Enantioselective total syntheses of the cyclotryptamine alkaloids hodgkinsine and hodgkinsine B

Article abstract of DOI:10.1002/anie.200351261

A late-stage resolution of the meso-3a, 3a′-bispyrrolidinoindoline unit of rac-7 in a catalytic asymmetric transformation ear-marks the remarkably short, ten-step, total syntheses of hodgkinsine and hodgkinsine B. The enantioselective total synthesis of hodgkinsine B establishes the relative and absolute configuration of this trispyrrolidinoindoline alkaloid.

Full text of DOI:10.1002/anie.200351261

Communications
Alkaloid Total Synthesis
Enantioselective Total Syntheses of the
Cyclotryptamine Alkaloids Hodgkinsine and
Hodgkinsine B**
Jeremy J. Kodanko and Larry E. Overman*
Hodgkinsine (1), first isolated in 1961 from the leaves of a
shrub (Hodgkinsonia frutescens) growing in the coastal and
[
1]
tableland region of tropical Queensland, Australia, was later
identified in the alkaloid extracts of numerous members of
the Psychotria genus,[2] including P. colorata, a plant tradi-
[
3]
tionally used in the Brazilian Amazon as a remedy for pain.
Early chemical
[
1,4]
[5]
and mass spectrometric evidence, the
latter complicated by the facile fragmentation of the
C3a–C3a’ bond connecting the contiguous benzylic quater-
nary carbons, suggested that hodgkinsine was a N -methyl-
b
tryptamine-derived dimer akin to chimonanthine and caly-
canthine. Single-crystal X-ray analysis of the trimethiodide
[*] Prof. Dr. L. E. Overman, J. J. Kodanko
Department of Chemistry
University of California, Irvine
516 Rowland 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.
We thank Professor Luisella Verotta, Università degli Studi, Milano,
Italy, for a sample of hodgkinsine B and its characterization data.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2
528
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DOI: 10.1002/anie.200351261
Angew. Chem. Int. Ed. 2003, 42, 2528 – 2531

Angewandte
Chemie
derivative subsequently established that hodgkinsine (1) is
composed of three pyrrolidinoindoline units,[ and it is thus
the first member of the higher order polypyrrolidinoindoline
alkaloids to be fully characterized.[
would be accessed from the known di-tert-butoxycarbonyl
derivative 8 of meso-chimonanthine in a fashion similar to
6]
that employed in our recent total synthesis of quadrigemine C
7]
[12]
(4).
Recent pharmacological studies have shown hodgkinsine
1) to be a micromolar agonist of the m-opiod receptor and to
meso-Chimonanthine (3), the starting point for preparing
hodgkinsine (1) and hodgkinsine B (2), is available by stereo-
controlled total synthesis, or more conveniently in 30%
(
[
13]
show potent dose-dependent analgesic activity against cap-
saicin-induced pain, the latter of which also implies the
involvement of NMDA receptors.[ In this communication we
report the first total synthesis of hodgkinsine (1) as well as its
stereoisomer 2, a previously undisclosed alkaloid isolated
from Amazon Psychotria species for which the name hodg-
kinsine B has been suggested.[
overall yield from tryptamine by a recently reported three-
8]
[14]
step, stereorandom sequence.
dicarbamate 8 (Scheme 2),
After conversion of 3 to
[
12]
this latter intermediate was
ortho-lithiated by reaction with 2 equiv sec-butyllithium at
9]
The approach we pursued (Scheme 1) to synthesize
hodgkinsine (1) and hodgkinsine B (2) was based on a
number of considerations. The vicinal quaternary stereo-
centers of 1 and 2 (3a and 3a’) have opposite relative
configurations, making the hexacyclic 3a,3a’-bispyrrolidinoin-
Scheme 2. Reaction conditions: a) Boc O, THF, RT; NaHMDS (77%,
2
ref. [ ); b) 1) sBuLi, TMEDA, THF, ꢀ788C; 2) diiodoethane, ꢀ788C to
13]
0
8C (64%); c) TMSOTf, CH Cl (97%); d) 10, Pd (dba )·CHCl , P(2-
2 2 2 3 3
furyl) , CuI, DMA, RT (81%). Boc=tert-butoxycarbonyl, dba=dibenzyl-
3
ideneacetone, DMA=N,N-dimethylacetamide, NaHMDS=sodium
bis(trimethylsilyl)amide, RT=room temperature, TMEDA=N,N,N’,N’-
tetramethylethylenediamine, TMSOTf=trimethylsilyl trifluoromethane-
sulfonate.
Scheme 1. Retrosynthesis for hodgkinsine (1) and hodgkinsine B (2).
doline moieties of these alkaloids similar to those of meso-
chimonanthine (3) and quadrigemine C (4).[
2b,7]
In both
[
15]
alkaloids the third all-carbon-substituted quaternary stereo-
center C3a’’ has the R absolute configuration. What differ-
entiates hodgkinsine and hodgkinsine B is the opposite
absolute configurations of their contiguous quaternary ster-
eocenters. Thus, the synthetic problem in preparing 1 and 2
reduces to selectively joining a pyrrolidinoindoline having the
R absolute configuration at C3a’’ to either the enantiotopic C7
or C7’ peri position of meso-chimonanthine (3). We envi-
sioned accomplishing this stereochemical differentiation by
catalyst-controlled asymmetric Heck cyclization of the race-
mic triflate rac-7 to generate the octacyclic oxindoles 5 and
ꢀ788C in THF containing 2 equiv TMEDA. Quenching of
the resulting lithium species with an excess of 1,2-diiodo-
ethane delivered the monoiodide rac-9 in 64% yield.
Cleavage of the Boc groups followed by Stille cross-coupling
[
10b,12]
of rac-10 with stannane 11
furnished the racemic intra-
molecular Heck precursor rac-7 in 39% overall yield from
meso-chimonanthine (3).
The critical catalyst-controlled Heck cyclization of rac-7
was investigated in some detail (Scheme 3 and Table 1). First
we established that there was little substrate-controlled
diastereoselection in the cyclization of rac-7 with palladium
catalysts containing achiral diphosphane ligands such as dppb
(5:6 = 2:1). Of the chiral, enantiopure diphosphanes
[
10,11]
6.
This late-stage catalytic asymmetric transformation
would resolve the meso-3a,3a’-bispyrrolidinoindoline unit of
rac-7 while appending the diaryl-substituted quaternary
stereocenter C3a’’. The heptacyclic triflate rac-7 in turn
[
16]
screened, Tol-BINAP
catalyst control.
provided the highest degree of
With this ligand, stereoselectivity was
[
17]
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Communications
hodgkinsine B (2), each in 29% overall yield (Scheme 3).
1
13
NMR spectra ( H and C) for synthetic 1 at room temper-
ature and at 243 K were identical to those reported for natural
[
2e]
hodgkinsine.
Synthetic 2 was identical to an authentic
1
sample of hodgkinsine B (2) by comparison of H and
C NMR spectroscopic and mass spectrometric data and by
1
3
[
18a]
HPLC coinjection.
Synthetic 1 (79% ee) showed an optical
2
7
D
rotation [a] = ꢀ25 (c = 0.8, CHCl ); rotations at the D line in
3
CHCl ranging from ꢀ26 to ꢀ42 (typically at c = 1) have been
3
[
2a,e,19]
reported for natural samples of hodgkinsine.
Synthetic 2
2
7
(
83% ee) showed an optical rotation [a] = ꢀ55 (c = 0.8,
D
2
D
7
CHCl ), whereas [a] = ꢀ77 (c = 1, CHCl ) was reported for
3
3
[
18b]
a natural sample.
In summary, the first total syntheses of hodgkinsine (1)
and hodgkinsine B (2) were accomplished from tryptamine by
highly concise sequences of ten total steps. The alkaloid
products were produced in enantioenriched form (~ 80% ee)
and in 1.5% overall yield. The stereorational total synthesis of
2
establishes the relative and absolute configuration of this
Psychotria natural product. To the best of our knowledge, the
conversion of rac-7 to enantioenriched 5 and 6 represents the
first successful use of an asymmetric intramolecular Heck
[
20]
reaction for resolution. This work, together with our recent
Scheme 3. Reaction conditions: a) 10% Pd(OAc) , 20% (R)-Tol-BINAP,
[21]
2
enantioselective total syntheses of idiospermuline
and
PMP, MeCN, 808C, (93%,1:1 ratio of 5:6); b) Pd(OH) , 80 psi H ,
2
2
[12]
quadrigemine C, firmly establishes the utility of catalytic
asymmetric Heck cyclizations for
EtOH, 808C; c) Na/NH ꢀ788C, NH Cl quench (29%, 2 steps).
3
4
appending
pyrrolidinoindoline
Table 1: Intramolecular Heck reactions of rac-7.[a]
units in stereocontrolled fashion to
Ligand
Solvent
Base
Yield of % 5 [%] (%ee)[b]
Yield of 6 [%] (%ee)[b] hindered peri positions of either
dppb[c]
[d]
chiral or meso 3a,3a’-bispyrrolidi-
noindoline (chimonanthine) frag-
ments. This chemistry, and the dia-
stereoselective dialkylation chemis-
try we developed contemporane-
ously for preparing either enan-
MeCN
MeCN
MeCN
MeCN
DMA
PS
PS
PS
PS
PS
PS
50 (–)
40 (68)
24 (–)
38 (69)
[
d]
(
(
(
(
(
(
R)-BINAP
R)-Tol-BINAP
S)-Cy-BINAP[
R)-Tol-BINAP
R)-Tol-BINAP
R)-Tol-BINAP
[
e]
[d]
[d]
37 (78)
37 (82)
f]
[g]
(11)[h]
[g]
7
6
(6)
[
[
d]
d]
31 (71)
24 (55)
48 (79)
28 (82)
24 (48)
45 (83)
toluene
MeCN
[
i]
PMP
tiomer
bispyrrolidinoindolines,
of
chiral
3a,3a’-
[a] Conditions: 10 mol% Pd(OAc) , 20 mol% ligand, 4.0 equiv base, substrate concentration (0.05m),
[13b,c,22]
2
1
2 h. [b] Determined by HPLC analysis with a Chiracel OD-R column. [c] dppb=1,4-bis(diphenylphos-
should allow a wide variety of
polypyrrolidinoindoline alkaloids
and their analogues to be prepared
phanyl)butane. [d] PS=1,8-bis(dimethylamino)naphthalene (Proton-Sponge). [e] (R)-Tol-BINAP=(R)-
2
1
,2’-bis(di-p-tolylphosphanyl)-1,1’-binaphthyl. [f] (S)-Cy-BINAP=(S)-2,2’-bis(dicyclohexylphosphanyl)-
,1’-binaphthyl. [g] Yields measured by HPLC with an internal standard (2-aminophenol). [h] The major
enantiomer formed is ent-5. [i] PMP=1,2,2,6,6-pentamethylpiperidine.
by stereocontrolled chemical syn-
thesis. Use of these tools to prepare
all eight hodgkinsine stereoisomers
slightly enhanced in more polar solvents, whereas the yields of
and preliminary pharmacological assessment of this series will
be reported elsewhere.
5
and 6 were improved upon substitution of PMP (1,2,2,6,6-
pentamethylpiperidene) for 1,8-bis(dimethylamino)naphtha-
lene (Proton-Sponge). Temperature changes over the range
Received: February 24, 2003 [Z51261]
6
5–808C had no discernable effect on enantioselectivity.
Keywords: alkaloids · asymmetric catalysis · C–C coupling ·
chiral resolution · Heck reactions
Under optimized conditions Heck cyclization of rac-7 in
acetonitrile at 808C using the catalyst generated from
1
.
0 mol% Pd(OAc) and 20 mol% (R)-Tol-BINAP provided
2
a separable 1:1 mixture of diastereomers 5 (48% yield) and 6
45% yield). The enantiopurity of these products (5 79% ee, 6
3% ee) shows that under these conditions (R)-Tol-BINAP
(
8
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3
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2
530
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Angewandte
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Angew. Chem. Int. Ed. 2003, 42, 2528 – 2531
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