Diastereoselection in the formation of spirocyclic oxindoles by the intramolecular heck reaction

Article abstract of DOI:10.1021/jo052335a

Diastereoselective double Heck cyclizations of cyclohexene diamides 1 and 3 form contiguous quaternary stereocenters, with diastereoselection being controlled by the trans-diol protecting group. In this, the first in a series of two papers, the origin of

Full text of DOI:10.1021/jo052335a

Diastereoselection in the Formation of Spirocyclic Oxindoles by the
Intramolecular Heck Reaction
Larry E. Overman* and Donald A. Watson
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025
leoVerma@uci.edu
ReceiVed NoVember 10, 2005
Diastereoselective double Heck cyclizations of cyclohexene diamides 1 and 3 form contiguous quaternary
stereocenters, with diastereoselection being controlled by the trans-diol protecting group. In this, the
first in a series of two papers, the origin of diastereoselection in the first ring-closure step of these reactions
is examined. Nine simplified analogues of 1 and 3 were synthesized and cyclized to discern what structural
features are required to realize high diastereoselection in the first intramolecular Heck reaction. These
studies show that high stereoselection (>20:1) does not arise from a single structural feature: it is seen
only in substrates that contain both a trans-acetonide and a tertiary amide substituent at C2. Two subtle
factors appear to be involved: (1) Avoidance of eclipsing interactions between the forming C-C bond
and the pseudoaxial hydrogen atom at C6 and between the pseudoequatorial hydrogen atom at C6 and
the carbonyl carbon of the forming spirooxindole. (2) The vinylic amide substituent that is not involved
in the insertion event preferentially adopts a perpendicular conformation, placing the sterically bulky
NR2 over the alkene π bond. syn-Pentane-like interactions between this substituent and the C3 of the
cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce
a highly diastereoselective process.
Introduction
1).2 These cyclizations are exceptional in their ability to establish
vicinal quaternary carbon stereocenters by a catalytic reaction.3,4
Remarkably, the relative configuration of the products was
dependent upon the group used to protect the trans-diol, a
functional group that is remote from the site of the Heck
Diastereoselective Heck cyclizations that form spirocyclic
products without the use of chiral additives are rare.1 In the
context of the total syntheses of meso- and (-)-chimonanthine,
this research group described recently the diastereoselective
sequential double Heck cyclization of C2-symmetric diiodides
1a and 3a to provide spirocyclic dioxindoles 2 and 4 (Scheme
(2) Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem. Soc.
1999, 121, 7702-7003.
(3) There are limited methods known for the construction of contiguous
all-carbon quaternary centers. To our knowledge, the examples described
from our laboratories are the only catalytic reactions reported for the
synthesis of vicinal quaternary carbon stereocenters. See: Peterson, E. A.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943-11948.
(4) For general methods for the construction of quaternary carbon
stereocenters, see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363-5367. (b) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105-10146. (c) Christoffers, J.; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688-1690. (d) Christoffers, J.; Mann, A. Angew.
Chem., Int. Ed. 2001, 40, 4591-4597. (e) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388-401.
(1) (a) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-
2964. (b) Link, J. T. The Intramolecular Heck Reaction. In Organic
Reactions; Overman, L. E., Ed.; John Wiley and Sons: New York, 2002;
Vol. 60, pp 157-534. (c) Overman, L. E.; Link, J. T. Intramolecular Heck
Reactions in Natural Products Chemistry. In Metal Catalyzed Cross-
Coupling Reactions; Stang, P. J., Diederich, F., Eds.; Wiley-VCH: New
York, 1998. (d) de Meijere, A.; Brase, S. Palladium-Catalyzed Coupling
of Organyl Halides to Alkenes - The Heck Reaction. In Metal Catalyzed
Cross-Coupling Reactions; Stang, P. J., Diederich, F., Eds.; Wiley-VCH:
New York, 1998. (e) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2379-2411.
10.1021/jo052335a CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/02/2006
J. Org. Chem. 2006, 71, 2587-2599
2587

Overman and Watson
SCHEME 1a
SCHEME 2a
a Key: (a) 6, 2,6-lutidine, Et2O; (b) TBAF; (c) PhNTf2, Cs2CO3; (d)
m-CPBA; (e) cat. TFA, H2O, 80 °C; (f) 2,2-DMP, CSA; (g) TBDMSOTf,
2,6-lutidine.
determined at the time of the previous report.2 In addition, minor
products formed alongside 4 were not characterized in our earlier
study.2 At the time the present study began, aryltriflates had
emerged in our laboratories as preferred substrates in Heck
cyclization routes to synthesize pyrrolidinoindoline alkaloids.5
Therefore, we elected to study in detail the Heck cyclization of
disiloxy ditriflate 3b.
Heck cyclization substrates 1b and 3b are available in only
a few synthetic steps (Scheme 2). Amination of diacyl dichloride
5 with N-benzyl-2-(triethylsiloxy)aniline (6) provided the cor-
responding diamide. Installation of the triflate groups was
accomplished in two routine steps to provide 7 in 65% overall
yield. The disubstituted alkene then was converted to the
corresponding trans-diol by a reaction with m-chloroperbenzoic
acid (m-CPBA), followed by acid hydrolysis of the resultant
epoxide. Treatment of this diol with 2,2-dimethoxypropane (2,2-
DMP) and catalytic camphorsulfonic acid (CSA) in acetone
provided the acetonide ditriflate 1b in 74% yield over three
steps. Alternatively, protection of the diol by a reaction with
excess TBDMSOTf in the presence of 2,6-lutidine provided
disiloxy ditriflate 3b in 76% yield over three steps.
a Key: (a) 20 mol % Pd(PPh3)2Cl2, 10 equiv Et3N, DMA, 100 °C, 24 h.
cyclizations. In the case of acetonide-protected diiodide 1a,
dioxindole 2, having a trans relationship of its spirooxindole
fragments, was formed in 90% yield as a single diastereoisomer.
On the other hand, cyclization of trans-disiloxy substrate 3a
produced preferentially dioxindole 4 (isolated in 64% yield),
having a cis relationship of its spirooxindole units; additional
minor products were observed in the unpurified reaction mixture
formed upon the cyclization of 3a.2 Although not disclosed
previously, the related ditriflate substrates 1b and 3b provided
nearly identical product mixtures when cyclized under the same
conditions.5
The cyclization reactions described in Scheme 1 are unique
in terms of their diastereoselectivity, the role played by the diol
protecting groups, and their ability to construct contiguous
quaternary carbon stereocenters. Thus, we sought to better
understand these transformations. We chose to pursue this
objective by the synthesis and subsequent Heck cyclization of
simplified analogues of 1 and 3, hoping to discern the structural
features required to realize high diastereoselection. In this paper
we disclose our investigations of the factors controlling stereo-
selection in the first cyclization event. These studies show that
the origin of diastereoselection in these systems is subtle,
resulting from several cooperative factors. In the following
paper, we describe related studies directed at understanding the
second ring-closure event in the sequential double Heck
cyclizations of 1 and 3.6
Cyclizations of acetonide ditriflate 1b and disiloxy ditriflate
3b were investigated using the reaction conditions summarized
in Scheme 1. Similar to diiodide 1a, acetonide-protected
ditriflate 1b underwent double Heck cyclization cleanly to
provide trans-dioxindole 2 in 87% yield as the single detectable
product (by 1H NMR analysis). In contrast, subjection of
disiloxy ditriflate 3b to the same conditions resulted in a more
1
complex mixture of products. Analysis of this mixture by H
NMR showed that it was similar to that obtained in the
cyclization of disiloxy diiodide 3a.7 Purification of the crude
reaction product by column chromatography provided 4 in 56%
yield, together with the shunt reduction product 10 (10% yield)
and a 10% yield of an equimolar mixture of two additional
products, 11 and 12 (Scheme 3).
The relative configuration of the major product 4 was
rigorously defined. After extensive efforts, we found that
diffusion of n-hexane into a solution of dioxindole 4 in about
3:1 Et2O/EtOAc resulted in crystals suitable for X-ray diffraction
analysis. This study, although unable to provide exact metric
Results
Diastereoselection in the Cyclization of Disiloxy Substrates
3. We began our study by more thoroughly defining the product
mixture produced upon cyclization of disiloxy substrate 3.
Unlike acetonide 1, which cyclizes to provide a single product
(as determined by NMR analysis), precursor 3 provides a
mixture of products upon Heck cyclization. One epimer of
dioxindole 4 (isolated in 64% yield) was the major product
reported from the cyclization of diiodide 3a; the configuration
of the allylic siloxy substituent in this product was not
(5) Stearns, B. A. A Formal Synthesis of Loracarbef and Total Synthesis
of Polypyrrolidinoindoline Alkaloids. Ph.D. Thesis, University of Californias
Irvine, Irvine, CA, 2000.
(7) To allow complete conversion of intermediates produced from the
ditriflate precursor to the observed final products 4 and 10-12, longer
reaction times were required than those in the cyclizations of the corre-
sponding diiodide.
(6) Overman, L. E.; Watson, D. A. J. Org. Chem. 2006, 71, 2600-2608.
2588 J. Org. Chem., Vol. 71, No. 7, 2006

Diastereoselection in the Formation of Oxindoles
SCHEME 3a
a Key: (a) 20 mol % Pd(PPh3)2Cl2, 10 equiv Et3N, DMA, 100 °C, 30 h.
SCHEME 4a
data because of disorder in the silyl groups, clearly demonstrated
the all-cis relationship of the aryl fragments of the spirooxindoles
and the allylic siloxy substituent.8
Structures of the minor products formed upon Heck cycliza-
tion of 3b were determined as follows. The relative configuration
of the shunt reduction product 10 was assigned by the
1
comparison of its H NMR spectrum with those of related
compounds of established configuration (see below). Although
attempts to separate the two additional products led only to their
decomposition, the relative configurations of 11 and 12 could
1
be assigned by the comparison of the H NMR spectrum of a
mixture of these compounds to the 1H NMR spectra of authentic
samples of each material.9 Each of these products has a trans
relationship of its spirooxindole groups. C2-symmetric 11 arises
from a cyclization process terminated by a reduction, a
transformation that is discussed further in the accompanying
article.
a Key: (a) 6, Mukaiyama’s salt, 2,4,6-collidine, PhMe, 80 °C; (b) K2CO3,
H2O; (c) PhNTf2, Cs2CO3; (d) m-CPBA; (e) cat. TFA, H2O, 80 °C; (f)
2,2-DMP, CSA; (g) TBDMSOTf, 2,6-lutidine.
group was removed, and the triflate was installed to provide
diene 14. The disubstituted alkene was then converted to trans-
diol 15,12 which was in turn protected as either an acetonide or
a disilyl derivative giving substrate 16a or 16b.
Methyl ester congeners 20a and 20b were prepared in a
similar fashion. The low-temperature addition of methoxide to
anhydride 1713 provided the corresponding methyl ester (Scheme
5).14 This monoacid was converted to the corresponding anilide
by the in situ formation of the acid chloride and subsequent
coupling of this intermediate with aniline 6.15,16 The resultant
aryl silyl ether was then converted directly to triflate 18 in 59%
overall yield from anhydride 17 by treatment with CsF and
PhNTf2. The syntheses of esters 20a and 20b were completed
The ratio of products 4:10:11:12 (65:11:11:13, determined
by 1H NMR analysis of the crude cyclization product mixture),
generated from the Heck cyclization of 3b, suggests that the
first spirocyclization in the disiloxy series occurred with
moderate diastereoselection, generating an approximate 86:14
mixture of monocyclization products 8 and 9. Intermediate 8
then partitions to pentacyclic products 4 and 11 and the shunt
product 10, whereas intermediate triflate 9 cyclizes to provide
the pentacyclic product 12.
Synthesis of Model Substrates. To study the origins of
diastereoselection in the first spirocyclization step, a number
of monoaryl triflates were synthesized and studied. These model
compounds contained various structural features of the C2-
symmetric substrates 1 and 3. Cyclization of these model
substrates was then undertaken to study the consequence of each
substructure on the diastereoselection of the first Heck cycliza-
tion.
(11) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-1166.
(12) A minor byproduct from the competitive oxidation of the cyclo-
hexadiene to the corresponding arene was observed also in the epoxidation
step. This material proved difficult to separate from the desired product
prior to conversion to diol 15.
(13) Maier, G.; Sayrac, T.; Reisenauer, H. P. Chem. Ber. 1982, 115,
2202-2213.
(14) Attempts to use other nucleophiles in this reaction, in particular
anilines or their metal salts, led to complex mixtures of products.
(15) Other activation strategies, such as the use of Mukaiyama’s salt,
provided the coupled product in low yield only. Increased steric crowding
imparted by the proximity of the C2 ester likely makes amide formation
more challenging in this series.
(16) The choice of ethyl ether as the solvent proved critical in this
sequence; the use of methylene chloride as solvent yielded only trace
amounts of product.
To begin, monotriflates 16a and 16b, in which the cyclo-
hexene double bond is trisubstituted, were prepared. Cyclo-
hexadienoic acid 1310 was coupled to aniline 6 using 2-chloro-
1-methylpyridinium iodide (Mukaiyama’s salt)11 to provide the
corresponding anilide (Scheme 4). The triethylsilyl protecting
(8) See Supporting Information for additional details.
(9) See the accompanying article for preparation and characterization of
11 and 12.6
(10) Emerman, S. L.; Meinwald, J. J. Org. Chem. 1956, 21, 375.
J. Org. Chem, Vol. 71, No. 7, 2006 2589

Overman and Watson
SCHEME 5a
SCHEME 6a
a Key: (a) NaOMe/MeOH, -78 °C; (b) (COCl)2, CH2Cl2, then 6, 2,6-
lutidine, Et2O; (c) PhNTf2, CsF; (d) m-CPBA; (e) cat. TFA, H2O, 80 °C;
(f) 2,2-DMP, CSA; (g) TBDMSOTf, 2,6-lutidine.
by the installation of the trans-ether functionalities, using a
sequence similar to the one described previously.
We wished also to study substrates such as 23, having amide
substituents at C2. Initially, we hoped to access these materials
from esters 20a or 20b. Unfortunately, all attempts to carry out
these transformations failed. For example, as shown in Figure
1, we were unable to hydrolyze ester 21 to give acid 22 using
a Key: (a) n-BuLi or LiHMDS, then CO2, -78 °C; (b) EDCI, 25; (c)
1,3-butadiene, EtAlCl2, 2,6-di-tert-butyl-4-methylpyridine, PhMe, rt, 48 h;
(d) PhNTf2, CsF; (e) m-CPBA; (f) cat. TFA, H2O, 80 °C; (h) 2,2-DMP,
CSA; (i) TBDMSOTf, 2,6-lutidine.
SCHEME 7a
FIGURE 1. Failed strategy for preparing diamide 23.
a variety of reagents (LiOH, KOTMS, etc.). We believe that
cleavage of the ester occurred smoothly, but the resultant
carboxylate engaged the C7 anilide, ejecting N-benzylaniline
and providing a pathway for further decomposition.
As earlier studies had shown that metal-mediated methods17
for the direct conversion of esters to tertiary ortho-alkoxyanilides
were not effective in these systems,18 an alternative route to
the diamide substrates was devised. This sequence, which
installed both acylamino groups prior to the formation of the
cyclohexene ring, is shown in Scheme 6. Lithiation of propiolic
acid anilide 24a,19 followed by quenching with CO2, provided
the corresponding acid. Subsequent coupling of this acid with
N-benzyl-2-(tert-butyldimethylsiloxy)aniline (25) promoted by
1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride
(EDCI) resulted in the formation of dianilide 26a.20 Attempts
to carry out the cycloaddition of 26a and 1,3-butadiene thermally
were not successful. At 150 °C, Diels-Alder products were
observed, but extensive polymerization of 1,3-butadiene at this
temperature made the reaction impractical. After screening
a Key: (a) 5-10 mol % Pd(PPh3)2Cl2, 25, CO (1 atm), Bu3N, 100 °C;
(b) PhNTf2, CsF, Cs2CO3.
several Lewis acids, the desired cyclohexadiene was obtained
in high yield by the reaction of 26a and 1,3-butadiene at room
temperature in the presence of excess EtAlCl2.21 The cyclo-
hexadiene product was converted easily to triflate 27a. Ac-
etonide 29a and disilyl ether 29b then were obtained by
processing triflate 27a by a standard sequence of steps.
Beginning with N,N-dimethylpropynamide (24b), the prepara-
tion of dimethyl amide 29c proceeded in a similar fashion to
that of anilides 29a and 29b.22
Two additional substrates lacking oxidation at C4 and C5
were synthesized also (Scheme 7). tert-Butyl-substituted sub-
strate 31 was assembled in two steps from the known triflate
30.23 In the first step, the anilide was constructed by palladium-
catalyzed carbonylation of 30 in the presence of aniline 25.24
The TBDMS group was then exchanged for triflate by a reaction
(17) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
48, 4171-4174. (b) Willimas, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini,
G.; Dolling, U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461-
5464.
2590 J. Org. Chem., Vol. 71, No. 7, 2006

Diastereoselection in the Formation of Oxindoles
SCHEME 8a
a Key: (a) 20 mol % Pd(PPh3)2Cl2, 10 equiv Et3N, DMA, 100 °C, 24 h.
SCHEME 9a
with CsF, Cs2CO3, and PhNTf2 to provide 31 in 66% overall
yield. Octalin 33, and its double-bond isomer 34, were prepared
in 56% combined yield by a similar two-step sequence from
the known mixture of alkene isomers of triflate 3225 and were
separated by preparative HPLC.
Heck Cyclizations. Intramolecular Heck reactions of model
substrates were carried out in identical fashion [20 mol %
Pd(PPh3)2Cl2, 10 equiv of Et3N, N,N-dimethylacetamide (DMA),
100 °C, 24 h], with product ratios being determined by analysis
1
of the H NMR spectra of unpurified reaction products. We
began by studying the cyclization of acetonide diamide 29a and
disiloxy diamide 29b, substrates that contain the dianilide
framework of the C2-symmetric double Heck precursors 1 and
3, but lack one triflate functional group. Similar to its C2-
symmetric counterpart, acetonide-protected substrate 29a cy-
clized to provide spirooxindole 35 as a single detectable isomer
(96% yield; Scheme 8). The relative configuration of this
product was determined by the observation of a 4% NOE for
the aromatic hydrogen atom at C12 upon irradiation of the
methine hydrogen atom at C5.8 On the other hand, cyclization
of disiloxy analogue 29b provided a mixture of three products.
The two major products, spirooxindoles 10 and 36, were formed
in a 2:1 ratio. These products differ in relative configuration at
their spiro stereocenters as determined by a comparison of the
1H NMR spectra of these materials with those of the two
products produced upon cyclization of disiloxy congener 16b
(vide infra), with the signals for the C6 hydrogen atoms being
particularly diagnostic. The relative configuration of the enox-
ysilane 37 was assigned by the observation of a series of NOE
a Key: (a) 20 mol % Pd(PPh3)2Cl2, 10 equiv Et3N, DMA, 100 °C, 24 h.
enhancements, including a 1.7% enhancement for the C2
methine hydrogen atom upon irradiation of the pseudoaxial
hydrogen atom at C6 and a 1.8% enhancement for the C12
hydrogen atom upon irradiation of the C2 methine hydrogen
atom.8 Presumably, enoxysilane 37 arose from the palladium
hydride complex of the major Heck product 10 by double-bond
migration. Thus, the overall diastereoselectivity of the Heck
cyclization of disiloxy monotriflate 29b was 72:28, favoring
the formation of the spirooxindole isomer having the aryl
fragment cis to the C5 siloxy substituent.
The results obtained from the cyclizations of aryl triflate
substrates 16a and 16b, which have no substituent at C2, are
summarized in Scheme 9. Cyclization of acetonide precursor
16a gave rise to an 80:20 mixture of epimeric spirooxindoles
38 and 39. Conversely, cyclization of the disiloxy congener 16b
occurred with no stereoselection to give an equal mixture of
epimeric spirooxindoles 40 and 41. The relative configurations
(18) Watson, D. A. Investigation into the Origins of Diastereoselection
in Spirocyclic Oxindole Forming Intramolecular Heck Cyclizations. Ph.D.
Thesis, University of CaliforniasIrvine, Irvine, CA, 2004.
(19) Alkyne 24a is available in one step from propiolic acid and
N-benzylaniline.
(20) Several reagents were examined as promoters for this coupling, but
only carbodiimide reagents were successful.
(21) (a) Milder Lewis acids such as Me2AlCl did not promote the reaction
at room temperature. (b) Substoichiometric quantities of 2,6-di-tert-butyl-
4-methylpyridine were added to prevent Bro¨nsted acid-promoted side
reactions such as alkene migration.
(22) Crow, W. D.; Leonard, N. J. J. Org. Chem. 1965, 30, 2660-2665.
(23) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
(24) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 37, 3931-3934.
(25) Collins, C. J.; Martinez, A. G.; Alvarez, R. M.; Aguirre, J. A. Chem.
Ber. 1984, 117, 2815-2824.
J. Org. Chem, Vol. 71, No. 7, 2006 2591

Overman and Watson
SCHEME 10a
a Key: (a) 20 mol % Pd(PPh3)2Cl2, 10 equiv Et3N, DMA, 100 °C, 24 h.
SCHEME 11a
of products 38-41 were established by the removal of their
respective protecting groups to provide the corresponding diols.
The relative configuration of the diol derived from the disiloxy
product 41 was then determined by X-ray crystallography.8
Substrates that lacked oxidation at C4 and C5 were studied
to see if there was any intrinsic preference for forming an axial
C-C bond. A small preference of this type was seen with octalin
33, which cyclized to provide a 70:24:6 mixture of spirooxin-
doles 42, 43, and 44 in 72% yield (Scheme 10). The relative
configurations of the two major products 42 and 43, which are
epimeric at the C1 spiro stereocenter, were defined by X-ray
crystallographic analysis of 42.8 A series of NOE studies showed
that the minor product 44 had the same relative configuration
as 42; diagnostic signals included a 1.7% enhancement for the
C12 aryl hydrogen atom and a 1.0% enhancement for the
pseudoaxial C6 hydrogen atom upon irradiation of the pseudo-
axial C2 hydrogen atom.
Little axial preference was seen in the cyclization of the
related substrate 31, in which the cyclohexene ring was anchored
with a tert-butyl group. Thus, three spirooxindoles 45, 46, and
47 were formed in a ratio of 50:40:10, with a 93% combined
yield.26 The relative configurations of epimers 45 and 46 were
determined by the observation of a 2.2% NOE enhancement
for the C12 aryl hydrogen atom, and a 2.4% NOE enhancement
for the hydrogen atom at C4 upon irradiation of the pseudoaxial
hydrogen atom at C6 in compound 46. This NOE correlation
establishes a trans relationship between the tert-butyl group and
the aryl fragment of the spirooxindole in compound 46. Alkene
isomer 47 must arise by double-bond isomerization; however,
as the initial C4 stereocenter of substrate 31 is destroyed in
this process, it is not possible to establish how 47 was formed.27
As the presence of an amide substituent at C2 enhances
cyclization diastereoselection in both the acetonide and disiloxy
series, we investigated whether a simple methyl ester substituent
would have a similar effect. Acetonide ester 20a cyclized with
low selectivity, providing a 45:21:34 mixture of spirocyclic
products 48, 49, and 50, with an 86% combined yield (Scheme
a Key: (a) 20 mol % Pd(PPh3)2Cl2, 10 equiv Et3N, DMA, 100 °C, 24 h.
11). Again, the relative configuration of these products could
1
be assigned by H NMR NOE analysis. The major product 48
displayed a 4.6% NOE enhancement for the C12 aryl hydrogen
atom when the C5 methine hydrogen atom was irradiated,
indicative of an axial orientation of the aryl portion of the
spirooxindole. Conversely, irradiation of the pseudoaxial C6
hydrogen atom of compound 49 resulted in a 4.3% enhancement
for the C4 hydrogen atom, and importantly, a 1.5% enhancement
for the C12 aryl hydrogen atom, confirming the pseudoequatorial
disposition of the aryl fragment of the oxindole in this epimer.
(26) This ratio matches the ratio previously observed in a similar reaction.
See: Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52,
4130-4133.
(27) Resubjection of the isolated products to the cyclization conditions
resulted in no further alkene migration.
2592 J. Org. Chem., Vol. 71, No. 7, 2006

Diastereoselection in the Formation of Oxindoles
The aryl portion of the oxindole was also pseudoaxial in the
enol ether product 50, as signaled by the observation of a 4.6%
NOE enhancement of the C12 aryl hydrogen atom upon
irradiation of the C5 hydrogen atom. Irradiation of the C2
methine hydrogen atom of enol ether 50 resulted in a 1.4% NOE
of the pseudoaxial C6 hydrogen atom, establishing that the
methyl ester substituent is pseudoequatorial. Thus, in the
acetonide series, the overall diastereoselection in forming the
spirooxindole was 79:21 favoring the product in which the aryl
fragment of the oxindole is pseudoaxial. As observed with other
model substrates, disiloxy congener 20b cyclized with lower
diastereoselection, providing in this case a 59:41 mixture of
spirooxindoles 51 and 52 in high yield. Diagnostic signals for
the C6 hydrogen atoms (at approximately 2 ppm) were similar
to those seen in the 1H NMR spectra of spirooxindoles 40 and
41, thus allowing the relative configuration of products 51 and
52 to be specified.
The presence of a methyl ester or an N-benzylanilide
substituent at C2 had quite different effects on cyclization
diastereoselectivity. Thus, we examined Heck cyclization of the
N,N-dimethylamide congener 29c, which in size would be more
similar to the methyl ester (eq 1). Like the dianilide substrates
1b and 29a (Schemes 1 and 8), amide 29c cyclized with high
stereoselectivity to provide a single spirooxindole 53, isolated
in 76% yield. The observation of a 3.1% NOE for the C12
hydrogen atom upon irradiation of the C5 hydrogen atom
allowed the relative configuration of 53 to be specified.
FIGURE 2. Chair conformations of the two possible products resulting
from syn insertion and tabulated Heck insertion diastereoselectivity as
a function of the C2 alkenyl substituent; the product resulting from
intermediate A is produced predominantly.
configuration of the spirooxindole of the major product places
the larger aryl portion of the oxindole axial and the smaller car-
bonyl group pseudoequatorial.28,29 Second, arguments based on
the notion that syn insertion would take place preferentially to
form the most stable chair conformation of the cyclohexylpal-
ladium intermediate also are not consistent with the observed re-
sults. Because of conformational constraints, only two chair inter-
mediates are possible in the acetonide series (Figure 2): in A,
which would lead to the observed predominant stereoisomer of
the Heck product, the new C-C bond is axial, whereas in B,
the C-Pd bond is axial. As the R group at C2 would experience
two destabilizing 1,3-diaxial interactions in intermediate A, the
observation that stereoselection does not decrease as the size
of the C2 substituent R increases is not consistent with this
model.30
A consideration of the transition structures for migratory
insertion to the alkene faces of the acetonide substrates provides
a rationale for the observed diastereoselection (Figure 3).
Because of the rigid half-chair conformation of the cyclohexene,
the C6 methylene hydrogen atoms are in distinct environments.
The same is true for the methylene hydrogen atoms at C3. In
the transition structure leading to the minor products, disfavored
transition structure 54a, two major destabilizing interactions
result from the C6 hydrogen atoms. First, as migratory insertion
occurs to the alkene face proximate to the pseudoaxial C6
hydrogen atom, formation of the new C-C σ bond at C1 results
in a developing eclipsed interaction between this new bond and
the axial C6-H bond. Second, as migratory insertion occurs,
C1 and C2 undergo rehybridization from sp2 to sp3. As a result,
the alkene substituents move away from the incoming palladium
arene. In the disfavored transition structure 54a, this motion
results in an eclipsing interaction between the C1-C7 σ bond
and the pseudoequatorial C6-H bond. These destabilizing
interactions are illustrated in the modified Newman projection
of the disfavored transition structure 54b.
Discussion
Two trends are apparent in the diastereoselective Heck
cyclizations examined in the present study. First, substrates
containing a trans-C4,C5 acetonide undergo Heck cyclization
with higher diastereoselectivity (>20-4:1; Schemes 1, 8, 9, and
11; eq 1) than congeners having the trans-C4,C5 diol protected
with TBDMS groups (diastereoselectivity ) 6-1:1; Schemes
3, 8, and 11). In the acetonide series, the relative configuration
of the spirooxindole in the major product is the same as that of
the “first-formed” spirooxindole unit in the cyclization of
acetonide ditriflate 1a f 2 (Scheme 1): an axial C-C bond is
formed preferentially upon insertion. When modest stereose-
lectivity is seen in the disiloxy series, the relative configuration
of the newly formed spirooxindole is the opposite: the aryl
fragment of the spirooxindole is cis to the C5 siloxy substituent.
Second, the presence of a tertiary amide substituent at C2
significantly enhances diastereoselection in the acetonide-
protected substrates compared to that of the substrates lacking
this functionality. These two substitution effects are reinforcing;
only substrates that contain both a trans-C4,C5 acetonide and
a C2 tertiary amide substituent (1, 29a, and 29c) cyclize with
high levels (>20:1) of diastereoselection.
(28) For example, molecular mechanics calculations indicate that 38 is
0.76 kcal/mol less stable than its spirooxindole epimer 39; Monte Carlo
conformation searches performed using the Macromodel 8.0 implementation
of the MM2* force field and the Maestro 5.0 interface.29
(29) Available from Schro¨dinger, L. L. C., 101 SW Main Street, Suite
1300, Portland, OR 97204.
(30) Models based on the notion that increases or decreases in the
torsional strain of the fused trans-acetonide in different insertion topogra-
phies could be important also does not rationalize the observed results.18
Diastereoselection in the Acetonide Series. Several potential
models for interpreting diastereoselection are easily dismissed.
First, diastereoselection in the acetonide series does not reflect
the thermodynamic stability of the Heck products, as the relative
J. Org. Chem, Vol. 71, No. 7, 2006 2593

Overman and Watson
FIGURE 3. Representation of the two syn insertion pathways in the
acetonide series. Destabilizing eclipsing interactions are avoided in the
insertion topography of 55.
On the other hand, in the transition structure leading to the
major product (55a, Figure 3), migratory insertion to the alkene
face opposite the axial C6 hydrogen atom avoids eclipsing
interactions between the C1 and C6 substituents (see 55b). Here,
the developing eclipsing interactions are predicted to occur
between the C2 and C3 substituents. One of these interactions
involves the developing long Pd-C σ bond and the axial C3-H
bond, and the second involves the interaction of two C-H
bonds. Both of these interactions should be less energetically
costly than the two C-C/C-H bond interactions in 54a.
Although the energy differences imparted by these competing
eclipsing interactions are not large, only small energy differences
between diastereomeric transition structures are required to
rationalize stereoselection in Heck cyclizations of substrates
lacking amide substituents at C2.
FIGURE 4. Calculated (DFT) transition states for competing syn
insertion pathways in substrates lacking the C2 amide.
cyclization of acetonide triflate 16a, which lacks a C2 substitu-
ent. In the higher-energy transition state 57, the calculated
dihedral angle between the pseudoequatorial C6-H bond and
the C1-C7 σ bond is 6.4°. Likewise, the calculated dihedral
angle between the forming C-C σ bond and the pseudoaxial
C6-H bond is 14.3°. These calculations support the hypothesis
that the avoidance of developing eclipsing interactions in the
competing transition states controls face selectivity in the Heck
cyclization.
As noted previously, diastereoselection is strongly dependent
upon the nature of the C2 alkene substituent (summarized in
Figure 2). The high diastereoselectivity observed in Heck
cyclizations of acetonide triflates 29a and 29c demonstrates that
the C2 anilide substituent is critical for realizing high diaste-
reoselectivity in the sequential double Heck cyclization of
acetonide ditriflates 1. The similar diastereoselectivities observed
in Heck cyclizations of methyl ester 20a (Scheme 11) and
trisubstituted alkene 16a (Scheme 9) demonstrate that a simple
electronic effect is not the origin of the enhanced diastereose-
lectivity seen with substrates having C2 amide substituents.
Insight into the role of a C2 amide substituent is gained by
an examination of the structures of the Heck cyclization
substrates obtained from X-ray crystallographic studies. Figure
5 shows the solid-state structure of methyl ester 20a and
dimethyl amide 29c.35 Whereas, the carbomethoxy of 20a adopts
a conformation in which the carbonyl and the alkene π bonds
are coplanar, and the acyl group of amide 29c is nearly
perpendicular to the π system of the alkene. In both structures,
the triflato anilide substituent adopts a similar conformation,
placing the carbonyl group perpendicular to the alkene.36
Molecular mechanics minimizations and dihedral driving ex-
periments show that the favored conformations of the amide
To gain support for our explanation of the observed diaste-
reoselection in the acetonide series in the absence of a C2
substituent, DFT calculations of the two competing transition
states for migratory insertion were performed using a slightly
simplified model structure.31-34 As shown in Figure 4, the
energies of the calculated transition states 56 and 57 predict
the formation of the observed diastereomer with a calculated
∆∆G‡
) 1.45 kcal/mol. This free energy difference is
373K
roughly consistent with the observed 4:1 ratio of diasteromeric
products (corresponding to a ∆∆G‡373K ) 1.02 kcal/mol) in the
(31) Transition-state optimizations were preformed using B3LYP/
LACVP**+ level of theory as implemented in Jaguar 5.5.29 Transition states
were characterized by a single imagery frequency. The energies reported
were calculated at 373K, corresponding to the experimental reaction
temperature for the Heck cyclizations.
(32) For computational ease, a methylidene acetyl was used in place of
the acetonide, the benzyl group was replaced with a hydrogen atom, and a
phosphine replaced the triphenylphosphine.
(33) We assume that the neutral trans-Ar/Cl palladium fragment is the
catalytically active species in solution on the basis of the demonstrated
importance of anionic ligands in solution in palladium-catalyzed processes.34
The calculated transition-state energies shown in the text are specific for
the trans-Ar/Cl palladium fragment, as shown. Other possibilities were also
considered. The two transition states for the cis-Ar/Cl palladium isomer
+
were also calculated but found higher in energy. The cationic LPd(PH3)2
transition states were also calculated. The energies of these cationic isomers
are difficult to compare to the neutral species. However, in all cases, the
(35) For both methyl ester 20a and dimethyl amide 29c, X-ray crystal-
lographic studies revealed two conformations in the solid state that differ
in the orientation of the triflato anilide substituent about the C2-C7 bond
(Figure 4). In both conformations, the amides adopt nonconjugated
conformations. For clarity, Figure 8 shows only one of these conformations.
Complete depictions of the unit cells of the compounds can be found in
the Supporting Information.
calculated ∆∆G‡ favored the transition state leading to the observed
373
diastereomer by approximately the same energetic difference. Details of
these additional calculations can be found in the Supporting Information.
(34) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-321 and
references therein.
2594 J. Org. Chem., Vol. 71, No. 7, 2006

Diastereoselection in the Formation of Oxindoles
FIGURE 7. Representation of the four syn insertion pathways in the
acetonide series for substrates having a perpendicularly oriented amide
substituent at C2. Destabilizing steric interactions between the cis-amide
substituent and the arylpalladium fragment are avoided in the insertion
topographies of 60 and 61.
FIGURE 8. More detailed representation of the syn insertion
topographies of 60 and 61. syn-Pentane-like interactions between the
cis-amide substituent and C3 of the cyclohexene are avoided in the
favored insertion topography of 60.
FIGURE 5. ORTEP representation of the X-ray model of methyl ester
20a and dimethyl amide 29c.
migratory insertion would be 60 and 61, in which the organo-
metallic fragment approaches the alkene from the face of the
carbonyl group of the C2 amide substituent.37
Further analysis of potential transition structures 60 and 61
provides a reasonable explanation for the role of the C2 amide
substituent in augmenting face diastereoselectivity of the inser-
tion step. As migratory insertion involves the rehybridization
of the alkene carbons to sp3, the original alkene substituents
would be deflected away from the incoming palladium arene
fragments in transition structures 60 and 61 (depicted in more
detail in Figure 8).38 Of these two possible insertion topogra-
phies, 61 would experience a developing syn-pentane-like steric
interaction between the s-trans substituent of the amide and the
pseudoaxial hydrogen atom at C3. This destabilizing interaction
is avoided in the favored diastereomeric transition structure 60.39,40
Again, to further explore the role played by the C2 amide,
we undertook a DFT study of the two competing transition states
FIGURE 6. Coplanar conformations of cyclization substrates having
a methyl ester or tertiary amide substituent at the C2 vinylic carbon,
showing the destabilizing steric interactions present in the latter.
substituents result from steric interactions between the s-trans-R
substituent of the amide and the adjacent methylene fragment
of the cyclohexene ring (see 59, Figure 6). This interaction
destabilizes the conjugated conformation by about 5.5 kcal/mol.8
No analogous destabilizing steric interaction is present in the
coplanar conformation of the s-trans-methyl ester (see 58, Figure
6). The favored perpendicular conformation of the amide places
the steric bulk of the NR2 fragment either above or below the
alkene π bond.
Although not shown in Figure 5, X-ray crystallographic
studies suggest that the C2 amide substituents could adopt either
of the two possible perpendicular conformations with respect
to the C1-C2 alkene during the insertion step (Figure 7).35 The
steric bulk of the s-trans-nitrogen substituent in these conforma-
tions would shield an approach to the alkene face that is
proximal to the NR2 group. Thus, favored conformations for
(36) X-ray crystallographic studies were also performed on ditriflate 1b
and dianilide 29a. The results from these studies show similar amide
conformations to that of 29c and are presented in the Supporting Information.
(37) Mechanical and computational models,18 as well as crystallographic
data, show that the two possible conformations of the C2 amides have similar
energies. Therefore, diastereoselection in the Heck cyclizations of these
substrates does not derive from the ground-state conformational preferences
of the amide.
(38) This analysis assumes a relatively early transition state for the
migratory insertion. As previously argued, the trend of increased diaste-
reoselection with large C2 amides precludes a late transition state, as the
developing 1,3-diaxial interaction between the amide and the C4 hydrogen
atom would result in lowered diastereoselection.
J. Org. Chem, Vol. 71, No. 7, 2006 2595

Overman and Watson
mixture of diastereomeric products. In this case, as in the cycli-
zation of C2-symmetric disiloxy ditriflate 3b, the sense of dias-
tereoselection is opposite to that seen in the acetonide series.
Because of the low levels of diastereoselection observed in the
disiloxy series, ∆∆G‡ ) 0.7 kcal/mol in the case of the Heck
cyclization of 29b, and the fact that these substrates are not
conformationally fixed, no convincing rationalization can be
provided.41
Conclusion
The intramolecular Heck reaction remains among the most
powerful reactions available for assembling complex polycyclic
organic compounds, particularly those that contain congested
all-carbon quaternary stereocenters. This study investigated the
origin of stereoselectivity in the first ring-closing event in
sequential Heck cyclizations of C2-symmetric ditriflates 1b and
3b that construct complex hexacyclic products containing vicinal
all-carbon quaternary stereocenters. The former substrate, in
which the trans-C3,C4 diol is masked as an acetonide, undergoes
a remarkably stereoselective transformation to provide hexacy-
clic product 2 in nearly quantitative yield. By examining the
diastereoselection in Heck cyclizations of simpler congeners in
the acetonide series and by the consideration of both compu-
tational and crystallographic models, we established that the
high diastereoselectivity of the first cyclization step (likely >20:
1) derives from two subtle factors: (1) The avoidance of
eclipsing interactions between the forming C-C bond and the
pseudoaxial hydrogen atom at C6 and between the pseudoequa-
torial hydrogen atom at C6 and the carbonyl carbon of the
forming spirooxindole leads to a moderate preference for
insertion from the alkene face proximate to the pseudoequatorial
hydrogen atom at C6. (2) The vinylic amide substituent that is
not involved in the insertion event preferentially adopts a
perpendicular conformation, placing the sterically bulky NR2
over the alkene π bond. syn-Pentane-like interactions between
this substituent and C3 of the cyclohexene are avoided in the
favored insertion topography. These two effects, when com-
bined, produce a highly diastereoselective process.
FIGURE 9. Calculated (DFT) transition states for competing syn
insertion pathways in substrates containing the C2 amide.
for migratory insertion in a substrate that contained the C2
dimethyl amide.31-33 Although multiple rotamers of the C2
amide were investigated computationally, structures 62 and 63
were the only transition states located (Figure 9). As predicted,
the calculated transition states place the bulky NR2 group over
the cyclohexene ring to avoid steric interactions of this group
with the palladium atom and its ligands and the C3 methylene.
These calculations largely confirm the model for increased
diastereoselection by the C2 amide advanced above. The lower-
energy transition state 62 leads to the observed diastereomer of
the cyclization product. The calculated ∆∆G‡
value (2.16
In contrast, substrates in which the trans-C3,C4 diol is
protected with TBDMS groups cyclize with much lower levels
of diastereoselection. In the following paper, studies directed
at understanding the second ring-closure event in the sequential
double Heck cyclizations of 1 and 3 are described.6
373K
kcal/mol) corresponds to higher calculated diastereoselection
than in the cases lacking the C2 amide substituent. As predicted,
in the higher-energy transition state 63 the s-trans-methyl group
of the dimethyl amide is forced into close proximity (2.4 Å) to
the axial hydrogen atoms at C3. There is also a close contact
(2.5 Å) between this methyl group and the C5 hydrogen atom.
Evidently, this interaction with the C3 hydrogen atom is
sufficiently severe to cause rotation of the amide group toward
C5. On the other hand, in the lower-energy transition state 62,
the s-trans-methyl group of the C2 amide abuts the hydrogen
atom at C4 with a H-H distance of 2.2 Å. Although this latter
interaction is the closest contact calculated in either pathway,
it appears the energetic cost is less severe than the sum of the
two interactions in the opposing diastereomeric transition state.
When these steric interactions are combined with the eclipsing
interactions also present in the transition state (vide infra), a
highly diastereoselective transformation results.
Diastereoselection in the Disiloxy Series. As expected from
the stereoselectivity of the double Heck cyclization of the C2-
symmetric disiloxy ditriflate 3b, little diastereoselection was
observed in the Heck cyclizations of model disiloxy substrates.
Of these substrates, disiloxy diamide 29b, having the dianilide
framework of 3b but lacking one triflate functional group,
cyclized with the highest diastereoselectivity, providing a 2.6:1
Experimental Section42
General Procedure for Heck Reactions. In a glovebox under
a nitrogen atmosphere, the triflate substrate, Pd(PPh3)2Cl2, Et3N,
and DMA were combined in a base-washed, glass vial containing
(39) The developing C-Pd bond in 58 and 59 is long and, therefore,
the potential steric interactions between it and the adjacent hydrogen atoms
are expected to be of minimal consequence.
(40) Similar gearing effects have been previously noted in other systems,
see, inter alia: (a) Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95-98.
(b) Walsh, P. J.; Lurain, A. E.; Balsells, J. Chem. ReV. 2003, 103, 3297-3344.
(41) Previously, it was postulated that the ability of the siloxy groups to
adopt a trans-diaxial orientation and, thus, the cyclohexene ring, the opposite
half-chair conformation as that enforced in the acetonide series might be
important in influencing diasteroselection in the Heck cyclizations of 3a.2
More than this factor must be involved as disiloxy triflate 16b, which lacks
a C2 substituent, cyclized with no stereoselectivity.
(42) (a) General experimental details have been described: MacMillan,
D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2001,
123, 9033-9044. (b) CCDC 288970-288975 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
2596 J. Org. Chem., Vol. 71, No. 7, 2006

Diastereoselection in the Formation of Oxindoles
a magnetic stir bar. The vial was sealed with a Teflon-lined cap
and placed in a 100 °C aluminum heating block (bored to the
diameter of the vial) atop a magnetic stir plate. The reaction was
maintained with stirring for 24 h, during which time the initial
yellow suspension became a deep red, homogeneous solution. On
occasion, precipitous Pd black was observed toward the end of the
reaction. At the end of the indicated time, the reaction was cooled
to room temperature, removed from the glovebox, opened to the
atmosphere, and diluted with Et2O. The resultant solution was
washed with water twice and once with brine, dried over MgSO4,
and concentrated in vacuo. 1H NMR analysis of the crude reaction
mixture was then used to determine the diastereomeric ratio of the
products formed.
Heck Cyclization of Ditriflate 1b. According to the general
procedure, triflate 1b (313 mg, 360 µmol), Pd(PPh3)2Cl2 (101 mg,
144 µmol), Et3N (546 mg, 0.75 mL, 540 mmol), and DMA (4.7
mL) were heated to give dioxindole 2 as a single detectable isomer.
Column chromatography (80:20, hexanes/EtOAc) provided 180 mg
(87%) of dioxindole 2 as a colorless solid. Data for 2 matched that
previously reported.2
Heck Cyclization of Ditriflate 3b. Using a modification of the
general procedure, triflate 3b (196 mg, 185 µmol), Pd(PPh3)2Cl2
(26.9 mg, 37.0 µmol), Et3N (188 mg, 0.26 mL, 1.85 mmol), and
DMA (1.9 mL) were heated for 30 h to give an approximate 65:
11:11:13 mixture of 4, 10, 11, and 12. As a result of the complexity
of the spectrum, precise integrations of the species present was not
possible. Column chromatography (90:10 to 70:30 hexanes/Et2O)
allowed for the isolation of 78.5 mg (56%) of 4 as a colorless oil,
13.3 mg (10%) of 10 as an off-white solid, and 14.8 mg (10%) of
an inseparable, approximate equimolar mixture of 11 and 12 as a
white solid. Pure samples of 11 and 12 were independently prepared
and characterized, see accompanying article.6 The slow diffusion
of hexanes into an EtOAc/Et2O solution of 4 provided crystals
suitable for X-ray crystallographic analysis.
Data for 4: IR (film) 2954, 2929, 2858, 1719, 1652, 1611, 1360,
1250, 1171 cm-1; 1H NMR (500 MHz, C6D6, rt) δ 8.43 (br s, 1H),
7.29 (br s, 2H), 7.05 (br s, 2H), 6.82-6.70 (m, 7H), 6.76 (br s,
1H), 6.15-6.43 (m, 5H), 4.93-5.10 (m, 3H), 4.64-4.80 (m, 2H),
4.26 (br s, 1H), 3.80 (br d, J ) 15.0 Hz, 1H), 2.01 (br d, J ) 13.0
Hz, 1H), 1.02 (s, 9H), 0.89 (s, 9H), 0.15-0.25 (m, 9H), -0.14 (br
s, 3H); 13C NMR (125 MHz, C6D6, rt) δ 177.1, 176.4, 156.5, 144.6,
143.7, 137.2, 136.3, 131.3, 130.6, 130.1, 129.3, 129.2, 129.1, 129.0,
128.7, 127.7, 127.4, 126.8, 125.9, 122.2, 121.8, 109.7, 109.4, 106.4,
67.1, 55.1, 52.0, 45.0, 43.7, 37.2, 26.6, 26.4, 19.1, 18.5, -3.3, -3.4,
-3.9, -4.2; LRMS (ESI, m/z) 757.73 (M + H)+, 779.7 (M + Na)+;
HRMS (ESI, m/z) calcd for C46H56N2O4Si2, 779.3676 (M + Na)+;
found, 779.3684. The 1H NMR spectrum was also recorded in
toluene-d8 at 100 °C and CDCl3 at room temperature, see Supporting
Information for details.
79.3 mg (96%) of 35 as a colorless oil. IR (film) 3035, 2985, 1717,
1646, 1613, 1495, 1227, 1073 cm-1; 1H NMR (500 MHz, C6D6) δ
7.39 (d, J ) 7.4 Hz, 2H), 7.10-7.14 (m, 5H), 6.78-7.04 (m, 11H),
6.56 (d, J ) 7.6 Hz, 1H), 6.22 (d, J ) 1.2 Hz, 1H), 5.03 (d, J )
14.7 Hz, 1H), 4.96 (d, J ) 16.1 Hz, 1H), 4.87 (d, J ) 16.1 Hz,
1H), 4.37 (dd, J ) 8.3, 1.7 Hz, 1H), 4.31 (d, J ) 14.7 Hz, 1H),
3.90 (ddd, J ) 12.6, 8.3, 4.1 Hz, 1H), 2.69 (t, J ) 12.1 Hz, 1H),
2.18 (dd, J ) 11.9, 4.1 Hz, 1H), 1.29 (s, 3H), 1.27 (s, 3H); 13C
NMR (125 MHz, C6D6) δ 179.0, 166.8, 144.3, 144.2, 138.2, 137.7,
137.1, 135.4, 133.8, 129.5, 129.2, 128.9, 128.84, 128.81, 128.76,
128.0, 127.8, 127.64, 127.60, 123.6, 122.2, 112.5, 110.2, 78.2, 75.7,
54.8, 54.4, 45.0, 37.9, 27.3, 27.1; LRMS (ESI, m/z) 571.28 (M +
H)+, 593.27 (M + Na)+; HRMS (ESI, m/z) calcd for C37H34N2O4,
593.2416 (M + Na)+; found, 593.2412.
Heck Cyclization of Triflate 29b. According to the general
procedure, triflate 29b (280 mg, 0.308 mmol), Pd(PPh3)2Cl2 (43.2
mg, 55.6 µmol), Et3N (310 mg, 0.43 mL, 3.08 mmol), and DMA
(3.1 mL) were heated to give a 60:28:12 mixture of spirooxindoles
10, 36, and 37. Column chromatography (90:10, hexanes/EtOAc)
allowed for the partial separation of the isomers, giving a combined
yield of 470 mg (73%) of the mixture of isomers. Preparative HPLC
(95:4.5:0.5, hexanes/EtOAc/Et3N; 30 mL/min; 300 × 50 mm, 5
µm silica-gel column) provided analytically pure samples of 10,
36, and 37 each as colorless oils. Data for 10 matched that reported
above.
Data for 36: IR (film) 2930, 2856, 1710, 1633, 1104 cm-1; 1H
NMR (500 MHz, C6D6) δ 7.46 (br s, 1H), 7.34-7.40 (m, 3H),
7.13-7.16 (m, 3H), 7.10 (t, J ) 7.8 Hz, 2H), 6.95-7.02 (m, 5H),
6.87-6.92 (m, 2H), 6.77-6.84 (m, 2H), 6.48 (d, J ) 7.7 Hz, 1H),
5.01 (d, J ) 2.5 Hz, 1H), 5.03-5.13 (m, 2H), 4.52-4.61 (m, 2H),
4.46 (ddd, J ) 11.8, 7.4, 3.7 Hz, 1H), 4.18 (dd, J ) 7.5, 2.5 Hz,
1H), 2.67 (t, J ) 12.5 Hz, 1H), 1.95 (dd, J ) 12.6, 3.7 Hz, 1H),
0.97 (s, 9H), 0.84 (s, 9H), 0.09 (s, 6H), -0.13 (s, 3H), -0.15 (s,
3H); 13C NMR (125 MHz, C6D6) δ 179.4, 168.2, 145.3, 143.2,
143.0, 138.2, 136.7, 135.6, 132.6, 129.8, 129.3, 128.9, 128.7, 128.4,
127.8, 127.6 (b), 123.7, 122.5, 110.4, 74.8, 71.0, 54.7, 54.2, 44.2,
42.5, 26.7, 26.4, 18.6, 18.4, -3.4, -3.7, -4.2, -4.3; LRMS (ESI,
m/z) 759.61 (M + H)+, 781.60 (M + Na)+; HRMS (ESI, m/z) calcd
for C46H58N2O4Si2, 759.4014 (M + H)+; found, 759.3994.
Data for 37: IR (film) 2930, 2856, 1718, 1664, 1613, 1494, 1085
cm-1; 1H NMR (500 MHz, C6D6) δ 7.38 (d, J ) 7.4 Hz, 2H), 7.09
(t, J ) 7.5 Hz, 2H), 6.97-7.03 (m, 4H), 6.85-9.95 (m, 4H), 6.76-
6.84 (m, 6H), 6.50 (d, J ) 7.8 Hz, 1H), 5.24-5.28 (m, 1H), 5.11
(d, J ) 2.0 Hz, 1H), 4.93 (d, J ) 15.9 Hz, 1H), 4.87 (d, J ) 15.9
Hz, 1H), 4.62 (d, J ) 15.9 Hz, 1H), 4.56 (d, J ) 15.9 Hz, 1H),
4.18 (t, J ) 2.3 Hz, 1H), 2.34 (dd, J ) 13.4, 6.7 Hz, 1H), 2.17 (dd,
J ) 13.5, 8.8 Hz, 1H), 1.12 (s, 9H), 0.91 (s, 9H), 0.41 (s, 3H),
0.40 (s, 3H), 0.10 (s, 3H), 0.01 (s, 3H); 13C NMR (125 MHz, C6D6)
δ 178.1, 170.8, 154.2, 144.4, 143.1, 138.7, 137.7, 132.7, 130.0,
129.1 (b), 129.0 (b), 128.8, 128.7, 127.7, 122.8, 121.8, 109.6, 101.6,
68.0, 53.7, 50.2, 48.6, 44.4, 42.3, 26.9, 26.5, 19.3, 26.5, 19.3, 18.7,
-3.1, -3.2, -3.7, -4.1; LRMS (ESI, m/z) 759.59 (M + H)+,
781.58 (M + Na)+; HRMS (ESI, m/z) calcd for C46H58N2O4Si2,
781.3833 (M + Na)+; found, 781.3849.
Heck Cyclization of Triflate 16a. According to the general
procedure, triflate 16a (109 mg, 0.213 mmol), Pd(PPh3)2Cl2 (29.9
mg, 42.6 µmol), Et3N (0.22 mL), and DMA (1.5 mL) were heated
to give an 80:20 mixture of diastereomers 38 and 39. Purification
by column chromatography (90:10, hexanes/acetone) afforded 65.0
mg (84%) of 38 and 39 as an inseparable mixture. Spirooxindoles
38 and 39 were characterized as the corresponding diols upon
removal of the acetonides, see Supporting Information for details.
Heck Cyclization of Triflate 16b. According to the general
procedure, triflate 16b (1.24 g, 1.77 mmol), Pd(PPh3)2Cl2 (250 mg,
0.355 mmol), Et3N (1.35 g, 13.3 mmol, 1.85 mL), and DMA (10
mL) were heated to give a 50:50 mixture of diastereomers 40 and
41. Column chromatography (90:10, hexanes/Et2O) afforded 940
mg (96%) of a mixture of 40 and 41. Further chromatography by
medium pressure liquid chromatography partially separated these
Data for 10: IR (film) 2930, 2856, 1714, 1629, 1100 cm-1; 1H
NMR (500 MHz, C6D6) δ 7.37 (d, J ) 7.5 Hz, 2H), 7.13-7.16
(m, 2H), 6.86-7.07 (m, 10H), 6.84-6.80 (m, 2H), 6.70-6.75 (m,
2H), 6.57 (d, J ) 7.8 Hz, 1H), 5.88 (d, J ) 1.8 Hz, 1H), 5.27 (d,
J ) 16.0 Hz, 1H), 5.13 (d, J ) 14.8 Hz, 1H), 5.07 (ddd, J ) 11.4,
7.7, 3.6 Hz, 1H), 4.57 (d, J ) 15.7 Hz, 1H), 4.14 (d, J ) 14.8 Hz,
1H), 4.04 (dd, J ) 7.7, 1.7 Hz, 1H), 2.06 (dd, J ) 13.7, 3.7 Hz,
1H), 1.94 (t, J ) 11.8 Hz, 1H), 0.96 (s, 18H), 0.19 (s, 3H), 0.18 (s,
3H), 0.12 (s, 3H), -0.11 (s, 3H); 13C NMR (125 MHz, C6D6) δ
178.5, 167.2, 145.1, 144.4, 143.2, 138.3, 137.7, 133.1, 129.8, 129.2,
129.0, 128.9, 128.8, 128.72, 128.68, 128.1, 127.8, 127.6, 127.5,
123.4, 121.9, 110.0, 74.1, 69.2, 54.4, 53.3, 44.8, 41.2, 26.68, 26.66,
18.7, 18.4, -3.46, -3.49, -4.2 (b); LRMS (ESI, m/z) 759.59 (M
+ H)+, 781.58 (M + Na)+; HRMS (ESI, m/z) calcd for C46H58N2O4-
Si2, 781.3833 (M + Na)+; found, 781.3857.
Heck Cyclization of Triflate 29a. According to the general
procedure, triflate 29a (104 mg, 184 µmol), Pd(PPh3)2Cl2 (20.3 mg,
29.0 µmol), Et3N (146 mg, 0.20 mL, 1.46 mmol), and DMA (1.5
mL) were heated to give spirooxindole 35 as a single detectable
isomer. Column chromatography (50:50, hexanes/Et2O) provided
J. Org. Chem, Vol. 71, No. 7, 2006 2597

Overman and Watson
diastereomers, yielding 350 mg of 40 and 400 mg of 41, which
2.66 (br s, 1H), 2.49 (dq, J ) 17.6, 2.6 Hz, 1H), 2.14-2.39 (m,
3H), 1.68-1.90 (m, 5H), 1.38-1.51 (m, 1H), 1.23-1.31 (m, 1H),
1.04-1.14 (m, 1H); 13C NMR (125 MHz, C6D6) δ 179.8, 142.0,
141.1, 136.3, 135.3, 128.8, 127.54, 127.46, 127.3, 122.6, 122.3,
114.9, 108.7, 45.6, 43.3, 38.8, 34.8, 34.6, 33.7, 33.1, 27.5, 26.2;
LRMS (ESI, m/z) 344.12 (M + H)+, 366.11 (M + Na)+; HRMS
(ESI) calcd for C24H25NO, 366.1834 (M + H)+; found, 366.1830.
Heck Cyclization of Triflate 31. According to the general
procedure, triflate 31 (255 mg, 0.514 mmol), Pd(PPh3)2Cl2 (72.0
mg, 103 µmol), Et3N (521 mg, 5.15 mmol, 0.65 mL), and DMA
(5 mL) were heated to give a 50:40:10 mixture of 45, 46, and 47.
Column chromatography (95:5, hexanes/Et2O) afforded 76 mg
(43%) of 45 as a colorless foam, 73 mg (41%) of 46 as a colorless
solid, and 15 mg (8%) of 47 as a colorless foam (93% combined
yield).
1
were diastereomerically pure by H NMR analysis.
1
Data for 40: IR (film) 2928, 2856, 1715, 1098, 832 cm-1; H
NMR (500 MHz, CDCl3) δ 7.31-7.37 (m, 5H), 7.21-7.24 (m,
2H), 7.08 (td, J ) 7.8, 1.0 Hz, 1H), 6.80 (d, J ) 7.6 Hz, 1H), 5.94
(dd, J ) 9.8, 1.9 Hz, 1H), 5.29 (dt, J ) 8.0, 1.9 Hz, 1H), 5.06 (d,
J ) 15.5 Hz, 1H), 4.84 (d, J ) 15.5 Hz, 1H), 4.64-4.66 (m, 1H),
4.31 (dt, J ) 7.2, 2.0 Hz, 1H), 2.00-2.08 (m, 2H), 1.02 (s, 9H),
0.95 (s, 9H), 0.23 (s, 3H), 0.22 (s, 3H), 0.20 (s, 3H), 0.18 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 178.1, 142.1, 136.0, 135.6, 133.3,
128.8, 128.3, 127.6, 127.3, 125.5, 123.7, 122.8, 108.9, 73.2, 69.8,
51.7, 43.7, 39.4, 26.0 (b), 18.1, 18.0, -4.1 (b), -4.6, -4.8; LRMS
(ESI, m/z) 550.29 (M + H)+, 572.27 (M + Na)+; HRMS (ESI,
m/z) calcd for C32H47NO3Si2, 572.2992 (M + H)+; found, 572.2985.
Data for 41: IR (film) 2928, 2856, 1719, 1610, 1100, 836 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.26-7.36 (m, 6H), 7.21 (td, J )
7.8, 1.2 Hz, 1H), 7.18 (td, J ) 7.6, 1.0 Hz, 1H), 6.78 (d, J ) 7.8
Hz, 1H), 5.89 (dd, J ) 9.9, 1.7 Hz, 1H), 5.25 (dt, J ) 9.8, 1.9 Hz,
1H), 5.03 (d, J ) 15.7 Hz, 1H), 4.89 (d, J ) 15.7 Hz, 1H), 2.80
(dt, J ) 7.6, 1.9 Hz, 1H), 4.12-4.17 (m, 1H), 2.37 (t, J ) 12.5
Hz, 1H), 1.76-1.82 (m, 1H), 1.00 (s, 9H), 0.88 (s, 9H), 0.21 (s,
3H), 0.19 (s, 3H), 0.12 (s, 3H), -0.01 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 178.7, 141.7, 135.8, 135.3, 133.2, 128.8, 128.3, 127.7,
127.2, 124.8, 124.2, 122.7, 109.3, 73.3, 71.2, 52.6, 43.9, 39.0, 26.0,
25.9, 18.2, 17.9, 18.2, 17.9, -3.9, -4.0, -4.7 (b); LRMS (ESI,
m/z) 550.29 (M + H)+, 572.28 (M + Na)+; HRMS (ESI, m/z) calcd
for C32H47NO3Si2, 572.2992 (M + H)+; found, 572.2998.
Heck Cyclization of Triflate 33. According to the general
procedure, triflate 33 (142 mg, 288 µmol), Pd(PPh3)2Cl2 (40.3 mg,
58.1 µmol), Et3N (290 mg, 0.40 mL, 2.87 mmol), and DMA (2.8
mL) were heated to give a 70:24:6 mixture of isomers 42, 43, and
44 for an overall diastereoselection of 70:30. Column chromatog-
raphy (93:7, hexanes/Et2O) allowed for isolation of 56.1 mg (57%)
of 42 as a colorless solid and 15.1 mg (15%) of a mixture of 43
and 44. Crystallization of a small sample of 42 from hot n-heptane
gave crystals suitable for X-ray crystallographic analysis. Prepara-
tive HPLC (40 mL/min; 97.5:2.5, hexanes/EtOAc; 300 × 50 mm,
5 µm silica-gel column) allowed for the separation of 43 and 44.
By this process, 43 could be obtained as an analytically pure
colorless oil. The alkene isomer 44 was obtained at about a 90%
purity as a colorless oil.
Data for 45: IR (film) 3031, 2958, 1710, 1609, 1364, 1179 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.20-7.30 (m, 6H), 7.12 (td, J )
7.7, 1.2 Hz, 1H), 6.97 (td, J ) 7.6, 0.9 Hz, 1H), 6.69 (d, J ) 7.7
Hz, 1H), 6.15 (d, J ) 10.2 Hz, 1H), 5.41 (ddd, J ) 10.1, 2.6, 1.8
Hz, 1H), 4.98 (d, J ) 15.7 Hz, 1H), 4.83 (d, J ) 15.7 Hz, 1H),
2.21 (td, J ) 13.5, 3.0 Hz, 1H), 2.13-2.16 (m, 1H), 1.90-1.94
(m, 1H), 1.68-1.78 (m, 2H), 1.00 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 180.4, 141.9, 135.9, 134.5, 133.4, 128.7, 127.8, 127.5,
127.1, 125.2, 124.2, 122.3, 109.0, 50.0, 44.8, 43.7, 32.7, 32.5, 27.3,
20.3; LRMS (CI, NH3, m/z) 345.1 (M)+; HRMS (CI, NH3, m/z)
calcd for C24H27NO, 345.2093 (M)+; found, 345.2099.
Data for 46: IR (film) 3029, 2960, 1711, 1611, 1345, 1167 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.19-7.28 (m, 5H), 7.09-7.12 (m,
2H), 6.98 (t, J ) 7.5 Hz, 1H), 6.67 (d, J ) 7.5 Hz, 1H), 6.15 (dd,
J ) 10.1, 1.1 Hz, 1H), 5.36 (dt, J ) 10.1, 1.6 Hz, 1H), 4.93 (d, J
) 15.7 Hz, 1H), 4.73 (d, J ) 15.7 Hz, 1H), 2.26-2.37 (m, 1H),
2.02-2.06 (m, 1H), 1.95-2.00 (m, 1H), 1.86 (td, J ) 13.3, 3.1
Hz, 1H), 1.74-1.77 (m, 1H), 0.98 (m, 9H); 13C NMR (125 MHz,
CDCl3) δ 179.1, 142.3, 136.1, 135.2, 134.2, 128.7, 127.8, 127.5,
127.2, 126.0, 123.2, 122.5, 108.8, 48.9, 45.1, 43.6, 33.1, 32.9, 27.3,
19.8; LRMS (CI, NH3, m/z) 345.1 (M)+; HRMS (CI, NH3, m/z)
calcd for C24H27NO, 345.2093 (M)+; found, 345.2096.
Data for 47: IR (film) 3054, 2962, 1710, 1613, 1486, 1360 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.27-7.36 (m, 5H), 7.22 (d, J )
7.4 Hz, 1H), 7.18 (t, J ) 7.8 Hz, 1H), 7.00 (d, J ) 7.5 Hz, 1H),
6.77 (d, J ) 7.8 Hz, 1H), 5.71 (br s, 1H), 5.05 (d, J ) 15.7 Hz,
1H), 4.88 (d, J ) 15.7 Hz, 1H), 2.80 (d, J ) 17.4, 1H), 2.31-2.48
(m, 2H), 2.08-2.18 (m, 2H), 1.65-1.71 (m, 1H), 1.19 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 181.2, 144.9, 141.8, 136.1, 134.7,
128.7, 127.48, 127.45, 127.1, 123.9, 122.2, 115.5, 108.9, 45.9, 43.6,
35.5, 32.4, 30.3, 29.1, 20.93; LRMS (CI, NH3, m/z) 345.1 (M)+;
HRMS (CI, NH3, m/z) calcd for C24H27NO, 345.2093 (M)+; found,
345.2098.
Data for 42: IR (film) 2921, 2852, 1711, 1609, 1486, 1347 cm-1
;
1H NMR (500 MHz, C6D6) δ 7.29-7.38 (m, 6H), 7.21 (td, J )
7.7, 1.0 Hz, 1H), 7.07 (t, J ) 7.3 Hz, 1H), 6.78 (d, J ) 7.8 Hz,
1H), 5.97 (dd, J ) 9.7, 1.1 Hz, 1H), 5.31 (d, J ) 9.7 Hz, 1H), 5.06
(d, J ) 15.7 Hz, 1H), 4.92 (d, J ) 15.7 Hz, 1H), 2.13 (t, J ) 13.3
Hz, 1H), 2.01 (t, J ) 10.4 Hz, 1H), 1.84-1.97 (m, 2H), 1.64-
1.72 (m, 2H), 1.41-1.53 (m, 2H), 1.18-1.32 (m, 4H); 13C NMR
(125 MHz, C6D6) δ 180.3, 141.7, 136.6, 135.9, 134.9, 128.7, 127.8,
127.5, 127.1, 124.2, 123.8, 122.4, 109.0, 51.6, 43.7, 41.3, 39.3,
37.5, 32.9, 32.8, 29.7, 26.7, 26.6; LRMS (ESI, m/z) 344.11 (M +
H)+, 366.08 (M + Na)+; HRMS (ESI) calcd for C24H25NO,
344.2014 (M + H)+; found, 344.2005.
Heck Cyclization of Triflate 20a. According to the general
procedure, triflate 20a (166 mg, 291 µmol), Pd(PPh3)2Cl2 (40.7 mg,
58.1 µmol), Et3N (294 mg, 0.41 mL, 2.91 mmol), and DMA (2.9
mL) were heated to give a 45:21:34 mixture of isomers 48, 49,
and 50 for an overall diastereoselection of 79:21. Column chro-
matography (75:25, hexanes/Et2O) afforded 105 mg (86%) of a
mixture of the three isomers as a slightly yellow oil. These isomers
were further purified by preparative HPLC (40 mL/min; 65:35,
hexanes/EtOAc; 300 × 50 mm, 5 µm silica-gel column) to give
analytically pure samples of each isomer, each as colorless oils.
Data for 48: IR (film) 3035, 2952, 1717, 1611, 1358, 1167, 1071
Data for 43: IR (film) 2921, 2850, 1710, 1609, 1488, 1345 cm-1
;
1H NMR (500 MHz, C6D6) δ 7.28-7.33 (m, 4H), 7.23-7.27 (m,
1H), 7.13 (m, 2H), 7.00 (td, J ) 7.6, 1.0 Hz, 1H), 6.71 (d, J ) 7.3
Hz, 1H), 5.93 (d, J ) 10.6 Hz, 1H), 5.22 (ddd, J ) 9.3, 2.5, 1.5
Hz, 1H), 4.92 (d, J ) 15.6 Hz, 1H), 4.87 (d, J ) 15.6 Hz, 1H),
2.10-2.24 (m, 1H), 1.64-1.84 (m, 7H), 1.26-1.50 (3H), 1.02-
1.10 (m, 1H); 13C NMR (125 MHz, C6D6) δ 179.4, 142.2, 137.3,
136.1, 134.9, 128.7, 127.8, 127.5, 127.3, 124.4, 123.3, 122.7, 108.8,
50.5, 43.7, 41.8, 39.8, 36.2, 32.9, 32.5, 27.0, 26.4; LRMS (ESI,
m/z) 344.11 (M + H)+, 366.10 (M + Na)+; HRMS (ESI) calcd for
C24H25NO, 366.1834 (M + H)+; found, 366.1826.
1
cm-1; H NMR (500 MHz, C6D6) δ 7.59 (d, J ) 1.6 Hz, 1H),
7.30-7.31 (m, 2H), 7.09-7.12 (m, 2H), 7.02 (t, J ) 7.4 Hz, 1H),
6.83-6.87 (m, 2H), 6.66 (td, J ) 7.6, 0.9 Hz, 1H), 6.48 (d, J )
7.8 Hz, 1H), 4.8 (s, 2H), 4.33 (dd, J ) 8.5, 1.7 Hz, 1H), 4.11 (ddd,
J ) 12.5, 8.5, 3.5 Hz, 1H), 2.96 (s, 3H), 2.66 (t, J ) 12.7 Hz, 1H),
2.11 (dd, J ) 11.7, 3.6 Hz), 1.46 (s, 3H), 1.36 (s, 3H); 13C NMR
(125 MHz, C6D6) δ 178.6, 164.6, 143.5, 141.3, 137.1, 135.7, 131.9,
129.3, 128.7, 128.1, 128.0, 122.69, 122.68, 112.6, 109.9, 78.5, 75.0,
54.0, 51.8, 44.7, 38.6, 27.4, 27.1; LRMS (ESI; this compound
partially decomposed in MeCN, t1/2 ∼ 5 min, during MS analysis,
Data for 44 (ca. 90% purity): IR (film) 2923, 2854, 1711, 1613,
1490, 1466, 1358, 1169 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.23-
7.33 (m, 5H), 7.18 (d, J ) 6.6 Hz, 1H), 7.12 (td, J ) 7.7, 1.2 Hz,
1H), 7.00 (td, J ) 7.5, 1.0 Hz, 1H), 6.70 (d, J ) 7.8 Hz, 1H), 5.43
(br s, 1H), 4.90 (d, J ) 15.4 Hz, 1H), 4.84 (d, J ) 15.4 Hz, 1H),
2598 J. Org. Chem., Vol. 71, No. 7, 2006

Diastereoselection in the Formation of Oxindoles
resulting in a more complex spectrum, m/z) 420.14 (M + H)+,
442.11 (M + Na)+; HRMS (ESI) calcd for C25H25NO3, 420.1811
(M + H)+; found, 420.1797.
Data for 52: IR (film) 2931, 2858, 1719, 1611, 1254, 1115, 1092
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.39 (d, J ) 7.2 Hz, 2H),
7.32 (t, J ) 7.2 Hz, 2H), 7.24-7.27 (m, 1H), 7.14-7.18 (m, 2H),
7.05 (d, J ) 2.0 Hz, 1H), 6.98 (t, J ) 7.7 Hz, 1H), 6.74 (d, J ) 7.7
Hz, 1H), 4.97 (m, 2H), 4.32 (dd, J ) 7.2, 1.9 Hz, 1H), 4.09 (ddd,
J ) 11.4, 7.6, 3.5 Hz, 1H), 3.49 (s, 3H), 2.29 (t, J ) 12.7 Hz, 1H),
1.65 (dd, J ) 13.0, 3.6 Hz, 1H), 0.99 (s, 9H), 0.80 (s, 9H), 0.21 (s,
3H), 0.17 (s, 3H), 0.03 (s, 3H), -0.16 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 178.7, 164.5, 147.0, 142.3, 136.0, 133.2, 128.7, 128.2,
127.5, 127.4, 122.8, 122.1, 109.5, 73.6, 70.1, 52.1, 52.0, 44.1, 41.4,
26.0, 25.8, 18.2, 17.9, -4.0, -4.1, -4.7, -4.9; LRMS (ESI, m/z)
608.11 (M + H)+, 630.10 (M + Na)+; HRMS (ESI, m/z) calcd for
C34H49NO5Si2, 630.3047 (M + Na)+; found, 630.3057.
Data for 49: IR (film) 3035, 2987, 1713, 1613, 1360, 1067 cm-1
;
1H NMR (500 MHz, C6D6) δ 7.64 (d, J ) 1.8 Hz, 1H), 7.28-7.30
(m, 2H), 7.06-7.09 (m, 2H), 7.00 (t, J ) 7.3 Hz, 1H), 6.86 (td, J
) 7.6, 1.4 Hz, 1H), 6.75 (td, J ) 7.4, 0.9 Hz, 1H), 6.71 (dd, J )
7.3, 1.2 Hz, 1H), 6.48 (d, J ) 7.8 Hz, 1H), 4.76-4.85 (m, 2H),
4.72 (d, J ) 15.8 Hz, 1H), 4.24 (dd, J ) 8.4, 1.6 Hz, 1H), 2.96 (s,
3H), 2.52 (dd, J ) 12.6, 3.8 Hz), 1.97 (t, J ) 12.6 Hz, 1H), 1.44
(s, 3H), 1.41 (s, 3H); 13C NMR (125 MHz, C6D6) δ 178.8, 164.9,
144.0, 141.9, 137.2, 134.6, 128.8, 128.7, 128.2, 127.9, 123.0, 122.8,
112.6, 109.8, 78.7, 74.6, 53.2, 51.8, 44.7, 38.0, 27.5, 27.1; LRMS
(ESI; this compound partially decomposed in MeCN, t1/2 ∼ 5 min,
during MS analysis, resulting in a more complex spectrum, m/z)
420.14 (M + H)+, 442.12 (M + Na)+; HRMS (ESI) calcd for
C25H25NO3, 420.1811 (M + H)+; found, 420.1802.
Heck Cyclization of Triflate 29c. According to the general
procedure, triflate 29c (108 mg, 184 µmol), Pd(PPh3)2Cl2 (25.9 mg,
36.9 µmol), Et3N (187 mg, 0.24 mL, 1.85 mmol), and DMA (1.8
mL) were heated to give oxindole 53 as a single detectable isomer.
Column chromatography (50:50-30:70, hexanes/EtOAc) provided
59.6 mg (76%) of 53 as a colorless oil: IR (film) 2827, 2856, 1717,
Data for 50: IR (film) 3035, 2989, 2939, 1740, 1713, 1611, 1196,
1
1127 cm-1; H NMR (500 MHz, C6D6) δ 7.26-7.27 (m, 2H),
7.15-7.17 (m, 1H), 7.05-7.08 (m, 2H), 7.00 (t, J ) 7.4 Hz, 1H),
6.84 (td, J ) 7.2, 1.2 Hz, 1H), 6.65 (td, J ) 7.6, 1.0 Hz, 1H), 6.48
(d, J ) 7.8 Hz, 1H), 5.25 (dd, J ) 3.3, 1.7 Hz, 1H), 4.81 (d, J )
15.5 Hz, 1H), 4.69-4.73 (m, 1H), 4.58 (d, J ) 15.5 Hz, 1H), 4.30
(t, J ) 2.9 Hz, 1H), 2.4 (s, 3H), 2.47 (t, J ) 11.4 Hz, 1H), 1.96
(dd, J ) 11.6, 5.3 Hz, 1H), 1.41 (s, 3H), 1.27 (s, 3H); 13C NMR
(125 MHz, C6D6) δ 179.0, 171.3, 152.6, 143.6, 137.1, 131.4, 129.2,
128.8, 128.7, 128.1, 125.1, 122.4, 112.3, 109.6, 91.2, 71.1, 51.4,
50.4, 47.3, 44.5, 38.0, 27.5, 25.2; LRMS (ESI; this compound was
found to decompose while in MeCN solution as required for MS
analysis and resulted in a more complex spectrum, t1/2 ∼ 5 min,
m/z) 420.17 (M + H)+, 442.14 (M + Na)+; HRMS (ESI) calcd for
C25H25NO3, 420.1811 (M + H)+; found, 420.1805.
1
1644, 1611, 1355, 1160 cm-1; H NMR (500 MHz, C6D6) δ 7.30
(d, J ) 7.4 Hz, 2H), 7.10 (t, J ) 7.5 Hz, 2H), 6.96-7.03 (m, 2H),
6.72 (t, J ) 6.7 Hz, 1H), 6.40 (d, J ) 7.8 Hz, 1H), 6.23 (d, J ) 1.5
Hz, 1H), 4.79 (m, 2H), 4.56 (dd, J ) 8.2, 1.5 Hz, 1H), 4.15 (ddd,
J ) 12.7, 8.2, 4.3 Hz, 1H), 2.77 (t, J ) 12.3 Hz, 1H), 2.32 (br s,
2H), 2.23 (dd, J ) 12.0, 4.3 Hz, 1H), 1.54 (s, 3H), 1.42 (s, 3H);
13C NMR (125 MHz, C6D6) δ 178.2, 167.6, 143.9, 137.1, 134.7,
134.6, 131.5, 129.2, 128.9, 128.7, 128.0, 127.8, 123.3, 122.4, 112.7,
110.0, 77.9, 76.9, 54.4, 44.9, 37.7, 27.6, 27.2; LRMS (ESI, m/z)
433.45 (M + H)+, 455.43 (M + Na)+; HRMS (ESI, m/z) calcd for
C26H28N2O4, 433.2127 (M + Na)+; found, 433.2130.
Heck Cyclization of Triflate 20b. According to the general
procedure, triflate 20b (211 mg, 0.278 mmol), Pd(PPh3)2Cl2 (39.0
mg, 55.6 µmol), Et3N (281 mg, 0.39 mL, 2.78 mmol), and DMA
(2.8 mL) were heated to give a 59:41 mixture of diastereomers 51
and 52. Column chromatography (90:10, hexanes/Et2O) allowed
for the partial separation of the isomers, giving a combined yield
of 149 mg (88%) of 51 as a colorless foam and 52 as a colorless
oil.
Acknowledgment. This research was supported by the NIH
National Institutes of General Medical Sciences (GM-30859)
and by predoctoral fellowships from Pharmacia Co. and the UC
Regents for D.A.W. Dr. Rob Hinkle and Dr. Brian Stearns are
thanked for the development of the synthesis of 1b and 3b. NMR
and mass spectra were determined at UC Irvine using instru-
ments acquired with the assistance of NSF and NIH shared
instrumentation grants. DFT calculations were preformed by
D.A.W. at the UC Berkeley Molecular Graphics Facility.
Data for 51: IR (film) 2929, 2858, 1717, 1613, 1252, 1100 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.39 (d, J ) 7.5 Hz, 2H), 7.32 (t,
J ) 7.3 Hz, 2H), 7.24-7.28 (m, 1H), 7.16 (t, J ) 7.4 Hz, 1H),
7.02-7.03 (m, 2H), 6.96 (t, J ) 7.5 Hz, 1H), 6.76 (d, J ) 7.8 Hz,
1H), 5.08 (d, J ) 15.6 Hz, 1H), 4.81 (d, J ) 15.6 Hz, 1H), 4.50
(ddd, J ) 11.1, 7.3, 4.0 Hz, 1H), 4.33 (dd, J ) 7.3, 1.9 Hz, 1H),
3.40 (s, 3H), 1.90-1.99 (m, 2H), 0.97 (s, 9H), 0.86 (s, 9H), 0.21
(s, 3H), 0.17 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 178.0, 165.2, 147.0, 142.7, 136.3, 133.4, 129.5,
128.7, 128.1, 127.6, 127.5, 122.5, 122.3, 108.9, 73.2, 68.9, 51.8,
51.3, 44.0, 40.8, 26.0 (b), 19.1, 17.9, -4.1, -4.2, -4.6, -4.8;
LRMS (ESI, m/z) 608.14 (M + H)+, 630.12 (M + Na)+; HRMS
(ESI, m/z) calcd for C34H49NO5Si2, 630.3047 (M + Na)+; found,
630.3039.
Supporting Information Available: Complete experimental
details for the preparation of substrates and the chemical correlation
of products, copies of 1H and 13C NMR spectra of all new
compounds, 1H NMR spectra of unpurified Heck products used in
the assignment of diastereoselection, and NOE data used in the
assignment of the configuration of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO052335A
J. Org. Chem, Vol. 71, No. 7, 2006 2599