rearrangement of the double bond of a pyrroline
or b-position
of a prolinate,
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.140

9560
J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
4,5-dihydropyrrole-2-carboxylate ring system of the
cycloaddition substrates.
1
.1. Synthesis plan
The retrosynthetic analysis that led to the convergent
synthesis sequence described herein is outlined in Scheme
2
. We saw the 4,5-dihydropyrrole-2-carboxylate 8 arising
2
3
by RCM of densely-functionalized diene 9. The dehy-
droalanine functionality of diene 9 would be formed from an
appropriate amino acid analog, whereas the a-keto ester
functionality would be installed by elaboration of an
aldehyde precursor. Thus, diene amino ester 9 simplifies
to pyrrole acid 10 and unsaturated a-aminoester 11. Further
retrosynthetic simplification of aminoester 11 leads to the
simple a-amino ester and homoallylic alcohol precursors 12
and 13, respectively.
2. Results and discussion
2
.1. Model system for the ring-closing metathesis
As there were no previous examples of forming 4,5-
dihydropyrrole-2-carboxylates by RCM of dehydroalanine
2
3–27
precursors,
initially with a simple model substrate. The known diene
4
we decided to pursue this transformation
2
8
1 was chosen for these studies (Scheme 3). We were
pleased to observe that addition of 10 mol% of the Grubbs
2
3
N-heterocyclic carbene catalyst 15 to diene 14 at 40 8C led
to the formation of the desired 4,5-dihydropyrrole-2-
carboxylate 16 in 77% yield after only 4 h. We turned to
prepare more elaborate dehydroalanine precursors.
Scheme 1.
2
.2. Synthesis of homoallylic amines 22
The synthesis of the RCM precursors was designed so that
enantioenriched intermediates could be prepared from a
readily available enantioenriched epoxy alcohol pre-
1
6,17
precursor.
access these heterocycles employ as key steps: oxidative
Other constructions that have been used to
1
decarboxylations; metalation of enamides; carbonyl-
8
19
29
cursor. However, for convenience, our initial survey of
this chemistry was carried out in a racemic series. Thus,
preparation of homoallylic alcohol 19 began with m-CPBA
2
ation of lactam-derived enol triflates or enol phosphates;
0
21
2
2
or intramolecular Mitsunobu alkylations. In this paper, we
report the development of a convergent strategy to prepare
potential palau’amine precursors that utilizes an alkene–
enamide ring-closing metathesis (RCM) to construct the
3
0
31
epoxidation of allylic alcohol 17, followed by copper
catalyzed regioselective opening of the epoxy alcohol
product with vinylmagnesium bromide to produce 1,3-diol
Scheme 2.

J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
9561
With the homoallylic alcohols in hand, it was necessary to
elaborate these intermediates to a-aminoesters. Initial
attempts at alkylating serine methyl ester with a triflate
derivative of 19b were unsuccessful, so a reductive
amination sequence was developed (Scheme 5). Alcohol
1
aldehyde 20 with negligible double bond migration by
9a could be oxidized cleanly to the b,g-unsaturated
3
3
reaction with the Dess–Martin periodinane. Subsequent
reductive amination of this intermediate with serine-derived
3
4
amino ester 21 and sodium triacetoxyborohydride pro-
vided secondary amine 22a in 70% yield from the alcohol.
A small amount of allylic amine 23, resulting from
isomerization of the double bond during the reductive
amination step, was also produced. The analogous homo-
allylic secondary amines 22b–e were prepared by a similar
series of transformations.
Scheme 3.
3
8 in 65% overall yield (Scheme 4). Employing CuI or
2
1
CuI–PBu in the epoxide opening step was less effective
3
because significant quantities of a product resulting from
halide opening of the epoxide were produced; the use of
CuBr–SMe minimized formation of this halide by-product.
2.3. Coupling of the homoallyl amines 22 with pyrrole
carboxylic acid 10
2
The secondary alcohol of diol 18 could be selectively
protected to provide homoallylic alcohol 19a in good yield
by a three step sequence that involved sequential masking of
the primary alcohol as a pivalate ester, protection of the
secondary alcohol, and reductive cleavage of the piva-
Coupling of the homoallylic amine to the acylpyrrole
fragment proved to be quite demanding. Initial attempts to
couple the TBS-protected serine analog 22b with pyrrole
acid 10, mediated by standard coupling reagents (PyBrOP,
HATU, or DCC), were unsuccessful (Scheme 6). Related
condensations of 22b with the corresponding pyrrole
3
2c
late. A similar sequence was employed to prepare
congeners 19b,c.
Scheme 4.
Scheme 5.

9562
J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
Scheme 6.
Table 1.
Amine
R
P
Y
Coupling agent
Amide
Yield (%)
a
22b
22c
22d
22e
22e
22e
22e
22a
CH
H
2
OTBS
TBS
TBS
Bn
Bn
Bn
Bn
Bn
PMB
OH
OH
OH
OH
OH
PyBrOP
24b
24c
24d
24e
24e
24e
24e
24a
0
95
78
0
0
0
a
PyBrOP
a
Me
CH
CH
CH
CH
CH
PyBrOP
a,b
PyBrOP
2
2
2
2
2
OMe
OMe
OMe
OMe
OMe
c
HATU
d
OC
OH
OH
6
F
5
N/A
BOPCl
e
87
O95
e
BOPCl
a
b
c
d
e
PyBrOP, i-Pr
2
NEt, DMAP, CH
NEt, DMAP, DMF, rt.
NEt, DMF, rt.
NEt, DMAP, CH Cl or NaH, THF, rt.
BOPCl, i-Pr NEt, MeCN, 0 8C to rt.
2 2
Cl , rt.
PyBrOP, i-Pr
2
HATU, HOAt, i-Pr
i-Pr
2
2
2
2
2
carboxylic acid fluoride or trichloromethyl ketone failed
also.
2.4. Ring-closing metathesis and assembly of the
potential palau’amine precursor 31
To examine the role of the steric environment around the
amino acid substituent in the amide formation, we
investigated the coupling of simpler amino acid analogs
with the pyrrole acid. As can be seen in Table 1, PyBrOP-
mediated coupling of pyrrole acid 10 with glycine
derivative 22c proceeded in high yield. Under the same
reaction conditions, alanine derivative 22d was converted to
the amide 24d in 78% yield. Taken together with the failure
of the TBS-protected serine derivative 22b to couple with
pyrrole acid 10, these experiments indicated that the size of
the amino acid side chain had a large effect on the efficiency
of the amide coupling. Fortunately, we discovered that the
O-methyl serine analog 22e could be coupled to pyrrole acid
With the acylpyrrole installed, we turned to investigate
formation of the dehydroalanine functionality (Scheme 7).
Treatment of the methyl ether derivative 24e with sodium
methoxide in methanol resulted in elimination of methanol
to give the dehydroamino ester 25 in an unoptimized 65%
3
5
36
yield, 89% based on consumed starting material. Exposure
of this diene to metathesis catalyst 15 delivered dihydro-
pyrrole 26 in 78% yield, demonstrating that alkene–enamide
RCM would be a viable strategy for forming highly
functionalized 4,5-dihydropyrrole-2-carboxylates.
In our earlier preparations of substrates for intramolecular
azomethine imine cycloadditions, a Horner–Emmons reac-
1
2
tion was employed to install the a-ketoester functionality.
We hypothesized that the basic conditions employed to
generate the dehydroalanine might also facilitate the
1
0 if BOPCl, rather than PyBrOP, was used as the coupling
agent. Using BOPCl, secondary amines 22a and 22e were
converted to amides 24a and 24e in O95 and 87% yields,
respectively.
3
7
‡
Horner–Emmons reaction. To pursue this possibility,
p-methoxybenzyl ether 24a was cleaved selectively with
DDQ to give primary alcohol 27 in high yield (Scheme 8).
This intermediate was then oxidized with the Dess–Martin
reagent and the aldehyde product was immediately
3
8
‡
condensed at room temperature with phosphonate 28 in
the presence of sodium tert-butoxide in a tert-butanol-THF
solvent mixture. As hoped, these conditions promoted both
After these results were obtained, BOPCl-mediated coupling of the TBS
derivative 22b with acid 10 was attempted; however this reaction
proceeded to only 10–15% conversion.

J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
9563
Scheme 7.
the Horner–Emmons condensation and the b-elimination of
methanol to deliver dehydroalanine derivative 29 in 73–
83% yield as an inconsequential 2:1 mixture of enoxysilane
stereoisomers.
other geometric isomer. Obviously, ring formation was
occurring more rapidly with one of the two side chain
stereoisomers. To avoid this complication, we decided to
examine the pivotal RCM step after discharge of the siloxy
group. Therefore, siloxy diene 29 was allowed to react with
buffered CsF to generate a-keto ester 9. Cyclization of this
intermediate with RCM catalyst 15 at 40 8C for 2 days at
substrate concentrations as high as 0.1 M now delivered the
desired dihydropyrrole 8 in excellent yield (75–80%).
We turned to examine RCM for generating a fully
constituted cycloaddition substrate. Cyclization of 29
using the RCM conditions optimized earlier with less
intricate substrates provided dihydropyrrole 30 in 51%
yield, together with 28% of recovered starting material
(Scheme 8). It was significant that the dihydropyrrole
product was highly enriched in one enoxysilane stereo-
isomer, whereas recovered diene 29 was enriched in the
Although the main focus of this study was to develop a
practical route to fully functionalized cycloaddition sub-
strates such as 8, we briefly examined the condensation of 8
Scheme 8.

9564
J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
Scheme 9.
with thiosemicarbazide to form triazatriquinane 31. Using
conditions we had employed earlier with less elaborate
Although certain compounds were isolated as inseparable
mixtures of diastereomers, the various resonances are
distinct in the H NMR spectra. In these instances, the
signal has been reported in the following format: [3.30 (s),
3.25 (s), 3H]. This particular example would represent a
methyl ether present in the diastereomeric mixture. In one
diastereomer, the methyl group appears as a singlet at d
3.30, whereas in the other diastereomer it appears at d 3.25
as a singlet.
1
2
1
substrates (AcOH, 70 8C), this conversion was extremely
slow, requiring O7 days to go to completion. After a brief
survey of reaction conditions, we found that heating an
ethanolic solution of dihydropyrrole 8 and thiosemicarba-
zide in a sealed tube at 110 8C provided triazacyclo-
penta[cd]pentalene 31 in 69–71% yield after only two days
(
Scheme 9).
4
.1.1. 4-(4-Methoxybenzyloxy)-2-vinylbutane-1,3-diol
3
. Conclusion
(18). A 3 L three-neck reaction flask equipped with a low
temperature thermometer and an addition funnel was
charged with freshly prepared CuBr–SMe2 (7.65 g,
37.2 mmol), 1.7 L of Et O, and 335 mL of SMe at room
A RCM is the central step in the practical synthesis of 4,5-
dihydropyrrole-2-carboxylate 8. As this product contains a
wealth of diverse functionality—acylpyrrole, bromide, a,b-
unsaturated ester, a-keto ester and silyl ether—this RCM
reaction superbly highlights the remarkable functional
group tolerance of the Grubbs ruthenium metathesis
catalysts. Efforts to further elaborate triazacyclopenta-
cd]pentalene-containing cycloadducts such as 31 to
palau’amine and congeners are underway.
2
2
temperature. This clear, colorless solution was cooled to
K50 8C, during which time a small amount of a fine white
precipitate formed. A solution of freshly prepared vinyl-
magnesium bromide (370 mL of a 1 M solution in THF,
370 mmol) was added via cannula such that the internal
temperature remained below K50 8C, then the slurry was
maintained at K50 8C for an additional 1 h. The slurry
initially turned a deep brown color upon addition of the
Grignard reagent and over the course of the addition
changed to a greenish-yellow and then a reddish-brown
color. A solution of the (E)-2,3-epoxy-4-(4-methoxybenzyl-
2
3
[
4
. Experimental
4
.1. General methods
oxy)butanol (21.0 g, 93.0 mmol) in 170 mL of Et O was
2
added dropwise via an addition funnel such that the internal
temperature remained below K50 8C, then the slurry was
maintained at K50 8C for an additional 1 h. The slurry was
allowed to warm to K30 8C over 2 h then maintained at
K30 8C for an additional 2 h. The reaction mixture was
cooled to K45 8C and then allowed to warm to 10 8C over
an 11 h period to give a purplish solution. Excess Grignard
reagent was quenched by the addition of 100 mL of a 2:1
solution of saturated aqueous NH Cl-concentrated NH OH,
The procedure we employ to purify THF, CH Cl , Et O,
2
2
2
DME, and toluene has been described: Pangborn, A. B.;
Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers,
F. J.; Organometallics 1996, 15, 1518–1520. Triethylamine,
i-Pr NEt, DMF, and MeCN were purified in a similar
2
manner using modified alumina columns provided by
GlassContour. All reactions were conducted using flame-
dried glassware under a nitrogen atmosphere unless stated
otherwise. Commercial reagents were used as received
unless otherwise indicated.
4
4
then the mixture was poured into an additional 1.5 L of this
buffer and was stirred vigorously until all of the solids had
dissolved and the aqueous layer was a deep blue. The layers
were separated and the organic layer was washed with this
ammonia buffer solution (200 mL) and brine (200 mL). This
solution was dried (Na SO ) and concentrated to give a
Analytical thin layer chromatography was carried out using
0
.25 mm silica plates from Merck. Eluted plates were
visualized first with UV light and then by staining with ceric
sulphate/molybic acid or basic potassium permanganate.
Flash chromatography was performed using 230–400 mesh
2
4
yellow oil containing crude 18 and the regioisomeric
1,2-diol.
(
particle size 0.04–0.063 mm) silica gel purchased from
1
13
Merck. H NMR (500 MHz) and C NMR (125 MHz)
spectra were obtained on Bruker 500 FT NMR instruments.
NMR spectra were typically recorded in CDCl as solvent
This yellow oil was diluted with 230 mL of MeOH, 50 mL
of THF, and 230 mL of H O, and then NaIO (19.8 g,
93.0 mmol) was added in one portion. The NaIO initially
2
4
3
4
and were reported as d values in ppm relative to chloroform.
Infrared (IR) spectra were obtained were obtained using a
ASI React IR module.
starts to dissolve, but a heavier white precipitate quickly
forms. After the suspension was rapidly stirred for 1 h, it
was poured into 1 L of EtOAc and washed with saturated

J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
9565
aqueous NaHCO (3!100 mL) and brine (100 mL). The
3
(100 mL) and brine (100 mL) then dried (Na SO ) and
2 4
combined aqueous layers were back-extracted with EtOAc
concentrated. Purification of the residue on silica gel
(gradient elution, hexanes to 5% EtOAc–hexanes) gave
30.5 g (98%) of a pale yellow oil that consisted of a 9.9:1
(
(
3!50 mL) and the combined organic layers were dried
Na SO ) and concentrated. Purification of the residue on
2
4
1
silica gel (gradient elution, 30% EtOAc–hexanes to 45%
EtOAc–hexanes) gave 15.8 g of 18 as a pale yellow oil that
was contaminated with approximately 340 mg of the
starting epoxide and 460 mg of material from bromide
opening of the epoxide. Another 2.11 g of material was
isolated that contained an additional 2.1 mmol of diol 18
mixture of regioisomers: H NMR (500 MHz, CDCl ) d
3
7.23–7.28 (m, 2H), 6.86–6.90 (m, 2H), 5.69–5.77 (m, 1H),
5.08–5.13 (m, 2H), 4.40–4.46 (m, 2H), 4.22 (dd, JZ11.0,
5.0 Hz, 1H), 4.16 (dd, JZ11.0, 7.3 Hz, 1H), 3.89 (ddd, JZ
5.8, 5.8, 4.3 Hz, 1H), 3.82 (s, 3H), 3.49 (dd, JZ10.0, 4.5 Hz,
1H), 3.38 (dd, JZ10.0, 5.8 Hz, 1H), 2.59–2.67 (m, 1H),
1
3
along with 5.1 mmol of bromide. Total yield of diol 18 was
1.19 (s, 9H), 0.88 (s, 9H), 0.053 (s, 3H), 0.050 (s, 3H);
NMR (125 MHz, CDCl ) d 178.6, 159.3, 136.7, 130.5,
C
1
9%: H NMR (500 MHz, CDCl ) d 7.24–7.28 (m, 2H),
.88–6.92 (m, 2H), 5.62 (ddd, JZ17.3, 10.3, 9.0 Hz, 1H),
6
6
5
1
3
3
129.5, 117.6, 113.9, 73.2, 72.5, 64.1, 55.4, 47.2, 39.0, 27.4,
26.1, 18.4, K4.0, K4.8; IR (film) 2958, 2931, 2858, 1729,
.13–5.19 (m, 2H), 4.48 (AB , JABZ11.5 Hz, DnAB
Z
q
K1
1613, 1515, 1465, 1362, 1248, 1036 cm ; HRMS (CI)
4.9 Hz, 2H), 3.80–3.90 (m, 2H), 3.82 (s, 3H), 3.66–3.71
C
calcd for C H O Si (MCH) : 451.2880, found:
451.2879.
(
m, 1H), 3.56 (dd, JZ9.8, 3.3 Hz, 1H), 3.39 (dd, JZ9.8,
2
5
43
5
7
1
1
.3 Hz, 1H), 2.80 (br s, 1H), 2.73 (br s, 1H), 2.38–2.45 (m,
H); C NMR (125 MHz, CDCl ) d 159.6, 135.6, 130.0,
29.6, 118.6, 114.1, 73.3, 73.1, 72.8, 65.4, 55.5, 49.1; IR
1
3
3
4.1.4. 2-[1-(tert-Butyldimethylsiloxy)-2-(4-methoxyben-
zyloxy)ethyl]but-3-en-1-ol (19a). A three-neck reaction
flask equipped with a mechanical stirrer, a low temperature
thermometer, and an addition funnel was charged with the
(
film) 3391, 3082, 2904, 1614, 1514, 1305, 1244, 1174,
081 cm ; HRMS (CI) calcd for C H O (M): 252.1362,
14 20 4
K1
1
found: 252.1362.
9.9:1 mixture of TBS ethers (30.5 g, 67.6 mmol combined)
and 750 mL of CH Cl . The solution was cooled to K78 8C
4
.1.2. 2,2-Dimethylpropionic acid 2-[1-hydroxy-2-(4-
2
2
methoxybenzyloxy)-ethyl]but-3-enyl ester. The mixture
of diol 18 (15.8 g, 62.7 mmol) contaminated with bromide
and a solution of DIBAL-H (99.0 mL of a 1.5 M solution in
toluene, 149 mmol) was added dropwise via addition funnel
over 90 min. After the addition was complete, the solution
was maintained at K78 8C for 40 min, then allowed to
warm to 0 8C. Excess DIBAL-H was quenched by the
careful addition of 500 mL of a half-saturated potassium–
sodium tartrate solution to give a gelatinous mixture. Then
100 mL of THF were added and the mixture was stirred
rapidly for 2 h at room temperature, during which time it
gradually turned from a gel to a heterogeneous mixture. The
layers were separated and the organic layer was washed
(
460 mg, 1.5 mmol) and epoxide (340 mg, 1.5 mmol)
impurities was diluted with 1.3 L of CH Cl and NEt
3
2
2
(22.6 mL, 161 mmol) and cooled to 0 8C. Pivaloyl chloride
(8.34 mL, 67.4 mmol) and DMAP (393 mg, 3.21 mmol)
were added and the solution was allowed to warm to room
temperature overnight. The yellow solution was poured into
saturated aqueous NaHCO (400 mL) and the organic layer
3
was washed with NaHCO (200 mL) and brine (200 mL),
3
then dried (Na SO ) and concentrated. Purification of the
2
4
residue on silica gel (gradient elution, 8% EtOAc–hexanes
to 15% EtOAc–hexanes to 25% EtOAc–hexanes) gave
with H O (2!100 mL) and brine (100 mL). The combined
2
aqueous layers were back extracted with EtOAc (100 mL)
and the combined organic layers were dried (Na SO ) and
1
mixture of the primary and secondary pivalate esters: H
9.9 g (92%) of a pale yellow oil that consisted of a 9.9:1
2
4
1
concentrated. Purification of the residue on silica gel
(gradient elution, 5% EtOAc–hexanes to 20% EtOAc–
hexanes) gave 21.1 g of isomerically pure 19a (94% based
NMR (500 MHz, CDCl ) d 7.24–7.28 (m, 2H), 6.87–6.91
3
(
m, 2H), 5.62–5.71 (m, 1H), 5.11–5.16 (m, 2H), 4.48 (ABq,
JABZ11.3 Hz, DnABZ11.7 Hz, 2H), 4.31 (dd, JZ11.0,
on the amount of primary pivalate ester in the starting
mixture) as a pale yellow oil: H NMR (500 MHz, CDCl ) d
7.23–7.27 (m, 2H), 6.86–6.90 (m, 2H), 5.84 (ddd, JZ17.0,
1
6
.5 Hz, 1H), 4.21 (dd, JZ11.0, 4.5 Hz, 1H), 3.82 (s, 3H),
.74–3.80 (m, 1H), 3.56 (dd, JZ9.5, 3.0 Hz, 1H), 3.40 (dd,
3
3
JZ9.5, 7.0 Hz, 1H), 2.57 (d, JZ4.5 Hz, 1H), 2.50–2.57 (m,
10.5, 8.5 Hz, 1H), 5.15–5.20 (m, 2H), 4.44 (AB , JABZ
q
1
3
H), 1.19 (s, 9H); C NMR (125 MHz, CDCl ) d 178.7,
1
1
6
2
11.5 Hz, DnABZ6.1 Hz, 2H), 3.94 (app q, JZ5.5 Hz, 1H),
3.82 (s, 3H), 3.74–3.80 (m, 1H), 3.67–3.73 (m, 1H), 3.52
(dd, JZ10.0, 5.5 Hz, 1H), 3.43 (dd, JZ10.0, 5.5 Hz, 1H),
2.52–2.57 (m, 1H), 2.44–2.51 (m, 1H), 0.89 (s, 9H), 0.08 (s,
3
59.5, 135.6, 130.1, 129.6, 118.5, 114.1, 73.3, 72.4, 70.2,
4.5, 55.5, 47.1, 39.0, 27.4; IR (film) 3494, 3078, 2975,
906, 2871, 1725, 1613, 1515, 1285, 1248, 1165 cm
K1
;
1
3
HRMS (CI) calcd for C H O (M): 336.1937, found:
1
3H), 0.06 (s, 3H); C NMR (125 MHz, CDCl ) d 159.5,
3
9
28
5
3
36.1937.
.1.3. 2,2-Dimethylpropionic acid 2-[1-(tert-butyldi-
methylsiloxy)-2-(4-methoxybenzyloxy)ethyl]but-3-enyl
137.3, 130.2, 129.6, 117.8, 114.0, 74.4, 73.3, 73.0, 63.3,
55.5, 49.1, 26.1, 18.3, K4.1, K4.7; IR (film) 3445, 3074,
2935, 2858, 1614, 1514, 1468, 1251 cm ; HRMS (CI)
calcd for C16
309.1521.
K1
4
C
H O Si (MKtBu) : 309.1522, found:
25 4
ester. The 9.9:1 mixture of pivalate esters (23.2 g,
6
9.2 mmol combined) was diluted in 350 mL of CH Cl .
2 2
Imidazole (20.7 g, 304 mmol) was added and the mixture
was allowed to stir until all of the imidazole had dissolved.
Then TBSCl (20.9 g, 138 mmol) was added (a colorless
precipitate immediately formed), followed by the addition
of DMAP (422 mg, 3.46 mmol). The slurry was allowed to
stir overnight, then poured into saturated aqueous NaHCO3
4.1.5. 2-{2-[1-(tert-Butyldimethylsiloxy)-2-(4-methoxy-
benzyloxy)ethyl]but-3-enylamino}-3-methoxypropionic
acid methyl ester (22a). To a solution of alcohol 19a
(10.3 g, 28.1 mmol) in 400 mL of wet CH Cl was added
2
2
Dess–Martin periodinane (17.9 g, 42.1 mmol). A fine white
precipitate quickly formed to give a milky suspension. After
30 min, the mixture was diluted with 400 mL of Et O and
(
100 mL) and the organic layer was washed with NaHCO3
2

9566
J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
then 200 mL of a 1:1 solution of saturated aqueous NaHCO3
K10% (w/w) aqueous Na S O was added, and the mixture
oil. NMR spectra are complex due to slow rotation on the
NMR timescale so only distinct resonances are noted: H
1
2
2 3
was allowed to stir until all of the solids had dissolved. The
layers were separated and the organic layer was washed
with the 1:1 solution (2!100 mL) and brine (100 mL), then
dried (Na SO ) and concentrated. The crude aldehyde was
passed through a short plug of silica gel (10% EtOAc–
hexanes) then concentrated to give a pale yellow oil, which
was immediately used in the following reaction.
NMR (500 MHz, CDCl ) d 7.22–7.28 (m, 2H), 6.85–6.90
3
(m, 2H), 6.57 (br s, 1H), 4.38–4.44 (m, 2H), 3.81 (s, 3H),
[3.72 (s), 3.71 (s), 3H], 3.51 (app t, JZ3.0 Hz, 2H), 3.34 (s,
3H), [2.69–2.77 (m), 2.58–2.66 (m), 1H], [0.87 (s), 0.86 (s),
2
4
1
3
9H]; C NMR (125 MHz, CDCl ) d 169.8, 169.5, 159.4,
3
138.1, 137.8, 129.55, 129.52, 128.1, 128.0, 113.91, 113.89,
99.5, 75.5, 73.6, 73.19, 73.16, 66.6, 66.32, 66.29, 59.1, 59.0,
55.5, 52.5, 47.1, 44.1, 41.6, 26.0, 18.3, 18.1, 18.0, K1.18,
K1.22, K3.90, K3.94, K4.8; IR (film) 2954, 2896, 1744,
The crude aldehyde 20 was dissolved in 280 mL of MeCN,
˚
then 4 A molecular sieves (23 g) were added and the
K1
1636, 1515, 1248, 1094 cm ; HRMS (EI) calcd for
C
C H Br N O Si Na (MCNa) : 885.1980, found:
885.1970.
mixture was allowed to stir for 5 min. A solution of serine
methyl ester 21 (7.48 g, 56.1 mmol) in 10 mL of MeCN
3
6
58
2
2
8
2
3
4
was added via syringe. The mixture was allowed to stir for
1
in one portion. After stirring for 1 h, 300 mL of a half-
saturated potassium–sodium tartrate solution was added,
and the mixture was stirred vigorously for an additional 1 h.
The mixture was diluted with EtOAc (600 mL), washed
0 min, then NaBH(OAc) (23.8 g, 112.0 mmol) was added
3
4
.1.7. 2-{{2-[1-(tert-Butyldimethylsiloxy)-2-hydroxy-
ethyl]but-3-enyl}-[4,5-dibromo-1-(2-trimethylsilylethoxy-
methyl)-1H-pyrrole-2-carbonyl]amino}-3-methoxypro-
pionic acid methyl ester (27). To a solution of PMB ether
2
6
1
bright green color then slowly faded to a brownish-green
color. After 2 h, the mixture was quenched with aqueous
NaHCO (100 mL) and diluted with EtOAc (300 mL). The
3
4a (10.27 g, 11.90 mmol) in 115 mL of CH Cl and
2 2
.8 mL of pH 7 phosphate buffer was added DDQ (3.92 g,
7.3 mmol) in one portion. The mixture turned an initial
with NaHCO (2!75 mL) and brine (75 mL), then dried
3
(
Na SO ) and concentrated. Purification of the residue on
2 4
silica gel (gradient elution, 10% EtOAc–hexanes to 15%
EtOAc–hexanes to 35% EtOAc–hexanes) gave 11.1 g
(
with small quantities of the isomeric internal olefins 23: H
82%) of 22a as a pale yellow oil that was contaminated
1
organic layer was washed with saturated aqueous NaHCO3
until the washes were no longer colored yellow (4!
NMR (500 MHz, CDCl ) d 7.22–7.27 (m, 2H), 6.85–6.90
3
(
(
(
(
m, 2H), 5.67–5.76 (m, 1H), 5.11–5.19 (m, 2H), 4.38–4.44
m, 2H), 3.74–3.84 (m, 1H), 3.81 (s, 3H), [3.731 (s), 3.728
s), 3H], 3.51–3.62 (m, 2H), 3.40–3.49 (m, 2H), 3.31–3.38
m, 1H), [3.334 (s), 3.331 (s), 3H], [2.88 (dd, JZ11.0,
1
00 mL) and then washed with brine (100 mL). The
combined aqueous layers were extracted with EtOAc
100 mL) and then the combined organic layers were
dried (Na SO ) and concentrated. Purification of the residue
(
2
4
4
9
1
0
1
1
6
3
3
.0 Hz), 2.72 (dd, JZ11.0, 4.0 Hz), 1H], [2.59 (dd, JZ9.5,
.5 Hz), 2.52 (dd, JZ11.0, 9.0 Hz), 1H], 2.41–2.50 (m, 1H),
.79 (br s, 1H), [0.88 (s), 0.87 (s), 9H], [0.041 (s), 0.037 (s),
on silica gel (gradient elution, 10% EtOAc–hexanes to 30%
EtOAc–hexanes) gave 7.37 g (83%) of the alcohol 27 as a
pale yellow oil: NMR spectra are complex due to slow
rotation on the NMR timescale so only distinct resonances
are noted; H NMR (500 MHz, CDCl ) d 6.50–6.70 (m,
1
3
.03 (s), 6H]; C NMR (125 MHz, CDCl ) d 174.0, 173.6,
3
59.3, 138.4, 130.7, 129.44, 129.43, 129.2, 117.9, 117.7,
13.9, 74.0, 73.9, 73.6, 73.4, 73.3, 73.2, 73.12, 73.11, 62.0,
1.8, 59.4, 59.3, 55.5, 52.1, 52.0, 48.6, 48.4, 47.9, 47.8,
1
3
1
[
H), [3.74 (s), 3.72 (s), 3H], 3.52 (app t, JZ8.0 Hz, 2H),
3.38 (s), 3.36 (s), 3H], 2.63–2.78 (m, 1H), [0.90 (s), 0.89
(s), 9H], 0.04–0.10 (m, 6H), [K0.01 (s), K0.02 (s), 9H];
4.5, 26.13, 26.11, 18.4, K3.9, K4.67, K4.69; IR (film)
K1
346, 2929, 2856, 1740, 1613, 1515, 1472, 1246, 1036 cm
;
1
3
C
C NMR (125 MHz, CDCl ) d 169.6, 169.4, 137.7, 127.9,
3
27.7, 99.60, 99.57, 75.6, 75.5, 74.5, 66.4, 64.5, 64.3,
9.2, 59.1, 52.6, 34.5, 26.0, 18.2, 18.1, K1.2, K4.05,
HRMS (EI) calcd for C H NO Si (MCH) : 482.2938,
6
2
5
44
1
5
found: 482.2947.
K4.10, K4.57, K4.58; IR (film) 3464, 3120, 3078, 2954,
1
C H Br N O Si Na (MCNa) : 765.1404, found:
4
.1.6. 2-{{2-[1-(tert-Butyldimethylsiloxy)-2-(4-methoxy-
K1
744, 1629, 1530, 1250, 1094 cm ; HRMS (EI) calcd for
benzyloxy)ethyl]but-3-enyl}-[4,5-dibromo-1-(2-tri-
methylsilylethoxymethyl)-1H-pyrrole-2-carbonyl]-
amino}-3-methoxypropionic acid methyl ester (24a). To
a suspension of pyrrole acid 10 (31.1 g, 79.9 mmol) in
C
2
8
50
2
2
7
2
7
65.1402.
5
9
00 mL of MeCN at 0 8C was added BOPCl (23.4 g,
1.8 mmol) and the mixture was stirred at 0 8C for 90 min.
4.1.8. 2,4-Bis-(tert-butyldimethylsiloxy)-5-{[[4,5-
dibromo-1-(2-trimethylsilylethoxymethyl)-1H-pyrrole-
2-carbonyl]-(1-methoxycarbonylvinyl)amino]methyl}-
hepta-2,6-dienoic acid methyl ester (29). To a solution of
alcohol 27 (2.62 g, 3.53 mmol) in 50 mL of wet CH Cl was
Then a solution of amine 22a (13.4 g, 27.8 mmol) in 50 mL
of MeCN was added via syringe (30 mL plus 2!10 mL
rinses), followed by the addition of i-Pr NEt (20.8 mL,
2
2
2
1
20.0 mmol). The mixture was allowed to warm to room
added Dess–Martin periodinane (2.24 g, 5.29 mmol). A fine
white precipitate quickly formed to give a milky suspension.
After 30 min, the mixture was diluted with 150 mL of Et O
temperature and the solids slowly dissolved. The reaction
mixture was stirred overnight, during which time a white
precipitate formed. This slurry was diluted with EtOAc
2
and then 75 mL of a 1:1 solution of saturated aqueous
NaHCO —10% (w/w) aqueous Na S O , and the mixture
(
500 mL), washed with saturated aqueous NaHCO (2!
3
3
2 2 3
2
00 mL) and brine (200 mL), then dried (Na SO ) and
2
was allowed to stir until all of the solids had dissolved. The
layers were separated and the organic layer was washed
with the 1:1 solution (3!50 mL) and brine (50 mL), then
dried (Na SO ) and concentrated. The crude aldehyde was
4
concentrated. Purification of the residue on silica gel
gradient elution, 5% EtOAc–hexanes to 10% EtOAc–
hexanes) gave 17.4 g (93% recovered) of the acid anhydride
(
2
4
together with 23.3 g (99%) of amide 24a as a pale yellow
diluted in 15 mL of CH Cl then dried (Na SO ) and
2 2 2 4

J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
9567
C
C H Br N O Si Na (MCNa) : 801.1213, found:
30 48 2 2 8 2
801.1237.
concentrated to give a pale yellow oil which was
immediately used in the following reaction.
This crude aldehyde and phosphonate 28 (1.65 g,
5
Bu (14.1 mL of a 0.5 M solution in t-BuOH, 7.06 mmol)
was added dropwise via syringe to give a bright yellow
solution. The resulting solution was poured into saturated
4
.1.10. 4-[1-(tert-Butyldimethylsiloxy)-3-methoxycarbo-
.29 mmol) were dissolved in 70 mL of THF. Then NaOt-
nyl-3-oxo-propyl]-1-[4,5-dibromo-1-(2-trimethylsilyl-
ethoxymethyl)-1H-pyrrole-2-carbonyl]-4,5-dihydro-1H-
pyrrole-2-carboxylic acid methyl ester (8). A flame dried
25 mL two-neck reaction flask was equipped with a reflux
aqueous NaHCO (100 mL) and then diluted with Et O
2
3
condenser topped with a three-way gas flow adapter and a
teflon stopcock (all ground glass connections were greased).
Diene 9 (414 mg, 0.530 mmol) was transferred to the
reaction apparatus in 4.3 mL of CH Cl (degassed by
(
was washed with saturated aqueous NaHCO (50 mL) and
150 mL). The layers were separated and the organic layer
3
brine (50 mL), then dried (Na SO ) and concentrated.
4
2
2
2
Purification of the residue on silica gel (5% EtOAc–
hexanes) gave 2.30 g (73% from 27) of the enol ether 29 as a
sparging with Ar for 2 h) via syringe. A solution of the
metathesis catalyst 15 (1.0 mL of a 0.027 M solution in
CH Cl , 0.027 mmol) was added via syringe and the
solution was brought to reflux. After 23 h, H NMR analysis
of an aliquot indicated the reaction had gone to about 90%
completion. After 41 h, the brown solution was concen-
trated and purified on silica gel (gradient elution, hexanes
to 5% EtOAc–hexanes to 7.5% EtOAc–hexanes to 15%
EtOAc–hexanes) to give 414 mg (80%) of dihydropyrrole 8
as an oil, along with 25 mg of recovered diene 9; keto ester 8
pale yellow oil (on smaller scales the yield approached
8
2
2
1
3%): H NMR (500 MHz, CDCl ) d [6.34 (s), 6.33 (s), 1H],
1
3
[
9
(
6.10 (s), 6.08 (s), 1H], [5.89 (d, JZ9.0 Hz), 5.34 (d, JZ
.0 Hz), 1H], 5.69–5.84 (m, 1H), 5.56–5.67 (m, 2H), [5.48
d, JZ10.5 Hz), 5.47 (d, JZ10.5 Hz), 1H], [5.11 (dd, JZ
9
2
3
2
9
.0, 6.5 Hz), 4.69 (dd, JZ8.5, 5.0 Hz), 1H], 4.99–5.08 (m,
H), 4.01–4.12 (m, 1H), [3.77 (s), 3.76 (s), 3H], [3.69 (s),
.67 (s), 3H], 3.64–3.71 (m, 1H), 3.55–3.62 (m, 2H), 2.55–
.69 (m, 1H), [0.96 (s), 0.94 (s), 9H], [0.878 (s), 0.881 (s),
is a 8:1 mixture of keto and enol tautomers in CDCl . Only
3
1
3
1
the keto peaks are reported in the H NMR, but all the peaks
H], 0.85–0.97 (m, 2H), K0.02K0.21 (m, 21H); C NMR
1
3
1
(
125 MHz, CDCl ) d 165.1, 164.9, 164.49, 164.47, 162.0,
3
are reported in the C NMR; H NMR (500 MHz, CDCl ) d
3
1
1
1
5
1
41.2, 140.9, 140.2, 139.7, 137.6, 137.4, 128.80, 128.76,
26.4, 122.8, 122.4, 121.7, 118.2, 118.0, 116.6, 116.4,
10.0, 109.9, 99.3, 75.6, 70.1, 69.5, 66.5, 66.4, 52.80,
2.78, 52.3, 51.9, 51.3, 49.9, 49.2, 49.1, 26.2, 26.0, 25.8,
8.9, 18.4, 18.3, 18.23, 18.17, K1.2, K3.7, K3.8, K4.09,
6
1
4
1
2
2
9
.63 (s, 1H), 5.99 (d, JZ2.5 Hz, 1H), 5.73 (d, JZ10.5 Hz,
H), 5.61 (d, JZ10.5 Hz, 1H), 4.34 (dt, JZ7.0, 5.0 Hz, 1H),
.13 (dd, JZ11.0, 10.0 Hz, 1H), 4.01 (dd, JZ7.0, 6.5 Hz,
H), 3.88 (s, 3H), 3.71 (s, 3H), 3.59 (app dd, JZ8.5, 7.5 Hz,
H), 3.22–3.28 (m, 1H), 3.09 (dd, JZ17.0, 7.0 Hz, 1H),
.87 (dd, JZ17.0, 5.0 Hz, 1H), 0.86–0.92 (m, 2H), 0.84 (s,
K4.14, K4.5, K4.6, K4.8, K4.9; IR (film) 3078, 2954,
2860, 1731, 1648, 1524, 1437, 1324, 1250, 1198 cm C
HRMS (EI) calcd for C H Br N O Si Na (MCNa) :
K1
1
3
;
H), 0.07 (s, 3H), 0.02 (s, 3H), K0.02 (s, 9H); C NMR
3
6
62
2
2
8
3
(125 MHz, CDCl ) d 192.0, 161.5, 161.1, 160.0, 140.3,
3
9
15.2078, found: 915.2073.
1
1
38.7, 138.3, 127.5, 124.0, 123.3, 117.5, 117.1, 113.0,
12.0, 99.8, 75.3, 68.9, 68.6, 66.52, 66.48, 53.7, 53.45,
4
(
.1.9. 4-(tert-Butyldimethylsiloxy)-5-{[[4,5-dibromo-1-
2-trimethylsilyl ethoxymethyl)-1H-pyrrole-2-carbo-
53.40, 52.9, 52.5, 52.4, 49.3, 48.5, 44.3, 25.9, 18.2, 18.14,
18.10, K1.0, K1.2, K1.4, K4.3, K4.4, K4.5, K4.9; IR
(film) 3450, 3124, 2954, 2858, 1733, 1632, 1524, 1426,
nyl]-(1-methoxycarbonylvinyl)-amino]methyl}-2-oxo-
hept-6-enoic acid methyl ester (9). To a solution of enol
ether 29 (2.30 g, 2.57 mmol) and AcOH (0.72 mL,
K1
1391, 1250, 1082 cm ; HRMS (EI) calcd for C H Br -
44
2
8
2
C
N O Si Na (MCNa) : 773.0901, found: 773.0904.
2
8
2
1
(
2.9 mmol) in 51 mL of MeCN at 0 8C was added CsF
977 mg, 6.43 mmol) in one portion. The mixture was
4.1.11. Azomethine imine cyclization product 31. A
sealable tube was charged with a-keto ester 8 (433 mg,
allowed to warm to room temperature and then stirred for an
additional 75 min. The reaction mixture then was diluted
with 200 mL of EtOAc and 50 mL of saturated aqueous
NaHCO . The layers were separated and the organic layer
3
was washed with saturated aqueous NaHCO (50 mL) and
3
0
1
.575 mmol), thiosemicarbazide (315 mg, 3.45 mmol) and
2 mL of EtOH. The mixture was sparged with argon for 20
minutes, then the vessel was sealed and heated to 110 8C.
After 2 d, the bright yellow solution was cooled to below
78 8C, the tube was opened, and the mixture was adsorbed
onto silica gel with 10% CH OH/CH Cl and purified on
brine (50 mL), then dried (Na SO ) and concentrated.
2
4
Purification of the residue on silica gel (gradient elution,
0% EtOAc–hexanes to 15% EtOAc–hexanes) gave 1.74 g
3
2
2
1
silica gel (gradient elution, 7.5% EtOAc–hexanes to 15%
EtOAc–hexanes) to give 82 mg (71%) of cycloadduct 31 as
1
87%) of the a-keto ester 9 as a pale yellow oil: H NMR
(
(
§
a colorless solid: H NMR (500 MHz, CDCl ) d 6.65 (s,
1
500 MHz, CDCl ) d 6.34 (s, 1H), 6.12 (s, 1H), 5.76 (ddd,
3
3
JZ17.0, 10.0, 9.0 Hz, 1H), 5.62 (s, 1H), 5.52 (AB , JABZ
q
1H), 5.65 (d, JZ11.0 Hz, 1H), 5.50 (d, JZ10.5 Hz, 1H),
5.35 (s, 1H), 4.41–4.47 (m, 1H), 4.08 (d, JZ10.0 Hz, 1H),
1
0.5 Hz, DnABZ23.8 Hz, 2H), 5.05–5.15 (m, 2H), 4.32 (dt,
JZ6.5, 5.5 Hz, 1H), 3.86 (s, 3H), 3.72–3.86 (m, 2H), 3.69
s, 3H), 3.56–3.61 (m, 2H), 3.21 (dd, JZ17.5, 5.0 Hz, 1H),
4.01 (app d, JZ5.0 Hz, 2H), 3.71 (s, 3H), 3.48–3.56 (m,
2H), 2.79 (ddt, JZ10.5, 10.5, 5.8 Hz, 1H), 2.36 (dd, JZ
14.5, 5.5 Hz, 1H), 2.26 (dd, JZ14.5, 7.3 Hz, 1H), 0.86–0.93
(
3
0
9
1
7
1
1
.02 (dd, JZ17.5, 6.5 Hz, 1H), 2.60–2.67 (m, 1H), 0.87–
.95 (m, 2H), 0.84 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H), 0.00 (s,
H); C NMR (125 MHz, CDCl ) d 192.2, 164.3, 162.0,
1
3
3
§
Under these conditions, an unidentified by-product is isolated in
approximately 5–8% yield. This product appears when the reaction is
carried out at temperatures greater than 70 8C. Attempts to conduct the
condensation with thiosemicarbazide at temperatures greater than 110 8C
resulted in larger amounts of this byproduct.
61.4, 140.9, 137.0, 128.5, 122.2, 118.8, 116.6, 110.3, 99.3,
5.6, 69.7, 66.5, 53.2, 52.9, 49.3, 49.2, 44.5, 25.9, 18.2,
8.1, K1.2, K4.4, K4.5; IR (film) 2954, 2858, 1731, 1654,
K1
621, 1524, 1248, 1092, 1081 cm ; HRMS (EI) calcd for

9568
J. D. Katz, L. E. Overman / Tetrahedron 60 (2004) 9559–9568
(
m, 2H), 0.89 (s, 9H), 0.11 (s, 3H), 0.01 (s, 3H), 0.00 (s, 9H);
C NMR (125 MHz, CDCl ) d 186.4, 171.6, 168.6, 161.7,
19. Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; Jagdmann, G. E.
J. Org. Chem. 1985, 50, 1019–1026.
1
3
3
1
5
26.5, 117.3, 112.2, 100.0, 91.2, 78.5, 78.0, 75.8, 66.7,
8.6, 54.8, 53.5, 49.8, 42.6, 25.8, 18.14, 18.07, K1.2, K4.3,
20. Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997,
62, 8131–8140.
K4.5; IR (film) 3272, 2954, 2858, 1773, 1750, 1640, 1426,
21. Nicolaou, K. C.; Shi, G.-Q.; Namoto, K.; Bernal, F. Chem.
Commun. 1998, 1757–1758.
K1
1
N O SSi Na (MCH) : 792.0917, found: 792.0941.
252, 1200, 1094 cm ; HRMS (EI) calcd for C H Br -
28 44 2
C
5
6
2
22. Kimura, R.; Nagano, T.; Kinoshita, H. Bull. Chem. Soc. Jpn
2
002, 75, 2517–2525.
2
2
3. For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18–29. (b) F u¨ rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012–3043. (c) F u¨ rstner, A. Adv. Synth.
Catal. 2002, 6/7, 567–793.
Acknowledgements
This research was funded by the National Heart, Lung, and
Blood Institute (HL-25854). J. D. K. was supported by an
NIH NRSA postdoctoral fellowship (5 F32 GM064946).
NMR and mass spectra were determined at UC Irvine using
instruments acquired with the assistance of NSF and NIH
shared instrumentation grants.
4. For the synthesis of other 2-substituted-4,5-dihydropyrroles
by ring-closing metathesis, see: Kinderman, S. S.; van
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