Enantioselective synthesis of (-)-idiospermuline

Article abstract of DOI:10.1016/S0040-4020(03)00855-X

The enantioselective total synthesis of the nonacyclic polypyrrolidinoindoline (-)-idiospermuline is described. Stereocontrolled formation of the vicinal quaternary carbon centers is achieved in a single step by dialkylation of an unsymmetrical prostereog

Full text of DOI:10.1016/S0040-4020(03)00855-X

Tetrahedron 59 (2003) 6905–6919
Enantioselective synthesis of (2)-idiospermuline
*
Larry E. Overman and Emily A. Peterson
Department of Chemistry, University of California, 516 Rowland Hall, Irvine, CA 92697-2025, USA
Received 28 April 2003; revised 27 May 2003; accepted 29 May 2003
Dedicated to Professor K. C. Nicolaou in recognition of his award of the 2003 Tetrahedron Prize
Abstract—The enantioselective total synthesis of the nonacyclic polypyrrolidinoindoline (2)-idiospermuline is described. Stereocontrolled
formation of the vicinal quaternary carbon centers is achieved in a single step by dialkylation of an unsymmetrical prostereogenic dienolate
with a tartrate-derived chiral dielectrophile. A catalyst-controlled diastereoselective Heck cyclization is employed to form the diaryl-
substituted quaternary center.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
the polypyrrolidinoindoline family whose absolute and
relative configuration has been established by single-crystal
X-ray crystallography. TheC2-symmetric(2)-chimonanthine
moietyembedded within idiospermuline (4) is desymmetrized
byboththeattachmentofathirdpyrrolidinoindolinesubunitat
C70 and the unsymmetrical methyl substitution of its indoline
nitrogens. This latter feature is extremely rare in the
polypyrrolidinoindoline alkaloids.1
Polypyrrolidinoindoline alkaloids are isolated from a wide
variety of natural sources including bacteria, fungi and
higher plants such as shrubs and trees.1 Characterized by the
linkage of cyclotryptamine subunits through quaternary
carbon centers, members of this alkaloid class are
characterized by two general structural motifs. The first,
seen in meso-chimonanthine (1) and its C2-symmetric
stereoisomer (2)-chimonanthine (2), is a 3a,3a0-bispyrroli-
dinoindoline moiety linking the benzylic quaternary stereo-
centers of two pyrrolidinoindoline fragments (Fig. 1). The
second, present in higher order members of this alkaloid
family, is a 3a,7-bispyrrolidinoindoline unit joining the C7
peri position of one pyrrolidinoindoline unit and the
benzylic quaternary stereocenter of another. This latter
motif is found in quadrigemine C (3),2 idiospermuline (4),
and numerous other higher order polypyrrolidinoindoline
alkaloids.3 Members of this alkaloid family containing up to
eight linked pyrrolidinoindoline fragments have been
described.1 Relative and absolute configuration is known
for only the chimonanthines,1 and some members of the
tris-3,4 and tetrapyrrolidinoindoline groups.5–7
As part of ongoing studies aimed at developing chemistry to
allow diverse members of the polypyrrolidinoindoline
alkaloids to be prepared by stereorational chemical synthesis,
we undertook the total synthesis of idiospermuline (4). Full
details of our successful enantioselective total synthesis of
this trispyrrolidinoindoline alkaloid are recorded herein.8
2. Results and discussion
2.1. Synthesis plan
Our plan for preparing idiospermuline (4) drew heavily on
chemistry recently developed to prepare quadrigemine C (3)
and psycholeine.5 Disconnection of the pyrrolidine ring of
the C70-linked pyrrolidinoindoline fragment of 4 leads to
octacyclic oxindole00 5 (Scheme 1). In the first key
disconnection, the 3a diaryl-substituted quaternary stereo-
center of 5 was seen as arising from catalyst-controlled9
diastereoselective Heck cyclization of (Z)-butenanilide 6.
This latter intermediate would logically derive from Stille
coupling of bispyrrolidinoindoline iodide 7 and a-stannyl
(E)-butenanilide 8.
Idiospermuline (4) was isolated by Duke and co-workers from
the seed of Idiospermum australiense, a rare tree found in
lowland rain forests of North Queensland, Australia.3 This
alkaloid was identified in a search for naturally occurring
substances acting on neurochemical transmission. Idiosper-
muline was subsequently characterized as a mM cholinergic
antagonist.3 Idiospermuline (4) is one of the few members of
Keywords: cyclotryptamine alkaloids; dialkylation; Heck cyclization;
vicinal quaternary centers.
A major challenge in the synthesis of 4 would be
enantioselective preparation of (2)-chimonanthine congener
*
Corresponding author. Tel.: þ1-9498247156; fax: þ1-9498243866;
e-mail: leoverma@uci.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00855-X

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L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
Figure 1. Representative cyclotryptamine alkaloids.
Scheme 1. Retrosynthesis.
7, an intermediate having both an unsymmetrical methyl-
ation pattern and functionality at the peri position of0only its
mono-methylated pyrrolidinoindoline unit. The C7 iodide
of 7 should be available by Boc-directed ortho-lithiation10
of bispyrrolidinoindoline carbamate 9. This latter inter-
mediate, with its indoline nitrogens differentially func-
tionalized, was seen arising from the hexacyclic
trans-spirooxindole 10.11 In the second key disconnection,
10 would arise by diastereoselective dialkylation of a
dienolate derivative of dihydroisoindigo 12 and (S)-tartrate-
derived ditriflate 11.11,12 In this plan, the different
substituents on the indoline nitrogens of 9 would arise
from the unsymmetrical functionalization of dihydroiso-
indigo 12, this latter feature being easily incorporated in the
assembly of 12 from isatin and oxindole precursors.
2.2. Preparation of bispyrrolidinoindoline iodide 7
The synthesis of idiospermuline (4) began by benzylation of
isatin (13), followed by condensation of N-benzylisatin with
oxindole to give mono-protected isoindigo 14 in 75%
overall yield (Scheme 2). Methylation of the free oxindole
Scheme 2. Reaction conditions: (a) NaH, BnBr, DMF, rt; (b) oxindole, HOAc, HCl, 1108C, (75%, 2 steps); (c) NaH, MeI, DMF, rt.

L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
6907
second alkylation event occurred with the enolate
oxygen and oxindole carbonyl groups oriented away
from each other as depicted in Scheme 5.
Salient results of our study of this pivotal dialkylation of
dihydroisoindigo 12 with ditriflate 11 are summarized in
Table 1. Dialkylation of the LHMDS-derived dienolate of
12 with ditriflate 11 in a 7:3 mixture of THF–HMPA at
2408C, conditions found optimal in an earlier study of
dialkylation of related symmetrical dienolates,13† delivered
10 in low yield albeit it with good stereoselectivity (Table 1,
entry 1). Several reaction variables were investigated to
maximize yield of 10. The best solvents were found to be
THF and DME, however, reproducibility was better in THF
(Table 1, entries 2–5). Variations in reaction temperatures
over the range 230 to 2508C were found to have little effect
on stereoselection or yield (Table 1, entries 5–7). However,
the yield of the desired product 10 was improved
significantly by lowering the substrate concentration and
HMPA loading (Table 1, entries 7–11). Carrying out the
dialkylation at a substrate concentration of 0.05 M in a 9:1
mixture of THF–HMPA at 2408C provided 10 in 75%
yield; the other three stereoisomers, 25, 26, and 27, were
isolated in 15% combined yield (Table 1, entry 10).‡
Substituting DMPU for HMPA resulted in a slight decrease
in stereoselection and a corresponding decrease in the yield
of 10 (Table 1, entry 12).
Scheme 3. Reaction conditions: (a) Cs2CO3, MeI, DMF, rt; (b) PtO2, H2,
EtOAc, rt (85%, 2 steps).
nitrogen of 14 initially proved problematic. When this
intermediate was exposed to excess MeI and 1.5 equiv. of
NaH in DMF at 258C, a 1:1:2 mixture of isoindigos 15, 16,
and 17 resulted. We hypothesized that adventitious
hydroxide was initiating a retro-aldol/aldol sequence that
scrambled the isoindigo products.
To test this hypothesis, symmetrically-protected isoindigos
15 and 16 were synthesized and crossover experiments were
performed. These experiments showed that 17 was pro-
duced when an equimolar mixture of isoindigos 15 or 16
was treated in DMF with either NaH or NaOH (2 equiv. of
base at 258C in each case). This retro-aldol/aldol scrambling
could be prevented by the use of rigorously dried DMF and
dry Cs2CO3 as the base (Scheme 3). Subsequent catalytic
hydrogenation of 17 over PtO2 provided dihydroisoindigo
12 in 85% overall yield for the 2 steps.
The configuration of dialkylation products 10, 25, 26, and
27 was secured in the following fashion. Bis-spirooxindole
10 was correlated chemically to the enantiomer of C2-
symmetric trans-bis-spirooxindole 19 (see Section 4),
whose structure had been secured earlier by single-crystal
X-ray analysis.11 Products 26 and 27 were inseparable by
silica gel chromatography; however, their derived diols
could be resolved. Reprotection of these products provided
pure samples of 26 and 27. The cis orientation of the
spirooxindole groups in these two stereoisomers was
apparent by analysis of their 1H NMR spectra. As depicted
in Figure 2, the chemical shifts of the acetonide methine
hydrogens Ha and Hb of 26 and 27 differ by ,1.3 ppm. This
difference in chemical shift is expected in the cis
stereoisomers, because of the proximity of Ha to the
oxindole carbonyl and Hb to the nearby arene ring.11 In
contrast, Ha and Hb have nearly identical environments in
trans stereoisomer 10 as signaled by the nearly identical
chemical shifts of these methine hydrogens. The minor
trans stereoisomer 25 also exhibits coincident chemical
shifts for Ha and Hb.
With dihydroisoindigo 12 in hand, diastereoselective
dialkylation to form the 3a,3a0 vicinal quaternary stereo-
centers of idiospermuline (4) was explored. Previous
investigations in our laboratories had shown that the union
of prostereogenic bisoxindole dienolates with chiral dielec-
trophile 11 could efficiently construct contiguous
stereogenic quaternary carbon centers. For example, in the
synthesis of (þ)-chimonanthine, reaction of the LHMDS-
derived dienolate of 18 with ditriflate ent-11 in a 9:1
mixture of THF–DMPU at 2408C generated the enantio-
pure C2-symmetric product 19 in 55% yield (Scheme 4).11
However, a preliminary investigation had shown that
stereoselection in this reaction was lower when the indoline
nitrogens of the dienolate nucleophile were protected with
hexyl or cyclohexylmethyl substituents.13 Whether the
N-methyl substituent of 12 would lead to an erosion in
stereoselection in its union with ditriflate 11 was a pivotal
issue to be addressed early in our idiospermuline synthesis
endeavor.
In the dialkylation experiments summarized in Table 1, the
undesired cis-spirooxindole products 26 and 27 were always
formed in a ,1:1 ratio; in the majority of experiments, only
trace amounts of the minor trans-spirooxindole product 25
was obtained. These observations can be rationalized in the
following way. Initial alkylation of the dienolate of 12 with
ditriflate 11 from the Si face would generate mono-alkylated
Dialkylation of dienolate 20 (derived from unsymme-
trical dihydroisoindigo 12) with ditriflate 11 could
generate four different bis-spirooxindole products, 10,
25, 26 and 27 (Scheme 5). Preferential formation of the
desired trans stereoisomer 10 in this union would
require two elements of stereocontrol: facial selectivity
in the initial alkylation step, and the absence of chelate
organization in the subsequent intramolecular alkylation
step. Specifically, the bimolecular alkylation must occur
from the Re face of the dienolate to generate 23 and 24.
However, chemoselectivity in this step would not be
required, as both 23 and 24 would evolve to 10 if the
†
Symmetrical substrates can lead to three possible products, two of which
are C2-symmetric and one C1-symmetric.
Dialkylation of N,N0-dibenzyldihydroisoindigo 18 with ditriflate 11 under
‡
these conditions provided the corresponding C2-symmetric product 19 in
80% yield, a notable improvement in efficiency of this previously
reported11 transformation (see Scheme 4).

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L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
Scheme 4. Dialkylation of symmetrical N,N0-bisbenzyldihydroisoindigo 18.
1
Figure 2. Diagnostic H NMR chemical shifts of dialkylation products 10, 25, 26 and 27.
intermediates 21 and 22 (Scheme 5). If the subsequent
intramolecular alkylation occurs without chelate organiz-
ation, trans-spirooxindole 25 would be produced. However,
this trans-spirooxindole isomer would be higher in energy
than the other three possible bis-spirooxindole products as
both aryl groups of 25 would be axially oriented on the
newly formed cyclohexane ring.§ This destabilizing steric
interaction is apparently present to a sufficient extent in the
transition state leading to 25 that mono-alkylated inter-
mediates 21 and 22 cyclize preferentially, even in the
presence of HMPA, to generate the cis-spirooxindole
products 26 and 27. The production of 26 and 27 in nearly
equivalent amounts indicates that the closely related
nitrogen substituents, methyl and benzyl, have little effect
on the site of the initial bimolecular alkylation.
hexacyclic intermediate 10 was elaborated to the
differentially protected chiral bispyrrolidinoindoline 9 as
summarized in Scheme 6. Removal of the acetonide of
10, followed by oxidative cleavage of the resulting
vicinal diol and immediate reduction of the ensuing
dialdehyde with sodium borohydride provided diol 28 in
85% yield over the 3 steps. Reduction of the oxindole14
carbonyl groups of this intermediate with sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Alw) in refluxing
THF triggered in situ condensation to provide the
unstable pentacyclic diol 29. Installation of the nitrogen
functionality that would be required to form the outer
pyrrolidine rings of 32 was achieved by a double
Mitsunobu reaction.15 This transformation required
optimization of a previously employed procedure,16
because of facile formation of pentacyclic diether 31.
Competitive formation of 31 was minimized by increas-
ing the equivalents of the azide donor and by using a
more reactive azide source, HN3, instead of diphenylpho-
sphoryl azide. In this way, diazide 30 was formed in 75%
overall yield from 28. Staudinger reduction of this
diazide and dehydration of the resulting diamine in
methanol at 1108C formed the corresponding bispyrroli-
dinoindoline. Reductive methylation of the pyrrolidine
nitrogens of this latter intermediate and subsequent
N-debenzylation with Na/NH3 gave 32 in 75% yield for
the 4 steps.
With the vicinal quaternary stereocenters in place,
§
Single-crystal X-ray analysis shows that the diol derivative of the
corresponding isomer in which both nitrogen substituents are benzyl
exists in a chair conformation; unpublished studies of J. Larrow
The free indoline nitrogen of bispyrrolidinoindoline 32 was
exploited next to introduce iodine selectively at the peri
position of the mono-methylated pyrrolidinoindoline frag-
ment. Premixing 32 with Boc2O at 2788C and then slowly
adding an excess of NaHMDS followed by quenching at
2788C with saturated aqueous NaHCO3 delivered 9 in 74%
yield. Low temperature and slow addition of the base were
necessary to prevent alkoxycarbonylation of a pyrrolidine
nitrogen, leading ultimately to fragmentation of the 3a,3a0

L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
6909
Scheme 5. Intermediates and products potentially generated from dienolate 20 and ditriflate 11.
Table 1. Optimization of the dialkylation reaction
Entry
Solvent
HMPA (%)
Temperature (8C)
Conc. 12 (M)
Ratioa 10:26 and 27:25
Ratio 10:26 and 27
Yielda of 10 (%)
1
2
3
4
5
6
7
8
THF
Toluene
Et2O
DME
THF
THF
THF
THF
THF
THF
THF
THF
42%
30%
30%
30%
30%
30%
30%
30%
20%
10%
5%
10% DMPU
240
250
250
250
250
240
230
240
240
240
240
240
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.05
0.05
0.05
0.05
0.05
70:7.3:1
29:14:1
6.6:1.3:1
56:5:1
20:3:1
30:3.2:1
33:9:1
5:1:2.4
8.6:1.2:1
24:3.5:1
85:10:1
20:5.5:1
9.7:1
2:1
5:1
11:1
7:1
55
24b
12b
18–54
48
55
46
41
7:1
3.7:1
5:1
7:1
7:1
8.5:1
3.6:1
9
45
10
11
12
75c
62
51
a
Product ratios and yields determined by 1H NMR using 3-methylanisole as an internal standard.
Residual starting material was observed in crude reaction mixture.
Isolated yield.
b
c

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L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
Scheme 6. Reaction conditions: (a) CSA, MeOH, CH2Cl2, rt; (b) NaIO4, THF, H2O, rt; (c) NaBH4, MeOH, rt (85%, 3 steps); (d) Red-Al, THF, 678C; (e)
DEAD, PPh3, HN3, THF, 08C (75% from 28); (f) PPh3, THF, H2O; (g) MeOH, 1108C (77%, 2 steps); (h) CH2O, NaBH(OAc)3; (i) Na, NH3, THF, 2788C (98%,
2 steps); (j) Boc2O, NaHMDS, 2788C (74%); (k) (i) TMEDA, sBuLi, 2788C; (ii) diiodoethane, 2788C to rt; l) TfOH, CH2Cl2 (85%, 2 steps).
Scheme 7. Reaction conditions: (a) (i) TMSOTf, i-Pr2NEt, Et2O, 08C; (ii) nBuLi, 2788C, 34 or 35; (iii) PhNTf2, 2108C; TsCl, silica gel, rt (42%); (b)
Pd(PPh3)4, Bu3SnH, THF, 08C (88%); (c) Pd2dba3·CHCl3, P(2-furyl)3, 8, CuI, NMP, rt (94%).
bond joining the vicinal quaternary carbons. Boc-directed
ortho-lithiation of 9 with excess sBuLi at 2788C, and
subsequent quenching of the aryllithium intermediate with
an excess of diiodoethane provided, following removal of
the Boc group with trifluoromethanesulfonic acid, iodo
bispyrrolidinoindoline 7 in 85% yield.17
triflimide generated the N-silyl-protected triflato alkyne
amide.{ Finally, addition of TsCl and silica gel to the
reaction resulted in cleavage of the TMS group and
tosylation of the amine to give alkyne amide 36 in 42%
yield. Palladium catalyzed hydrostannanylation of 36
generated a-stannyl (E)-butenanilide 8 in 88% yield. A
similar sequence employing N-benzylbenzoxazolidinone
(35) yielded stannane 38 in similar overall yield. Finally
chemoselective palladium catalyzed coupling of stannane 8
with bispyrrolidinoindoline iodide 7, using conditions we
had optimized earlier for related transformations,5 provided
triflato anilide 6 in 94% yield.18
With differentiated bispyrrolidinoindoline 7 now in hand,
our attention focused on preparing stannane 8. For the
synthesis of quadridgemine C, analogous stannane 38 was
synthesized in 33% yield by a four-step sequence.5 This
sequence proved somewhat less efficient for the production
of stannane 8. As a result, a more convenient two-pot
procedure was developed for the synthesis of this inter-
mediate (Scheme 7). Treatment of an ether solution of
N-methylpropargyl amine (33) with TMSOTf and i-Pr2NEt
at 08C, followed by deprotonation of the resulting
N-silylated alkyne with nBuLi at 2788C and sequential
addition of N-methylbenzoxazolidinone (34) and N-phenyl-
With the necessary carbon and nitrogen atoms of the third
and final pyrrolidinoindoline subunit of idiospermuline (4)
installed, our attention focused on diastereoselective
{
In situ silyl-protection of the amine was required to prevent competitive
formation of the urea.

L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
Table 2. Heck cyclization of (Z)-butenanilide 6
6911
formation of the remaining diaryl-substituted 3a00 quaternary
stereocenter. An asymmetric Heck cyclization19 was
employed in our earlier total synthesis of quadridgemine
C (3) to desymmetrize an advanced meso intermediate to
form the diaryl quaternary stereocenters of this alkaloid.5
We anticipated that related catalyst control would be
required to install the final quaternary stereocenter of
idiospermuline (4) with high diastereoselectivity. Heck
cyclizations of 6 were performed initially with achiral
chelating bisphosphines such as bis(1,4-diphenylphos-
phino)butane (dppb). Modest substrate control (2.5:1) was
realized in forming the desired 3a00R stereoisomer 5 (Table 2,
entry 1). This selectivity increased to 6:1 using (S)-tol-
BINAP,20 Pd(OAc)2 as the precatalyst (entry 3), 1,2,2,6,6-
pentamethylpiperidine (PMP) in acetonitrile at 808C.
Identical cyclization of 6 using (R)-tol-BINAP reversed
the selectivity, yielding 5 and 39 in a 1:18 ratio (entry 4).
The higher diastereoselectivity in the latter case reflects
proper matching of substrate and catalyst control.
Epimers 5 and 39 proved difficult to separate by flash
chromatography. As a result, mixtures enriched in either
epimer were advanced to the end of the synthesis where the
final products could be separated by preparative HPLC.
Catalytic hydrogenation of the 6:1 mixture of 5 and 39 over
palladium hydroxide at high hydrogen pressure (1000 psi)
provided saturated sulfonamides 40 and 41 (Scheme 8).
Entry
Ligand
Dppb
rac-Tol-BINAP
(S)-Tol-BINAP
(R)-Tol-BINAP
Isolated yield (%)
Ratio 5:39
1
2
3
4
90
97
97
99
2.5:1
1:2
6:1
1:18
Attempts to remove the tosyl group of 40, reduce the
oxindole carbonyl group and cyclize to form idiospermuline
Scheme 8. Reaction conditions: (a) Pd(OH)2, H2 (1000 psi), EtOH, 808C; (b) Red-Al, toluene, rt; (c) Na, NH3, THF, 2788C.

6912
L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
in a single transformation with sodium in ammonia at
2788C, conditions employed in our synthesis of quad-
rigemine C (3),5 met little success. The presence of the
methyl group on the oxindole nitrogen perhaps thwarting
reduction of the carbonyl group.21k
vacuum filtration and subsequently washed with H2O
(400 mL) then hexanes (200 mL) to yield 104.6 g (99%)
of 1H-indole-2,3-dione. The spectral data was consistent
with that reported previously.23
4.1.2. 1-Benzyl-1H,10H-[3,30]biindolylidene-2,20-dione
This final problem was overcome by reducing the oxindole
carbonyl before removal of the tosyl group. Thus, a 6:1
mixture of saturated sulfonamides 40 and 41 was treated with
an excess of sodium bis(2-methoxyethoxy)aluminum hydride
in toluene at room temperature.14 The resulting crude product
was immediately reduced with excess sodium in ammonia at
2788C. Finally, HPLC purification of the resulting products
provided idiospermuline (4), [a]D¼2267 (c 0.85 CHCl3), in
47% overall yield from the mixture of Heck products.p p
Synthetic idiospermuline (4) was identical to a natural sample
by 1H NMR, 13C NMR, CD, and HRMS comparisons, as well
as by HPLC co-injection. An analogous seq0u0 ence carried out
with a 1:18 mixture of 5 and 39 gave 3a ,8a00-bis-epiidio-
spermuline (42), [a]D¼2156 (c 0.25 CHCl3), in 57% yield.
(14).
A
solution of 1-benzyl-1H-indole-2,3-dione23
(32.7 g, 138 mmol), oxindole (18.3 g, 138 mmol), acetic
acid (450 mL) and HCl (5 mL) was heated at 1108C for 6 h.
The solution was allowed to cool to rt at which time hexanes
(200 mL) were added. A maroon precipitate formed, which
was collected by vacuum filtration. This solid was washed
with H2O (200 mL) then hexanes (100 mL), and dried in
vacuo to yield 36.8 g (76%) of isoindigo 14 as a maroon
solid: mp 225–2288C; 1H NMR (500 MHz, (CD3)2SO)
10.99 (s, 1H), 9.15 (t, J¼7.5 Hz, 2H), 7.42–7.36 (m, 6H),
7.31 (t, J¼6.9 Hz, 1H), 7.09–7.03 (m, 2H), 7.00 (t,
J¼8.4 Hz, 1H) 6.90 (d, J¼7.7 Hz, 1H), 5.06 (s, 2H); 13C
NMR (125 MHz, (CD3)2SO)‡‡ d 168.8, 167. 3, 144.3, 143.9,
136.2, 134.3, 133.0, 132.4, 131.8, 129.5, 129.1, 128.7,
127.4, 127.2, 121.9, 121.6, 121.2, 120.9, 109.6, 108.9, 42.7;
IR (film) 3134, 3030, 1698, 1606, 1467, 1332 cm21. Anal.
calcd for C23H16N2O2: C, 78.39; H, 4.58; N, 7.95. Found: C,
78.51; H, 4.74; N, 7.90.
3. Conclusion
This total synthesis of idiospermuline (4) and that of
hodgkinsine, which we reported recently,22 are the first total
syntheses of trispyrrolidinoindoline alkaloids. Starting with
isatin, idiospermuline was formed in 6% overall yield by a
sequence involving 22 steps (longest linear sequence) and
14 isolated and purified intermediates. This stereocontrolled
total synthesis demonstrates for the first time that the
dienolate dialkylation chemistry we described earlier for
synthesis of symmetrical 3a,3a0-bispyrrolidinoindolines11
can be employed for enantioselective preparation of
unsymmetrical congeners. This synthesis of idiospermuline
also provides an additional illustration of the ability of
asymmetric intramolecular Heck reactions to generate
congested quaternary carbon centers in high yield, and the
first demonstration of using such a transformation to
elaborate a pyrrolidinoindoline unit at the peri position of
a chiral 3a,3a0-bispyrrolidinoindoline fragment.
4.1.3. 10-Benzyl-1-methyl-1H,10H-[3,30]biindolylidene-
2,20-dione (17). Anhydrous DMF (80 mL) was added to
14 (9.89 g, 28.4 mmol) and Cs2CO3 (13.1 g, 34.1 mmol).
Methyl iodide (2.1 mL, 34 mmol) was added by syringe and
the reaction mixture was stirred at rt for 24 h. The mixture
then was poured into aqueous NH4Cl at 08C and a dark
maroon solid precipitated. This solid was collected by
vacuum filtration, washed with H2O (200 mL), then hexanes
(100 mL), and dried in vacuo to yield 10.0 g (97%) of
1
isoindigo 17 as a maroon solid: mp 175–1778C; H NMR
(500 MHz, (CD3)2SO) d 9.18 (d, J¼8.0 Hz, 2H), 7.49 (dt,
J¼7.7, 1.1 Hz, 1H), 7.42–7.35 (m, 5H), 7.31 (tt, J¼6.9,
1.6 Hz, 1H), 7.12–7.05 (m, 3H), 7.01 (d, J¼7.8 Hz, 1H),
5.06 (s, 2H), 3.27 (s, 3H); 13C NMR (125 MHz,
(CD3)2SO)‡‡ d 167.2, 167.0, 145.2, 144.0, 136.2, 133.2,
132.9, 132.6, 132.2, 129.3, 129.2, 128.7, 127.4, 127.2,
121.9, 121.8, 120.8, 120.7, 109.0, 108.6, 42.7, 26.1; IR
(film) 2926, 1691, 1610, 1471, 1351, 1181, 1096 cm21
.
Anal. calcd for C24H18N2O2: C, 78.67; H, 4.95; N, 7.65.
Found: C, 78.75; H, 5.09; N, 7.65.
4. Experimental††
4.1. Data for compounds
4.1.4. 10-Benzyl-1-methyl-1,10,3,30-tetrahydro-[3,30]biin-
dolyl-2,20-dione (12). Platinum (IV) oxide (0.19 g,
0.84 mmol) was added to a dark maroon solution of 17
(6.11 g, 16.7 mmol) and EtOAc (150 mL). The flask was
evacuated and backfilled with H2 (5£) from a balloon. The
heterogeneous reaction mixture was stirred vigorously
under H2 (1 atm) until the dark maroon color dissipated.
The mixture was then filtered through Celite and the filter
cake was washed with EtOAc (100 mL). The filtrate was
concentrated in vacuo and the resulting residue was purified
on silica gel (3:1 hexanes–EtOAc) to yield 5.41 g (88%) of
12 (a mixture of two stereoisomers) as a colorless foam: 1H
NMR (1.3:1 mixture of stereoisomers, 500 MHz, CDCl3)
diagnostic signals: d 7.36–7.28 (m, 4.7H), 7.21–7.16 (m,
4.1.1. 1-Benzyl-1H-indole-2,3-dione. Sodium hydride
(19.6 g, 0.49 mol, 60% in oil) was added as one portion to
a slurry of isatin (65.5 g, 445 mmol) and anhydrous DMF
(800 mL) at rt. After 10 min, benzyl bromide (58 mL,
489 mmol) was added rapidly by syringe. After 15 min, the
solution was poured into cold swirling brine and a bright
orange solid precipitated. The precipitate was collected by
k
To the best of our knowledge, formation of a pyrrolidinoindoline by the
original Julian procedure (Na/NH3)14 has only been described with
oxindole precursors lacking a substituent on nitrogen.
p p
The rotation of 4 was reported as [a]D¼22.5 (c 1.0 CHCl3).3 The
rotation of natural 4 measured in our hands (c¼g/100 mL) is
[a]D¼2241 (c 0.2 CHCl3). We thank Professor Rujee K. Duke for
providing a sample of natural idiospermuline.
General experimental details have been described: Minor, K. P.;
Overman, L. E. J. Org. Chem. 1997, 62, 6379–6387.
††
‡‡
Due to the nearly symmetrical nature of this compound, some carbon
resonances are coincidental.

L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
6913
4H), 7.09 (t, J¼7.7 Hz, 1H), 7.05 (t, J¼6.9 Hz, 2H), 7.02–
6.90 (m, 3.4H), 6.84 (t, J¼8.3 Hz, 2H), 6.78 (t, J¼6.7 Hz,
1.6H), 6.67 (dd, J¼14.4, 7.7 Hz, 3.2H), 6.51 (d, J¼7.3 Hz,
1H), 5.00 (d, J¼15.2 Hz, 0.8H), 4.97 (br s, 0.8H), 4.95 (d,
J¼15.4 Hz, 0.8H), 4.56 (d, J¼15.8 Hz, 1H), 4.39 (m, 2.4H),
4.17 (d, J¼3.4 Hz, 1H), 3.28 (s, 2.3H), 3.21 (s, 3H); 13C
NMR (1.3:1 mixture of stereoisomers, 125 MHz, CDCl3)
diagnostic signals: d 176.2, 176.1, 175.3, 174.8, 145.5,
144.4, 144.3, 135.8, 135.7, 129.1, 129.0, 128.9, 128.8, 128.7,
128.6, 128.0, 127.9, 127.6, 127.4, 126.4, 125.7, 125.1, 124.9,
124.2, 123.9, 123.8, 123.7, 122.8, 122.7, 122.6, 122.5, 109.6,
109.2, 108.6, 108.2, 46.8, 46.4, 46.3, 44.3, 44.0, 26.6, 26.5;
IR (film) 3061, 2934, 1702, 1613, 1490, 1467, 1351, 1089,
911 cm21. Anal. calcd for C24H20N2O2: C, 78.24; H, 5.47;
N, 7.60. Found: C, 77.96; H, 5.51; N, 7.54.
was added dropwise to generate a bright yellow solution.
After 15 min, O2 was bubbled vigorously through the
reaction mixture from a balloon until the yellow color
dissipated (10 min). This solution was allowed to warm to rt
under an O2 atmosphere. Saturated aqueous NH4Cl (1 mL)
was added and the aqueous layer was extracted with Et2O
(3£10 mL). The combined organic layers were washed with
brine (10 mL), dried (MgSO4), filtered, and concentrated in
vacuo. The residue was then taken up in DMF (1 mL) and
treated sequentially with NaH (10.0 mg, 0.250 mmol, 60%
in oil) and MeI (0.22 mL, 3.2 mmol). After 10 min,
saturated aqueous NaHCO3 (1 mL) was added and the
aqueous layer was extracted with Et2O (3£10 mL). The
combined organic layers were washed with brine (5 mL),
dried (MgSO4), filtered, and concentrated in vacuo. The
residue was purified on silica gel (5:1 hexanes–EtOA0c) to
yield 3.2 mg (14%) of the C2-symmetric (3S,300S,30aR,7 aR)-
1,100-dimethyl-020,20-dimethyl-30a,40,70,70a-tetrahydrospiro-
[3H-indol0e0 -3,5 (60H)-[1,3]benzodioxole-60,300-[3H]indole]-
2,200(1H,1 H)dione (the N,N0-methyl congener of 10) as
4.1.5. (3S,300S,30aR,70aR)-1-Benzyl-100-methyl-20,20-
dimethyl-30a,40,70,70a-tetrahydrospiro[3H-indole-
3,50(60H)-[1,3]benzodioxole-60-300-[3H]indole]-2,200-
(1H,100H)dione (10). Because of the oxygen sensitivity of
this reaction, all solvents and prepared solutions were
rigorously sparged for 45 min with Ar prior to their addition
to the reaction vessel. A solution of 12 (1.03 g, 2.79 mmol),
THF (35 mL) and HMPA (6 mL) was sparged for 45 min
with Ar and cooled to 2408C at which time a THF solution
of LHMDS (9.3 mL, 0.7 M) was added by syringe pump at a
rate of 0.20 mL/min. After 30 min, a THF solution of
ditriflate 11 (15.0 mL, 0.2 M) was added using a syringe
pump at a rate of 0.20 mL/min. The solution was warmed to
2358C, maintained at 2358C for 12 h (cryocool), then
allowed to warm to rt over 1 h. The solution was partitioned
between EtOAc (25 mL) and brine (15 mL). The layers
were separated and the aqueous layer was washed with
EtOAc (2£15 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The foam
26
26
a
colorless foam: [a] ¼2604, [a] ¼2446,
405
435
[a] ¼2206, [a] ¼2176, [a]2D6¼2167 (c 0.60,
26
546
26
577
1
CH2Cl2); H NMR (500 MHz, C6D6) d 7.31 (dd, J¼7.5,
0.9 Hz, 1H), 6.68 (dt, J¼6.5, 1.2 Hz, 1H), 6.60 (dt, J¼7.6,
0.9 Hz, 1H), 5.85 (d, J¼7.6 Hz, 1H), 5.41–5.34 (m, 1H),
3.29–3.22 (m, 1H), 2.52 (s, 3H), 2.05 (dd, J¼12.5, 3.6 Hz,
1H), 1.55 (s, 3H); 13C NMR (125 MHz, C6D6) d 177.2,
143.7, 129.4, 128.9, 128.7, 124.8, 122.5, 110.3, 108.0, 74.7,
53.4, 33.2, 28.0, 25.6; IR (film) 2984, 1698, 1613, 1494,
1471, 1374, 1355, 1143, 1069, 756 cm21. Anal. calcd for
C25H26N2O4: C, 71.75; H, 6.26; N, 6.69. Found: C, 72.08;
H, 6.65; N, 6.38.
Following an identical procedure, ent-19 (44 mg,
0.025 mmol) was converted to its C2-symmetric N,N0-
methyl congener, (3S,300S,30aR,70aR)-1,100-dimethy0l-20,20-
dimethyl-30a,40,70,70a-tetrahydrospiro[3H-indo0l0e-3,5 (60H)-
[1,3]benzodioxole-60,300-[3H]indole]-2,200(1H,1 H)dione, in
33% yield.
residue was purified on silica gel (5:1 hexanes–EtOAc) to
yield 1.03 g (75%) of 10 as a colorless foam: [a] ¼2698,
28
405
[a] ¼2528, [a] ¼2259, [a] ¼2224, [a]2D8¼2213
28
435
28
546
28
577
1
(c 0.94, MeOH); H NMR (500 MHz, C6D6) d 7.37 (dd,
J¼7.2, 1.5 Hz, 1H), 7.34 (d, J¼7.6 Hz, 1H), 6.95
(t, J¼3.2 Hz, 3H), 6.90–6.86 (m, 2H), 6.70 (t, J¼7.7 Hz,
1H), 6.57–6.50 (m, 3H), 5.98 (d, J¼7.5 Hz, 1H), 5.84
(d, J¼7.8 Hz, 1H), 5.46–5.39 (m, 2H), 4.63 (d, J¼15.7 Hz,
1H), 4.29 (d, J¼15.7 Hz, 1H), 3.34 (m, 2H), 2.52 (s, 3H),
2.18 (dd, J¼12.7, 3.4 Hz, 1H), 2.09 (dd, J¼12.7, 3.4 Hz,
1H), 1.57 (s, 6H); 13C NMR (125 MHz, C6D6) d 177.6,
177.3, 143.7, 143.0, 136.3, 129.5, 129.4, 129.3, 129.1,
128.9, 128.0, 127.9, 125.4, 125.1, 123.0, 122.8, 110.3,
109.3, 108.1, 74.7, 74.6, 53.7, 53.3, 43.9, 34.1, 33.6, 32.3,
28.0, 25.7, 23.4, 14.7; IR (film) 2980, 1698, 1610, 1370,
4.1.7. Isolation of pure samples of hexacycles 26 and 27.
The cis products 26 and 27 were collected as an inseparable
,1:1 mixture from several dialkylation reactions. A 0.250 g
(0.505 mmol) sample of this mixture was dissolved in
CH2Cl2 (3 mL) and MeOH (3 mL) and treated with (^)-
camphorsulfonic acid (0.012 g, 0.051 mmol) at rt. This
solution was maintained at rt for 4 h at which time it was
concentrated and purified on silica gel (6:1 EtOAc–
hexanes) to yield 0.10^0.01 g of each stereoisomer.
1073, 841, 752 cm21
C31H30N2O4 (Mþ) 494.2206, found 494.2206.
;
HRMS (EI) m/z calcd for
The pure vicinal diols were separately reprotected by
treatment with 2,2-dimethoxypropane (8.3 g, 80 mmol) and
(^)-camphorsulfonic acid (7.0 mg, 0.03 mmol) in acetone
(2.5 mL) at rt for 12 h. The reaction was quenched with
solid NaHCO3, and the resulting mixture was filtered and
concentrated. The resulting residue was purified on silica
gel (3:1 hexanes–EtOAc) to yield 0.069 g (63%) of isomer
A and 0.078 g (72%) of isomer B. It has not been established
which of these cis-bis-spirooxindole stereoisomers is 26 and
which is 27.
A larger scale dialkylation of 12 (4.9 g, 13.3 mmol)
proceeded with similar efficiency; however, mixed chro-
matography fractions were discarded in this case, providing
4.2 g (64%) of pure 10.
4.1.6. Chemical correlation of 10 with ent-19. The
N-benzyl group of 10 was removed24 and replaced with a
methyl group in the following manner. A solution of 10
(27.2 mg, 0.055 mmol) in Et2O (1 mL) was cooled to
2788C and a hexane solution of tBuLi (0.22 mL, 1.3 M)
1
Data for hexacycle A. H NMR (400 MHz, C6D6) d 7.56
(d, J¼7.5 Hz, 1H), 7.28 (d, J¼7.3 Hz, 2H), 7.05

6914
L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
(t, J¼7.7 Hz, 2H), 6.99–6.93 (m, 2H), 6.74 (dt, J¼7.6,
1.0 Hz, 1H), 6.58 (dt, J¼7.8, 1.2 Hz, 1H), 6.29–6.24
(m, 2H), 6.05 (d, J¼7.2 Hz, 2H), 5.74 (ddd, J¼13.8, 9.2,
4.6 Hz, 1H), 4.93 (d, J¼15.7 Hz, 1H), 4.71 (d, J¼15.7 Hz,
1H), 4.53 (ddd, J¼13.4, 9.3, 4.1 Hz, 1H), 3.73 (t, J¼12.2 Hz,
1H), 2.60 (t, J¼12.7 Hz, 1H), 2.26 (dd, J¼13.1, 4.6 Hz, 1H),
2.20 (s, 3H), 1.92 (dd, J¼11.9, 4.2 Hz, 1H), 1.56 (s, 6H);
13C NMR (125 MHz, C6D6) d 176.7, 175.3, 144.7, 144.0,
137.2, 131.5, 129.2, 129.16, 129.1, 129.0, 127.8, 127.4,
125.0, 121.9, 121.6, 110.3, 109.3, 109.1, 76.2, 74.1, 56.0,
52.7, 44.7, 35.6, 33.5, 28.0, 27.7, 25.9; IR (film) 2930, 1718,
1610, 1471, 1351 cm21; HRMS (ESI) m/z calcd for
C31H30N2O4 (MþNa) 517.2103, found 517.2122.
portion-wise with NaBH4 (2.72 g, 71.9 mmol). After
10 min, the reaction mixture was concentrated in vacuo
and the residue was partitioned between EtOAc (50 mL)
and H2O (40 mL). The aqueous layer was extracted with
EtOAc (3£25 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. The resulting residue was purified on silica
gel (9:1 EtOAc–hexanes) to yield 4.06 g (87%) of 28 as a
25
25
colorless
25
546
foam:
[a] ¼2722,
405
[a] ¼2544,
435
25
577
[a] ¼2266, [a] ¼2229, [a]2D5¼2218 (c 0.84,
1
MeOH); H NMR (500 MHz, C6D6) d 7.20 (d, J¼7.5 Hz,
2H), 7.10–7.04 (m, 4H), 6.98 (t, J¼7.4 Hz, 1H), 6.73
(dt, J¼7.7, 1.0 Hz, 1H), 6.60–6.53 (m, 3H), 6.08 (dd,
J¼6.7, 2.1 Hz, 1H), 5.97 (d, J¼7.7 Hz, 1H), 5.01
(d, J¼15.8 Hz, 1H), 4.28 (d, J¼15.8 Hz, 1H), 3.68–3.60
(m, 2H), 3.58–3.50 (m, 2H), 3.35–3.25 (m, 2H), 2.97–2.93
(m, 2H), 2.66 (s, 3H), 1.98–1.80 (m, 2H); 13C NMR
(125 MHz, C6D6)‡‡ d 179.1, 178.9, 144.4, 143.9, 136.7,
129.2, 128.7, 128.6, 128.5, 128.2, 127.9, 124.8, 124.4,
122.2, 121.9, 109.3, 108.0, 60.0, 59.9, 55.2, 55.1, 44.6, 33.3,
33.1, 26.0; IR (film) 3397, 2949, 2883, 1687, 1610, 1490,
1467, 1378, 1050, 926 cm21; HRMS (EI) m/z calcd for
C28H28N2O4 (Mþ) 456.2049, found 456.2045.
1
Data for hexacycle B. H NMR (400 MHz, C6D6) d 7.57
(d, J¼7.4 Hz, 1H), 6.92 (d, J¼7.2 Hz, 1H), 6.86
(t, J¼7.6 Hz, 2H), 6.81 (dt, J¼7.7, 1.1 Hz, 1H), 6.74
(dt, J¼7.7, 1.2 Hz, 1H), 6.67 (dt, J¼7.6, 1.2 Hz, 1H), 6.29
(dt, J¼7.6, 1.0 Hz, 1H), 6.15–6.10 (m, 3H), 6.061
(d, J¼7.6 Hz, 1H), 6.059 (d, J¼7.6 Hz, 1H), 5.73 (ddd,
J¼13.8, 9.3, 4.6 Hz, 1H), 4.79 (d, J¼16.4 Hz, 1H), 4.53
(ddd, J¼13.4, 9.3, 4.1 Hz, 1H), 3.74 (t, J¼6.4 Hz, 1H), 3.71
(d, J¼16.4 Hz, 1H), 2.79 (s, 3H), 2.56 (t, J¼12.5 Hz, 1H),
2.14 (dd, J¼13.0, 4.6 Hz, 1H), 1.96 (dd, J¼11.8, 4.1 Hz,
1H), 1.57 (s, 3H), 1.56 (s, 3H); 13C NMR (125 MHz, C6D6)
d 176.4, 175.5, 145.1, 143.5, 135.8, 131.4, 129.2, 129.13,
129.08, 127.44, 127.39, 126.6, 125.3, 122.0, 121.6, 110.4,
110.3, 108.1, 76.0, 74.0, 56.23, 52.6, 43.5, 34.9, 33.4, 28.0,
27.7, 26.4; IR (film) 2934, 1710, 1610, 1471, 1351,
1077 cm21; HRMS (ESI) m/z calcd for C31H30N2O4
(MþNa) 517.2103, found 517.2090.
4.1.9. 5-Benzyl-(5aR,6aR,11bS,11cS)-bis(2-azidoethyl)-
7-methyl-5,5a,6a,7-tetrahydrofuro[2,3-b:5,4-b0]diindole
(30). A THF solution of diol 28 (50 mL, 0.18 M) was
transferred to a sealed tube and the solution was sparged
with N2 for 30 min. A toluene solution of Red-Alw (30 mL,
65 wt%) was added to the sealed tube slowly by syringe to
avoid vigorous H2 evolution. After the addition was
complete, the tube was sealed and the solution heated at
678C. After 1.5 h, the solution was allowed to cool to rt and
then added slowly to a swirling saturated aqueous solution
of NaF (500 mL) at 08C. The layers were separated and the
aqueous layer was extracted with EtOAc (3£100 mL). The
combined organic layers were washed with brine (20 mL),
dried (MgSO4), filtered, and concentrated in vacuo. The
residue was azeotroped with benzene (2£50 mL). The
resulting unstable pentacyclic diol 29 was used directly in
the Mitsunobu reaction.
4.1.8. 10-Benzyl-3,30-bis-(2-hydroxyethyl)-1-methyl-
1,10,3,30-tetrahydro-[3S,30S]biindolyl-2,20-dione (28). Cam-
phorsulfonic acid (0.244 g, 1.05 mmol) was added to a
solution of 10 (5.21 g, 10.5 mmol), MeOH (50 mL), and
CH2Cl2 (50 mL) at rt. After 3 h, the solvent was removed in
vacuo and the residue was purified on silica gel (1:1 EtOAc–
hexanes–9:1 EtOAc–hexanes) to yield 4.67 g (98%) of the
corresponding vicinal diol as a colorless foam: [a] ¼2665,
26
405
[a] ¼2507, [a] ¼2254, [a] ¼2219, [a]2D6¼2208
26
435
26
546
26
577
(c 0.79, MeOH); 1H NMR (500 MHz, C6D6) d 7.32
(d, J¼1.5 Hz, 1H), 7.28 (d, J¼7.5 Hz, 1H), 7.00–6.96 (m,
5H), 6.69 (dt, J¼7.7, 1.1 Hz, 1H) 6.55 (m, 3H), 6.01
(d, J¼7.2 Hz, 1H), 5.87 (d, J¼7.7 Hz, 1H), 5.02–4.98
(m, 2H), 4.61 (d, J¼15.7 Hz, 1H), 4.39 (d, J¼15.7 Hz, 1H),
3.33–3.28 (m, 2H), 2.58 (s, 3H), 2.45–2.02 (br s, 2H),
1.93–1.85 (m, 2H); 13C NMR (125 MHz, C6D6)‡‡ d 178.1,
177.9, 143.7, 143.1, 136.6, 130.2, 130.1, 129.2, 128.9,
128.7, 127.8, 125.0, 124.7, 122.9, 122.8, 109.2, 108.1, 70.9,
70.8, 53.4, 53.0, 44.0, 36.9, 36.3, 25.9; IR (film) 3428, 2936,
1695, 1610, 1490, 1467, 1378, 1050, 752, 698 cm21; HRMS
(EI) m/z calcd for C28H26N2O4 (Mþ) 454.1893, found
454.1888.
A solution of this crude pentacyclic diol 29 and PPh3
(22.2 g, 84.5 mmol) in THF (75 mL) was cooled to 08C and
a toluene solution of HN3 (56.0 mL, 1.56 M) was added by
syringe. To this solution, diethyl azodicarboxylate
(14.0 mL, 88.9 mmol) was added using a syringe pump at
a rate of 0.16 mL/min. The resulting solution was allowed to
warm to rt where it was maintained for 30 min before being
quenched by the addition of silica gel (5 g). The residual
solvent was removed in vacuo and the resulting residue was
purified on silica gel (10:1 petroleum ether–EtOAc) to
1
provide 3.27 g (75%) of 30 as a colorless oil: H NMR
(500 MHz, C6D6) d 7.17 (d, J¼7.1 Hz, 2H), 7.10 (s, 1H),
7.09–7.01 (m, 3H), 6.97 (dt, J¼7.8, 1.2 Hz, 1H), 6.80
(dt, J¼6.9, 0.8 Hz, 2H), 6.68 (ddd, J¼10.2, 7.5, 7.5 Hz, 2H),
6.29 (d, J¼7.8 Hz, 1H), 6.2 (d, J¼7.8 Hz, 1H), 4.74 (s, 1H),
4.63 (s, 1H), 4.23 (s, 2H), 2.54 (s, 3H), 2.50–2.44 (m, 4H),
1.20–1.84 (m, 2H), 1.71 (ddd, J¼13.6, 9.1, 7.0 Hz, 1H),
1.65 (ddd, J¼13.3, 9.4, 6.6 Hz, 1H); 13C NMR (125 MHz,
C6D6)‡‡ d 151.2, 150.7, 138.8, 129.7, 129.6, 129.2, 129.0,
127.9, 126.5, 126.3, 118.7, 118.6, 108.1, 107.8, 103.0,
101.7, 61.4, 61.3, 50.0, 48.6, 48.5, 35.8, 35.6, 31.6; IR (film)
Sodium periodate (22.0 g, 102 mmol) was added to a
solution of the vicinal diol (4.67 g, 10.3 mmol), H2O
(65 mL) and THF (65 mL) at rt. After 12 h, saturated
aqueous NH4Cl (100 mL) was added and the phases were
separated. The aqueous layer was extracted with EtOAc
(3£25 mL) and the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The resulting
residue was dissolved in MeOH (100 mL) and treated
3053, 2926, 2088, 1702, 1602, 1486, 1355, 1258 cm21
;

L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
6915
HRMS (FAB) m/z calcd for C28H28N8O (Mþ) 492.2386,
found 492.2375. Anal. calcd for C28H28N8O: C, 68.27;
H, 5.73; N, 22.75. Found: C, 68.08; H, 5.84; N, 22.37.
A two-neck flask fitted with a liquid NH3 condenser was
charged with sodium metal (0.93 g, 40.6 mmol) under a
positive flow of N2. The reaction flask and condenser were
cooled to 2788C. A separate three-neck flask with an
attached bubbler was cooled to 2788C and NH3 (50 mL) was
condensed directly from the tank into this flask. The NH3 was
redistilled from the 3-neck flask into the reaction vessel
through a cannula to create a dark blue solution.0 A THF
solution of 80-b0enzyl-1,8,10-trimethyl-2,3,8,8aR,20,3 ,80,80aR-
octahydro-1H,1 H-[3aS,30aS]bipyrrolo[2,3-b]indole (40 mL,
0.10 M) was added to this dark blue solution. Following
complete addition, MeOH (5 mL) was added immediately at
2788C and the mixture became clear. This solution was
allowed to warm slowly to rt allowing NH3 to evaporate.
The resulting THF solution was partitioned between EtOAc
(30 mL) and saturated aqueous NH4Cl (40 mL). The layers
were separated and the aqueous layer was extracted with
EtOAc (2£30 mL) and CHCl3 (saturated with NH3)
(3£30 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The residue
was azeotroped with benzene (2£50 mL) to yield 1.46 g
(100%) of 32 as a colorless foam, which was of sufficient
purity for further use. A comparable sample was purified on
silica gel (10:1:0.01 CH2Cl2–MeOH–NH4OH) for charac-
4.1.10. 1,8,10-Trimethyl-2,3,8,8aR,20,30,80,80aS-octa-
hydro-1H,10H-[3aS,30aS]bipyrrolo[2,3-b]indole (32). Tet-
rahydrofuran (70 mL) and H2O (1 mL) were added to a flask
containing 30 (3.51 g, 7.13 mmol) at rt. To this solution,
PPh3 (4.67 g, 17.8 mmol) was added. After 12 h, the
solution was concentrated in vacuo and azeotroped with
benzene (2£50 mL). The residue was taken up in MeOH
(50 mL), transferred to a sealed tube and heated at 1108C for
12 h. The solution was concentrated in vacuo and purified
on silica gel (10:1 CH2Cl2–MeOH) to yield 2.32 g (77%)
of 80-benzyl-8-methyl-2,3,8,8aR,20,30,80,80aR-octahydro-1H-
10H-[3aS,30aS]bipyrrolo[2,3-b]indole as a colorless foam:
27
27
27
27
[a] ¼2887, [a] ¼2601, [a] ¼2241, [a] ¼2200,
405
435
546
577
[a]2D7¼2189 (c 0.84, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 7.30–7.23 (m, 6H), 7.17 (d, J¼7.3 Hz, 1H), 7.07 (ddd,
J¼15.4, 7.7, 7.7 Hz, 1H), 7.03 (ddd, J¼15.4, 7.7, 7.7 Hz,
1H), 6.58 (ddd, J¼13.9, 7.4, 7.1 Hz, 2H), 6.26 (d, J¼7.9 Hz,
2H), 4.50 (s, 1H), 4.45 (d, J¼16.2 Hz, 1H), 4.43 (s, 1H),
4.35 (d, J¼16.2 Hz, 1H), 3.05–2.95 (m, 2H), 2.78 (s, 3H),
2.57–2.43 (m, 4H), 2.27–2.15 (m, 2H); 13C NMR
(100 MHz, CDCl3)‡‡ d 153.0, 152.1, 139.0, 131.2, 131.1,
128.6, 128.5, 128.4, 127.1, 126.8, 124.3, 124.2, 116.3,
116.1, 105.0, 104.8, 87.3, 85.9, 62.1, 62.0, 48.0, 45.9, 45.8,
39.3, 38.8, 30.8; IR (film) 3331, 3049, 2937, 1602, 1490,
1351, 1158, 1027, 733 cm21; HRMS (ESI) m/z calcd for
C28H30N4 (MþNa) 423.2549, found 423.2537.
1
terization: H NMR (500 MHz, (CD3)2SO, 373 K) d 7.08
(dd, J¼7.4, 0.8 Hz, 1H), 6.99 (d, J¼7.4 Hz, 1H), 6.92 (dt,
J¼7.7, 1.2 Hz, 1H), 6.84 (dt, J¼7.6, 1.2 Hz, 1H), 6.49–6.41
(m, 2H and d, J¼7.8 Hz, 1H), 6.28 (d, J¼7.8 Hz, 1H), 5.83
(br s, 1H), 4.55 (s, 1H), 4.45 (s, 1H), 2.96 (s, 3H), 2.68–2.59
(m, 2H), 2.51–2.42 (m, 3H), 2.40–2.36 (m, 1H and s, 3H),
2.33 (s, 3H), 2.0–1.86 (m, 2H); 13C NMR (125 MHz,
(CD3)2SO, 373 K)‡‡ d 152.3, 151.2, 132.4, 127.0, 126.7,
123.1, 122.7, 115.9, 115.7, 107.2, 104.9, 91.1, 84.0, 62.1,
62.0, 51.3, 51.2, 36.9, 35.6, 34.9, 34.6, 34.4; IR (film) 3385,
An aqueous solution of formaldehyde (3.2 mL, 42.5 mmol,
37%, wt/wt) was added to a flask containing this product
(1.80 g, 4.25 mmol) and MeOH (50 mL). The solution
turned opaque white and NaBH(OAc)3 (9.00 g, 42.5 mmol)
was added. After 10 min, the solution was partitioned
between saturated aqueous NaHCO3 (100 mL) and EtOAc
(75 mL). The layers were separated and the aqueous layer
was extracted with EtOAc (2£50 mL) and CHCl3 (saturated
with NH3) (3£20 mL). The combined organic extracts were
dried (MgSO4), filtered, and concentrated in vacuo. The
residue was azeotroped with benzene (2£50 mL) then
heptane (2£25 mL) to yield 1.83 g (95%) of 80-benzyl-
1,8,10-trimethyl-2,3,8,8aR,20,30,80,80aR-octahydro-1H,10H-
[3aS,30aS]bipyrrolo[2,3-b]indole as a colorless foam, which
was of sufficient purity for further use. A comparable
sample was purified on silica gel (10:1 CH2Cl2–MeOH) for
2934, 2791, 1602, 1490, 1251, 1154, 1023, 733 cm21
;
HRMS (CI) m/z calcd for C23H28N4 (Mþ) 360.2314, found
360.2314.
4.1.11. 1,10,80-Trimethyl-1,2,3,8aR,20,30,80,80aR-octahy-
dro-10H-[3aS,30aS]bi[pyrrolo[2,3-b]indolyl]-8-carboxylic
acid tert-butyl ester (9). A THF solution of di-tert-butyl
dicarbonate (Boc2O, 8.8 mL, 0.56 M) was added to a
solution of 32 (1.48 g, 4.12 mmol) and THF (100 mL) at
2788C. To this solution, NaHMDS (15 mL, 1.0 M in THF)
was added using a syringe pump at a rate of 0.16 mL/min.
The resulting solution was maintained at 2788C and
carefully monitored by TLC. Upon complete consumption
of starting material, NaHCO3 (5 mL) was added imme-
diately by syringe at 2788C. The solution was allowed to
warm to rt and was then partitioned between saturated
aqueous NH4Cl (50 mL) and EtOAc (30 mL). The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (2£10 mL), and CHCl3 (saturated with NH3)
(1£20 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The residue
was purified on silica gel using gradient elution (10:1
1
characterization: H NMR (500 MHz, (CD3)2SO, 353 K) d
7.42–7.36 (m, 4H), 7.29 (t, J¼6.9 Hz, 1H), 7.06 (d,
J¼7.2 Hz, 1H), 7.01 (d, J¼7.3 Hz, 1H), 6.95 (dt, J¼6.7,
1.1 Hz, 1H), 6.88 (dt, J¼6.8, 1.1 Hz, 1H), 6.55–6.47 (dd,
J¼7.4, 7.4 Hz, 1H and dd, J¼7.4, 7.4 Hz, 1H), 6.29 (d,
J¼7.8 Hz, 1H), 6.20 (d, J¼7.8 Hz, 1H), 4.57 (d, J¼16.3 Hz,
1H), 4.50 (s, 1H), 4.44 (d, J¼16.3 Hz, 1H), 4.39 (s, 1H),
2.95 (s, 3H), 2.68–2.60 (m, 2H), 2.57–2.45 (m, 3H), 2.41–
2.35 (m, 1H and s, 3H), 2.23 (s, 3H), 2.01–1.90 (m, 2H); 13C
NMR (125 MHz, (CD3)2SO, 353 K)‡‡ d 152.2, 151.6, 138.8,
132.3, 132.2, 127.7, 127.3, 127.1, 126.8, 126.1, 123.1,
123.0, 116.1, 115.8, 105.4, 104.9, 91.4, 91.3, 62.2, 61.9,
51.8, 51.7, 51.1, 38.6, 37.6, 34.7, 34.6, 33.9; IR (film) 3049,
CH2Cl2–MeOH–10:1:0.01 CH2Cl2–MeOH–NH4OH) to
yield 1.41 g (74%) of 9 as a colorless oil: [a] ¼2685,
27
405
[a] ¼2505, [a] ¼2242, [a] ¼2206, [a]2D7¼2198
27
435
27
546
27
577
(c 0.55, CH2Cl2); 1H NMR (500 MHz, (CD3)2SO, 353 K) d
7.44 (d, J¼7.9 Hz, 1H), 7.24 (d, J¼7.6 Hz, 1H), 7.07 (dt,
J¼8.3, 1.2 Hz, 1H), 6.94–6.88 (m, 3H), 6.42 (t, J¼7.3 Hz,
1H), 6.24 (d, J¼7.7 Hz, 1H), 5.09 (s, 1H), 4.35 (s, 1H), 2.91
2930, 2795, 1602, 1490, 1351, 1258, 1158, 1027 cm21
;
HRMS (ESI) m/z calcd for C30H34N4 (MþH) 451.2862,
found 451.2869.

6916
L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
(s, 3H), 2.66–2.61 (m, 2H), 2.50–2.38 (m, 4H), 2.39 (s, 3H),
2.37 (s, 3H), 2.09–1.99 (m, 2H), 1.59 (s, 9H); 13C NMR
(125 MHz, (CD3)2SO, 353 K) d 151.6, 151.5, 142.4, 135.2,
131.4, 127.6, 127.1, 123.5, 122.1, 121.8, 115.9, 114.6,
105.1, 90.9, 84.9, 80.1, 61.5, 60.4, 52.1, 51.7, 37.3, 36.8,
34.4, 33.9, 33.2, 27.6; IR (film) 2934, 2795, 1698, 1602,
1482, 1251, 1162, 1023, 745 cm21; HRMS (ESI) m/z calcd
for C28H36N4O2 (MþHþ) 461.2917, found 461.2917.
(film) 3397, 2930, 2791, 1602, 1494, 1471, 1351, 1251,
1158, 1023 cm21; HRMS (ESI) m/z calcd for C23H27IN4
(MþNaþ) 509.1178, found 509.1163.
4.1.13. Trifluoromethanesulfonic acid 2-(methyl{4-
[methyl(toluene-4-sulfonyl)amino]but-2-ynonyl}amino)-
phenyl ester (36). Diisopropylethylamine (5.0 mL,
28.7 mmol) and trimethylsilyl trifluoromethanesulfonate
(TMSOTf) (5.0 mL, 26.1 mmol) were added sequentially
to an Et2O solution of N-methylpropargylamine (75 mL,
0.35 M) at 08C. A colorless precipitate formed immediately
upon addition of TMSOTf. This mixture was maintained at
08C for 10 min, then warmed to rt. The reaction mixture
then was filtered through a Schlenk filter to give a clear
yellow solution. This solution was cooled to 2788C and a
hexane solution of n-BuLi (12.5 mL, 2.6 M) was added.
After 10 min, 3-methylbenzoxazolinone (34) (3.89 g,
26.1 mmol) was added as a solid with positive N2 flow
followed by THF (30 mL). The solution was warmed to
2208C and maintained at this temperature for 2 h at which
time N-phenylbis(trifluoromethanesulfonimide) (9.32 g,
26.1 mmol) was added as a solid under positive N2 flow.
The solution was warmed to 2108C and after 30 min at
2108C, tosyl chloride (4.98 g, 26.1 mmol) and silica gel
(3 g) were added. This mixture was stirred and allowed to
warm to rt. After 6 h at rt, additional silica gel was added
and the mixture was concentrated in vacuo, loaded onto a
silica gel column, and purified using gradient elution (3:1
hexanes–EtOAc–1:2 hexanes–EtOAc) to yield 4.66 g
4.1.12. 7-Iodo-1,10,80-trimethyl-2,3,8,8aS,20308080aR-octa-
hydro-1H,10H-[3aS,30aS]bipyrrolo[2,3-b]indole (7).
A
pentane solution of s-BuLi (2.1 mL, 1.2 M) was added
dropwise to a solution of 9 (0.392 g, 0.851 mmol), TMEDA
(0.40 mL, 2.6 mmol), and Et2O (10 mL) at 2788C. The
solution was maintained at 2788C for 45 min, at which time
an Et2O solution of diiodoethane (8.1 mL, 1.05 M) was
added by syringe. Upon complete addition of diiodoethane,
the solution was warmed to 08C where it was maintained for
20 min and then allowed to warm to rt. The solution was
partitioned between saturated aqueous Na2S2O4 (20 mL)
and CH2Cl2 (20 mL). The phases were separated and the
aqueous layer was extracted with CH2Cl2 (3£20 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified on silica gel
using gradient elution (10:1 CH2Cl2–MeOH–10:1:0.01
CH2Cl2–MeOH–NH4OH) to yield 0.455 g (90%) of the
tert-butoxycarbonyl protected bispyrrolidinoindoline mono-
1
iodide as a colorless foam: H NMR (500 MHz, CDCl3) d
7.62 (d, J¼7.8 Hz, 1H), 7.16 (d, J¼7.1 Hz, 1H), 7.06
(t, J¼7.5 Hz, 1H), 6.98 (d, J¼7.1 Hz, 1H), 6.73 (t, J¼7.7 Hz,
1H), 6.59 (t, J¼7.4 Hz, 1H), 6.33 (d, J¼7.8 Hz, 1H), 5.14
(br s, 1H), 4.38 (br s, 1H), 2.99 (s, 3H), 2.70–2.61 (m, 2H),
2.54–2.47 (m, 1H and s, 3H), 2.43 (s, 3H), 2.36–2.29
(m, 1H), 2.27–2.21 (m, 2H), 2.07–2.01 (m, 1H), 1.87–1.81
1
(41%) of 36 as a yellow oil: H NMR (500 MHz, CDCl3)
a mixture of rotamers, only major peaks are listed d 7.75
(d, J¼8.3 Hz, 2H), 7.47 (dt, J¼7.6, 1.8 Hz, 1H), 7.44–7.40
(m, 2H), 7.37 (dd, J¼8.0, 1.5 Hz, 1H), 7.32 (d, J¼8.0 Hz,
2H), 7.28 (dd, J¼6.0, 1.6 Hz, 1H), 3.99 (d, J¼18.1 Hz, 1H),
3.77 (d, J¼18.1 Hz, 1H), 2.45 (s, 3H), 2.44 (s, 3H), 2.38
(s, 3H); 13C NMR (125 MHz, CDCl3) a mixture of rotamers,
only major peaks are listed d 152.8, 145.2, 144.0, 135.42,
130.6, 130.3, 129.7, 129.3, 127.6, 122.6, 117.1, 84.8,
78.3, 39.6, 35.7, 33.9, 21.4; IR (film) 3069, 2247, 1659,
1498, 1351, 1212, 1162, 1139 cm21; HRMS (ESI) m/z
calcd for C20H19F3N2O6S2 (MþNaþ) 527.0534, found
527.0540.
(m, 1H), 1.59 (s, 9H); 13C NMR (125 MHz, CDCl3)‡‡
d
152.4, 146.5, 139.8, 139.1, 131.9, 128.6, 125.6, 124.5,
123.9, 117.0, 106.0, 92.2, 88.0, 84.8, 81.6, 62.6, 61.8, 52.9,
52.3, 38.8, 36.6, 35.3, 34.5, 28.3; IR (film) 2934, 2798,
1718, 1606, 1494, 1444, 1351, 1247, 1158, 1046,
1023 cm21; HRMS (ESI) m/z calcd for C28H35IN4O2
(MþNaþ) 609.1702, found 609.1705.
A CH2Cl2 (25 mL) solution of this crude product (1.23 g,
2.1 mmol) was treated with TMSOTf (1.2 mL, 6.3 mmol) at
rt. The flask was left open to the atmosphere and a drop of
H2O (,0.01 mL) was added. After 10 min the solution
turned pink and was partitioned between saturated aqueous
NaHCO3 (20 mL) and CH2Cl2 (15 mL). The phases were
separated and the aqueous phase was extracted with EtOAc
(3£10 mL) and CHCl3 (saturated with NH3) (1£15 mL).
The combined organic layers were dried (MgSO4), filtered,
and concentrated in vacuo. The residue was purified on
silica gel with gradient elution (20:1:0–10:1:0.01 CH2Cl2–
MeOH–Et3N) to yield 0.96 g (94%) of 7 as a colorless
4.1.14. Trifluoromethanesulfonic acid 2-(benzyl{4-
[methyl(toluene-4-sulfonyl)amino]but-2-ynonyl}amino)-
phenyl ester (37). Following the procedure used to prepare
36, N-methylpropargyl amine (150 mL, 0.33 M) and
3-benzylbenzoxazolinone25 (11.1 g, 49.3 mmol) were ela-
borated to give a crude product which was purified using
gradient elution (5:1 hexanes–EtOAc–1:3 hexanes–
EtOAc) to yield 11.3 g (40%) of 37 as a yellow oil. Spectral
data for 37 was identical to that previously published.9
4.1.15. Trifluoromethanesulfonic acid 2-{methyl[4-
[methyl(toluene-4-sulfonyl)amine]-2-(tributylstannyl)-
but-2E-enoyl]amino}phenyl ester (8). Degassed (sparged
with Ar for 1 h) THF (80 mL) was added to a flask charged
with 36 (4.66 g, 9.24 mmol) and the solution was cooled to
08C. Under a positive Ar flow, Pd(PPh3)4 (0.39 g,
0.37 mmol) was added to this solution. A THF solution of
Bu3SnH (10.0 mL, 0.93 M) then was added dropwise at 08C
over 20 min using a syringe pump. After 2 h, the solution
was concentrated and the residue was purified on silica gel
1
foam: H NMR (500 MHz, (CD3)2SO, 383 K) d 7.24 (d,
J¼7.8 Hz, 1H), 7.10 (d, J¼7.4 Hz, 1H), 7.01 (d, J¼7.2 Hz,
1H), 6.95 (t, J¼8.5 Hz, 1H), 6.50 (t, J¼7.6 Hz, 1H), 6.34–
6.28 (m, 2H), 5.67 (s, 1H), 4.81 (br s, 1H), 4.62 (br s, 1H),
3.00 (s, 3H), 2.92–2.84 (m, 2H), 2.82–2.73 (m, 2H), 2.51–
2.46 (m, 2H and s, 3H), 2.43 (s, 3H), 2.02–1.94 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 152.9, 152.3, 136.2, 133.2,
132.3, 128.3, 124.2, 123.5, 119.5, 116.9, 111.0, 106.0, 91.9,
83.6, 74.5, 65.3, 62.9, 52.4, 52.3, 37.6, 36.6, 35.6, 34.5; IR

L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
6917
using gradient elution (3:1 hexanes–EtOAc–2:1 hexanes–
1
EtOAc) to yield 6.44 g (88%) of 8 as a colorless oil: H
with Ar for 15 min until the solution was a deep red color.
The reaction vessel was sealed and heated at 808C for 18 h
at which time it was allowed to cool to rt and partitioned
between saturated aqueous NaCN (10 mL) and EtOAc
(15 mL). The layers were separated and the aqueous layer
was extracted with EtOAc (2£10 mL) and CH2Cl2
(2£10 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The residue
was purified on silica gel using gradient elution (10:1
CH2Cl2–MeOH–10:1:0.05 CH2Cl2–MeOH–NH4OH) to
yield 0.130 g (97%) of 5 and 39 as a 6:1 mixture of epimers
(determined by analytical HPLC: Zorbax Extend-C18,
5 mm, 250£4.6 mm, 70:30 MeCN–H2O (1% NH4OH),
1 mL/min, UV detection at 254 nm). For characterization of
5, a comparable sample was purified by reverse-phase
HPLC: Zorbax Extend-C18, 5 mm, 150£21.2 mm, 70:30
CH3CN–H2O (1% NH4OH), 16 mL/min, UV detection at
NMR (500 MHz, CDCl3) a ,1:1 mixture of rotamers, only
major peaks are listed d 7.71 (dd, J¼8.2, 6.6 Hz), 7.46–7.33
(m), 7.30–7.27 (m), 5.74 (ddd, JSn–H¼21.5 Hz, J¼6.5,
6.5 Hz), 3.86 (m,), 3.29 (s), 3.28 (s), 2.76 (s), 2.73 (s), 2.46
(s), 2.45 (s), 1.81 (s), 1.65–1.51 (m), 1.40 (t, J¼7.3 Hz),
1.35 (t, J¼7.3 Hz,), 1.28 (t, J¼7.3 Hz), 1.24 (t, J¼7.3 Hz),
1.10 (tt, JSn–H¼26.2 Hz, J¼8.3 Hz), 0.94 (t, J¼7.3 Hz),
0.89 (t, J¼7.3 Hz); 13C NMR (125 MHz, CDCl3) a ,1:1
mixture of rotamers, only major peaks are listed d 172.6,
172.3, 145.7, 143.2, 136.6, 134.6, 129.6, 127.4, 121.9,
119.6, 117.1, 53.4, 50.9, 38.4, 34.6, 34.4, 28.7 (t), 28.5 (t),
27.1 (d), 21.3, 13.5, 10.7 (d); IR (film) 2926, 1640, 1602,
1424, 1212, 1162 cm21; HRMS (ESI) m/z calcd for
C32H47F3N2O6SnS2 (MþHþ) 797.1932, found 797.1923,
calcd for (MþNaþ) 819.1751, found 819.1761.
27
27
27
254 nm) [a] ¼2472, [a] ¼2353, [a] ¼2165,
405
435
546
27
577
4.1.16. E-Butenanilide 6. A solution of Pd2(dba)3·CHCl3
(21 mg, 0.020 mmol), P(2-furyl)3 (19 mg, 0.08 mmol) and
N-methylpyrrolidinone (NMP) (1 mL) was charged to a
base-washed, sealable reaction flask and sparged with Ar for
1 h. In a separate flask, a solution of 7 (97 mg, 0.200 mmol),
8 (0.237 g, 0.298 mmol) and NMP (1 mL) was sparged with
Ar for 1 h and then transferred to the catalyst solution. The
resulting dark green solution was degassed using the freeze-
pump-thaw technique (3£, 2788C cooling bath, 0.05 mm).
Copper (I) iodide (39 mg, 0.20 mmol) was added in one
portion under positive Ar flow and the flask was sealed. The
solution was maintained at rt for 36 h at which time it was
partitioned between an aqueous solution of NH4OH (10 mL,
5% in H2O) and EtOAc (15 mL). The layers were separated
and the aqueous layer was extracted with EtOAc (2£5 mL)
and CH2Cl2 (2£10 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo.
The residue was purified on silica gel using gradient elution
(10:1 CH2Cl2–MeOH–10:1:0.5 CH2Cl2–MeOH–NH4OH)
[a] ¼2141, [a]2D7¼2133 (c 0.64, MeOH); 1H NMR
(500 MHz, (CD3)2SO, 360 K) d 7.52 (d, J¼8.3 Hz, 2H),
7.46 (ddd, J¼7.7, 7.7, 1.3 Hz, 1H), 7.43 (d, J¼8.0 Hz, 2H),
7.21 (t, J¼7.5 Hz, 1H), 7.17 (d, J¼7.9 Hz, 1H), 7.01 (d,
J¼7.9 Hz, 1H), 6.91 (d, J¼7.6 Hz, 1H), 6.87 (t, J¼7.6 Hz,
1H), 6.74 (br d, J¼7.2 Hz, 1H), 6.66 (d, J¼7.2 Hz, 1H), 6.60
(d, J¼14.3 Hz, 1H), 6.45 (t, J¼7.6 Hz, 1H), 6.34 (t,
J¼7.4 Hz, 1H), 6.22 (d, J¼7.8 Hz, 1H), 5.37 (d,
J¼14.3 Hz, 1H), 4.45 (br s, 1H), 4.35 (br s,1H), 4.19 (br
d, J¼3.6 Hz, 1H), 3.24 (s, 3H), 2.91 (s, 3H), 2.89 (s, 3H),
2.60–2.52 (m, 2H), 2.44 (s, 3H), 2.42–2.36 (m, 2H), 2.35
(s, 3H), 2.32–2.26 (m, 1H), 2.22–2.17 (m, 1H), 2.15 (s,
3H), 1.89–1.85 (m, 1H), 1.80 (ddd, J¼11.8, 5.6, 2.4 Hz,
1H); 13C NMR (125 MHz, (CD3)2SO, 360 K) d 176.0,
152.3, 149.1, 143.5, 142.4, 134.8, 133.6, 132.6, 130.0,
129.41, 129.38, 128.1, 126.9, 126.1, 125.7, 124.3, 122.5,
122.1, 122.0, 120.0, 117.2, 115.9, 110.1, 108.5, 104.9, 91.0,
82.8, 61.96, 61.92, 55.5, 51.1, 50.7, 36.9, 34.7, 34.63, 34.59,
31.8, 25.7, 20.4 (one 13C signal is apparently overlapping with
another at this field strength); IR (film) 3385, 2930, 1702,
1602, 1459, 1351, 1254, 1158 cm21; HRMS (ESI) m/z calcd
for C42H46N6O3S (MþHþ) 715.3430, found 715.3421.
1
to yield 0.162 g (94%) of 6 as a colorless foam: H NMR
(500 MHz, CD2Cl2, 200 K) a mixture of rotamers,§§ only
major peaks are listed d 7.59 (t, J¼9.7 Hz, 2H), 7.37
(t, J¼9.3 Hz, 2H), 6.28 (d, J¼7.6 Hz, 0.5H), 6.12
(d, J¼7.7 Hz, 0.5H), 5.86 (t, J¼7.6 Hz, 0.3H), 5.62
(d, J¼7.4 Hz, 0.3H), 4.85 (br s, 1H), 4.77 (br s, 1H), 4.67
(br s, 0.5H), 4.61 (br s, 0.5H), 3.21 (s, 1.3H), 3.07 (s, 2H),
2.95 (s, 2H), 2.91 (s, 1H), 2.58 (s, 1H), 2.54 (s, 2H), 2.45–
2.38 (m, 9H), 2.31 (s, 2H); 13C NMR (125 MHz, CD2Cl2) a
mixture of rotamers, only major peaks are listed d 169.4,
147.1, 144.7, 143.9, 134.5, 131.2, 129.6, 127.4, 121.9,
117.2,110.8, 110.8, 105.5, 90.5 (br), 84.5 (br), 62.1, 49.0,
36.9, 34.6, 21.4; IR (film) 3416, 2937, 1648, 1602, 1498,
1216, 1162, 1139 cm21; HRMS (ESI) m/z calcd for
C43H47F3N6O6S2 (MþHþ) 887.2849, found 887.2876.
4.1.18. Heck cyclization of 6 with (R)-tol-BINAP to form
3a00S-enamine 39. Following the procedure employed to
cyclize 6 with (S)-tol-BINAP, 6 (0.117 g, 0.136 mmol),
Pd(OAc)2 (3 mg, 0.014 mmol), and (R)-tol-BINAP (18 mg,
0.027 mmol) yielded 96 mg (99%) of 39 and 5 as an 18:1
mixture of epimers as determined by 1H NMR. For
characterization of 39, a comparable sample was purified
by reverse-phase HPLC: Zorbax Extend-C18, 5 mm,
150£21.2 mm, 70:30 CH3CN–H2O (1% NH4OH), 16 mL/
27
27
min, UV detection at 254 nm) [a] ¼2587, [a] ¼2438,
405
435
[a] ¼2203, [a] ¼2174, [a]2D7¼2165 (c 0.51,
27
546
27
577
1
CH2Cl2); H NMR (500 MHz, (CD3)2SO, 360 K) d 7.57
(d, J¼8.3 Hz, 2H), 7.45 (d, J¼7.9 Hz, 2H), 7.43–7.38 (m,
2H), 7.20–7.13 (m, 3H), 7.05 (d, J¼7.2 Hz, 1H), 6.93 (t,
J¼7.5 Hz, 1H), 6.64 (d, J¼14.3 Hz, 1H), 6.62 (d, J¼6.8 Hz,
1H), 6.48 (t, J¼7.5 Hz, 2H), 6.30 (d, J¼7.7 Hz, 1H), 5.35
(d, J¼14.3 Hz, 1H), 4.90 (s, 1H), 4.27 (s, 1H), 4.16 (s, 1H),
3.25 (s, 3H), 2.93 (s, 3H), 2.92 (s, 3H), 2.44 (s, 3H), 2.43–
2.38 (m, 4H), 2.35–2.31 (m, 1H), 2.30 (s, 3H), 2.24–2.19
(m, 1H), 1.95 (s, 3H), 1.90–1.84 (m, 2H); 13C NMR
(125 MHz, (CD3)2SO, 360 K) d 176.1, 152.3, 149.0, 143.6,
142.3, 134.7, 133.6, 132.4, 130.6, 129.4, 128.0, 127.2,
4.1.17. Heck cyclization of 6 with (S)-tol-BINAP to form
3a00R-enamine 5. A sealed tube was charged with 6
(0.162 g, 0.188 mmol), Pd(OAc)2 (4 mg, 0.019 mmol),
(S)-tol-BINAP (26 mg, 0.038 mmol), MeCN (2 mL, pre-
viously sparged with Ar for 3 h) and 1,2,2,6,6-pentamethyl-
piperidine (0.14 mL, 0.75 mmol). This solution was sparged
§§
Attempts to resolve peaks in the 1H NMR at high temperature led to
extensive decomposition, low temperature 1H and 13C were performed to
decrease the rate of conformer interconversion.

6918
L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
126.1, 125.8, 124.3, 123.1, 123.0, 122.9, 122.0, 119.2,
116.9, 115.9, 110.3, 108.5, 105.1, 91.0, 84.0, 61.6, 55.8,
51.4, 51.3, 37.0, 35.4, 34.8, 34.5, 31.8, 25.8, 20.4 (two 13C
signals are apparently overlapping with others at this field
strength); IR (film) 3385, 2930, 1702, 1602, 1459, 1351,
1254, 1158 cm21; HRMS (ESI) m/z calcd for C42H46N6O3S
(MþHþ) 715.3430, found 715.3428.
a cannula to create a dark blue solution. The THF solution of
the crude Red-Alw reduction product was added dropwise to
the dark blue solution at 2788C. After 10 min, NH4Cl
(1.0 g) was added to the solution at 2788C. The mixture was
warmed slowly to rt, partitioned between saturated aqueous
NH4Cl (10 mL) and EtOAc (15 mL). The layers were
separated and the aqueous layer was extracted with EtOAc
(2£5 mL) and CHCl3 (saturated with NH3) (3£10 mL). The
combined organic extracts were dried (MgSO4), filtered,
and concentrated in vacuo. The residue was purified by
preparative HPLC (Zorbax Extend 5 mm C18,
250£15.5 mm, 80:20 MeOH–1% NH4OH in H2O,
16 mL/min, UV detection at 254 nm, retention time
10.6 min) to provide 9.2 mg (46% over 3 steps from 5) of
idiospermuline (4) a0s0 an amorphous solid. Additionally,
3.5 mg (17%) of 3a ,8a00-bis-epiidiospermuline (42) was
isolated (retention time 13.5 min). Data for synthetic 4:
HRMS (ESI) m/z calcd for C35H42N6 (MþHþ) 547.3549,
found 547.3543. Other spectral (1H and 13C NMR in CDCl3)
and analytical properties (TLC and HPLC: Zorbax Extend
5 mm C18, 250£4.60 mm, 80:20 MeOH–1% NH4OH in
H2O, 0.8 mL/min, UV detection at 254 nm) were indis-
tinguishable from those of a sample of natural 4; the CD
spectrum in MeOH at 0.2 mg/mL of synthetic 4 compared
well with that the CD spectrum in MeOH at 0.1 mg/mL
taken of authentic 4.3 Copies of 1H and 13C NMR spectra of
synthetic idiospermuline have been deposited as Supporting
Information for Ref. 8.
4.1.19. Catalytic hydrogenation of 5 to form N-tosyla-
mine 40. A 6:1 mixture of 5, and 39 (0.142 g, 0.198 mmol,
generated from Heck cyclization of 6 with (S)-tol-BINAP),
Pd(OH)2/C (0.150 g, 20 wt%), and EtOH (3 mL) was stirred
in a glass sleeve within a pressure reactor (Parr bomb,
120 cm3) under 1500 psi of H2 at 808C for 48 h. The
reaction vessel was cooled and the mixture taken up in a
syringe and pushed through a nylon filter (0.45 mm,
d¼3 cm). The glass sleeve and filter were repeatedly
washed with hot MeOH (50 mL). The resulting solution
was concentrated to afford 0.127 g (90%) of 40 (which was
contaminated with the corresponding amount of 41). This
crude product was taken on directly to the next step. For
characterization of 40, a comparable sample was purified by
reverse-phase HPLC: Zorbax Extend-C18, 5 mm,
150£21.2 mm, 70:30 CH3CN–H2O (1% NH4OH), 16 mL/
1
min, UV detection at 254 nm. Diagnostic data for 40: H
NMR (500 MHz, (CD3)2SO, 360 K) d 7.52 (d, J¼8.3 Hz,
2H), 7.44 (dt, J¼6.5, 2.4 Hz, 1H), 7.39 (d, J¼8.0 Hz, 2H),
7.20 (t, J¼7.4 Hz, 1H), 7.14 (d, J¼7.1 Hz, 1H), 7.10 (d,
J¼7.8 Hz, 1H), 6.88 (d, J¼7.2 Hz, 1H), 6.83 (t, J¼7.5 Hz,
1H), 6.78 (d, J¼7.2 Hz, 1H), 6.69 (d, J¼7.8 Hz, 1H), 6.46
(t, J¼7.6 Hz, 1H), 6.32 (t, J¼7.3 Hz, 1H), 6.20 (d,
J¼7.9 Hz, 1H), 5.05 (br d, J¼3.9 Hz, 1H), 4.57 (br s, 1H),
4.40 (br s, 1H), 3.21 (s, 3H), 2.90 (s, 3H), 2.90–2.83 (m,
2H), 2.64 (s, 3H), 2.65–2.62 (m, 3H), 2.42 (s, 3H), 2.41–
2.37 (m, 1H), 2.36 (s, 3H), 2.35–2.29 (m, 1H), 2.27 (s, 3H),
2.23–2.18 (m, 1H), 1.90–1.80 (m, 2H); 13C NMR
(125 MHz, (CD3)2SO, 360 K) d 176.9, 152.3, 149.7,
143.0, 142.6, 135.2, 134.3, 132.6, 129.5, 129.1, 128.1,
126.9, 126.4, 124.8, 124.1, 122.4, 122.1, 121.9, 119.2,
117.4, 115.9, 108.4, 104.9, 91.0, 82.7, 62.0, 61.9, 53.4, 51.0,
50.6, 45.4, 36.9, 34.9, 34.8, 34.7, 34.1, 30.5, 25.6, 20.3 (one
13C signal is apparently overlapping with another at this
field strength); IR (film) 2934, 1695, 1606, 1494, 1347,
1162; HRMS (ESI) m/z calcd for C42H48N6O3S (MþHþ)
717.3587, found 717.3569.
4.1.21. Catalytic hydrogenation of 39 to form N-
tosylamine 41. Following the procedure employed for the
catalytic hydrogenation of 5, a 1:18 mixture of 5 and 39
(0.191 g, 0.267 mmol, generated from Heck cyclization of 5
with (R)-tol-BINAP), and Pd(OH)2/C (0.134 g, 20 wt%),
yielded 0.171 g (89%) of 41, (which was contaminated with
the corresponding amount of 40). This crude product
mixture was taken on directly to the next step. For
characterization of 41, a comparable sample was purified
by reverse-phase HPLC: Zorbax Extend-C18, 5 mm,
150£21.2 mm, 70:30 CH3CN–H2O (1% NH4OH), 16 mL/
1
min, UV detection at 254 nm. Diagnostic data for 41: H
NMR (500 MHz, (CD3)2SO, 360 K) d 7.55 (d, J¼8.2 Hz,
2H), 7.40 (m, 3H), 7.23 (d, J¼6.9 Hz, 1H), 7.17 (t,
J¼7.4 Hz, 1H), 7.11 (d, J¼7.8 Hz, 1H), 7.06 (d,
J¼6.2 Hz, 1H), 6.97 (d, J¼7.3 Hz, 1H), 6.90 (t, J¼7.5 Hz,
1H), 6.65 (d, J¼7.7 Hz, 1H), 6.47 (t, J¼7.6 Hz, 1H), 6.40 (t,
J¼7.3 Hz, 1H), 6.27 (d, J¼7.8 Hz, 1H), 5.91 (br s, 1H), 4.23
(br s, 1H) 3.21 (s, 3H), 2.90 (s, 3H), 2.92–2.89 (m, 1H),
2.82–2.75 (m, 1H), 2.65 (s, 3H), 2.66–2.55 (m, 2H), 2.40
(s, 3H), 2.42–2.35 (m, 3H), 2.30 (s, 3H), 2.33–2.25 (m,
2H), 2.24–2.19 (m, 1H), 2.17 (s, 3H), 1.90–1.83 (m, 2H);
13C NMR (125 MHz, (CD3)2SO, 360 K) d 177.1, 152.3,
149.5, 143.0, 142.6, 135.1, 134.6, 132.2, 129.5, 129.2,
128.0, 127.1, 126.4, 125.1, 124.3, 123.0, 122.9, 121.9,
118.3, 116.9, 115.8, 108.5, 105.1, 91.0, 84.5, 61.8, 61.7,
53.7, 51.5, 51.4, 45.3, 36.9, 35.9, 34.8, 34.7, 34.6, 33.9,
30.4, 25.7, 20.4; HRMS (ESI) m/z calcd for C42H48N6O3S
(MþHþ) 717.3587, found 717.3599.
4.1.20. Idiospermuline (4). A toluene solution of Red-Alw
(0.1 mL, 65 wt%) was added to a solution of 40 (contami-
nated with ,15% of 41) (26 mg, 0.037 mmol) in toluene
(2 mL) at rt. After 15 min, the solution was cooled to 08C
and EtOAc (3 mL) was added dropwise. The resulting
solution was concentrated in vacuo and placed under high
vacuum for 1 h. The residue was dissolved in THF (5 mL)
and added to the Na/NH3 solution described below.
A two-neck reaction vessel fitted with a liquid NH3
condenser and magnetic stir bar was charged with sodium
metal (20 mg, 0.87 mmol) under a positive flow of N2. The
reaction flask and condenser were cooled to 2788C. A
separate three-neck flask with an attached bubbler was
cooled to 2788C and NH3 (50 mL) was condensed directly
from the tank into this flask. The NH3 was redistilled from
the three-neck flask into the reaction vessel (20 mL) through
4.1.22. 3a00,8a00-Bis-epiidiospermuline (42). Following the
procedure employed to furnish idiospermuline (4) from 40,
the crude catalytic hydrogenation product 41 (contaminated
with ,5% of 40) (33 mg, 0.046 mmol) was converted to

L. E. Overman, E. A. Peterson / Tetrahedron 59 (2003) 6905–6919
6919
7. Alisaad, H.-E. Ph.D. Thesis, University Louis Pasteur of
Strasbourg, 1986.
14.2 mg (57% from 39) of 42 as an amorphous solid.
Additionally, 1.2 mg (5%) of idiospermuline (4) was
28
405
8. Overman, L. E.; Peterson, E. A. Angew. Chem. Int. Ed. 2003,
42, 2525–2528.
isolated. Characterization data for 42: [a] ¼2492,
28
435
28
546
28
577
[a] ¼2372, [a] ¼2187, [a] ¼2164, [a]2D8¼2156
1
(c 0.25, CHCl3); H NMR (500 MHz, CDCl3) d 7.18 (d,
J¼7.0 Hz, 1H), 7.12 (t, J¼7.6 Hz, 1H and m, 1H), 7.05–
6.90 (m, 3H), 6.74 (t, J¼7.3 Hz, 1H), 6.60–6.52 (m, 1H),
6.48 (d, J¼7.8 Hz, 1H), 6.42–6.28 (m, 2H), 4.58 (s, 1H),
4.50–4.30 (m, 2H), 3.00 (s, 3H), 2.99–2.94 (m, 1H), 2.94
(s, 3H), 2.88–2.78 (m, 1H), 2.68–2.59 (m, 2H), 2.53–2.38
(m, 5H) 2.50 (s, 3H), 2.45 (s, 3H), 2.20 (s, 3H), 2.05–1.88
(m, 3H); 13C NMR (125 MHz, CDCl3) d 153.3, 153.0,
149.3, 133.2, 132.6, 132.4, 128.1, 128.0, 125.9, 125.2,
123.8, 117.7, 116.6, 115.1, 107.1, 105.9, 95.0, 91.7, 84.7,
62.7, 62.3, 59.6, 52.8, 52.7, 38.5, 37.4, 36.8, 36.5, 35.7,
35.4; IR (film) 3250, 2934, 2791, 1602, 1494, 1251, 1154,
1034 cm21; HRMS (ESI) m/z calcd for C35H42N (MþHþ)
547.3549, found 547.3541.
9. Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.;
Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem.
Soc. 2003, 125, 6261–6271.
10. Iwao, M.; Kuraishi, T. Org. Synth. 1996, 73, 85–93.
11. Overman, L. E.; Larrow, J. F.; Stearns, B. A.; Vance, J. M.
Angew. Chem. Int. Ed. 2000, 39, 213–215.
12. Hoyt, S. B.; Overman, L. E. Org. Lett. 2000, 2, 3241–3244.
13. Hoyt, S. B. Unpublished results, 2001.
14. Pei, X.-F.; Bi, S. Heterocycles 1994, 39, 357–360.
15. Loibner, H.; Zbiral, E. Helv. Chim. Acta 1976, 59, 2100–2113.
16. Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem.
Soc. 1999, 121, 7702–7703.
17. For examples of ortho-lithiation of N-(tert-butoxy)indolines
see: (a) Iwao, M.; Kuraishi, T. Org. Synth. 1996, 73, 85–93.
(b) Govek, S. P.; Overman, L. E. J. Am. Chem. Soc. 2001, 123,
9468–9469, and Ref. 5.
Acknowledgements
18. For examples of Stille cross-couplings at room temperature
and the effect of tri-2-furylphosphine see: (a) Farina, V.;
Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595. For
the role of CuI see: (b) Farina, V.; Kapadia, S.; Krishnan, B.;
Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59,
5905–5911. (c) Liebeskind, L. S.; Fengl, R. W. J. Org.
Chem. 1990, 55, 5359–5364.
This research was supported by the General Medical
Sciences Institute of the NIH (grant GM-30859). NMR
and mass spectra were determined at UC Irvine with
instruments purchased with the assistance of the NSF and
NIH shared instrumentation programs. We thank Professor
Rujee K. Duke for providing a sample of natural
idiospermuline.
19. For a recent review of the use of catalytic asymmetric
intramolecular Heck reactions in the synthesis of natural
products, see: Overman, L. E.; Dounay, A. B. Chem. Rev.
2003, 103, in press.
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