Enantioselective formal synthesis of ent-rhynchophylline and ent-isorhynchophylline

Article abstract of DOI:10.1039/c2cc38540f

Starting from (S)-tryptophanol, a formal synthesis of ent-rhynchophylline and ent-isorhynchophylline, involving stereoselective cyclocondensation, spirocyclization, and alkylation reactions, and the final adjustment of the oxidation level at the oxindole and piperidine moieties, is reported. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2cc38540f

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Enantioselective formal synthesis of
ent-rhynchophylline and ent-isorhynchophylline†
Cite this: Chem. Commun., 2013,
49, 1954
a
a
a
b
ac
´
Mercedes Amat,* Carlos Ramos, Maria Perez, Elies Molins, Pedro Florindo,
Maria M. M. Santosc and Joan Boscha
Received 27th November 2012,
Accepted 18th December 2012
DOI: 10.1039/c2cc38540f
www.rsc.org/chemcomm
Starting from (S)-tryptophanol, a formal synthesis of ent-rhyncho-
Although the stereogenic quaternary spirocenter and the three
phylline and ent-isorhynchophylline, involving stereoselective stereogenic centers on the piperidine ring make rhynchophyllines
cyclocondensation, spirocyclization, and alkylation reactions, and attractively challenging synthetic targets, they have received
the final adjustment of the oxidation level at the oxindole and limited attention from the synthetic standpoint.7 In fact, only
piperidine moieties, is reported.
two different strategies have been used to assemble the
spiro[pyrrolidine-3,30-oxindole] moiety of these alkaloids: either
Oxindole alkaloids are a diverse group of natural products1 a biomimetic oxidative rearrangement from an indolo[2,3-a]-
characterized by the presence of a spiro[pyrrolidine-3,30- quinolizidine derivative4g,7c,d or condensation of 2-hydroxytrypt-
oxindole] ring system,2 a privileged heterocyclic motif associated amine with an appropriate aldehyde.7a,b
with a variety of bioactivity profiles.3 Most of the oxindole
We present here an enantioselective synthesis of ent-rhyncho-
alkaloids incorporate an unrearranged secologanin skeleton phylline and ent-isorhynchophylline using (S)-tryptophanol as
and are biogenetically formed by oxidative rearrangement of the starting material, which not only incorporates the tryptamine
secoyohimbane- or heteroyohimbane-type indole alkaloids. moiety of the natural products but also acts as the source of
Representative members of this group are rhynchophylline and chirality. Our approach takes advantage of the methodology
isorhynchophylline (Fig. 1),4 a pair of C-7 epimers that can be we have reported for the enantioselective spirocyclization of
equilibrated through a ring-opened form via retro-Mannich/ tryptophanol-derived oxazolopiperidone lactams, involving a
Mannich reactions. These alkaloids exhibit a number of pharma- Lewis acid-promoted cyclization of the corresponding Nind-tosyl
cological effects5 and are the major tetracyclic oxindole compo-
nents of Uncaria species, which have long been used in
traditional Oriental medicine.6
Fig. 1 Oxindole alkaloids.
a Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of
Biomedicine (IBUB), University of Barcelona, 08028-Barcelona, Spain.
E-mail: amat@ub.edu; Fax: +34 93 402 45 39; Tel: +34 93 402 45 40
b
`
Institut de Ciencia de Materials (CSIC), Campus UAB, 08193-Cerdanyola, Spain
c Faculty of Pharmacy, Research Institute for Medicines and Pharmaceutical
Sciences, University of Lisbon, 1649-003 Lisbon, Portugal
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, copies of 1H and 13C NMR spectra for all compounds. CCDC 912142
(2) and 912143 (5). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc38540f
Scheme 1 Initial steps of the synthesis and synthetic strategy. Reagents and
conditions: (a) toluene, Dean–Stark, reflux, 24 h, 65% (7,8a-epi-2, 10%); (b) 30% NaOH,
Bu4NCl, PhSO2Cl, CH2Cl2, rt, 20 h, 90%; (c) Et3SiH, TiCl4, CH2Cl2, reflux, 20 h, 93%.
c
1954 Chem. Commun., 2013, 49, 1954--1956
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
derivatives in the presence of Et3SiH.8 Scheme 1 outlines the
initial steps of the synthesis and the overall synthetic strategy.
The required bicyclic lactam 2, which already incorporates
an acetate chain at the 4-position of the piperidone ring, was
prepared9 by cyclocondensation of (S)-tryptophanol with the
prochiral aldehyde–diester 1, in a process that involves the
enantioselective desymmetrization10 of two enantiotopic chains.11
The N-indole deactivating group, needed to direct the key cycliza-
tion at the indole 3-position, was benzenesulfonyl,12 which was
introduced in excellent yield under conventional solid–liquid
phase transfer conditions. Treatment of sulfonyl derivative 3
with TiCl4 in the presence of Et3SiH resulted in a regio- and
stereocontrolled cyclization, with concomitant reduction of
the initially formed spiroindoleninium intermediate, leading
to the tetracyclic spiroindoline 4 as a single stereoisomer in
93% yield. Interestingly, 4 already embodies three of the four
stereogenic centers of the target natural products, with the
appropriate relative configuration.
As outlined in Scheme 1, the synthesis of rhynchophyllines
from the spiroindoline 4 would involve the following transforma-
tions: (i) removal of the hydroxymethyl group, (ii) stereoselective
introduction of the C-20 ethyl substituent to obtain the required
trans C15–C20 stereochemistry, (iii) oxidation of the indoline
moiety to the oxindole functionality, (iv) chemoselective
reduction of the lactam carbonyl, and finally, (v) introduction
of the C-16 methoxyvinyl appendage.
The removal of the hydroxymethyl substituent, which has
acted as an element of stereocontrol during the spirocyclization
step, was accomplished by oxidation to a carboxylic acid, followed
by a radical reductive decarbonylation via a selenoester13 to give
the tetracyclic lactam 5 (Scheme 2).
Scheme 2 Formal enantioselective synthesis of ent-rhynchophylline and ent-
isorhynchophylline. Reagents and conditions: (a) IBX, DMSO, rt, 20 h, 79%;
(b) NaClO2, NaH2PO4, CH3CN, t-BuOH, H2O, 1-methylcyclohexene, rt, 1 h, then
(PhSe)2, n-PBu3, CH2Cl2, reflux, 16 h, 64%; (c) AIBN, n-Bu3SnH, benzene, reflux,
1 h, 65%; (d) LiBH4, Et2O, reflux, 48 h, 83%; (e) NaH, THF, rt, 2 h, then MPMCl,
Bu4NI, reflux, 16 h, 87%; (f) KHMDS, THF, rt, 2 h, then EtI, HMPA, rt, 16 h, 72%
(20-epi-7, 19%); (g) DDQ, CH2Cl2/H2O, rt, 1 h, 93%; (h) IBX, DMSO, rt, 20 h;
(i) NaClO2, NaH2PO4, CH3CN, t-BuOH, H2O, 1-Me-1-Chx, rt, 1.5 h, then Me3SiCl,
MeOH, rt, 24 h, 66% (three steps); (j) Na/Hg 5%, NaH2PO4, MeOH, 0 1C, 15 min,
88%; (k) PhIO, CH2Cl2, rt, 48 h, 70%; (l) AlH3, THF, ꢁ78 1C (addition) to ꢁ50 1C,
30 min, then MeOH, rt, 20 min, then NaBH3CN, AcOH, rt, 20 min, 47%.
At this point, to complete the carbon skeleton of 11, a
known7b synthetic precursor of rhynchophyllines, only the
introduction of the C-20 ethyl substituent remained to be done.
However, to avoid the competitive alkylation at the a-position of
the ester group, the alkylation was performed from the
protected alcohol derivative 6, which was obtained in good
yield by LiBH4 reduction of 5 followed by protection with
p-methoxybenzyl chloride. The alkylation of 6 was performed
with ethyl iodide, using KHMDS as the base and HMPA as
the cosolvent, to stereoselectively give the expected trans-3,4-
disubstituted 2-piperidone derivative 7.14 Then, the C-15 acetate
chain was reinstalled (compound 8) by oxidative removal of the
p-methoxybenzyl protecting group of 7 with DDQ, followed by
oxidation of the resulting alcohol to a carboxylic acid and a
subsequent esterification. After a smooth and efficient deprotec-
tion of the indoline nitrogen with 5% Na/Hg, spiroindoline 9 was
oxidized with PhIO, leading to oxindole 10 in 70% yield. Finally,
chemoselective reduction of the six-membered lactam carbonyl,
without affecting the oxindole moiety, was satisfactorily accom-
plished by sequential treatment of 10 with AlH3 and NaBH3CN.15
The resulting oxindole 11 showed 1H- and 13C-NMR spectral data
coincident with those reported7c for rac-11. Taking into account
that rac-11 has previously been converted7b to (ꢀ)-rhyncho-
phylline and (ꢀ)-isorhynchophylline, the synthesis of oxindole
11 constitutes a formal enantioselective synthesis of the non-
natural enantiomers of these alkaloids.
The results reported herein further illustrate the potential
of tryptophanol-derived oxazolopiperidone lactams for the
enantioselective synthesis of indole alkaloids.16 Two notable
aspects of the synthesis are the efficient, highly convergent, and
totally stereoselective assembling of the tetracyclic spiro[indoline-
3,10-indolizidine] ring system of rhynchophyllines and the
generation of the required oxindole functionality by oxidation
of an N-unsubstituted indoline.17
Financial support from the Spanish Ministries of Science
and Innovation (Project CTQ2009-07021/BQU) and Economy
and Competitiveness (Project CTQ2012-35250), and from the
AGAUR, Generalitat de Catalunya (Grant 2009-SGR-1111) is
gratefully acknowledged. Thanks are also due to the MICINN
(Spain) for a fellowship to C. R. and for a Spanish–Portuguese
Integrated Action (AIB2010PT-00324), also funded by the Portuguese
˜
ˆ
Fundaçao para a Ciencia e a Tecnologia (E-07/11).
Notes and references
1 For reviews, see: (a) J. E. Saxton, in The Alkaloids, ed. R. H. F.
Manske, Academic Press, New York, 1965, vol. 8, pp. 59–91;
(b) J. S. Bindra, in The Alkaloids, ed. R. H. F. Manske, Academic
Press, New York, 1973, vol. 14, pp. 84–121; (c) R. T. Brown, Indoles,
The Monoterpenoid Indole Alkaloids, in The Chemistry of Heterocyclic
Compounds, ed. J. E. Saxton, A. Weissberger and E. C. Taylor, Wiley,
New York, 1983, vol. 25, part 4, pp. 85–97.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 1954--1956 1955

View Article Online
ChemComm
Communication
2 For reviews on the synthesis of oxindole alkaloids, see: (a) C. Marti 10 For related desymmetrizations, see: (a) M. Amat, O. Bassas, N. Llor,
´
´
and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209; (b) B. M. Trost and
M. K. Brennan, Synthesis, 2009, 3003; (c) F. Zhou, Y.-L. Liu and
J. Zhou, Adv. Synth. Catal., 2010, 325, 1381.
3 C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007,
46, 8748.
4 Isolation: (a) H. Kondo, T. Fukuda and M. Tomita, J. Pharm. Soc.
Jpn., 1928, 48, 321; (b) H. Kondo and T. Ikeda, J. Pharm. Soc. Jpn.,
1937, 57, 881; structural elucidation: (c) J. C. Seaton and L. Marion,
Can. J. Chem., 1957, 35, 1102; (d) J. C. Seaton, R. Tondeur and
L. Marion, Can. J. Chem., 1958, 36, 1031; (e) J. C. Seaton, M. D. Nair,
O. E. Edwards and L. Marion, Can. J. Chem., 1960, 38, 1035; stereo-
chemistry: ( f ) Y. Ban and T. Oishi, Tetrahedron Lett., 1961, 791;
M. Canto, M. Perez, E. Molins and J. Bosch, Chem.–Eur. J., 2006,
12, 7872; (b) M. Amat, M. M. M. Santos, O. Bassas, N. Llor,
´
´
C. Escolano, A. Gomez-Esque, E. Molins, S. M. Allin, V. McKee
and J. Bosch, J. Org. Chem., 2007, 72, 5193. For reviews on the
desymmetrization of prochiral or meso substrates, see:
(c) R. S. Ward, Chem. Soc. Rev., 1990, 19, 1; (d) B. Danieli,
G. Lesma, D. Passarella and S. Riva, in Advances in the Use of
Synthons in Organic Chemistry, ed. A. Dondoni, JAI Press, London,
1993, vol. 1, pp. 143–219; (e) E. Schoffers, A. Golebiowski and
C. R. Johnson, Tetrahedron, 1996, 52, 3769; ( f ) M. C. Willis,
J. Chem. Soc., Perkin Trans. 1, 1999, 1765; (g) B. Danieli, G. Lesma,
D. Passarella and A. Silvani, Curr. Org. Chem., 2000, 4, 231.
(g) N. Finch and W. I. Taylor, J. Am. Chem. Soc., 1962, 84, 3871; 11 The absolute configuration of
2 and 5 was unambiguously
(h) Y. Ban and T. Oishi, Chem. Pharm. Bull., 1963, 11, 451;
(i) W. F. Trager, C. M. Lee, J. D. Phillipson, R. E. Haddock,
established by X-ray crystallographic analysis. For full crystal details,
see the ESI†.
D. Dwuma-Badu and A. H. Beckett, Tetrahedron, 1968, 24, 523; 12 Our initial studies were carried out starting from a lactam bearing a
X-Ray crystal structure: ( j) G. Laus and K. Wurst, Helv. Chim. Acta,
2003, 86, 181.
5 (a) T.-H. Kang, Y. Murakami, K. Matsumoto, H. Takayama,
M. Kitajima, N. Aimi and H. Watanabe, Eur. J. Pharmacol., 2002,
455, 27; (b) T.-H. Kang, Y. Murakami, H. Takayama, M. Kitajima,
tosyl substituent on the indole nitrogen. However, all attempts to
introduce the ethyl substituent at the a-position of the lactam
carbonyl from the Nind-tosyl analog of 6 were unsuccessful. In some
cases the alkylation occurred on the methyl group of the tosyl
substituent.
N. Aimi, H. Watanabe and K. Matsumoto, Life Sci., 2004, 76, 331; 13 S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle and M. R. J. Elsegood,
(c) C.-H. Chou, C.-L. Gong, C.-C. Chao, C.-H. Lin, C.-Y. Kwan, Tetrahedron Lett., 2004, 45, 7103.
C.-L. Hsieh and Y.-M. Leung, J. Nat. Prod., 2009, 72, 830; for reviews, 14 Minor amounts of 20-epi-7 were also formed (7 : 20-epi-7 ratio,
see: (d) J.-S. Shi, J.-X. Yu, X.-P. Chen and R.-X. Xu, Acta Pharmacol.
Sin., 2003, 24, 97; (e) J. Zhou and S. Zhou, J. Ethnopharmacol., 2010,
132, 15.
4 : 1). Performing the alkylation at a lower temperature resulted
in a lower yield.
15 S. F. Martin and M. Mortimore, Tetrahedron Lett., 1990, 31, 4557.
´
6 W. Tang and G. Eisenbrand, Handbook of Chinese Medicinal Plants, 16 For reviews, see: (a) M. Amat, M. Perez and J. Bosch, Synlett, 2011,
Wiley, 2011, vol. 2, pp. 1213–1221.
143; (b) M. M. M. Santos, in Heterocyclic Targets in Advanced Organic
Synthesis, ed. M. do C. Carreiras and J. Marco-Contelles, Research
Signpost, Kerala, India, 2011, pp. 69–82. See also: (c) S. M. Allin,
C. I. Thomas, K. Doyle and M. R. J. Elsegood, J. Org. Chem., 2005,
70, 357; (d) S. M. Allin, J. S. Khera, J. Witherington and M. R. J.
7 Partial synthesis: from dihydrocorynantheine, see ref. 4g; from
secologanin, see (a) R. R. Brown, C. L. Chapple and R. Platt,
Tetrahedron Lett., 1976, 1401; Total racemic synthesis: (b) Y. Ban,
M. Seto and T. Oishi, Chem. Pharm. Bull., 1975, 23, 2605; Formal
racemic synthesis: (c) A. Deiters, M. Pettersson and S. F. Martin,
J. Org. Chem., 2006, 71, 6547; Enantioselective formal synthesis:
(d) K. Nagata, H. Ishikawa, A. Tanaka, M. Miyazaki, T. Kanemitsu
and T. Itoh, Heterocycles, 2010, 81, 1791.
8 M. Amat, M. M. M. Santos, A. M. Gomez, D. Jokic, E. Molins and
J. Bosch, Org. Lett., 2007, 9, 2907.
9 Minor amounts (B10%) of the 7,8a-epi derivative were also formed
(2 : 7,8a-epi-2 ratio, 87 : 13).
´
Elsegood, Tetrahedron Lett., 2006, 47, 5737; (e) M. Amat, A. Gomez-
´
Esque, C. Escolano, M. M. M. Santos, E. Molins and J. Bosch, J. Org.
Chem., 2009, 74, 1205.
17 An enantioselective formal synthesis of rhynchophyllines involving
an organocatalyzed asymmetric Michael addition reaction to gen-
erate the first stereocenter has recently been reported: H. Zhang,
X. Ma, H. Kang, L. Hong and R. Wang, Chem.–Asian. J., DOI: 10.1002/
asia.201201046.
´
c
1956 Chem. Commun., 2013, 49, 1954--1956
This journal is The Royal Society of Chemistry 2013