Enantioselective total synthesis of the cyclotryptamine alkaloid idiospermuline

Article abstract of DOI:10.1002/anie.200351260

Stereogenic quaternary carbons present the primary challenge in the syntheses of trispyrrolidinoindoline alkaloids such as idiospermuline. In its synthesis the two contiguous quaternary centers are expediently addressed by combining the lithium dienolate

Full text of DOI:10.1002/anie.200351260

Angewandte
Chemie
Alkaloid Total Synthesis
Enantioselective Total Synthesis of the
Cyclotryptamine Alkaloid Idiospermuline**
Larry E. Overman* and Emily A. Peterson
A remarkable group of alkaloids that link together up to eight
pyrrolidinoindoline units has been isolated from higher
plants.[1] (ꢀ)-Chimonanthine (1) is representative of the
simplest of these. In higher order members of this group,
H
N
Me
N
H
H
N
Me
N
H
H
N
Me
N
H
H
N
H
N
H
Me
(–)-chimonanthine (1)
Me
N
1
Me
N
H
7
N
H
N
Me
2
3
8
3a
3a'
N
H
N
H
8'
N
H
Me
N
Me
7'
quadrigemine C (3)
H
3a''
8''
N
Me
N
Me
H
idiospermuline (2)
exemplified by idiospermuline (2) and quadrigemine C (3),
additional pyrrolidinoindoline units are attached at their
benzylic quaternary stereocenters to peri positions of the
aromatic ring of other pyrrolidinoindoline fragments. Stimu-
lated by the unusual structures and varied biological activities
of these cyclotryptamine alkaloids,[1] we have developed
chemistry to access these complex, configurationally diverse
alkaloids by stereocontrolled total synthesis.[2] We report
herein the first total synthesis of the trispyrrolidinoindoline
alkaloid idiospermuline (2), a naturally occurring cholinergic
antagonist isolated recently from the seeds of Idiospermum
australiense, a rare tree found in lowland rain forests of North
Queensland, Australia.[3]
[*] Prof. Dr. L. E. Overman, E. A. Peterson
Department of Chemistry
University of California, Irvine
516Rowland Hall, Irvine, CA 92697-2025 (USA)
Fax: (+1)949-824-3866
E-mail: leoverma@uci.edu
[**] 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.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 2525 – 2528
DOI: 10.1002/anie.200351260
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2525

Communications
Idiospermuline (2) contains three all-carbon-substituted
O
O
O
O
O
O
O
quaternary centers, two of which are vicinal (3a and 3a’) and
the third (3a’’), a diaryl-substituted quaternary carbon of the
flanking pyrrolidinoindoline subunit. Two of the three indo-
line nitrogens (8 and 8’’) carry methyl substituents, a
structural feature that is rarely seen in polypyrrolidinoindo-
line alkaloids.[1] The synthesis plan we followed is outlined in
antithetic format in Scheme 1. We envisaged forming the
diaryl-substituted quaternary stereocenter by catalytic asym-
H
H
TfO
OTf
a – d
7
O
O
NBn
NH
MeN
e
MeN
NBn
O
9
8
10
Scheme 2. Reaction conditions: a) NaH, BnBr, DMF, RT; b) oxindole,
AcOH, HCl, 1108C (75%, 2 steps); c) Cs2CO3, MeI, DMF, RT; d) PtO2,
H2, EtOAc, RT (87%,2 steps; e) 2 equiv LHMDS, 9:1 THF:HMPA, 7,
ꢀ408C (75%). DMF=dimethylformamide, HMPA=hexamethylphos-
phoramide, LHMDS=lithium bis(trimethylsilyl)amide, RT=room tem-
perature.
Me
N
Me
N
Me
N
Me
N
H
H
2
N
H
N
OTf
N
H
N
ature, and concentration were all important factors in
determining stereoselection.[7] The highest selectivity in
generating the desired hexacyclic product 10 was realized by
forming the lithium dienolate of 8 with LHMDS at ꢀ408C in a
9:1 mixture of THF/HMPA (0.05m substrate concentration)
and allowing this intermediate to react with 7 at this
temperature.[8,9] These optimized conditions provided cyclo-
hexanediol derivative 10 in 75% yield. Selective formation of
10 requires approach of the chiral dielectrophile from the re
face of the prostereogenic dienolate, followed by cyclization
of the resulting monoalkylated product without chelate
organization.[2c,8]
Me
N
H
H
Me
Me
3a''
N
NMeTs
O
O
NMeTs
Me
4
5
Me
N
Me
N
H
7
O
O
H
H
NMe
O
BnN
O
+
TfO
OTf
N
N
Me
7'
H
Boc
6
7
8
Elaboration of 10 by a ten-step sequence analogous to
that developed in our earlier total syntheses of (ꢀ)- and (þ)-
chimonanthine[2b,c] provided enantiopure 3a,3a’-bispyrrolidi-
noindoline 11 in 49% overall yield (Scheme 3).[10] Removal of
the benzyl group of 11 with Na/NH3, followed by Boc
Scheme 1. Retrosynthesis of idiospermuline (2). Bn=benzyl, Boc=
tert-butoxycarbonyl, Tf=trifluoromethanesulfonyl, Ts=toluenesulfonyl.
metric Heck cyclization of the heptacyclic triflate 5.[4] This
latter intermediate would be assembled from the (ꢀ)-
chimonanthine congener 6, whose contiguous quaternary
carbons we saw as arising from the combination of tartrate-
derived dielectrophile 7 and the lithium dienolate generated
from dihydroisoindigo 8.[2c] The asymmetric Heck cyclization
step in this sequence would explore the utility of this
transformation for appending a precursor of a pyrrolidinoin-
doline onto a chiral 3a,3a’-bispyrrolidinoindoline moiety.[5]
The unsymmetrical methylation pattern of 2, as well as the
requirement to differentiate the two peri positions of 6 (7 and
7’), would be addressed expediently by simply beginning the
synthesis with a dihydroisoindigo derivative having different
substituents on the oxindole nitrogens.
This total synthesis endeavor commenced with the
preparation of differentially functionalized dihydroisoindigo
8 (Scheme 2). Following a straightforward sequence, isatin (9)
was N-benzylated[6] and then condensed with oxindole to
provide the corresponding isoindigo. Methylation of this
latter intermediate, followed by catalytic hydrogenation of
the product over PtO2 furnished 8 in 65% overall yield, and
only one chromatographic purification was required in this
four-step sequence.
O
O
Me
N
Me
N
H
O
10 steps
a
d, e
MeN
NBn
O
N
R
N
Me
H
10
11, R = Bn
6, R = Boc
b, c
Me
N
Me
N
OTf
SnBu3
H
Me
Me
Me
N
H
N
N
O
NMeTs
13
f
OTf
N
H
N
Me
Me
N
H
N
H
N
Me
H
I
O
NMeTs
12
5
Scheme 3. Reaction conditions: a) for details of this sequence, see the
Supporting Information (49% overall yield); b) Na, NH3, THF, ꢀ788C
(99%); c) Boc2O, NaHMDS, THF, ꢀ788C (74%); d) 1) sBuLi, TMEDA,
Et2O, ꢀ788C; 2) diiodoethane, ꢀ78 to 08C (90%); e) TMSOTf, CH2Cl2,
RT (94%); f) 13, Pd2dba3·CHCl3, P(2-furyl)3, CuI, NMP, RT (94%).
dba=trans,trans-dibenzylideneacetone, NMP=1-methyl-2-pyrrolidi-
none, TMEDA=N,N,N’,N’-tetramethylethylenediamine, TMSOTf=tri-
methylsilyl trifluoromethanesulfonate.
The first critical step in the synthesis was the combination
of the lithium dienolate of dihydroisoindigo 8 with enantio-
pure ditriflate 7 (Scheme 2),[2c] a union that could produce
four distinct C1-symmetric dialkylation products. Detailed
examination of this reaction revealed that solvent, temper-
2526
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 2525 – 2528

Angewandte
Chemie
protection of the resulting indoline, delivered 6 in 74% yield
over the two steps. ortho-Lithiation of 6 with sBuLi at ꢀ788C
in pentane/TMEDA, quenching of the derived aryllithium
intermediate with excess diiodoethane, and removal of the
Boc group from the resulting product gave iodide derivative
12 in 85% yield.[11] The remaining carbon framework of
idiospermuline was introduced by chemoselective Stille cross-
coupling of 12 with the readily available stannyl butenanilide
13[12] to furnish (Z)-butenanilide derivative 5 in 94%
yield.[5,13]
With the Heck cyclization precursor in hand, we directed
efforts toward construction of the 3a’’ diaryl-substituted
quaternary stereocenter. Substrate-controlled Heck cycliza-
tion of 5 using simple chelating diphosphane ligands such as
bis(1,4-diphenylphosphanyl)butane (dppb) favored forma-
tion of the desired 3a’’ R diastereomer 4, albeit with poor
selectivity (Scheme 4). Optimum stereoselection in forming 4
BINAP provided 4 and 14 in a 1:18 ratio, reflecting in this case
a match of substrate and catalyst control.[15]
The total syntheses of idiospermuline (2) and its 3a’’,8a’’
isomer 15 were completed as follows: As epimers 4 and 14
were not readily separated, the 6:1 mixture of these products
produced by cyclization of 5 with the Pd/(S)-Tol-BINAP
catalyst was advanced to the end of the synthesis where 2 and
15 could be separated readily by preparative HPLC. This
conversion began with catalytic hydrogenation using palla-
dium hydroxide on carbon at high hydrogen pressure to
provide the corresponding saturated sulfonamides. The
oxindole carbonyl group of these intermediates then was
reduced with sodium bis(2-methoxyethoxy)aluminum hy-
dride (Red-Al) in toluene at room temperature,[16] and the
resulting product was immediately exposed to excess sodium
in ammonia at ꢀ788C. After purification by preparative
HPLC, idiospermuline (2), [a]D = ꢀ267 (c = 0.85 CHCl3),[17]
was isolated in 47% overall yield from the mixture of Heck
products. Synthetic idiospermuline (2) was identical to a
Me
N
Me
N
Me
N
H
Me
N
H
1
natural sample by comparison of H NMR, 13C NMR, CD,
and HRMS data, as well as by HPLC coinjection.[18] An
analogous sequence carried out with the 1:18 mixture of 4 and
14 generated from 5 with the Pd/(R)-Tol-BINAP catalyst gave
3a’’,8a’’-bisepiidiospermuline (15) in 57% yield.
a
+
5
N
H
N
N
H
N
H
Me
H
Me
3a''
N
3a''
N
The total synthesis of idiospermuline (2) described herein
and that of hodgkinsine reported in the following communi-
cation[19] are the first total syntheses of trispyrrolidinoindoline
alkaloids. Starting with isatin, idiospermuline was formed in
6% overall yield by way of 14 isolated and purified
intermediates. This stereocontrolled total synthesis demon-
strates for the first time the use of our dienolate dialkylation
chemistry[2,8] for enantioselective preparation of unsymmet-
rical 3a,3a’-bispyrrolidinoindolines. It also provides another
illustration of the ability of asymmetric intramolecular Heck
reactions to generate compounds having congested quater-
nary carbon centers in high yield and the first demonstration
of using such a transformation to elaborate a pyrrolidinoindo-
line unit at C7 of a chiral 3a,3a’-bispyrrolidinoindoline
fragment.
NMeTs
NMeTs
O
O
Me
Me
4
14
b, c
Me
N
Me
N
Me
N
Me
N
H
H
H
N
H
N
Me
N
H
N
Me
H
N
Me
N
N
Me
N
H
H
Me
Me
idiospermuline (2)
15
Scheme 4. Reaction conditions: a) 10 mol% Pd(OAc)2, 20 mol%
diphosphane ligand, PMP, MeCN, 808C (see Table 1); b) Pd(OH)2,
1500 psi H2, 808C, EtOH, (90%); c) 1) Red-Al, toluene, RT; 2) Na,
NH3, THF, ꢀ788C, (a 6:1 mixture of 4 and 14 yields 2 (47%) and 15
(16%), 2 steps).
Received: February 24, 2003 [Z51260]
Keywords: alkaloids · alkylation · asymmetric catalysis ·
.
C–C coupling · Heck reaction
was realized with Pd(OAc)2 as the precatalyst and (S)-Tol-
BINAP ((S)-2,2’-bis(di-p-tolylphosphanyl)-1,1’-binaphthyl)
as the ligand (Table 1).[4b,14] With this catalyst, cyclization of
5 in acetonitrile at 808C in the presence of excess 1,2,2,6,6-
pentamethylpiperidine (PMP) provided epimers 4 and 14 in
97% yield and a 6:1 ratio. Identical cyclization using (R)-Tol-
[1] For a recent review, see: U. Anthoni, C. Christophersen, P. H.
Nielsen, Alkaloids:Chemical and Biological Perspectives, Vol. 13
(Ed.: S. W. Pelletier), Pergamon, New York, 1999, pp. 163 – 236.
[2] a) J. T. Link, L. E. Overman, J. Am. Chem. Soc. 1996, 118, 8166 –
8167; b) L. E. Overman, D. V. Paone, B. A. Stearns, J. Am.
Chem. Soc. 1999, 121, 7702 – 7703; c) L. E. Overman, J. F.
Larrow, B. A. Stearns, J. M. Vance, Angew. Chem. 2000, 112,
219 – 221; Angew. Chem. Int. Ed. 2000, 39, 213 – 215.
Table 1: Heck cyclizations of (Z)-butenanilide 5.
[3] R. K. Duke, R. D. Allan, G. A. R. Johnston, K. N. Mewett, A. D.
Mitrovic, C. C. Duke, T. W. Hambley, J. Nat. Prod. 1995, 58,
1200 – 1208.
Entry
Ligand
Yield [%]
4:14
1
2
3
4
dppb
90
97
97
99
2.5:1
1:1.8
6:1
[4] a) M. Oestreich, P. R. Dennison, J. J. Kodanko, L. E. Overman,
Angew. Chem. 2001, 113, 1485 – 1489; Angew. Chem. Int. Ed.
2001, 40, 1439 – 1442; b) A. B. Dounay, K. Hatanaka, J. J.
Kodanko, M. Oestreich, L. E. Overman, L. A. Pfeifer, M. M.
rac-Tol-BINAP
(S)-Tol-BINAP
(R)-Tol-BINAP
1:18
Angew. Chem. Int. Ed. 2003, 42, 2525 – 2528
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2527

Communications
Weiss, J. Am. Chem. Soc. 2003, 125, in press (ASAP Web release
April 23, 2003).
[5] The utility of this transformation for attaching precursors of
pyrrolidinoindoline fragments to a meso bis-3a,3a’-bispyrrolidi-
noindoline moiety was demonstrated in our recent total syn-
thesis of quadrigemine C, see: A. D. Lebsack, J. T. Link, L. E.
Overman, B. A. Stearns, J. Am. Chem. Soc. 2002, 124, 9008 –
9009.
[6] R. L. Autrey, F. C. Tahk, Tetrahedron 1967, 23, 901 – 917.
[7] These studies were guided by our earlier systematic studies of
the related condensation of 7 with the dibenzyl analogue of 8 en
route to (ꢀ)-chimonanthine.[2c,8]
[8] For a detailed study and analysis of a related dialkylation
reaction, see S. B. Hoyt, L. E. Overman, Org. Lett. 2000, 2, 3241 –
3244.
[9] The HMPA additive was necessary not only to reduce chelation
during the intramolecular alkylation step,[8] but also to solvate
the substrate at low temperature.
[10] See the Supporting Information for reagents and yields for each
step in the elaboration of 10 to 11.
[11] For examples of ortho-lithiation of N-(tert-butoxy)indolines see:
a) M. Iwao, T. Kuraishi, Org. Synth. 1996, 73, 85 – 93; b) S. P.
Govek, L. E. Overman, J. Am. Chem. Soc. 2001, 123, 9468 – 9469,
and reference [5].
[12] Stannyl butenanilide 13 is available in two steps from N-
methylpropargylamine and 3-methylbenzoxazolinone, see the
Supporting Information.
[13] a) V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585 –
9595; b) V. Farina, S. Kapadia, B. Krishnan, C. Wang, L. S.
Liebeskind, J. Org. Chem. 1994, 59, 5905 – 5911; c) L. S. Liebe-
skind, R. W. Fengl, J. Org. Chem. 1990, 55, 5359 – 5364.
[14] (S)-Tol-BINAP = (S)-2,2’-bis(di-p-tolylphosphanyl)-1,1’-
binaphthyl: H. Takaya, K. Mashima, K. Koyano, M. Yagi, H.
Kumobayashi, T. Taketomi, S. Akutagawa, R. Noyori, J. Org.
Chem. 1986, 51, 629 – 635.
[15] HPLC analysis was used to determine the diastereometric ratios
in all cyclizations except that with (R)-Tol-BINAP. In this case a
small impurity coeluted with the minor product 4; thus, high-
temperature 1H NMR (360 K, for coalescence of rotamer
signals) was used to determine the diastereomer ratio.
[16] X.-F. Pei, S. Bi, Heterocycles 1994, 39, 357 – 360.
[17] The rotation of 2 was reported erroneously as [a]D = ꢀ2.5 (c =
1.0, CHCl3).[3] The rotation of natural 2[18] measured in our hands
(c = g/100 mL) is [a]D = ꢀ241 (c = 0.2, CHCl3).
[18] We thank Professor Rujee K. Duke for providing this sample.
[19] J. J. Kodanko, L. E. Overman, Angew. Chem. 2003, 115, 2632 –
2635; Angew. Chem. Int. Ed. 2003, 42, 2528 – 2531 (following
communication in this issue).
2528
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 2525 – 2528