The utility of the classical and oxidative Heck reactions in natural product synthesis: Studies directed toward the total synthesis of dragmacidin F

Article abstract of DOI:10.1055/s-2006-951492

The syntheses of complex pyrrole-fused [3.3.1] and [3.3.2] bicycles using classical and oxidative Heck cyclizations are described. While both [3.3.1] and [3.2.2] bicyclic products are formed in the classical Heck reaction, the oxidative Heck cyclization r

Full text of DOI:10.1055/s-2006-951492

LETTER
3081
The Utility of the Classical and Oxidative Heck Reactions in Natural Product
Synthesis: Studies Directed toward the Total Synthesis of Dragmacidin F
Studies
D
irected to
e
war
d
the
T
i
ota
l
Sy
l
nthesis of
D
ra
K
gmacidin F . Garg, Daniel D. Caspi, Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute
of Technology, 1200 East California Boulevard, MC 164-30, Pasadena, CA 91125, USA
Fax +1(626)5649297; E-mail: stoltz@caltech.edu
Received 20 April 2006
Dedicated to Professor Richard Heck for his outstanding contributions to organic synthesis
linkages, thereby generating stereogenic centers.3,4 Given
Abstract: The syntheses of complex pyrrole-fused [3.3.1] and
its high synthetic utility, it is not surprising that the Heck
[3.3.2] bicycles using classical and oxidative Heck cyclizations are
described. While both [3.3.1] and [3.2.2] bicyclic products are
formed in the classical Heck reaction, the oxidative Heck cycliza-
reaction has been used extensively in the synthesis of
complex natural products.3a
tion reaction furnishes solely the [3.3.1] bicycle. The [3.3.1] bicy-
clic product has been used as an intermediate to synthesize the
rine alkaloid dragmacidin F (1, Scheme 1),5 we envi-
complex marine alkaloid dragmacidin F.
In planning our recent total synthesis of the bioactive ma-
sioned two closely related Heck transformations for
Key words: Heck reaction, palladium, oxidative cyclization, bicy-
constructing the [3.3.1] bicyclic framework of the natural
clic compounds, total synthesis
product. In the first scenario, a Pd(0)-mediated intramo-
lecular Heck reaction of bromopyrrole 2 would be used to
assemble bicycle 5. In an alternative plan, Pd(II)-promot-
ed cyclization of substrate 3, which does not bear func-
tionalization at C(3), would be used to prepare the
Over the past several decades, transition-metal-mediated
cross-coupling reactions have emerged as powerful meth-
ods for the formation of carbon–carbon bonds.1 Of the
identical bicyclic product (5). Both of these routes would
common Pd-mediated cross-coupling processes, the Heck
presumably proceed via regioselective olefin insertion of
reaction2 is unique in its ability to construct sp2–sp3 bond
palladium(II) intermediate 4.6 The latter of the proposed
H
N
H
H2N
N
N
Br
H
HN
HO
N
H
O
N
O
H
(+)-dragmacidin F (1)
TBSO
A
Br
3
Pd(0)-mediated
HO
classical
Heck reaction
N
O
SEM
TBSO
HO
TBSO
2
H
PdX
N
B
HO
TBSO
O
N
O
SEM
H
SEM
Pd(II)-mediated
3
4
5
oxidative
Heck reaction
HO
N
O
SEM
3
Scheme 1
SYNLETT 2006, No. 18, pp 3081–3087
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951492; Art ID: S09406ST
© Georg Thieme Verlag Stuttgart · New York

3082
N. K. Garg et al.
LETTER
strategies, known as the ‘oxidative Heck’ cyclization,7–9 Heck substrate 2, but also complicated purification of the
was particularly attractive since it would not require the desired product.
synthesis of a prefunctionalized pyrrole substrate (i.e., 2)
and furthermore, it would allow us to study reaction meth-
With the pyrrole-fused cyclohexene substrates in hand,
we began investigating the classical Heck reaction of bro-
mopyrrole 2. Our initial attempts to effect intramolecular
odology that has been developed in our laboratories, in a
highly complex chemical environment.7 In this letter, we
cyclization involved the use of standard protocols3 where
report our findings regarding the use of classical and oxi-
bromide 2 was heated in the presence of Pd(0), phosphine
dative Heck reactions as viable methods for the construc-
ligand, and base, in either acetonitrile or DMF, under an
tion of complex bicycles.
inert atmosphere. Although trace quantities of product
To initiate our studies, the key Heck cyclization substrates were observed in a few rare cases, most experiments af-
were prepared as depicted in Scheme 2. (–)-Quinic acid forded recovered starting material accompanied by sub-
(6)10 was first elaborated to Weinreb amide 7 using our stantial decomposition. Likewise, exposure of bromide 2
previously reported protocol.5 Subsequent displacement to Jeffery’s conditions14 or Herrmann’s catalyst15 also re-
of Weinreb amide 7 with readily available 2-lithio-SEM- turned starting material with significant loss of mass. Hy-
pyrrole11 smoothly afforded oxidative Heck substrate 3 in pothesizing that the observed decomposition could
71% yield. Bromide 2 proved significantly more difficult partially be attributed to the thermal instability of sub-
to access as compared to its des-bromo counterpart; none- strate 2, we turned to conditions recently developed by Fu,
theless, an efficient route was developed. Commercially which are known to catalyze Heck reactions at room tem-
available 2-trichloroacetyl pyrrole (8) was dibrominated perature.16 Gratifyingly, the implementation of Fu’s con-
and hydrolyzed following a literature procedure.12 Heat- ditions, using one equivalent of Pd, led to the desired
ing dibromoacid 9 in ethanolamine at 100 °C facilitated [3.3.1] bicycle (5), albeit in modest yield (Scheme 3). Un-
decarboxylation to provide 2,3-dibromopyrrole (10), an fortunately, the formation of [3.3.1] bicycle 5 was ham-
unstable intermediate that could not be isolated.13 Thus, pered by competitive production of [3.2.2] bicycle 13.
the crude material (10) was treated with NaH and SEMCl
to afford protected derivative 11, which in contrast to 10,
could be chromatographed and stored for prolonged peri-
A considerable effort was undertaken to optimize the in-
tramolecular Heck cyclization for the production of de-
sired bicycle 5. To our dismay, varying parameters such
ods of time. Selective lithium–halogen exchange of dibro-
as temperature, solvent, base, concentration, and Pd:phos-
mide 11, followed by treatment with Weinreb amide 7,
phine ratio did not lead to more favorable product distri-
butions. Unexpectedly, however, it was found that by
increasing the quantity of palladium used in the Heck re-
action, the ratio of the desired [3.3.1] bicycle (5) to the un-
desired [3.2.2] bicycle (13) improved (Table 1). In fact,
the desired product (5) was favored in a 3:1 ratio when
furnished Heck substrate 2 in 56% yield. It should be not-
ed that 4-bromopyrrole 12 was observed as a major by-
product in the addition reaction. This by-product was pre-
sumably formed by anion scrambling after lithium–bro-
mide exchange. This not only led to modest yields of
OH
Li
TBSO
HO
OH
OH
TBSO
N
SEM
Me
THF, –78 °C to 0 °C
(71% yield)
N
HO
HO
HO
N
OMe
O
O
O
SEM
3
(–)-quinic acid (6)
7
Br
Br
SEMCl, NaH
THF, –20 °C
HO(CH2)2NH2
100 °C
1. Br2, AcOH
CCl3
Br
CO2H
Br
N
N
N
H
2. NaOH, H2O
(90% yield)
H
O
H
(79% yield,
2 steps)
8
9
10
TBSO
TBSO
Br
Br
n-BuLi, THF, –78°C
Br
+
Br
N
then 7, –78 °C to 0 °C
HO
HO
SEM
N
N
O
O
SEM
SEM
11
2
12
(56% yield)
major by-product
Scheme 2
Synlett 2006, No. 18, 3081–3087 © Thieme Stuttgart · New York

LETTER
Studies Directed toward the Total Synthesis of Dragmacidin F
3083
TBSO
OTBS
HO
H
O
Me
TBSO
HO
HO
SEMN
PdLnX
Pd[P(t-Bu)3]2, Pd2dba3
(1 equiv Pd; 1:1 Pd:P)
N
O
Br
N
SEM
5
+
(38% yield)
Cy2NMe, THF, 23 °C
OTBS
Me
O
SEM
HO
Me
TBSO
2
O
XLnPd
N
NSEM
HO
SEM
O
13
(33% yield)
Scheme 3
three equivalents of Pd were employed in the Heck reac- ticipated that the enone functionality of 14 would impose
tion (77% isolated yield). In contrast, carrying out the re- an electronic bias, thus favoring bicycle 15 in the intramo-
action with 0.5 equivalent of palladium led to undesired lecular Heck cyclization.3 To our surprise, however,
bicycle 13 as the major product. In an attempt to gain a [3.2.2] bicycle 16 was the only product generated from the
better understanding of these effects, a series of Heck re- Heck reaction of enone 14.
actions were carried out in THF-d8 and monitored closely
Although [3.2.2] bicycles 13 and 16 were not useful inter-
1
by H NMR spectroscopy. Interestingly, the ratio of 5 to
mediates for the total synthesis at hand, the fact that these
13 decreased as the reaction progressed, suggesting that
the active catalyst species varied during the course of the
products are observed demonstrates the utility and power
of the classical Heck reaction in assembling intricate mo-
reaction or that selectivity changed as the concentration of
lecular architectures. Moreover, the Heck reactions that
R3NH+Br– increased. The latter of these hypotheses was
afford 13 and 16 are particularly interesting since they
create sterically congested quaternary carbon stereo-
probed by examining several inorganic and organic bases.
While a few bases behaved comparably to Cy2NMe (e.g.,
centers, which are known to be synthetically challeng-
Et3N and Hünig’s base), most bases led to increased pro-
ing.17 To the best of our knowledge, these results are the
duction of undesired bicycle 13. Most notably, the use of
first use of Fu’s Heck reaction conditions to construct
molecules of such complexity.
pyridine led to the exclusive formation of [3.2.2] bicycle
13.
Having assessed the classical Heck reaction as a means to
prepare pyrrole-fused bicycles, we next explored the alter-
native Pd(II)-mediated oxidative Heck strategy involving
cyclization of des-bromo substrate 3 (Scheme 1). Our ini-
tial experiments in this area employed conditions discov-
ered in our laboratories for promoting related C–C bond-
forming reactions.7 Unfortunately, under these conditions
[i.e., catalytic or stoichiometric Pd(OAc)2, and pyridine-
derived ligands], formation of either desired bicycle 5 or
undesired bicycle 13 was not detected (Table 2, entry 1).
However, by using DMSO as a ligand,18 the desired cy-
clization product could be obtained in 56% yield (entry 2).
Subsequent optimization of temperature and reaction time
led to an ideal set of conditions whereby the desired
[3.3.1] bicycle (5) was isolated as the sole product in 74%
yield (entry 3).19 This transformation is particularly note-
worthy since it results in functionalization of the electron-
ically deactivated and sterically congested C(3) position
of acyl pyrrole 3.20,21 Importantly, the undesired [3.2.2]
bicycle (13) seen as a by-product in the classical Heck re-
action has never been observed as a product of the oxida-
tive Heck cyclization of substrate 3.
Table 1 Synthesis of Bicycles 5 and 13 with Various Quantities of
Palladium
TBSO
HO
TBSO
Pd[P(t-Bu)3]2,
Pd2dba3
Me
TBSO
+
H
Br
N
N
Cy2NMe
THF, 23 °C
HO
HO
SEM
O
N
O
O
SEM
SEM
2
5
13
Entry
Pd (equiv)
3.0
Ratio of 5:13
3:1
1
2
3
4
2.0
1.5:1
1.0
1.1:1
1.2
1.2:1
In an effort to promote the formation of the desired [3.3.1]
bicyclic framework, an alternate Heck substrate (14) was
prepared via treatment of TBS ether 2 with TBAF, fol-
lowed by Dess–Martin periodinane (Scheme 4). It was an-
Synlett 2006, No. 18, 3081–3087 © Thieme Stuttgart · New York

3084
N. K. Garg et al.
LETTER
TBSO
O
O
H
Br
N
Br
N
Pd(0)
1. TBAF, THF
2. Dess–Martin
CH2Cl2
HO
O
HO
HO
N
O
O
SEM
SEM
(quantitative)
SEM
2
14
15
Me
Pd[P(t-Bu)3]2, Pd2dba3
Cy2NMe, THF, 23 °C
O
N
HO
SEM
O
16
only product observed
Scheme 4
Table 2 Synthesis of Bicycles 5 and 13 under Various Reaction Conditions
TBSO
TBSO
Me
TBSO
H
Pd(II)-mediated
3
4
+
N
HO
HO
HO
oxidative
SEM
Heck reaction
O
N
N
O
O
SEM
SEM
5
13
3
Entry
1
Conditions
Result
no reaction, starting material recovered
Pd(OAc)2 (stoichiometric or catalytic with O2), pyridine or ethyl
nicotinate, t-BuOH, AcOH, 80 °C
2
3
Pd(OAc)2 (1 equiv), DMSO, t-BuOH, AcOH, 80 °C, 2 h
Pd(OAc)2 (1 equiv), DMSO, t-BuOH, AcOH, 60 °C, 10 h
5
13
Yield: 56%
not observed
5
13
Yield: 74%
not observed
AcO
Despite considerable experimentation, we were unable to
render the conversion of acyl pyrrole 3 to bicycle 5 cata-
lytic in Pd in the presence of a stoichiometric oxidant
(e.g., O2 or benzoquinone). This difficulty has been attrib-
uted to the extreme sensitivity of both the starting material
and desired product to oxidative decomposition.22,23 How-
ever, we have observed some catalysis in the cyclization
of a closely related substrate, acetate 17 (Scheme 5). In
this case, oxidative Heck cyclization using 20 mol%
Pd(OAc)2, under 1 atm of O2, afforded [3.3.1] bicycle 18
AcO
HO
H
20 mol% Pd(OAc)2, DMSO
t-BuOH, AcOH, O2, 80 °C, 6.5 h
HO
N
N
O
O
(37% yield, 55% yield
based on recovered 17)
SEM
SEM
18
17
Scheme 5
in 37% yield (55% based on recovered 17). As isolated loadings, the oxidative Heck cyclization provides bicycle
5 in nearly twice the chemical yield as the classical Heck
reaction; c) the oxidative Heck reaction furnishes bicycle
5 as a single product, whereas the classical Heck reaction
requires a more tedious chromatographic separation of the
undesired [3.2.2] bicycle (13). Although more detailed
mechanistic studies are pending, we partially attribute the
differences in product distribution between the two strat-
egies to the effects of ligands. More specifically, the use
of bulky P(t-Bu)3 ligands in the classical Heck cyclization
could favor olefin insertion transition state 20 over 19, as
it would place the large PdLnX away from the more sub-
stituted position of the olefin undergoing insertion.
yields and catalyst turnover for this process were low, and
bicycle 18 was not directly useful for our total synthesis
goals, we elected to utilize the stoichiometric Pd-mediated
oxidative Heck reaction (Table 2, entry 3) as a means to
advance material en route to dragmacidin F.
In the context of our total synthesis objective, the oxida-
tive Heck reaction strategy is advantageous compared to
the classical Heck route for preparing [3.3.1] bicycle 5 on
the basis of several factors (Scheme 6): a) the oxidative
Heck approach does not require the synthesis of a haloge-
nated starting material (i.e., 2), which can sometimes be
significantly challenging; b) using identical palladium
Synlett 2006, No. 18, 3081–3087 © Thieme Stuttgart · New York

LETTER
Studies Directed toward the Total Synthesis of Dragmacidin F
3085
Oxidative Heck Cyclization
TBSO
TBSO
Pd(OAc)2 (1 equiv)
H
DMSO
single
product
observed
t-BuOH, AcOH
60 °C, 10 h
HO
HO
N
O
N
O
SEM
SEM
3
5
74% yield
Classical Heck Cyclization
TBSO
TBSO
HO
Pd[P(t-Bu)3]2, Pd2dba3
Me
TBSO
(1 equiv Pd)
H
Br
N
+
Cy2NMe, THF, 23 °C
N
HO
HO
SEM
O
O
N
O
SEM
SEM
2
5
13
32% yield
more challenging
substrate synthesis
39% yield
OTBS
Me
OTBS
HO
HO
O
Me
O
XLnPd
NSEM
SEMN
PdLnX
20
favored when Ln is large
19
disfavored when Ln is large
Scheme 6
Representative Procedure for the Oxidative Heck Reaction of 3
(Table 2, Entry 3)
In conclusion, we have found that both the classical and
oxidative Heck cyclization reactions are powerful meth-
ods for the construction of complex bicyclic molecules.
The classical Heck reaction can be used to assemble either
[3.3.1] bicycles or [3.2.2] bicycles, the latter of which
contain sterically congested all-carbon quaternary stereo-
centers. In contrast, the oxidative Heck reaction was crit-
ical in its ability to deliver [3.3.1] bicycles with excellent
selectivity. Ultimately, the [3.3.1] bicycles prepared by
these reactions were used as intermediates in the total syn-
thesis of dragmacidin F.5
To acyl pyrrole 3 (106.0 mg, 0.227 mmol) was added Pd(OAc)2
(51.1 mg, 0.227 mmol), DMSO (32.3 mL, 0.455 mmol), t-BuOH
(18.2 mL), and AcOH (4.5 mL). The mixture was heated to 60 °C
for 10 h, cooled to 23 °C, and filtered over a plug of silica gel (hex-
anes–EtOAc, 3:1). The solvent was evaporated, and the residue was
again filtered over a plug of silica gel (hexanes–EtOAc, 3:1). After
removal of solvent in vacuo, the product was purified by flash chro-
matography on silica gel (hexanes–EtOAc, 6:1) to afford [3.3.1] bi-
cycle 5 (78.4 mg, 74% yield) as a pale yellow oil.
Characterization Data for Bicycles 5 and 13
[3.3.1] Bicycle (5): Rf = 0.20 (hexanes–EtOAc, 4:1). 1H NMR (300
MHz, CDCl3): d = 7.07 (d, J = 2.7 Hz, 1 H), 6.05 (d, J = 2.7 Hz, 1
H), 5.71 (d, J = 9.9 Hz, 1 H), 5.58 (d, J = 9.9 Hz, 1 H), 5.09–5.05
(m, 2 H), 4.00 (s, 1 H), 3.99–3.90 (m, 1 H), 3.84 (app. t, J = 3.0 Hz,
1 H), 3.55–3.47 (m, 2 H), 2.39 (app. dt, J = 7.4, 3.8 Hz, 1 H), 2.13–
2.03 (comp. m, 2 H), 1.73 (app. t, J = 11.8 Hz, 1 H), 0.98–0.76
(comp. m, 11 H), –0.04 (s, 9 H), –0.11 (s, 6 H). 1H NMR (300 MHz,
C6D6): d = 6.53 (d, J = 2.5 Hz, 1 H), 5.77 (d, J = 2.8 Hz, 1 H), 5.55
(d, J = 10.2 Hz, 1 H), 5.32 (app. t, J = 1.9 Hz, 1 H), 5.26 (d, J = 10.2
Hz, 1 H), 5.01–4.97 (m, 1 H), 4.29 (s, 1 H), 4.27–4.19 (m, 1 H),
3.59–3.47 (comp. m, 3 H), 2.45–2.31 (comp. m, 2 H), 2.16 (dd,
J = 12.1, 3.0 Hz, 1 H), 2.07 (app. t, J = 11.8 Hz, 1 H), 0.92–0.89
(comp. m, 11 H), 0.01 (s, 9 H), –0.06 (s, 3 H), –0.07 (s, 3 H). 13C
NMR (75 MHz, C6D6): d = 191.5, 149.4, 141.8, 132.0, 125.5, 108.5,
107.4, 76.8, 75.8, 68.4, 66.3, 48.9, 45.5, 40.7, 26.3 (3 C), 18.8, 18.2,
–0.8 (3 C), –4.4, –4.7. IR (film): 3480, 2953, 2858, 1651, 1420,
1318, 1251, 1100, 1077 cm–1. HRMS-FAB: m/z [M]+ calcd for
C24H41NO4Si2: 463.2574; found: 463.2577. [a]D23 –275.07° (c 1.0,
CHCl3).
Representative Procedure for the Heck Reaction of 2 (Table 1,
1.0 Equiv Pd)
Bromo acyl pyrrole 2 (52.0 mg, 0.0955 mmol), Pd2dba3 (21.9 mg,
0.0239 mmol), Pd[P(t-Bu)3]2 (24.4 mg, 0.0477 mmol), THF (1.2
mL), and Cy2NMe (24.3 mL, 0.115 mmol) were combined under a
glovebox atmosphere and stirred at 23 °C for 10 h. The reaction ves-
sel was removed from the glovebox, diluted with hexanes–EtOAc
(3:1, 2 mL), and filtered over a plug of silica gel topped with Celite®
(hexanes–EtOAc, 3:1). The solvent was removed under reduced
pressure and the residue was purified by flash chromatography
(CH2Cl2, then hexanes–EtOAc, 3:1). The crude product was further
purified by flash chromatography (hexanes–EtOAc, 6:1) to afford
[3.3.1] bicycle 5 (16.7 mg, 38% yield) and [3.2.2] bicycle 13 (14.4
mg, 33% yield), both as pale yellow oils.
Synlett 2006, No. 18, 3081–3087 © Thieme Stuttgart · New York

3086
N. K. Garg et al.
LETTER
[3.2.2] Bicycle (13): Rf = 0.42 (hexanes–EtOAc, 5:1). 1H NMR (300
MHz, CDCl3): d = 6.98 (d, J = 2.7 Hz, 1 H), 6.15 (d, J = 2.7 Hz, 1
H), 6.02 (d, J = 9.3 Hz, 1 H), 5.98 (d, J = 8.8 Hz, 1 H), 5.69 (d,
J = 9.9 Hz, 1 H), 5.62 (d, J = 9.9 Hz, 1 H), 4.93 (s, 1 H), 3.81 (d,
J = 7.7 Hz, 1 H), 3.50 (t, J = 8.0 Hz, 2 H), 2.36 (dd, J = 14.3, 7.7 Hz,
1 H), 1.94 (dd, J = 14.3, 1.6 Hz, 1 H), 1.55 (s, 3 H), 0.91–0.83
(comp. m, 11 H), 0.02 (s, 3 H), 0.01 (s, 3 H), –0.07 (s, 9 H). 1H NMR
(300 MHz, C6D6): d = 6.55 (d, J = 2.7 Hz, 1 H), 6.23 (d, J = 8.8 Hz,
1 H), 5.96 (d, J = 3.3 Hz, 1 H), 5.94 (d, J = 9.2 Hz, 1 H), 5.59 (d,
J = 10.4 Hz, 1 H), 5.40 (d, J = 9.9 Hz, 1 H), 5.32 (s, 1 H), 3.82–3.75
(m, 1 H), 3.46 (t, J = 7.7 Hz, 2 H), 2.46 (dd, J = 13.7, 7.7 Hz, 1 H),
2.25 (dd, J = 13.7, 1.6 Hz, 1 H), 1.52 (s, 3 H), 0.92 (s, 9 H), 0.82 (t,
(7) (a) Stoltz, B. M. Chem. Lett. 2004, 33, 362. (b) Ferreira, E.
M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578.
(c) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem.
Int. Ed. 2004, 43, 6144.
(8) For catalytic intermolecular oxidative Heck arylations that
employ main group organometallic arenes with a range of
olefinic coupling partners and Pd(II) catalysis, see:
(a) Andappan, M. M. S.; Nilsson, P.; von Schenck, H.;
Larhed, M. J. Org. Chem. 2004, 69, 5212. (b) Farrington,
E. J.; Brown, J. M.; Barnard, C. F. J.; Rowsell, E. Angew.
Chem. Int. Ed. 2002, 41, 169; and references cited therein.
(9) For related examples of Pd-mediated carbocyclizations in
natural product synthesis, see: (a) Baran, P. S.; Corey, E. J.
J. Am. Chem. Soc. 2002, 124, 7904. (b) Williams, R. M.;
Cao, J.; Tsujishima, H.; Cox, R. J. J. Am. Chem. Soc. 2003,
125, 12172.
(10) For reviews and examples regarding the use of (–)-quinic
acid in natural product synthesis, see: (a)Barco, A.; Benetti,
S.; De Risi, C.; Marchetti, P.; Pollini, G. P.; Zanirato, V.
Tetrahedron: Asymmetry 1997, 8, 3515. (b) Huang, P.-Q.
Youji Huaxue 1999, 19, 364. (c) Hanessian, S.; Pan, J.;
Carnell, A.; Bouchard, H.; Lesage, L. J. Org. Chem. 1997,
62, 465. (d) Hanessian, S. In Total Synthesis of Natural
Products: The ‘Chiron’ Approach; Baldwin, E. J., Ed.;
Pergamon Press: Oxford, 1983, 206–208.
J = 8.0 Hz, 2 H), –0.03 (s, 3 H), –0.08 (s, 3 H), –0.09 (s, 9 H). 13
C
NMR (75 MHz, CDCl3): d = 188.7, 144.1, 139.4, 134.5, 129.1,
121.8, 107.7, 78.2, 77.8, 73.3, 66.4, 45.7, 45.0, 26.0 (3 C), 22.2,
18.2, 18.0, –1.25 (3 C), –4.1, –4.6. IR (film): 3432, 2955, 2858,
1645, 1250, 1081 cm–1. HRMS (EI): m/z [M + H]+ calcd for
19
C24H42NO4Si2: 464.2652; found: 464.2665. [a]D +19.22° (c 1.0,
C6H6).
Acknowledgment
The authors thank the NIH-NIGMS (R01 GM65961-01), the ND-
SEG (predoctoral fellowship to N.K.G.), Eli Lilly (predoctoral fel-
lowship to D.D.C.), AstraZeneca, Boehringer Ingelheim, Johnson
& Johnson, Pfizer, Merck, Amgen, Research Corporation, Roche,
and GlaxoSmithKline for generous funding.
(11) (a) Edwards, M. P.; Ley, S. V.; Lister, S. G.; Palmer, B. D.
J. Chem. Soc., Chem. Commun. 1983, 630. (b) Muchowski,
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References and Notes
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Org. Chem. 1975, 40, 1083. (c) Tao, W.; Silverberg, L. J.;
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2550.
(3) For recent reviews of the Heck reaction, see: (a) Dounay,
A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
(b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
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(4) The Ni-catalyzed Negishi couplings of secondary halides
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(5) (a) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc.
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(6) In the case of the oxidative Heck route, an alternative
Wacker-type mechanism involving nucleophilic attack of a
Pd-activated olefin by the pyrrole species cannot be ruled
out. It should be noted that in two extensively studied
systems for oxidative Heck cyclization, both were shown to
involve initial palladation of the aromatic system followed
by olefin insertion and b-hydrogen elimination, see ref. 7.
(12) Bailey, D. M.; Johnson, R. E. J. Med. Chem. 1973, 16, 1300.
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(14) Jeffery, T.; David, M. Tetrahedron Lett. 1998, 39, 5751; see
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(15) (a) Herrmann, W. A.; Brossmer, C.; Öfele, K.; Reisinger, C.-
P.; Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int.
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(18) DMSO has commonly been employed in oxidative Pd(II)
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(19) Recently, related oxidative cyclizations of pyrrole substrates
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Synlett 2006, No. 18, 3081–3087 © Thieme Stuttgart · New York

LETTER
Studies Directed toward the Total Synthesis of Dragmacidin F
(23) The instability of the starting material and product to
3087
(20) Gilow, H. M.; Hong, Y. H.; Millirons, P. L.; Snyder, R. C.;
Casteel, W. J. Jr. J. Heterocycl. Chem. 1986, 23, 1475.
(21) Reactions conducted in the presence of CH3COOD led to
deuterium incorporation in the pyrrole ring of both the
starting material (3) and the product (5), mostly at C(4).
(22) The instability of pyrroles to oxidants is well known. See:
(a) Ciamician, G.; Silber, P. Ber. Dtsch. Chem. Ges. 1912,
45, 1842. (b) Bernheim, F.; Morgan, J. E. Nature (London)
1939, 144, 290. (c) Chierici, L.; Gardini, G. P. Tetrahedron
1966, 22, 53.
oxidation was confirmed by a series of control experiments
where aliquots of reactions were carefully monitored by 1H
NMR analysis with an internal standard. In the presence of
oxidants, substantial non-specific decomposition readily
took place.
Synlett 2006, No. 18, 3081–3087 © Thieme Stuttgart · New York