Terminating catalytic asymmetric Heck cyclizations by stereoselective intramolecular capture of η3-allylpalladium intermediates: Total synthesis of (-)-spirotryprostatin B and three stereoisomers

Article abstract of DOI:10.1016/j.tet.2010.05.048

A catalytic intramolecular Heck reaction, followed by capture of the resulting η³-allylpalladium intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (-)-spirotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral η³-allylpalladium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration.

Full text of DOI:10.1016/j.tet.2010.05.048

Tetrahedron 66 (2010) 6514e6525
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Terminating catalytic asymmetric Heck cyclizations by stereoselective
intramolecular capture of h
3-allylpalladium intermediates: total synthesis
of (ꢀ)-spirotryprostatin B and three stereoisomers
y
*
Larry E. Overman , Mark D. Rosen
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, USA
a r t i c l e i n f o
a b s t r a c t
A catalytic intramolecular Heck reaction, followed by capture of the resulting
h
3-allylpalladium
Article history:
Received 18 March 2010
Received in revised form 30 April 2010
Accepted 13 May 2010
intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (ꢀ)-spi-
rotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral
h
3-allylpalla-
dium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly
nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 20 May 2010
Dedicated with admiration to Professor
Steven Ley in honor of his receipt of the
2009 Tetrahedron Prize
Keywords:
Palladium catalysis
Total synthesis
Alkaloid
Mechanism
Cascade reaction
1. Introduction
cell progression at low micromolar concentrations; it is more active
than its saturated congener spirotryprostatin A, although consid-
Small-molecule natural products play an increasingly important
role in contemporary studies to understand and control cellular
proliferation.1 Using temperature-sensitive mammalian tsFT210
cells and rat normal fibroblast 3Y1 cells, Osada and co-workers have
identified a variety of structurally novel natural product inhibitors
of the cell cycle from the marine fungus Aspergillus.2 Among these
are the cyclotryprostatins AeC (1e4),3 tryprostatins A and B (5 and
6),4 and spirotryprostatins A and B (7 and 8), which combine dike-
topiperazine and prenylated indole structural motifs (Fig. 1).5
Spirotryprostatin B (8) was initially isolated from a 400 L
fermentation that yielded 11 mg of the pure natural product,
allowing its constitution and the relative configuration at C3 and
C18 to be determined; the relative configuration at C12 could not be
directly specified, although it was assumed to be the same as in
spirotryprostatin A.5 Spirotryprostatin B (8) inhibits G2/M-phase
erably less active than several simpler compounds in this family of
indole alkaloids.5 The unique structures of spirotryprostatins A and
B have attracted much attention from synthetic chemists, with the
first accomplishment in the area being registered by Danishefsky
and Edmondson in 1998, who exploited the oxidative rearrange-
ment of indoles to fashion the spirooxindole moiety of spiro-
tryprostatin A (7).6 The first total synthesis of spirotryprostatin B
was described by Williams,7 followed soon thereafter in 2000 by
distinctly different constructions of this target by the Danishefsky,8
Ganesan,9 and Overman laboratories.10 The stereoselective
assembly of the spiro[pyrrolidine-3,30-oxindole] core of the spiro-
tryprostatins continues to this day to inspire the development of
imaginative synthetic chemistry.11,12 In addition, this scaffold has
stimulated the discovery of cell-growth inhibitors that target the
regulatory protein MDM2,13 and diversity-oriented synthesis of
large bioactive compound libraries.14
The central challenge in a stereocontrolled synthesis of spiro-
tryprostatin B (8) is relating the configuration of the C3 quaternary
stereocenter to the adjacent secondary stereocenter of the
spiropyrrolidine ring (C18). We were attracted to this problem by
the considerations posed in Scheme 1, and our previous
* Corresponding author. Tel.: þ1 949 824 7156; fax: þ1 949 824 3866; e-mail
address: leoverma@uci.edu (L.E. Overman).
y
Present address: Johnson
& Johnson Pharmaceutical Research and De-
velopment, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.048

L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
6515
(13).17 In a complementary scenario, cyclization of (2Z)-2,4-hex-
adienamide 11 should generate
3-allylpalladium intermediate 12,
which if trapped in an anti sense would lead to C18 epimer 13,
whereas syn attack of nitrogen on the
would produce spirotryprostatin B (8).
R2 R3
O
O
R4
R1
h
N
H
N
h
3-allylpalladium fragment
N
H
It was of particular importance to us that pursuit of this syn-
thetic strategy would allow the investigation of several new aspects
of the use of organopalladium catalysis in synthesis: (1) catalytic
asymmetric Heck cyclization onto an internal double bond of
a conjugated triene, (2) the possibility of exploiting the relative
cyclotryprostatin A (1, R1 = OMe, R2 = H, R3 = OH, R4 = -OH)
cyclotryprostatin B (2, R1 = OMe, R2 = H, R3 = OMe, R4 = -OH
cyclotryprostatin C (3, R1 = H, R2 = H, R3 = OH, R4 = -OH)
cyclotryprostatin D (4, R1 = H, R2, R3 = O, R4 = -OH
configuration of an acyclic
an intramolecular Heck cyclization for a further stereocontrolled
bond construction,18e20 (3) trapping of 3-allylpalladium electro-
h
3-allylpalladium fragment produced in
O
H
O
H
N
N
h
H
O
H
O
philes by a weakly nucleophilic nitrogen of a diketopiperazine, and
(4) the stereoselectivity of the construction of such an allylic CeN
bond.21 As the absolute configuration of spirotryprostatin B had not
been established at the time our investigations began, the ability to
reach reaction manifolds enantiomeric to those depicted in Scheme
1 by simply changing the chirality of the ligand was deemed an
additional attractive aspect of this plan.
N
N
H
MeO
N
N
H
O
R
H
tryprostatin A (5, R = OMe)
tryprostatin B (6, R = H)
spirotryprostatin A (7)
Herein we describe initial model studies confirming that cata-
lytic asymmetric Heck cyclizations onto the internal double bond of
a conjugated triene can take place efficiently with useful levels of
enantiomeric induction, and describe in detail our investigation of
the strategy outlined in Scheme 1 that culminated in total
O
N12
H
N
O
18
3
N
H
O
syntheses of (ꢀ)-spirotryprostatin
B
(8), (ꢀ)-18-epi-spiro-
tryprostatin B (13), (ꢀ)-3-epi-spirotryprostatin B (40), and (ꢀ)-3,18-
spirotryprostatin B (8)
epi-spirotryprostatin B (56).
Figure 1. Cell-cycle inhibitors from the marine fungus Aspergillus.
2. Results and discussion
2.1. Model studies
demonstration that catalytic asymmetric intramolecular Heck re-
actions of a,b-unsaturated 2-haloanilides can efficiently construct
enantioenriched, chiral 3,3-disubstituted oxindoles.15 Controlled by
an appropriate chiral ligand and the suprafacial stereospecificity of
organopalladium insertions, intramolecular Heck cyclization of
(2E)-2,4-hexadienamide 9 in a favored 5-exo sense should generate
Recent investigations in our laboratories had demonstrated that
intramolecular catalytic asymmetric Heck reactions were efficient
transformations for preparing chiral 3,3-disubstituted oxindoles
with high levels of enantiocontrol.15 However, our previous studies
had not examined such reactions of conjugated di- or trienamide
precursors. As a result, we chose to study catalytic asymmetric Heck
cyclizations of (Z)- and (E)-2,5-dimethyl-N-(2-iodophenyl)-2,4-
hexadienamides 19 and 23 prior to examining the more elaborate
transformations proposed in Scheme 1. The preparation of
h
3-allylpalladium intermediate 10.16 If this complex was trapped by
the nitrogen of the tethered diketopiperazine at the proximal
carbon of the allyl unit more rapidly than the
h
3-allylpalladium
fragment underwent stereomutation, spirotryprostatin B (8) would
be produced if bond formation occurred anti to the metal; cycli-
zation syn to the metal would lead to 18-epi-spirotryprostatin B
H
O
O
N
O
N
N
H
O
NH
Pd(0)-(S)-BINAP
H
O
anti
O
X
N
H
N
E
N
R
O
N
R
O
N
R
O
PdL2X
spirotryprostatin B (8)
9
10
syn
H
O
syn
anti
N
O
N
O
N
NH
H
O
Pd(0)-(S)-BINAP
H
N
H
O
N
O
18
PdL2X
Z
N
R
O
N
R
O
N
R
O
12
X
11
18-epi-spirotryprostatin B (13)
Scheme 1. Potential construction of spirotryprostatin B by catalytic asymmetric Heck cyclization and intramolecular capture of h
3-allylpalladium intermediates.

6516
L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
stereoisomer 19 began with a StilleGennari olefination reaction
between 3-methyl-2-butenal (14) and trifluoroethylphosphonate
ester 15, which provided (Z)-dienyl ester 16 as a single alkene ste-
reoisomer (by 1H NMR analysis) in 86% yield (Scheme 2).22,23 Sa-
ponification of ester 16 gave acid 17, which was converted to the
corresponding acid chloride and allowed to react with 2-iodoaniline
to provide anilide 18 in 90% yield. Subsequent protection of the
secondary amide with (2-trimethylsilyl)ethoxymethyl chloride
(SEM-Cl) delivered (Z)-2,4-hexadienamide 19 in high yield.
Catalytic asymmetric Heck cyclizations of (Z)- and (E)-2,5-di-
methyl-N-(2-iodophenyl)-2,4-hexadienamides 19 and 23 were
conducted using conditions previously demonstrated to be optimal
for similar reactions of simpler
a,b-unsaturated 2-iodoanilides
(Scheme 4).15 We were pleased to find that cyclization of (Z)-hex-
adienamide 19 with 10 mol % Pd-(S)-BINAP and 1,2,2,6,6-pentam-
ethylpiperidine (PMP) in N,N-dimethylacetamide (DMA) at 100 ꢁC
provided oxindole 24 in 92% yield. Removal of the SEM group
yielded oxindole 25, which was found by enantioselective HPLC
analysis to be highly enantioenriched (90% ee). Under identical
conditions, cyclization of (E)-hexadienamide precursor 23 provided
oxindole 24 in 86% yield, albeit with a somewhat lower level of
enantioselection (72% ee). The absolute configuration of oxindole
24 was determined by its conversion to oxindole alcohol 27, which
was found to be enantiomeric to an intermediate employed to
synthesize (þ)-esermethole.15b,27 To this end, oxindole 24 was
converted in standard fashion to its N-methyl derivative 26. Dihy-
droxylation of the exo-methylene group of the diene side chain of
26, followed by cleavage of the diol intermediate, catalytic hydro-
genation of the resulting enone, BaeyereVilliger oxidation, and
ester saponification provided oxindole alcohol 27. The yield of this
sequence was low, owing largely to low selectivity in the
BaeyereVilliger oxidation. Nonetheless, sufficient quantity of
oxindole 27 was obtained to establish its S absolute configuration.
MeO2C
PO(OCH2CF3)2
15
OHC
KHMDS, 18-crown-6
(86%)
CO2R
16: R = Me
14
NaOH (97%)
17: R = H
(COCl)2;
2-iodoaniline
(90%)
N
R
O
I
18: R = H
19: R = SEM
NaH, SEM-Cl (85%)
Scheme 2. Preparation of (Z)-2,5-dimethyl-N-(2-iodophenyl)-2,4-hexadienamide 19.
The synthesis of the corresponding E stereoisomer began with
a Wittig reaction between aldehyde 14 and stabilized ylide 20
providing (E)-dienyl ester 21 in 92% yield (Scheme 3).24,25 Trime-
thylaluminum-mediated conversion of ester 21 to anilide 22 pro-
ceeded smoothly in 80% yield.26 Protection of the resulting amide
nitrogen with SEM-Cl afforded (E)-2,4-hexadienamide substrate 23
in good overall yield.
Pd2(dba)3·CHCl3
(S)-BINAP, PMP
DMA, 100 °C
19 or 23
N
R
O
19
23
24: 92%, 90% ee
24: 86%, 72% ee
24: R = SEM
25: R = H
Bu4NF, THF (90%)
NaH, MeI (97%)
26: R = Me
EtO2C
(1) OsO4; Pb(OAc)4 (20%)
(2) H2, Pd/C (90%)
OH
20 PPh3
EtO2C
OHC
14
N
Me
O
(92%)
(3) Urea·H2O2, (CF3CO)2 (10%)
(4) LiOH, THF/H2O (70%)
21
27
Scheme 4. Catalytic asymmetric Heck cyclizations of (Z)- and (E)-2,4-hexadienamides
19 and 23.
AlMe3
O
2-iodoaniline
N
2.2. Total synthesis of (L)-18-epi-spirotryprostatin B (13) and
(L)-3-epi-spirotryprostatin B (40)
R
(80%)
I
22: R = H
NaH, SEM-Cl (85%)
23: R = SEM
Although the catalytic asymmetric Heck cyclizations of 2,4-
hexadienamides 19 and 23 were not optimized, we were sufficiently
Scheme 3. Preparation of (E)-2,5-dimethyl-N-(2-iodophenyl)-2,4-hexadienamide 23.
COOMe
OTBDPS
Red-Al; I2
(75%)
Pd(dppf)Cl2
HO
I
OTBDPS
R
OTBDPS
CO, MeOH
(89%)
28
31
29: R = OH
30: R = CHC(CH3)2
1. DMSO, (COCl)2
2. i-Pr=PPh3
(98%)
H
O
N
O
H
O
NH
N
1. 2-iodoaniline, Me3Al
2. NaH, SEM-Cl
R
NH
PO(OMe)2
34
O
I
3. Bu4NF
(60%)
KOt-Bu, 18-crown-6
(75%, >10:1 Z:E)
N
O
SEM
I
N
O
SEM
35
32: R = CH2OH
33: R = CHO
DMSO, (COCl)2
(98%)
Scheme 5. Preparation of (2Z)-2,4-hexadienamide cyclization precursor 35.

L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
6517
encouraged by the efficiency and enantioselectivity of these re-
actions to proceed ahead to investigate the plan outlined in Scheme
1. The preparation of (2Z)-2,4-hexadienamide 35 commenced with
reductive iodination of monoprotected-propargyl alcohol 28,28
furnishing (Z)-vinyl iodide 29 in 75% yield (Scheme 5).29 Swern
oxidation of allylic alcohol 29 provided a highly unstable alde-
hyde,30 which was immediately allowed to react with iso-propyli-
dene triphenylphosphorane to afford diene 30 in near quantitative
yield over the two steps. Palladium-catalyzed carbonylation of
dienyl iodide 30 in the presence of methanol provided methyl ester
31,31 and subsequent conversion to anilide alcohol 32 proceeded in
60% yield for the three steps. Swern oxidation of alcohol 32 gave
aldehyde 33. After extensive experimentation, we found that
HornereWadswortheEmmons coupling of aldehyde 33 with dike-
topiperazine phosphonate ester 3432 was best carried out with
potassium tert-butoxide and 18-crown-6 in CH2Cl2, providing
trienyl anilide 35 in 75% yield and >10:1 Z/E selectivity.
and 2-methylpropenyl groups in both 13 and 40 was apparent from
the large NOE enhancement between H4 and H18, whereas the
stereorelationship of the pyrrolidine and dihydropyrrole rings was
established from long-range NOE enhancements observed be-
tween H12 and H21 of product 13 using double-pzulsed field gra-
dient spin echo (DPFGSE) NOE experiments.33 The absolute
configuration of the quaternary carbon centers of 41 and 42 is
logically assigned to be analogous to that of pentacyclic oxindoles
13 and 40, respectively.
2.3. Total synthesis of (L)-spirotryprostatin B (12) and (L)-
3,18-epi-spirotryprostatin B (56)
The Pd-(BINAP) catalyzed bis-cyclizations of (2Z)-2,4-
hexadienamide precursor 35 demonstrated that: (a) Heck in-
sertion occurs with high regioselectivity at the internal double
bond of the triene system, (b) the
is generated and captured with high stereochemical fidelity, and
(c) the nitrogen of the tethered diketopiperazine attacks the h3
h
3-allylpalladium intermediate
The pivotal catalytic asymmetric Heck cyclization/h
3-allyl-
palladium capture reaction of (2Z)-2,4-hexadienamide precursor
35 was initially carried out using 20 mol % Pd-(S)-BINAP and excess
1,2,2,6,6-pentamethylpiperidine in DMA at 100 ꢁC (Scheme 6).
These conditions produced pentacyclic products 36 and 37 in a 6:1
ratio and 28% combined yield. The identical cyclization of precursor
35 using Pd-(R)-BINAP proceeded with similar efficiency and se-
lectivity to provide a 6:1 mixture of pentacyclic products 37 and 36.
In each case, the major by-products were tetracyclic oxindoles 38
and 39, resulting from elimination of palladium hydride from the
-
allylpalladium complex anti to the metal center. Consequently, we
turned our attention to the preparation of stereoisomeric (2E)-
2,4-hexadienamide 49, which should serve as a precursor to spi-
rotryprostatin B (8).
The synthesis of (2E)-N-(2-iodophenyl)-2,4-hexadienamide 49
began with the BayliseHillman adduct 43 (Scheme 7).34 Acylation
of alcohol 43 under standard conditions provided the corre-
sponding allylic acetate, which was allowed to react sequentially
with MgBr2$Et2O and i-Pr2EtN/AcOH to provide primary allylic
acetate 44 in 94% overall yield and high stereoselectivity (>20:1 E:
Z).35 Saponification of ester 44, followed by protection of the
resulting allylic alcohol as a tert-butyldiphenylsilyl (TBDPS) ether
gave intermediate 45 in 88% yield. For the preparation of aryl iodide
precursor 49, carboxylic acid 45 was coupled with 2-iodoaniline,
providing anilide 47 in 91% yield.36 Subsequent alkylation of the
amide nitrogen with SEM-Cl, followed by removal of the TBDPS
intermediate
h
3-allylpalladium complex. Unfortunately, efforts to
increase the yield of pentacyclic products 36 and 37 having the
spirotryprostatin ring system by variation of chiral ligands, solvent,
base, and reaction temperature met with little success. Attempts to
access a potentially more electrophilic h
3-allylpalladium complex
by a silver salt-mediated intramolecular Heck reaction proceeding
via cationic Pd(II) intermediates led to rapid decomposition of
precursor 35.
H
O
O
O
N
H
N
H
N
N
N 12
Pd2(dba)3·CHCl3,
O
O
O
O
NH
(S) or (R)-BINAP
H
O
H
O
I
4
NH
NH
N
18 N
O
+
+
+
O
3
PMP, DMA,
100 °C
21
N
R
O
N
N
O
R
N
R
O
N
R
O
SEM
35
36: R = SEM
13: R = H
37: R = SEM
40: R = H
38: R = SEM
41: R = H
39: R = SEM
42: R = H
a
a
a
a
a
Me2AlCl; i-Pr2NEt (90–95%)
(S)-BINAP:
(R)-BINAP:
28%, 6:1 36/37
26%, 1:6 36/37
20%, 6:1 38/39
21%, 1:6 38/39
Scheme 6. Cascade catalytic asymmetric Heck cyclization/intramolecular capture to prepare (ꢀ)-18-epi-spirotryprostatin B (13) and (ꢀ)-3-epi-spirotryprostatin B (40).
Removing the SEM-protecting group from pentacyclic products
36 and 37 proved to be extremely challenging. Numerous fluoride
sources and protic acids were investigated, with all producing
a complex mixture of products. After considerable experimenta-
tion, we discovered that the SEM group could be discharged from
these delicate intermediates by initial exposure to dimethylalu-
minum chloride, followed by heating the resulting N-hydro-
xymethyl derivatives in methanol in the presence of
diisopropylethylamine to remove the unit of formaldehyde. Ana-
lytically pure samples of (ꢀ)-18-epi-spirotryprostatin B (13), (ꢀ)-3-
epi-spirotryprostatin B (40), and oxindoles 41 and 42 were
obtained by preparative HPLC. The trans relationship of the aryl
group, yielded alcohol 48 (88% over two steps). DesseMartin
oxidation37 of intermediate 48, followed immediately by reaction
of the derived aldehyde with the potassium salt of diketopiperazine
phosphonate ester 3432 gave (2E)-N-(2-iodophenyl)-2,4-hex-
adienamide 49 in 64% yield.
In order to examine the efficiency of bis-cyclization reactions
proceeding via a cationic reaction manifold and potentially avoid
the decomposition observed upon attempted cyclization of (2Z)-N-
z
These assignments were corroborated by Danishefsky and Von Nussbaum, who
independently synthesized 13 and 40.8

6518
L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
NH2
R1
46 (R1 = I or OTIPS)
OH
1. Ac2O, pyridine
1. LiOH
MeO2C
HO2C
MeO2C
1-methyl-2-chloro-
pyridinium iodide
2. TBDPS-Cl
(89%)
2. MgBr2·Et2O, then
i-Pr2NEt, AcOH
(94%, >20:1 E:Z)
OAc
44
OTBDPS
43
45
H
O
N
O
O
NH
1. SEM-Cl, NaH
2. Bu4NF
1. Dess–Martin oxid.
O
I
N
N
2. 34, KOt-Bu
H
SEM
I
I
(64%)
OTBDPS
OH
(95%)
N
O
47 (91%)
48
SEM
49
H
O
N
O
O
NH
1. CsF, Cs2CO3, PhNTf2
(1) Dess-Martin oxid.
(2) 34, KHMDS
(55%)
O
N
R
N
SEM
2. 3% conc. HCl, MeOH
(82%)
TIPSO
TfO
OTBDPS
OH
N
O
50: R = H (84%)
51: R = SEM
52
SEM
53
OTf
SEM-Cl, NaH
(81%)
Scheme 7. Preparation of (2E)-2,4-hexadienamide cyclization precursors 49 and 53.
(2-iodophenyl)-2,4-hexadienamide 35 in the presence of silver
salts (see above), we also prepared (2E)-N-(2-triflatophenyl)-2,4-
hexadienamide 53. In this case, carboxylic acid 45 was coupled with
2-(triisopropylsilyloxy)aniline (46, R1¼OTIPS) to deliver anilide 50
in good yield.38 Protection of the amide nitrogen with SEM-Cl
proceeded smoothly to furnish tertiary amide 51. Removal of the
triisopropylsilyl group with CsF and trapping of the nascent
phenoxide with N-phenyltriflamide gave the corresponding triflate,
which, after removal of the TBDPS group, provided triflate 52 in 82%
yield. DesseMartin oxidation37 of this intermediate and immediate
coupling of the aldehyde product with phosphonate ester 3432 gave
(2E)-N-(2-triflatophenyl)-2,4-hexadienamide 53 in 55% yield.
Cyclization of (2E)-N-(2-iodophenyl)-2,4-hexadienamide 49
with Pd-(S)-BINAP under conditions identical to those employed
with stereoisomer 35unexpectedlyled tothe formation of oxindoles
36 and 37 as the sole pentacyclic reaction products (Scheme 8).
Control experiments conducted in the absence of Pd-(S)-BINAP
demonstrated that (2E)-N-(2-iodophenyl)-2,4-hexadienamide 49
underwent rapid isomerization of the internal double bond to give
the more stable 2Z stereoisomer 35 when heated above 80 ꢁC with
excess PMP in DMA. As the two most likely mechanisms for isom-
erization of the D2,3 double bond of 2,4-hexadienamide 49 were
base-promoted enolization followed by reprotonation, or reversible
1,4-addition of an adventitious nucleophile, we explored numerous
other reaction conditions thatmight minimize such processes. Many
HIscavengersother than PMP, including diisopropylethylamine, 2,6-
di-tert-butylpyridine, Na2CO3, NaHCO3, KOAc, AgOAc, Ag2CO3,
Ag3PO4, and AgBF4/diisopropylethylamine, were examined in
H
O
O
O
N
N
N
Pd2(dba)3·CHCl3
NH
(S)-BINAP, PMP
H
O
H
O
O
I
N
N
+
DMA, 100 °C
(22%)
N
R
O
N
R
O
N
O
SEM
35
H
O
(5:1)
36: R = SEM
13: R = H
37: R = SEM
40: R = H
N
a
a
NH
O
I
N
O
SEM
49
O
O
N
N
Pd2(dba)3·CHCl3
(o-tol)3P, KOAc
H
O
H
O
N
N
+
THF, 70 °C
(72%)
N
R
O
N
R
O
(1:1)
a
54: R = SEM
8: R = H
55: R = SEM
56: R = H
a
Me2AlCl; i-Pr2NEt (93–95%)
a
Scheme 8. Cascade catalytic Heck cyclization/intramolecular capture to prepare (ꢀ)-spirotryprostatin B (8) and (ꢀ)-3,18-epi-spirotryprostatin B (56).

L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
6519
various solvents (DMA, THF, PhMe, MeCN) without success. In
addition, attempts to cyclize triflate congener 53 with Pd-(S)-BINAP
using a variety of solvents and bases invariably either returned un-
changed triflate 53, or, under more forcing conditions, led to
intractable mixtures of reaction products. Furthermore, extensive
screening of chiral bidentate phosphine ligands other than
BINAP, including 4-tert-butyl-2-[2-(diphenylphosphino)phenyl]
oxazoline (PHOX) ligands, as well as chiral monodentate phosphines
such as 2-(diphenylphosphino)-20-alkoxy-1,10-binapthyls (MOP
ligands), failed to identify an enantioselective catalyst capable of
promoting the desired conversion of precursors 49 or 53 to penta-
cyclic product 54.
allowed to warm to room temperature (rt). The mixture was diluted
with pentane, the organic layer was separated and washed with
water and brine, dried, and concentrated to a yellow oil. Purifica-
tion of the residue by flash chromatography (pentane/Et2O 95:5)
gave ester 16 as a colorless oil (7.96 g, 86%): 1H NMR (500 MHz,
CDCl3)
d
6.88 (d, J¼11.7 Hz, 1H), 6.68 (d, J¼11.7 Hz, 1H), 3.76 (s, 3H),
1.98 (s, 3H), 1.87 (s, 3H), 1.82 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
186.5, 142.7, 136.4, 123.0, 122.4, 51.3, 26.8, 21.0, 18.2; IR (film)
2958, 2926, 1713, 1638, 1435, 1377, 1203 cmꢀ1; HRMS (EI) m/z calcd
for C9H14O2 154.0994, found 154.0994. Anal. Calcd for C9H14O2: C,
70.10; H, 9.15. Found: C, 70.40; H, 8.99.
Although our efforts to accomplish a catalytic asymmetric bis-
cyclization to prepare pentacyclic precursor 54 of spirotryprostatin
B (8) were unsuccessful, we were able to accomplish the desired
cascade cyclization of (2E)-N-(2-iodophenyl)-2,4-hexadienamide
49 with an achiral palladium catalyst. Thus, reaction of (2E)-2,4-
hexadienamide 49 with 10 mol % Pd2(dba)3$CHCl3, 40 mol % tri-o-
tolylphosphine, and excess KOAc in THF at 70 ꢁC gave a 1:1 mixture
of pentacyclic products 54 and 55 resulting from anti-capture of the
4.1.2. (2Z)-2,5-Dimethylhexa-2,4-dienoic acid (17). A solution of 16
(1.0 g, 6.0 mmol), NaOH (1.2 g, 30 mmol), MeOH (40 mL), and water
(10 mL) was heated at reflux for 12 h, then allowed to cool to rt. The
solution was concentrated to a volume of 15 mL, then diluted with
water (50 mL) and washed with hexane (2ꢂ30 mL). The aqueous
phase was cooled to 0 ꢁC, acidified with 2 M HCl to pH 2, and the
resulting suspension was extracted with EtOAc. The combined
organic extracts were washed with water, brine, dried, and
concentrated to provide acid 17 as a colorless crystalline solid
initially produced h
3-allylpalladium intermediate. The higher cat-
alytic activity of the Pd-(o-tolyl)3P catalyst system relative to Pd-
BINAP systems,39 and the presence of acetate in the reaction mix-
ture, which has been shown to promote oxidative addition of Pd[0]
complexes to aryl iodides,40 are likely responsible for allowing this
transformation to be carried out at lower temperature under con-
ditions that do not promote isomerization of the (2E)-N-(2-iodo-
phenyl)-2,4-hexadienamide precursor. Removal of the SEM group
(810 mg, 97%): mp 90e91 ꢁC; 1H NMR (500 MHz, CDCl3)
J¼11.8 Hz, 1H), 6.82 (d, J¼11.8 Hz, 1H), 2.00 (s, 3H), 1.89 (s, 3H), 1.84
(s, 3H); 13C NMR (125 MHz, CDCl3)
180.0, 144.2, 138.9, 122.8, 122.1,
d 6.99 (d,
d
26.9, 20.8, 18.2; IR (film) 3300e2700 (br), 1684, 1663, 1624, 1591,
1408, 1260 cmꢀ1; HRMS (CI/isobutane) m/z calcd for C8H12O2
140.0837, found 140.0837. Anal. Calcd for C8H12O2: C, 68.55; H, 8.63.
Found: C, 68.71; H, 8.57.
from products 54 and 55, followed by chromatographic purification
23
provided pure (ꢀ)-spirotryprostatin B (8), [
a
]
D
ꢀ159 (c 0.40,
4.1.3. (2Z)-2,5-Dimethylhexa-2,4-dienoic acid, N-(2-iodophenyl)am-
ide (18). Oxalyl chloride (1.47 mL, 17.0 mmol) was added drop-
wise to a solution of 17 (0.79 g, 5.6 mmol) and CH2Cl2 (10 mL) at
rt. After 10 min, one drop of DMF was added, and the reaction
was allowed to proceed for 2 h. The solution was concentrated to
a yellow oil, maintained under vacuum for 20 min, then redis-
solved in CH2Cl2 (20 mL), and cooled to 0 ꢁC. A solution of 2-
iodoaniline (1.24 g, 5.6 mmol), pyridine (0.48 g, 6.0 mmol), and
CH2Cl2 (5 mL) was then added dropwise. The reaction mixture
was then allowed to warm to rt where it was maintained for 3 h,
then diluted with Et2O (100 mL). This solution was washed with
water, saturated aqueous NaHCO3, water, brine, dried, and con-
centrated. The residue was passed through a pad of silica gel,
eluting with 50:50 pentane/Et2O, to afford amide 18 as a colorless
solid (1.74 g, 90%): mp 55e56 ꢁC; 1H NMR (500 MHz, CDCl3)
CHCl3), and (ꢀ)-3,18-epi-spirotryprostatin B (56).5,7
3. Conclusion
Enantioselective total syntheses of (ꢀ)-spirotryprostatin B (8),
(ꢀ)-18-epi-spirotryprostatin B (13), (ꢀ)-3-epi-spirotryprostatin B
(40), and (ꢀ)-3,18-epi-spirotryprostatin B (56) have been accom-
plished in a convergent fashion. The central feature of each syn-
thesis is a sequential Heck cyclization/h
3-allylpalladium trapping
reaction that allows the pentacyclic ring system and the pivotal
C3/C18 stereorelationship to be established in a single step. More-
over, these investigations demonstrate that: (a) intramolecular
Heck insertions can occur with high regioselectivity at the internal
double bond of triene precursors, (b) acyclic
h
3-allylpalladium
intermediates generated by catalytic asymmetric Heck cyclizations
d
8.40 (dd, J¼8.2, 1.3 Hz, 1H), 7.78 (dd, J¼8.3, 1.0 Hz, 1H), 7.71 (br s,
can captured with high stereochemical fidelity, and (c) the nitrogen
1H), 7.33e7.37 (m, 1H), 6.83e6.85 (m, 1H), 6.54e6.59 (m, 2H),
of the tethered diketopiperazine attacks such
h
3-allylpalladium
2.14 (s, 3H), 1.85 (s, 3H), 1.83 (s, 3H); 13C NMR (125 MHz, CDCl3)
intermediates anti to the metal center.
d 167.4, 144.3, 141.1, 138.8, 138.4, 131.5, 129.2, 127.9, 125.7, 121.5,
89.6, 26.6, 21.3, 18.3; IR (film) 3248, 1641, 1522, 1431, 1304, 1262,
1014, 756 cmꢀ1; HRMS (CI/isobutane) m/z calcd for C14H16INO
341.0278, found 341.0273. Anal. Calcd for C14H16INO: C, 68.55; H,
8.63. Found: C, 68.71; H, 8.57.
4. Experimental section
4.1. General details
N,N-Dimethylacetamide and 1,2,2,6,6-pentamethylpiperidine
were distilled from CaH under reduced pressure. Other general
experimental details have been described.41 Experimental details
for the synthesis of triflate 53 from acid 45 have been reported.42
4.1.4. (2Z)-2,5-Dimethylhexa-2(Z),4-dienoic acid, N-(2-iodophenyl)-
N-[(2-trimethylsilyl)ethoxymethyl]amide (19). A stirring suspension
of NaH (60% dispersion in oil, 200 mg, 5.0 mmol) in THF (20 mL)
was cooled to 0 ꢁC, then a solution of 18 (1.33 g, 3.9 mmol) and THF
(20 mL) was added dropwise. The resulting slurry was allowed to
warm to rt where it was maintained for 2 h, then recooled to 0 ꢁC.
Neat (2-trimethylsilyl)ethoxymethyl chloride (0.71 mL, 4.0 mmol)
was added and the reaction was allowed to slowly warm to rt. After
12 h, the mixture was carefully quenched with water (1 mL),
diluted with pentane, washed with water and brine, dried, and
concentrated to give an orange oil. Purification of the residue by
flash chromatography (hexanes/EtOAc 90:10) provided 1.56 g of
amide 19 as a pale yellow oil (85%): 1H NMR (500 MHz, CDCl3, 2:3
4.1.1. Methyl (2Z)-2,5-dimethylhexa-2,4-dienoate (16)23. A solution
of KHMDS (0.5 M in PhMe, 130 mL, 65 mmol) was added dropwise
to a solution of phosphonate 15 (21.7 g, 65.1 mmol) and 18-crown-6
(50 mg, 190 mmol) in THF (350 mL) at ꢀ78 ꢁC. The resulting yellow
solution was maintained at ꢀ78 ꢁC for 1 h, then a solution of
3-methyl-2-butenal (14) (5.0 g, 59 mmol) in THF (20 ml) was added
dropwise. The reaction was allowed to proceed for 2 h at ꢀ78 ꢁC,
then quenched with saturated aqueous NH4Cl (100 mL) and

6520
L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
mixture of amide rotamers, signals assignable to the major rotamer
are noted)
1H), 6.16 (d, J¼11.6 Hz, 1H), 6.04 (d, J¼11.6 Hz, 1H), 5.86 (d,
J¼10.3 Hz, 1H), 4.61 (d, J¼10.3 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H),
1.89 (s, 3H), 1.75 (s, 3H), 1.71 (s, 3H), 0.95e0.91 (m, 2H), 0.08 (s, 9H);
13C NMR (125 MHz, CDCl3, 2:3 mixture of amide rotamers, signals
836 cmꢀ1; HRMS (EI) m/z calcd for C20H30INO2Si 471.1092, found
471.1090. Anal. Calcd for C20H30INO2Si: C, 50.95; H, 6.41; N, 2.97.
Found: C, 51.12; H, 6.36; N, 2.96.
d
7.94 (dd, J¼7.9, 1.2 Hz, 1H), 7.24e7.35 (m, 2H), 7.03 (m,
4.2. General procedure for Pd-BINAP-catalyzed
intramolecular heck reactions. Preparation of (S)-3-methyl-3-
(3-methylbuta-1(E),3-dienyl)-1-[(2-trimethylsilyl)
ethoxymethyl]indolin-2-one (24) from (Z)-dimethylhexa-2,4-
dienamide 19
assignable to the major rotamer are noted)
d 172.5, 142.6, 139.7,
137.4, 131.9, 129.7, 129.0, 127.8, 121.9, 99.3, 76.1, 66.8, 66.4, 26.3,
20.4, 18.2, 18.1, ꢀ1.3; IR (film) 2952, 1660, 1469, 1385, 1248, 1074,
858, 836 cmꢀ1; HRMS (CI/isobutane) m/z calcd for C20H30IO2NSi
471.1092, found 471.1088. Anal. Calcd for C20H30IO2NSi: C, 50.95; H,
6.41; N, 2.97. Found: C, 51.14; H, 6.32; N, 2.91.
A mixture of Pd2(dba)3$CHCl3 (0.442 g, 0.427 mmol), (S)-BINAP
(0.745 g, 1.19 mmol), and DMA (20 mL) was stirred at rt for 4 h
until a bright orange homogeneous solution was obtained. A so-
lution of 24 (3.99 g, 8.47 mmol), 1,2,2,6,6-pentamethylpiperidine
(6.2 mL, 34 mmol), and DMA (10 mL) was added, the resulting
solution was degassed (three freezeepump,thaw cycles),43 then
heated at 100 ꢁC for 16 h. After cooling to rt, the crude reaction
mixture was poured into saturated NaHCO3 (50 mL) and extracted
with Et2O (3ꢂ50 mL). The combined extracts were washed with
water and brine, dried, and concentrated to give a brown oil.
Purification of this residue by flash chromatography (hexanes/
EtOAc 95:5) gave oxindole 24 as a pale yellow oil (2.66 g, 92%): 1H
4.1.5. Methyl (2E)-2,5-dimethylhexa-2,4-dienoate (21)23,25. A solu-
tion of 14 (0.76 g, 9.0 mmol), phosphorane 20,24 (2.72 g,
7.50 mmol) and CH2Cl2 (20 mL) was heated at reflux for 12 h, then
cooled to rt and diluted with pentane. The mixture was filtered
through Celite and the filtrate was concentrated to a yellow oil.
The residue was distilled (bulb-to-bulb, 5 mmHg, 105 ꢁC) to give
ester 21 as a colorless oil (1.39 g, 92%): 1H NMR (500 MHz, CDCl3)
d
7.44 (d, J¼11.8 Hz, 1H), 6.11 (dd, J¼11.8, 1.3 Hz, 1H), 4.20 (q,
J¼7.1 Hz, 2H), 1.91 (s, 3H), 1.89 (s, 3H), 1.88 (s, 3H), 1.29 (t, J¼7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3)
169.0, 144.3, 143.4, 124.4, 121.2,
d
NMR (500 MHz, CDCl3)
d
7.34 (t, J¼7.7 Hz, 1H), 7.25 (d, J¼6.6 Hz,
60.4, 26.9, 18.9, 14.4, 12.4; IR (film) 2981, 2929, 1703, 1445, 1258,
1111 cmꢀ1; HRMS (EI) m/z calcd for C10H16O2 168.1150, found
168.1150. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59. Found: C,
71.41; H, 9.43.
1H), 7.16 (t, J¼6.6 Hz, 1H), 7.12 (d, J¼7.7 Hz, 1H), 6.18 (d, J¼15.9 Hz,
1H), 5.81 (d, J¼15.9 Hz, 1H), 5.20 (dd, J¼11.0, 6.5 Hz, 2H), 4.98 (s,
1H), 4.93 (s, 1H), 3.57 (t, J¼7.4 Hz, 2H), 1.85 (s, 3H), 1.58 (s, 3H),
0.93 (q, J¼7.4 Hz, 2H), ꢀ0.03 (s, 9H); 13C NMR (125 MHz, CDCl3)
d
179.4, 141.3, 141.2, 133.1, 132.6, 129.8, 128.2, 124.1, 122.0, 117.3,
4.1.6. (2E)-2,5-Dimethylhexa-2,4-dienoic acid, N-(2-iodophenyl)am-
ide (22). Trimethylaluminum (1.9 M in PhMe, 2.85 mL, 5.4 mmol)
was added dropwise to a solution of 2-iodoaniline (975 mg,
4.56 mmol) and CH2Cl2 (15 mL) at 0 ꢁC.26 The resulting solution was
maintained at 0 ꢁC for 20 min, then allowed to warm to rt where it
was maintained for 2 h. The yellow reaction mixture was then
recooled to 0 ꢁC, and a solution of 21 (500 mg, 2.97 mmol) and
CH2Cl2 (10 mL) was added dropwise. The solution was then allowed
to warm to rt, and after 12 h was carefully poured into a stirring
mixture of 1 M sodium potassium tartrate (50 mL) and ice (25 g).
The mixture was extracted into Et2O, and the combined organic
extracts were washed with water and brine, dried, and concen-
trated to give a brown oil. Purification of the residue by flash
chromatography (hexane/EtOAc 95:5 to 90:10), followed by re-
crystallization from hexanes provided amide 22 as colorless nee-
dles (813 mg, 80%): mp 104e105 ꢁC; 1H NMR (500 MHz, CDCl3)
109.9, 69.4, 65.9, 50.8, 23.5, 18.6, 17.8, ꢀ1.5; IR (film) 3056, 2952,
2894, 1725, 1614, 1488, 1341, 1081 cmꢀ1; HRMS (CI/isobutane) m/z
26
calcd for C20H2296NO2Si 343.1967, found 343.1974; [
a
]
ꢀ27.2,
D
26
26
26
[
a
]
ꢀ80.5, [
a
]
435 ꢀ63.0, [
a
]
ꢀ29.2, [
a]
577
ꢀ25.6 (c 1.0, CHCl3,
405
546
90% ee). Anal. Calcd for C20H29NO2Si: C, 69.92; H, 8.51; N, 4.08.
Found: C, 69.88; H, 8.47; N, 4.06.
4.2.1. (S)-3-Methyl-3-(3-methylbuta-1(E),3-dienyl)indolin-2-one
(25). A solution of 24 (206 mg, 0.60 mmol), TBAF (1 M in THF,
6.0 mL, 6.0 mmol), and THF (10 mL) was heated at reflux for 16 h,
then cooled to rt and diluted with 30 mL of EtOAc. The solution was
washed with water and brine, dried, and concentrated to give
a brown oil. Purification of the residue by flash chromatography
(hexanes/EtOAc 90:10 to 60:40) provided 115 mg (90%) of 25 as
a colorless, crystalline solid (90% ee, HPLC, Chiralpak ASII column,
83:17 n-hexane/i-PrOH, 1 mL/min, retention time of major enan-
tiomer¼12.3 min, retention time of minor enantiomer¼10.0 min):
d
8.41 (dd, J¼8.3, 1.4 Hz, 1H), 7.95 (br s, 1H), 7.78 (dd, J¼8.3, 1.3 Hz,
1H), 7.42 (d, J¼11.5 Hz, 1H), 7.36 (m, 1H), 6.83 (m, 1H), 6.17 (d,
mp 130e131 ꢁC; 1H NMR (500 MHz, CDCl3)
d 9.20 (s, 1H), 7.22e7.26
J¼11.5 Hz, 1H), 2.12 (s, 3H), 1.93 (s, 6H); 13C NMR (125 MHz, CDCl3)
(m, 2H), 7.11 (t, J¼7.5 Hz, 1H), 7.02 (d, J¼7.7 Hz, 1H), 6.24 (d,
d
167.5, 144.3, 138.7, 138.6, 131.7, 129.4, 127.1, 125.6, 121.6, 120.9,
J¼15.9 Hz, 1H), 5.80 (d, J¼15.9 Hz, 1H), 4.99 (s, 1H), 4.95 (s, 1H), 1.86
90.0, 27.0, 18.0, 12.9; IR (film) 3252, 1640, 1520, 1431, 1298, 1013,
755 cmꢀ1; HRMS (EI) m/z calcd for C14H16INO 341.0278, found
341.0273. Anal. Calcd for C14H16INO: C, 49.28; H, 4.73; N, 4.11.
Found: C, 49.51; H, 4.83; N, 4.22.
(s, 3H), 1.60 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 182.4, 141.7, 140.7,
134.1, 133.6, 129.9, 128.5, 124.6, 123.0, 117.7, 110.7, 51.4, 23.4, 19.0; IR
(film) 3218, 2970, 1710, 1618, 1471, 1201, 969, 745 cmꢀ1; HRMS (CI/
26
isobutane) m/z calcd for C14H15NO 213.1154, found 213.1148; [a]
D
26
26
26
26
þ55.2, [
a
]
405 þ150.6, [
a
]435 þ121.3, [
a]
546 þ64.6, [ 577 þ56.0 (c 1.0,
a]
4.1.7. (2E)-2,5-Dimethylhexa-2(E),4-dienoic acid, N-(2-iodophenyl)-
N-[(2-trimethylsilyl)ethoxymethyl]amide (23). Following the pro-
cedure used to prepare tertiary amide 19, amide 22 (1.33 g,
3.90 mmol) was N-alkylated to yield, after chromatographic pu-
rification (hexane/EtOAc 100:0 to 85:15), tertiary amide 23 as
a pale yellow oil (1.46 g, 80%): 1H NMR (500 MHz, DMSO-d6, 60 ꢁC)
CHCl3). Anal. Calcd for C14H15NO: C, 78.85; H, 7.09; N, 6.57. Found: C,
78.99; H, 7.22; N, 6.46.
4.2.2. (S)-1,3-Dimethyl-3-(3-methylbuta-1(E),3-dienyl)indolin-2-one
(26). A suspension of NaH (0.36 g, 60% dispersion in oil, 9.0 mmol)
in THF (15 mL) was cooled to 0 ꢁC, then a solution of 25 (1.29 g,
6.06 mmol) and THF (10 ml) was added dropwise. This mixture was
allowed to warm to rt, then recooled to 0 ꢁC. Methyl iodide (1.28 g,
9.0 mmol) was added dropwise, and the reaction was allowed to
warm to rt. After 12 h, the reaction mixture was carefully poured
over ice (100 g), then extracted with Et2O. The combined organic
extracts were washed with water and brine, dried, and concen-
trated. Purification of the residue by flash chromatography
d
7.90 (dd, J¼7.9, 1.1 Hz, 1H), 7.42 (td, J¼7.6, 1.3 Hz, 1H), 7.31 (dd,
J¼7.9, 1.3 Hz, 1H), 7.05 (td, J¼7.6, 1.4 Hz, 1H), 6.36 (d, J¼11.2 Hz,
1H), 5.88 (d, J¼11.2 Hz, 1H), 5.67 (s, 2H), 3.57 (t, J¼7.9 Hz, 2H), 1.80
(s, 3H), 1.76 (s, 3H), 1.60 (s, 3H), 0.86 (t, J¼7.9 Hz, 2H), ꢀ0.03 (s,
13
9H); C NMR (125 MHz, d6-DMSO, 60 ꢁC)
d 171.8, 144.1, 139.7,
139.2, 130.3, 128.8, 128.7, 128.6, 127.5, 119.6, 99.8, 77.4, 65.4, 25.5,
17.8, 17.3, 13.8, ꢀ1.8; IR (film) 2951, 1654, 1470, 1285, 1072,

L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
6521
(hexanes/Et2O 60:40) provided 26 as a pale yellow oil (1.33 g, 97%):
1H NMR (500 MHz, CDCl3)
this compound were identical to those reported.15b,27 HPLC com-
26
d
7.31 (t, J¼7.7 Hz, 1H), 7.21 (d, J¼7.3 Hz,
parison to a sample of ent-27, [
a
]
þ14.0, was performed by both
D
1H), 7.10 (t, J¼7.4 Hz, 1H), 6.87 (d, J¼7.7 Hz, 1H), 6.16 (d, J¼15.9 Hz,
1H), 5.76 (d, J¼15.9 Hz, 1H), 4.94 (s, 1H), 4.90 (s, 1H), 3.22 (s, 3H),
independent injection and co-injection: Chiralpak AS column (n-
hexane/i-PrOH 90:10, 1 mL/min) 27 retention time¼18.7 min, ent-
27 retention time¼16.2 min.
1.82 (s, 3H), 1.52 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 179.0, 143.0,
141.4, 133.2, 132.9, 129.9, 128.1, 124.0, 122.6, 117.1, 108.3, 50.5, 26.4,
23.2, 18.6; IR (film) 2970, 1720, 1614, 1493, 1471, 1373, 1348 cmꢀ1
;
4.2.4. 3-Iodo-4-(tert-butyldiphenylsiloxy)-2(Z)-buten-1-ol (29). A
mechanically stirred suspension of sodium bis(2-methoxyethoxy)
aluminum hydride (Red-Al, 96.8 mL, 65% solution in PhMe,
320 mmol) in Et2O (500 mL) was cooled to 0 ꢁC, then a solution of
2828 (50.0 g, 154 mmol) in Et2O (100 mL) was added dropwise
over 30 min. The mixture was stirred at 0 ꢁC for 1 h, then EtOAc
(15 mL, 150 mmol) was added dropwise. The resulting solution
was maintained for 20 min, then solid I2 (58.7 g, 231 mmol) was
added in five portions at 10 min intervals with vigorous stirring.
Following the final addition, the brown mixture was stirred for
10 min, then the reaction was quenched with saturated Na2S2O3
(100 mL) and 1 M sodium potassium tartrate (100 mL). Hexanes
was added and the organic layer was separated, washed with
saturated Na2S2O3 and brine, dried, and concentrated to give
a yellow oil. Purification of this residue by flash chromatography
(hexanes/Et2O 90:10 to 70:30), followed by recrystallization from
hexanes afforded 29 as colorless plates (52.3 g, 75%): mp
26
26
26
26
[
a]
26 ꢀ59.5, [
a
]405 ꢀ183.5, [
a]
435 ꢀ142.8, [
a]
546 ꢀ64.7, [ 577 ꢀ64.1
a
]
D
(c 1.0, CHCl3); HRMS (CI/isobutane) m/z calcd for C15H17NO
227.1310, found 227.1312.
4.2.3. (S)-1,3-Dimethyl-3-(2-hydroxyethyl)indolin-2-one (27). A so-
lution of 26 (0.50 g, 2.2 mmol), pyridine (174 mL, 2.2 mmol), N-
methylmorpholine-N-oxide (0.23 g, 2.0 mmol), THF (15 mL), and
water (1.5 mL) was cooled to 0 ꢁC. A solution of osmium tetroxide
(0.1 M in t-BuOH, 2.2 mL, 0.22 mmol) was added, and the reaction
mixture was maintained at 0 ꢁC for 12 h. Additional N-methyl-
morpholine-N-oxide (0.13 g, 1.1 mmol) was added, then the solu-
tion was allowed to warm to rt where it was maintained for 6 h.
Solid NaHSO3 (1 g), Florisil (1 g), and EtOAc (30 mL) were added,
and the mixture was stirred rapidly for 30 min. This mixture was
filtered and the filtrate was concentrated to a yellow oil. This crude
diol was dissolved in MeOH (50 mL) and cooled to 0 ꢁC, then a so-
lution of NaIO4 (1.2 g, 5.7 mmol) and water (15 mL) was added
dropwise. The resulting mixture was maintained at 0 ꢁC for 6 h,
then allowed to warm to rt. After 12 h, the reaction mixture was
diluted with Et2O, washed with water and brine, dried, and con-
centrated. Purification of the residue by flash chromatography
(hexane/EtOAc 80:20 to 60:40) gave the corresponding enone as
49e50 ꢁC; 1H NMR (500 MHz, CDCl3)
d
7.73 (dd, J¼7.9, 1.4 Hz, 4H),
7.43e7.51 (m, 6H), 6.36 (m, 1H), 4.34 (d, J¼1.5 Hz, 2H), 4.30 (dt,
J¼5.9, 1.3 Hz, 2H) 1.72 (s, 1H), 1.15 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 136.0,133.4,132.9,130.4, 128.3, 107.6, 71.9, 67.0, 27.3, 19.8;
IR (film) 3332 (br), 3069, 2929, 2856, 1653, 1472, 1427, 1113,
701 cmꢀ1; HRMS (CI/isobutane) m/z calcd for C20H24IOSi (MꢀOH)
435.0641, found 435.0652. Anal. Calcd for C20H25IO2Si: C, 53.10; H,
5.57. Found: C, 52.96; H, 5.60.
a pale yellow oil (108 mg, 20%): 1H NMR (500 MHz, CDCl3)
d 7.31 (t,
J¼7.7 Hz, 1H), 7.17 (d, J¼7.3 Hz, 1H), 7.08 (t, J¼7.5 Hz, 1H), 6.87 (d,
J¼7.7 Hz, 1H), 6.79 (d, J¼16.1, 1H), 6.08 (d, J¼16.1, 1H), 3.20 (s, 3H),
2.22 (s, 3H), 1.54 (s, 3H).
4.2.5. (Z)-2-Iodo-1-(tert-butyldiphenylsiloxy)-5-methylhexa-2(Z),4-
diene (30). A solution of DMSO (14 mL, 194 mmol) and CH2Cl2
(150 mL) was added dropwise over 20 min to a solution of oxalyl
A portion of this product (83 mg, 0.36 mmol) was hydroge-
nated in MeOH (5 mL) over 10% palladium on carbon (10 mg)
under 1 atm of hydrogen for 6 h at rt. The flask was evacuated and
refilled with nitrogen, then the reaction mixture was filtered
through Celite and concentrated. The resulting mixture of ketone
and dimethyl ketal was dissolved in THF (5 mL) and 1 M HCl
(0.5 mL) was added to hydrolyze the small amount of acetal pro-
duced during the hydrogenation. After 20 min at rt, the reaction
was diluted with EtOAc and washed with water, brine, dried, and
concentrated. Purification of the residue by flash chromatography
(hexanes/EtOAc 70:30 to 60:40) provided the corresponding ke-
tone as a colorless oil (81 mg, 90%). A solution of trifluoroacetic
anhydride (0.41 mL, 2.9 mmol) in CHCl3 (3 mL) was cooled to 0 ꢁC,
then ureaeH2O2 complex (226 mg, 2.90 mmol) was added in
a single portion. The resulting mixture was stirred at 0 ꢁC for 1 h,
then a solution of the ketone (67 mg, 0.29 mmol) and CHCl3 (1 mL)
was added dropwise. The resulting solution was maintained at
0 ꢁC for 2 h, then allowed to warm to rt. After 30 min, the solution
was diluted with EtOAc and washed with 1 M Na2S2O3, saturated
NaHCO3, water, brine, dried, and concentrated. Purification of the
residue by flash chromatography (hexanes/EtOAc 50:50) afforded
7 mg (10%) of (S)-1,3-dimethyl-3-(2-acetoxyethyl)indolin-2-one
chloride (8.50 mL, 97.1 mmol) and CH2Cl2 (100 mL) at ꢀ78 ꢁC.30
A
solution of 29 (40.0 g, 88.3 mmol) and CH2Cl2 (150 mL) was then
added dropwise over 20 min, and the reaction mixture was stirred
for 20 min at ꢀ78 ꢁC. Triethylamine (49 mL, 350 mmol) was then
added, and the reaction was allowed to warm to rt. The mixture was
then diluted with hexanes (1 L), washed with water and brine,
dried, and concentrated. The resulting oil was passed through a pad
of silica gel, eluting with hexane/Et2O 50:50, to give the crude al-
dehyde as a highly unstable, yellow crystalline solid, which was
used without delay in the subsequent step (39.4 g, 99%): diagnostic
1H NMR (500 MHz, CDCl3)
suspension of iso-propyltriphenylphosphonium iodide
d
9.69 (d, J¼6.6 Hz, 1H).
A
(38.2 g, 88.3 mmol) in THF (400 mL) was cooled to 0 ꢁC, then n-
BuLi (2.5 M in hexane, 35.5 mL, 88.3 mmol) was added dropwise
over 10 min. The mixture turned bright red and was rapidly stirred
for 15 min at 0 ꢁC, and then cooled to ꢀ78 ꢁC. A solution of the
crude aldehyde (39.4 g, 87.4 mmol) and THF (150 mL) was then
added dropwise over 20 min. The reaction was allowed to warm to
rt, then diluted with 1.5 L of hexanes and filtered through Celite.
The resulting clear yellow solution was washed with water and
brine, then dried, and concentrated. The residue was passed
through a pad of silica gel, eluting with hexanes/Et2O 70:30, to
furnish 40.7 g (98% over two steps) of diene 30 as a light yellow
crystalline solid, which slowly decomposed above 0 ꢁC: mp
as a colorless oil: 1H NMR (400 MHz, CDCl3)
d
7.28 (t, J¼7.7 Hz, 1H),
7.18 (d, J¼7.1 Hz, 1H), 7.07 (t, J¼7.5, 1H), 6.84 (d, J¼7.7, 1H),
3.87e3.92 (m, 1H), 3.67e3.70 (m, 1H), 3.22 (s, 3H), 2.29e2.34 (m,
1H), 2.09e2.14 (m, 1H), 1.82 (s, 3H), 1.38 (s, 3H); MS (ES) m/z calcd
for C14H17NO3Na (MþNa) 270.3, found 270.2.
58e61 ꢁC (dec); 1H NMR (500 MHz, CDCl3)
d
7.75 (dd, J¼6.5, 1.3 Hz,
This acetate (7 mg, 0.028 mmol) was dissolved in THF (3 mL),
then a solution of LiOH$H2O (2 mg, 0.03 mmol) and water (1 mL)
was added. The resulting mixture was rapidly stirred at rt for 6 h,
then diluted with EtOAc and washed with water and brine (10 mL),
dried, and concentrated to afford oxindole 27 as a colorless oil
4H), 7.43e7.51 (m, 6H), 6.83 (d, J¼10.2 Hz, 1H), 6.04 (d, J¼10.2 Hz,
1H), 4.44 (s, 2H), 1.91 (s, 3H), 1.85 (s, 3H), 1.16 (s, 9H); 13C NMR
(125 MHz, CDCl3)
d 141.0, 136.0, 133.7, 130.3, 128.9, 128.2, 126.6,
104.8, 72.6, 27.3, 26.7, 20.1, 19.8; IR (film) 3071, 2929, 2856, 1421,
1112 cmꢀ1; HRMS (CI/isobutane) m/z calcd for C23H28IOSi (MꢀH)þ
475.0956, found 475.0955.
(4 mg, 70%): [
a
]
D
26 ꢀ11.2 (c 0.40, CHCl3). Spectroscopic properties of

6522
L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
4.2.6. (2-tert-Butyldiphenylsiloxymethyl)-5-methylhexa-2(Z),4-di-
enoic acid, methyl ester (31). A mixture of 30 (1.0 g, 2.1 mmol), [1,10-
bis(diphenylphosphino)ferrocene]dichloro-palladium[II]$CH2Cl2
(0.17 g, 0.21 mmol), diisopropylethylamine (1.4 mL, 8.2 mmol),
K2CO3 (0.32 g, 2.3 mmol), MeOH (4 mL), and DMF (20 mL) was
stirred under an atmosphere of CO at 50 psi for 12 h. The mixture
was then diluted with water (100 mL) and hexane (100 mL), then
filtered through Celite. The organic phase was separated, washed
with water and brine, dried, and concentrated. Purification of the
residue by flash chromatography (hexanes/ether 90:10) afforded
ester 31 as a colorless crystalline solid (0.763 g, 89%): mp
rotamer are noted)
d
9.14 (s, 1H), 7.79 (d, J¼7.4 Hz, 1H), 7.24e7.44
(m, 2H), 7.03 (d, J¼12.2 Hz, 1H), 6.94e6.97 (m, 1H), 6.60 (d,
J¼12.2 Hz, 1H), 5.84 (d, J¼10.6 Hz, 1H), 4.59 (d, J¼10.6 Hz, 1H),
3.93e3.99 (m, 1H), 3.68e3.75 (m, 1H), 1.95 (s, 3H), 1.87 (s, 3H),
0.81e1.06 (m, 2H), 0.03 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 190.1,
167.7, 153.2, 146.3, 140.3, 140.2, 132.7, 130.4, 129.0, 123.7, 122.4,
99.9, 76.0, 66.9, 27.7, 19.7, 18.5, ꢀ0.9; IR (film) 2951, 1683, 1659,
1627, 1470, 1417, 1376, 1264, 1078, 836 cmꢀ1; HRMS (CI/isobutane)
m/z calcd for C20H28INO3Si 485.0885, found 485.0886. Anal. Calcd
for C20H28INO3Si: C, 49.49; H, 5.81; N, 2.89. Found: C, 49.40; H,
5.83; N, 2.85.
75e76 ꢁC; 1H NMR (500 MHz, CDCl3)
d
7.72 (dd, J¼6.5, 1.4 Hz, 4H),
7.41e7.48 (m, 6H), 7.25 (d, J¼12.0 Hz, 1H), 7.04 (d, J¼12.0 Hz, 1H),
4.2.9. (S)-2-(1,4-Dioxohexahydropyrrolo[1,2-a]pyrazin-3(Z)-ylidene-
methyl)-5-methylhexa-2(Z),4-dienoic acid, N-(2-iodophenyl)-N-[2-
(trimethylsilyl)ethoxymethyl]amide (35). A solution of diketopi-
perazine phosphonate 34 (1.08 g, 4.12 mmol),32 18-crown-6
(4.30 g, 16.3 mmol), and CH2Cl2 (10 mL) was added to a stirring
suspension of potassium tert-butoxide (0.460 g, 4.12 mmol) in
CH2Cl2 (10 mL) at ꢀ78 ꢁC. The resulting mixture was stirred at
ꢀ78 ꢁC for 30 min, then a solution of 33 (1.00 g, 2.06 mmol) and
CH2Cl2 (5 mL) was added dropwise. The reaction mixture was
allowed to warm to rt and stirred. After 2 h, this solution was
diluted with EtOAc, washed with water and brine, dried, and
concentrated to give an oil. This residue was purified by flash
chromatography (hexanes/EtOAc 80:20 to 50:50) to furnish 35
as a light yellow solid (0.959 g, 75%): mp 70e72 ꢁC; 1H NMR
(500 MHz, CDCl3, complex because of mixture of rotamers, sig-
4.49 (s, 2H), 3.72 (s, 3H), 1.96 (s, 3H), 1.91 (s, 3H), 1.13 (s, 9H); 13C
NMR (125 MHz, CDCl3)
d 167.4, 145.3, 135.9, 135.3, 133.9, 130.1,
128.1, 125.9, 122.4, 64.2, 51.5, 27.3, 27.2, 19.7, 18.8; IR (film) 2931,
2857,1718, 1632,1428,1201, 1072, 823 cmꢀ1; HRMS (CI/isobutane)
m/z calcd for C25H31O3Si (MꢀH)þ 407.2043, found 407.2047. Anal.
Calcd for C25H32O3Si: C, 73.49; H, 7.89. Found: C, 73.21; H, 7.94.
4.2.7. 2-Hydroxymethyl-5-methylhexa-2(Z),4-dienoic acid, N-(2-io-
dophenyl)-N-[(2-trimethylsilyl)ethoxymethyl]amide (32). Ester 31
(5.03 g, 12.3 mmol) was allowed to react with the aluminum de-
rivative of 2-iodoaniline (5.67 g, 26.0 mmol)26 following the pro-
cedure described for the preparation of 22. The resulting crude
product was passed through a pad of silica gel (hexane/Et2O 50:50)
to provide 7.50 g of a mixture of the secondary amide and unreacted
2-iodoaniline as an oil. A solution of this crude product and THF
(40 mL) was added dropwise to a stirring suspension of NaH (60%
dispersion in oil, 0.740 g, 18.5 mmol) in THF (20 mL) at 0 ꢁC. This
mixture was allowed to warm to rt where it was maintained for 2 h,
then recooled to 0 ꢁC. Neat (2-trimethylsilyl)ethoxymethyl chloride
(3.27 mL, 13.0 mmol) was then added dropwise, and the reaction
was allowed to warm to rt. After 12 h, the reaction mixture was
carefully poured over crushed ice, and then extracted with hexanes.
The combined organic extracts were washed with water and brine,
then dried, and concentrated. The residue was passed through a pad
of silica gel, eluting with hexanes/Et2O 50:50 to give a pale yellow
oil. This material was dissolved in THF (30 mL), then TBAF (1 M in
THF, 26 mL, 26 mmol) was added in one portion. The resulting dark
brown solution was maintained at rt for 6 h, then diluted with Et2O
(150 mL). The solution was washed with water and brine, dried, and
concentrated to yield a brown oil. Purification of this residue by
flash chromatography (hexanes/EtOAc 70:30 to 50:50) gave amide
32 as a pale yellow oil (3.60 g, 60% over three steps): 1H NMR
(500 MHz, CDCl3, 2:1 mixture of amide rotamers, signals assignable
nals assignable to the major rotamer are noted)
d 8.64 (s, 1H),
7.98 (d, J¼7.9 Hz, 1H), 7.13e7.83 (m, 3H), 6.88 (d, J¼10.0 Hz, 1H),
6.34 (s, 1H), 5.91 (d, J¼10.0 Hz, 1H), 4.68 (s, 1H), 4.65 (s, 1H),
4.16e4.19 (m, 1H), 3.35e3.90 (m, 4H); 2.43e2.45 (m, 1H),
1.98e2.12 (m, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.73e1.76 (m, 2H),
0.75e1.20 (m, 2H), ꢀ0.04 (s, 9H); 13C NMR (125 MHz, CDCl3,
complex because of mixture of rotamers, signals assignable to
the major rotamer are noted)
131.3, 131.0, 130.1, 129.6, 128.5, 126.3, 122.1, 114.6, 113.9, 112.6,
d 165.7, 142.4, 142.2, 134.1, 132.9,
80.6, 67.1, 58.9, 45.6, 28.9, 26.7, 22.2, 21.8, 18.6, ꢀ1.57; IR (film)
3200, 2952, 1698, 1666, 1632, 1377, 1073 cmꢀ1; HRMS (FAB) m/z
26
calcd for C27H3266IN3O4Si 621.1522, found 621.1529; [
a
]
þ118,
D
26
26
[
a
]
þ401, [
a
]
þ154, [
a]
577
þ126 (c 0.5, CHCl3). Anal. Calcd
435
546
for C27H36IN3O4Si: C, 52.17; H, 5.84; N, 6.76. Found: C, 52.42; H,
5.84; N, 6.71.
4.2.10. 18-epi-Spirotryprostatin B (13) and 3-[3-(methyl-1(E),3-bu-
tadienyl)indolin-2-one-3-ylmethylene]hexahydropyrrolo[1,2-a]pyr-
azine-1,4-dione (41). A mixture of Pd2dba3$CHCl3 (103 mg,
0.100 mmol), (S)-BINAP (135 mg, 0.220 mmol), and DMA (5 mL)
was stirred at rt for 16 h, furnishing a bright orange homogeneous
to the major rotamer are noted)
d
7.95 (d, J¼8.0 Hz, 1H), 7.28e7.46
(m, 2H), 7.04e7.12 (m,1H), 6.62 (d, J¼11.7 Hz,1H), 6.41 (d, J¼11.7 Hz,
1H), 5.22 (d, J¼10.2 Hz, 1H), 4.60 (d, J¼10.2 Hz, 1H), 4.36e4.53 (m,
1H), 3.69e3.89 (m, 1H), 3.29e3.51 (m, 2H), 1.88 (s, 3H), 1.86 (s, 3H),
1.28 (br s, 1H), 0.91 (m, 2H), ꢀ0.02 (s, 9H); 13C NMR (125 MHz,
CDCl3, mixture of amide rotamers, signals assignable to the major
solution.
A solution of (2Z)-2,4-hexadienamide 35 (600 mg,
0.970 mmol), PMP (0.70 mL, 3.9 mmol), and DMA (5 mL) was
added, the reaction mixture was sparged with Ar for 15 min,
degassed (four freezeepumpethaw cycles), sealed, and heated at
100 ꢁC for 8 h. The resulting dark brown mixture was allowed to
cool to rt, diluted with EtOAc (50 mL), filtered through Celite, and
the filtrate was washed with water and brine, then dried, and
concentrated to yield a brown oil. The residue was chromato-
graphed (hexanes/EtOAc 70:30) to give a 6:1 mixture of tetracyclic
oxindole dienes 38 and 39 as a yellow solid (96 mg, 20%). Further
elution (hexanes/EtOAc 50:50) provided a 6:1 mixture of penta-
cyclic oxindoles 36 and 37 as a light yellow foam (135 mg, 28%); 36:
rotamer are noted)
129.1, 126.8, 120.0, 98.1, 80.4, 66.5, 65.3, 26.3, 18.3, 17.9, ꢀ1.6; IR
(neat) 3416 (br), 2952, 2921, 1651, 1470, 1408, 1249, 1075 cmꢀ1
d 171.8, 143.3, 141.3, 139.7, 132.3, 131.0, 129.6,
;
HRMS (CI/isobutane) m/z calcd for C20H30INO3Si 487.1041, found
487.1036. Anal. Calcd for C20H30INO3Si: C, 49.28; H, 6.20; N, 2.87.
Found: C, 49.54; H, 6.33; N, 2.80.
4.2.8. 2-Formyl-5-methylhexa-2(Z),4-dienoic acid, N-(2-iodophenyl)-
N-[(2-trimethylsilyl)ethoxymethyl]amide (33). Swern oxidation of 32
(1.18 g, 2.40 mmol),30 as described for the reaction of 29, gave
a crude residue that was passed through a pad of silica gel, eluting
with hexane/Et2O 50:50, to give aldehyde 33 as a colorless solid
(1.14 g, 98%): mp 104e105 ꢁC; 1H NMR (500 MHz, CDCl3, 4:1
mixture of amide rotamers, signals assignable to the major
1H NMR (500 MHz, CDCl3)
d 7.31 (m, 2H), 7.12 (m, 1H), 7.01 (m, 1H),
5.79 (s, 1H), 5.48 (d, J¼9.3 Hz, 1H), 5.27 (d, J¼9.3 Hz, 1H), 5.14 (d,
J¼11.1 Hz, 1H), 5.03 (d, J¼11.1 Hz, 1H), 4.41 (m, 1H), 3.82 (m, 1H),
3.53 (m, 3H), 2.39 (m, 1H), 2.03 (m, 1H), 1.97 (m, 2H), 1.65 (s, 3H),
1.22 (s, 3H), 0.90 (m, 2H), ꢀ0.01 (s, 9H); 13C NMR (125 MHz, CDCl3)
d
174.1, 162.6, 154.6, 142.3, 139.5, 137.8, 129.5, 124.1, 123.7, 119.7,

L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
6523
118.3, 115.1, 109.8, 69.8, 66.6, 66.1, 62.4, 61.7, 45.1, 28.8, 25.9, 22.0,
18.1, 17.8, ꢀ1.3; HRMS (FAB) m/z calcd for C27H36N3O4Si (MþH)þ
494.2476, found 494.2471.
(500 MHz, CDCl3)
d
7.60 (d, J¼12.2 Hz, 1H), 6.24 (d, J¼12.2 Hz, 1H),
4.36 (s, 2H), 3.80 (s, 3H), 1.96 (s, 3H), 1.93 (s, 3H). This allylic bro-
mide (11.3 g, 48.5 mmol) was dissolved in MeCN (50 mL), then
added in one portion to a stirring solution of AcOH (8.3 mL,
140 mmol), i-Pr2EtN (26.2 mL,150 mmol), and MeCN (200 mL) at rt.
After 12 h, the solution was concentrated to a volume of 100 mL,
hexane (300 mL) was added, the mixture was washed with 1 M
citric acid (2ꢂ200 mL), H2O, and saturated NaHCO3. The solution
was then dried and concentrated to provide allylic acetate 44 as
a pale yellow oil (9.76 g, 96%), which was sufficiently pure to be
used directly in the subsequent step. An analytical sample of 44 was
prepared by bulb-to-bulb distillation (1.0 mmHg, 125 ꢁC): 1H NMR
(500 MHz, CDCl3)
1H), 4.91 (s, 2H), 3.77 (s, 3H), 2.03 (s, 3H), 1.96 (s, 6H); 13C NMR
(125 MHz, CDCl3) 171.0, 167.8, 149.5, 140.3, 122.1, 120.3, 58.1, 51.9,
27.2, 21.0, 19.1; IR (film) 2952, 1736, 1710, 1632, 1246, 1112 cmꢀ1
HRMS (EI) m/z calcd for C11H16O4 212.1049, found 212.1047. Anal.
Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.19; H, 7.62.
The mixture of pentacyclic oxindoles 36 and 37 was dissolved in
CH2Cl2 (4 mL) and cooled to ꢀ78 ꢁC. A solution of dimethylalumi-
num chloride (1 M in hexane, 1.5 mL, 1.5 mmol) was added drop-
wise, and the solution was allowed to warm to rt. After 20 min, the
reaction mixture was recooled to 0 ꢁC and a saturated aqueous
solution of sodium potassium tartrate (5 mL) was carefully added,
and the mixture was warmed to rt and stirred 30 min. The mixture
then was diluted with EtOAc, washed with water and brine (20 mL),
dried, and concentrated to a light yellow solid. This residue was
dissolved in 5 mL of MeOH, 0.2 mL of diisopropylethylamine was
added, the solution was heated to 45 ꢁC for 16 h, then concentrated
to yield a yellow solid. Purification of this residue by flash chro-
matography (CH2Cl2/MeOH 97:3) gave a 6:1 mixture of 18-epi-
spirotryprostatin B (13) and 3-epi-spirotryprostatin B (40) as a light
yellow solid (94 mg, 95%). An analytical sample of the major di-
astereomer, 18-epi-spirotryprostatin B (13), was isolated by pre-
d
7.68 (d, J¼12.2 Hz, 1H), 6.25 (dd, J¼12.2, 1.1 Hz,
d
;
paratory HPLC (Alltech Altima C18 5
m
250 mmꢂ22 mm column,
4.2.13. 2-(tert-Butyldiphenylsiloxymethyl)-5-methyl-2(E),5-dienoic
acid (45). A solution of LiOH$H2O (24.8 g, 590 mmol) and H2O
(150 mL) was added in one portion to a solution of 44 (12.5 g,
59 mmol) and THF (250 mL). The mixture was heated to 40 ꢁC with
rapid stirring for 18 h, allowed to cool to rt, and concentrated to
a volume of 150 mL. This solution was cooled to 0 ꢁC, acidified with
concentrated HCl to pH 2, diluted with brine (50 mL), and extracted
with EtOAc (5ꢂ100 mL). The combined extracts were dried and
concentrated to a tan solid, which was used without further puri-
50:50 water/MeOH, 10 mL/min, retention time¼37 min) as a light
yellow solid: 1H and 13C NMR were identical to those described;8
HRMS (CI/isobutane) m/z calcd for C21H21N3O3 363.1609, found
363.1604; [
a
]
23 ꢀ23.3 (c 0.15, CHCl3), lit.8 [
a
]
D
23 ꢀ24 (c 0.14, CHCl3).
D
The 6:1 mixture of oxindoles 38 and 39 was deprotected in
identical fashion to give a 6:1 mixture of 41 and 42 (67 mg, 95%) as
a light yellow solid. An analytical sample of the major diastereomer
41 was obtained by HPLC (Alltech Altima SiO2 10
m
300 mmꢂ22 mm column, 80:20 hexanes/i-PrOH, retention time-
fication (9.31 g, 100%): 1H NMR (500 MHz, CDCl3)
d 7.68 (d,
¼31.2 min) as a light yellow solid: 1H NMR (500 MHz, CDCl3)
J¼12.2 Hz, 1H), 6.31 (d, J¼12.2 Hz, 1H), 4.45 (s, 2H), 1.94 (s, 6H).
A portion of this acid (8.81 g, 56.4 mmol) and imidazole (19.2 g,
283 mmol) were dissolved in CH2Cl2 (100 mL), and tert-butyldi-
phenylchlorosilane (20.3 mL, 78.9 mmol) was added in one portion.
The resulting solution was maintained at rt for 8 h, then Et2O
(500 mL) was added. The mixture was washed with 1 M citric acid,
H2O, and brine (300 mL), dried, and concentrated to an oil. This
residue was dissolved in MeOH (300 mL), then solid K2CO3 (5.0 g,
36 mmol) was added in one portion.x The resulting mixture was
stirred for 30 min, filtered, 1 M aqueous solution of citric acid
(100 mL) was added, and the mixture was extracted with Et2O. The
combined extracts were washed with water and brine, dried, and
concentrated to yield a solid. Purification of this residue by flash
chromatography (80:20 hexanes/EtOAc), provided 45 as a colorless
d
10.46 (s, 1H), 8.24 (s, 1H), 7.25e7.27 (m, 2H), 7.13 (td, J¼7.6, 1.2 Hz,
1H), 6.91 (t, J¼7.2 Hz, 1H), 6.27 (d, J¼15.5 Hz, 1H), 6.03 (s, 1H), 5.74
(d, J¼15.5 Hz, 1H), 5.00 (s, 1H), 4.95 (s, 1H), 4.21e4.23 (m, 1H),
3.71e3.77 (m, 1H), 3.58e3.62 (m, 1H), 2.43e2.47 (s, 1H), 2.00e2.10
(m, 2H), 1.89e1.96 (m, 1H), 1.80 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
179.0, 165.9, 158.2, 140.8, 139.3, 134.5, 133.0, 132.7, 128.9, 124.9,
124.5, 123.9, 118.6, 113.2, 110.3, 59.2, 55.3, 45.8, 28.9, 21.9, 18.6; IR
(film) 3182, 1693, 1632, 1444, 1384, 1228, 734 cmꢀ1; HRMS (FAB) m/
z calcd for C21H22N3O3 364.1661 (MþH), found 364.1665.
4.2.11. 3-epi-Spirotryprostatin B (40). Identical cyclization of 35
with Pd(R)-BINAP provided a 6:1 mixture of 37 and 36 in 26% yield.
After removing the SEM-protecting group, an analytical sample of
the major diastereomer 40 was isolated by preparatory HPLC (All-
crystalline solid (19.8 g, 89%): 1H NMR (500 MHz, CDCl3)
d 7.74 (dt,
tech Altima C18 5
m
250 mmꢂ22 mm column, 50:50 water/MeOH,
J¼6.3,1.5 Hz, 4H), 7.69 (d, J¼12.1 Hz,1H), 7.39e7.45 (m, 6H), 6.15 (dt,
10 mL/min, retention time¼29 min) as a light yellow solid: 1H and
J¼12.1, 1.2 Hz, 1H), 4.54 (s, 2H), 1.92 (s, 3H), 1.86 (s, 3H), 1.07 (s, 9H);
13C NMR were identical to those described;8 HRMS (CI/isobutane)
13C NMR (125 MHz, CDCl3)
d 173.1, 148.2, 139.6, 135.8, 133.5, 129.7,
m/z calcd for C21H21N3O3 363.1609, found 363.1607; [
a]
23 ꢀ240.2 (c
127.7, 125.9, 121.1, 58.0, 27.1, 26.8, 19.3, 19.0; IR (film) 2700e3300,
1679,1632,1598,1427,1287,1254,1068 cmꢀ1; HRMS (FAB) m/z calcd
for C24H30NaO3Si (MþNa) 417.1867, found 147.1872. Anal. Calcd for
C24H30O3Si: C, 73.05; H, 7.66. Found: C, 73.03; H, 7.67.
D
0.90, CHCl3), lit.8
[
a
]
23 ꢀ251 (c 0.87, CHCl3).
D
4.2.12. 2-Acetoxymethyl-5-methyl-2(E),5-dienoic acid, methyl ester
(44). A solution of 43 (20.0 g, 23.1 mmol),34 pyridine (20 mL), acetic
anhydride (40 mL), and CH2Cl2 (100 mL) was cooled to 0 ꢁC, then
solid N,N-dimethyl-4-aminopyridine (0.125 g,1.03 mmol) was added
in one portion and the solution was allowed to warm to rt. After 2 h,
the solution was diluted with Et2O (1 L), washed with H2O, saturated
NaHCO3, and brine. This solution was then dried, and concentrated
to an oil, which was used without further purification (24.5 g, 98%).
Following a general procedure,35 a portion of this acetate
(10.3 g, 48.5 mmol) was dissolved in THF (300 mL), then solid
MgBr2$Et2O (22.5 g, 87.3 mmol) was added in five portions over
20 min. This solution was heated at reflux for 45 min, and then
allowed to cool to rt. Hexane (600 mL) was added, and the mixture
was filtered. The resulting clear filtrate was washed with water and
brine, dried, and concentrated to give a pale yellow oil, which was
used directly in the subsequent step (11.3 g, 100%): 1H NMR
4.2.14. 2-(tert-Butyldiphenylsiloxymethyl)-5-methyl-2(E),5-dienoic
acid, N-(2-iodophenyl)amide (47). A mixture of 45 (344 mg,
0.872 mmol), 2-iodoaniline (229 mg, 1.04 mmol), N-methyl-2-
chloropyridinium iodide (492 mg, 1.6 mmol), collidine (421 mg,
3.48 mmol) and PhMe (10 mL) was vigorously stirred at 80 ꢁC for
4 h, then allowed to cool to rt.36 The mixture was diluted with
EtOAc (100 mL), washed with 1 M HCl and water, dried, and con-
centrated to give a brown oil. Purification of this residue by flash
chromatography (90:10 hexanes/Et2O) gave 47 as a pale yellow
solid (472 mg, 91%): mp 73e75 ꢁC; 1H NMR (500 MHz, CDCl3)
d 8.95
x
Treatment of the crude reaction mixture with MeOH/K2CO3 was necessary to
hydrolyze the small amount (ca. 10%) of tert-butyldiphenylsilyl ester formed.

6524
L.E. Overman, M.D. Rosen / Tetrahedron 66 (2010) 6514e6525
26
26
26
(s,1H), 8.31 (d, J¼8.1 Hz,1H), 7.84 (d, J¼7.9 Hz,1H), 7.74 (d, J¼6.9 Hz,
4H), 7.45 (d, J¼12.1 Hz, 1H), 7.43e7.47 (m, 7H), 6.88 (t, J¼7.3 Hz,1H),
5.44 (d, J¼12.1 Hz, 1H), 4.72 (s, 2H), 1.86 (s, 3H), 1.67 (s, 3H), 1.08 (s,
1378, 1072, 835, 730 cmꢀ1; [
a
]
D
þ121.2, [
a]
þ126.4, [
a]
546
577
26
þ158.1, [ 435 þ232.3 (c 0.2, CHCl3); HRMS (CI/isobutane) m/z calcd
a
]
for C27H36IN3O4Si 621.1522, found 621.1530.
9H); 13C NMR (125 MHz, CDCl3)
d 166.6, 146.4, 139.0, 135.9, 135.3,
132.9, 129.9, 129.0, 127.8, 126.0, 123.7, 119.8, 91.3, 58.8, 27.1, 26.9,
19.2, 18.3; IR (film) 3334, 2928, 2858, 1679, 1584, 1524, 1429, 1292,
1229, 1112, 702 cmꢀ1; HRMS (FAB) m/z calcd for C30H35INO2Si
596.1482 (MHþ), found 596.1466. Anal. Calcd for C30H34IO2Si: C,
60.50; H, 5.75; N, 2.35. Found: C, 60.73; H, 5.76; N, 2.21.
4.2.17. (ꢀ)-Spirotryprostatin B (8) and (ꢀ)-3,18-epi-spirotryprostatin
B (56). A mixture of Pd2(dba)3$CHCl3 (23 mg, 0.023 mmol), tri-or-
tho-tolylphosphine (27 mg, 0.090 mmol), and THF (1.5 mL) was
stirred at rt for 2 h, furnishing a bright red solution. This solution
was added to a mixture of 49 (140 mg, 0.23 mmol) and KOAc
(220 mg, 2.3 mmol) in a resealable tube. The mixture was sparged
with argon for 10 min, then sealed and heated at 70 ꢁC for 14 h. The
brown reaction mixture was allowed to cool to rt and then was
filtered through a pad of Celite, eluting with EtOAc. After concen-
tration, the residue was purified by flash chromatography (EtOAc/
hexanes 75:25) to afford a mixture of 54 and 55 as a light yellow
solid (80 mg, 72%). A portion of this mixture (65 mg, 0.13 mmol)
was deprotected, as described for the preparation of 13, to give
a yellow solid, which was chromatographed (CH2Cl2/MeOH 97:3) to
provide a mixture of crude (ꢀ)-spirotryprostatin B (8) and (ꢀ)-3,18-
epi-spirotryprostatin B (56) (44 mg, 93%). These diastereomers
were separated by preparatory TLC (CH2Cl2/MeOH 95:5) to give
samples of 8 (21 mg, 33% from 49) and 56 (19 mg, 29% from 49).
An analytical sample of (ꢀ)-spirotryprostatin B (8) was obtained
4.2.15. 2-Hydroxymethyl-5-methylhexa-2(E),4-dienoic acid, N-(2-
iodophenyl)-N-[(2-trimethylsilyl)ethoxymethyl]amide (48). Follow-
ing procedures analogous to those employed to prepare 32, the
sodium salt of amide 47 (9.80 g, 16.4 mmol) was N-alkylated with
(2-trimethylsilyl)ethoxymethyl chloride (4.40 ml, 25 mmol), and the
TBDPS group of the crude product was cleaved with tetrabuty-
lammonium fluoride (1.0 M, 50 mL, 50 mmol) to provide a brown oil.
Purification of this residue by flash chromatography (EtOAc/hexanes
30:70) gave 48 as a colorless solid (7.59 g, 95% over two steps): mp
114e115 ꢁC; 1H NMR (500 MHz, 75 ꢁC, CDCl3)
d
7.88 (dd, J¼8.6,1.2 Hz,
1H), 7.35 (m, 2H), 6.98 (m,1H), 6.48 (br d,1H), 6.02 (d, J¼11.5 Hz,1H),
5.91 (br s,1H), 4.66 (br d,1H), 4.45 (br s,1H), 4.33 (br s,1H), 3.71 (br s,
1H), 3.64 (br m,1H), 2.51 (br s,1H),1.79 (s, 3H),1.61 (s, 3H), 0.85e1.00
(m, 2H), 0.01 (m, 9H); 13C NMR (125 MHz, 75 ꢁC, CDCl3)
d
172.7, 145.1,
by preparatory HPLC (Alltech Altima C18 5
m
250 mmꢂ22 mm
143.8,140.2,132.7,131.2,130.8,129.2,129.1,119.8,99.8, 78.3, 66.9,59.3,
26.6,18.6,18.4, ꢀ1.4; IR (film) 3442, 2950,1634,1470,1291,1248,1072,
1018, 835 cmꢀ1; HRMS (CI/isobutane) m/z calcd for C20H30INO3Si
487.1041, found 487.1030. Anal. Calcd for C20H30INO3Si: C, 49.28; H,
6.20; N, 2.87. Found: C, 49.50; H, 6.17; N, 2.82.
column, H2O/MeOH 50:50, retention time¼44.0 min) to give a light
yellow solid (16 mg): 1H and 13C NMR data were identical to those
reported;5 HRMS (CI/isobutane) calcd for C21H21N3O3 363.1609,
found 363.1612; [
a
]
26 ꢀ159.4 (c 0.40, CHCl3), lit. 5
[
a2D6 ꢀ162 (c 0.92,
D
CHCl3). An analytical sample of (ꢀ)-3,18-epi-spirotryprostatin B
(56) was also obtained by preparatory HPLC (Alltech Altima C18 5
m
4.2.16. (S)-2-(1,4-Dioxohexahydropyrrolo[1,2-a]pyrazin-3(Z)-ylide-
nemethyl)-5-methylhexa-2(E),4-dienoic acid, N-(2-iodophenyl)-N-
[2-(trimethylsilyl)ethoxymethyl]amide (49). Alcohol 48 (609 mg,
1.25 mmol) was dissolved in CH2Cl2 (20 mL) at 23 ꢁC, then
DesseMartin periodinane37 (690 mg, 1.60 mmol) was added in two
equal portions with rapid stirring. The reaction mixture was stirred
20 min at rt, then a solution of saturated aqueous Na2S2O3 (1 mL)
was added, followed by saturated aqueous NaHCO3 (1 mL). The
resulting mixture was diluted with Et2O, washed with water and
brine, then dried, and concentrated to give 604 mg of (E)-2-formyl-
5-methylhexa-2,4-dienoic acid, N-(2-iodophenyl)-N-[2-(trime-
thylsilyl)ethoxymethyl]amide as a highly unstable yellow oil, which
was used without delay in the subsequent step: diagnostic 1H NMR
250 mmꢂ2 mm column, H2O/MeOH 50:50, retention time-
¼18.6 min): a light yellow solid (5 mg); 1H and 13C NMR data were
identical to those reported;7 HRMS (FAB) calcd for C21H22N3O3
26
(MH) 364.1661, found 364.1684; [
a]
ꢀ43.9 (c 0.40, CH2Cl2), lit.7
D
[a
]
26 ꢀ42.5 (c 0.8, CH2Cl2).
D
Acknowledgements
This research was supported by NIH NIGMS (GM-30859) and by
a graduate fellowship to M.D.R. from Bristol-Myers Squibb Phar-
maceuticals. We thank Professor A. J. Shaka and Nathan D. Taylor
(Department of Chemistry UC Irvine) for double-pulsed field gra-
dient spin echo (DPFGSE) NOE experiments and Robert M. Williams
and Paul Sebahar (Department of Chemistry, Colorado State Uni-
versity) for providing spectral data and a sample of synthetic ent-
56. We are also grateful to Professors Robert M. Williams and
Samuel J. Danishefsky for open exchange of information during the
course of this work. We thank Drs. John Greaves and John Mudd for
mass spectral analysis, and Matthew Gillingham for early in-
vestigations of the syntheses of 19 and 23. NMR and mass spectra
were determined with instruments purchased with the assistance
of the NSF and NIH shared instrumentation grants.
(500 MHz, CDCl3)
d 9.84 (s, 1H, CHO). Potassium tert-butoxide
(280 mg, 2.50 mmol) was suspended in CH2Cl2 (10 mL) with stir-
ring, and cooled to ꢀ78 ꢁC. A solution of diketopiperazine phos-
phonate 3432 (660 mg, 2.50 mmol) and CH2Cl2 (5 mL) was then
added dropwise with rapid stirring. The resulting mixture was
stirred at ꢀ78 ꢁC for 20 min, then a solution of the crude aldehyde
(604 mg, 1.25 mmol) and CH2Cl2 (5 mL) was added dropwise with
rapid stirring. The reaction mixture was allowed to warm to rt,
diluted with EtOAc (50 mL), washed with water and brine, dried,
and concentrated to give an oil. Flash chromatography of this res-
idue (hexane/EtOAc 50:50 to 25:75) gave 49 as a light yellow foam
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dimethylformamide-d7)
d
8.99 (br s, 1H), 7.95 (d, J¼7.9 Hz, 1H),
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7.40e7.46 (br m, 2H), 7.12 (td, J¼7.9, 1.7 Hz, 1H), 6.76 (br d, J¼9.6 Hz,
1H), 6.45 (br s, 1H), 6.03 (br d, J¼9.6 Hz, 1H), 5.54 (br s, 1H), 4.76 (br
s, 1H), 4.33 (t, J¼6.3 Hz, 1H), 3.64e3.78 (m, 3H), 3.45 (td, J¼8.8,
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either of the two potential
the CePd -bond would be either tertiary or neopentylic.
19. Coupling of catalytic asymmetric intramolecular Heck reactions with bi-
h
1-allylpalladium isomers would be slow, because
s
molecular trapping of
h
3-allylpalladium intermediates was pioneered by Shi-
basaki and co-workers.20 The stereochemical issues that were at the heart of
the present investigation were not probed in these earlier studies.
20. (a) Kagechika, K.; Shibasaki, M. J. Org. Chem. 1991, 56, 4093e4094; (b) Ka-
gechika, K.; Ohshima, T.; Shibasaki, M. Tetrahedron 1993, 49, 1773e1782; (c)