Total synthesis of the Kopsia lapidilecta alkaloid (±)-lapidilectine B [1]

Full text of DOI:10.1021/ja016007d

6724
J. Am. Chem. Soc. 2001, 123, 6724-6725
Scheme 1a
Total Synthesis of the Kopsia lapidilecta Alkaloid
(()-Lapidilectine B
William H. Pearson,* Yuan Mi, Ill Young Lee, and
Patrick Stoy
Department of Chemistry, UniVersity of Michigan
Ann Arbor, Michigan 48109-1055
ReceiVed April 12, 2001
The genus Kopsia (Apocynaceae, subfamily Plumerioideae)
is comprised of about 30 species that grow in South and Southeast
Asia.1,2 Lapidilectine B (1) is one of several 5,6,12,13-tetrahydro-
11a,13a-ethano-3H-pyrrolo[1′,2′:1,8]azocino[5,4-b]indoles that
have been isolated from this genus of plants.3-5 It was isolated
by Awang, et al. from the leaves of the tree Kopsia lapidilecta in
1992, and its structure was elucidated by two-dimensional NMR
experiments.3,4,6 The absolute configuration of lapidilectine B is
proposed to be as shown based on biogenesis and a positive
Cotton effect.3 Although there are no reports on the pharmaco-
logical effects of Kopsia lapidilecta alkaloids, various medicinal
uses of other Kopsia alkaloids have been reported, including the
treatment of rheumatoid arthritis, dropsy, tonsillitis, and hyperten-
sion.2,5,7 No synthetic studies on Kopsia lapidilecta alkaloids have
been reported.8 We report herein the first total synthesis of a
Kopsia lapidilecta alkaloid, namely (()-lapidilectine B (1).
Notable elements of the synthesis are the assembly of the pyrroline
ring by the cycloaddition of a 2-azaallyllithium (2) with the
acetylene equivalent phenyl vinyl sulfide9 (Scheme 1) and the
assembly of a key 1,2-dihydro-3H-indol-3-one (an “indoxyl”) via
a Smalley cyclization10,11 of an azido enolate. Further, an
intramolecular N-alkylation is used to generate the perhydroazo-
cine ring.
a LDA, THF, -78 °C; PhNTf2, 0 °C, 2 h (82%). b (Me3Sn)2, LiCl,
cat. Pd(PPh3)4, THF, reflux, 5 h (91%). c CO (80 psi), cat. Pd2(dba)3,
Ph3As, LiCl, 4 Å molecular sieves, NMP, 70 °C, 12 h (98%). d 3 equiv
(2-thienyl)Cu(CN)Li, 3 equiv CH2dCH2MgBr, BF3‚OEt2, THF, -78 °C,
10 h (84%). e 10 equiv concd HCl, MeOH, rt, 30 min (68%). f 3 equiv
concd HCl, 2 equiv NaNO2, EtOH, 0 °C, 30 min; 4 equiv NaN3 in H2O.
g 5 equiv KOH iPrOH, 15 °C, 1 h (68%, two steps). h t-BuLi, THF, -78
to -50 °C, 1 h; 2 equiv MeOCOCl, 0 °C, 1 h (89%). i OsO4, N-methyl-
morpholine N-oxide, acetone, rt, 8 h (87%). j 3.1 equiv allylmagnesium
bromide, THF, -40 °C to rt, 3 h. k NaIO4, aq THF, pH 7, rt, 3 h (75%,
two steps). l 5 equiv camphorsulfonic acid, MeOH, rt, 2 h (82%). m O3,
pyridine, CH2Cl2, MeOH, -78 °C, 5 min; NaBH4 (80-87%). n TBDPSCl,
imidazole, CH2Cl2, 0 °C to rt, 3 h (88%). o Pd(OH)2, cyclohexene, EtOH,
reflux, 4 h (82-92%). p tetra-n-propylammonium perruthenate, N-methyl-
morpholine-N-oxide, 4 Å molecular sieves, CH2Cl2, rt, 1 h (95%).
q TeocCl, iPr2NEt, CH2Cl2, rt, 1 h (91%). r m-CPBA (1 equiv), NaHCO3,
CH2Cl2, -30 °C to rt, 2 h (88%). s pyridine, Cl2CdCCl2, 140 °C, 4 h
(85%). t BCl3, CH2Cl2, -10 °C, 1 h. u PCC, Celite, CH2Cl2, rt, 2 h (45%,
two steps). V HF‚pyridine, THF, rt, 2 h (88%). w MsCl, iPr2NEt, CH2Cl2,
A mixture of cis- and trans-cyclohexane-1,4-diol was monoben-
zylated and oxidized to give the known12 ketone 3 (Scheme 1).
Formation of the enol triflate of 313 followed by stannylation
according to Wulff and co-workers14 gave 4. Stille carbonylative
coupling15,16 of 4 with the known iodoaniline derivative 515 gave
(1) Margraf, F. Blumea 1972, 20, 416-425.
(2) Se´venet, T.; Allorge, L.; David, B.; Awang, K.; Hadi, A.; Hamid, A.;
Kan-Fan, C.; Quirion, J.-C.; Remy, F.; Schaller, H.; Teo, L. E. J. Ethnop-
harmacol. 1994, 41, 147-183.
(3) Awang, K.; Se´venet, T.; Pa¨ıs, M.; Hadi, A. H. A. J. Nat. Prod. 1993,
56, 1134-1139.
(4) Awang, K.; Se´venet, T.; Hadi, A. H. A.; David, B.; Pa¨ıs, M. Tetrahedron
Lett. 1992, 33, 2493-2496.
(5) (a) Kam, T.-S.; Yoganathan, K.; Chuah, C.-H. Tetrahedron Lett. 1995,
36, 759-762. (b) Kam, T.-S.; Yoganathan, K.; Koyano, T.; Komiyama, K.
Tetrahedron Lett. 1996, 37, 5765-5768. (c) Kam, T.-S.; Yoganathan, K.; Li,
H.-Y.; Harada, N. Tetrahedron 1997, 53, 12661-12670.
(6) The CAS name of lapidilectine B is [6aR-(6aR,11aâ,12R,13aâ)]-5,6,-
12,13-tetrahydro-16-oxo-11H-6a,12-(epoxymethano)-11a,13a-ethano-3H-pyr-
rolo[1′,2′:1,8]azocino[5,4-b]indole-11-carboxylic acid methyl ester. The re-
searchers who isolated this alkaloid (Awang, et al., refs 3, 4) use a different
numbering system, shown in parentheses after the corresponding CAS
numbers: 1(15), 2(14), 3(3), 4(4), 6a(7), 11a(2), 13a(20).
y
-10 °C to rt, 30 min (92%). x TFA, CH2Cl2, rt, 1 h. iPr2NEt, MeCN,
60 °C, 10 h; 3 equiv DBU (45%, two steps).
the enone 6. Conjugate addition of a vinyl group, which would
eventually supply the carbonyl group at C-16 of lapidilectine B,
was accomplished using vinylmagnesium bromide under Lip-
shutz’s conditions,17,18 producing a 3:1 mixture of diastereomeric
ketones 7 after hydrolysis of the perhydro-1,3-dimethyl-1,3,5-
triazin-2-one protecting group. Both stereoisomers of 7 bore a
trans relationship between the vinyl and benzyloxy groups, as
(7) (a) Burkhill, I. H. A Dictionary of the Economic Products of the Malay
Peninsula; Ministry of Agriculture and Cooperatives: Kuala Lumpur,
Malaysia, 1966. (b) Xiao, Z. F.; Kan, C.; Potier, P.; Kan, S. K.; Lounasmaa,
M. Planta Med. 1983, 48, 280-282. (c) Feng, X. Z.; Kan, C.; Husson, H. P.;
Potier, P.; Kan, S. K.; Lounasmaa, M. J. Nat. Prod. 1984, 47, 117-122. (d)
Mok, S. L.; Yoganathan, K.; Lim, T. M.; Kam, T.-S. J. Nat. Prod. 1998, 61,
328-332.
10.1021/ja016007d CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/14/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 27, 2001 6725
verified by the relative configuration of a later compound in the
synthesis (i.e., 12, vide infra). Diazotization of the aniline 7
followed by displacement with sodium azide gave the o-azido
ketone 8.19,20 Treatment of 8 with KOH according to Smalley
and co-workers10,11 caused cyclization to the diastereomeric 1,2-
dihydro-3H-indol-3-ones 9 (shown) and 10 (not shown) in good
overall yield from the aniline 7. The major diastereomer 9 was
subjected to N-acylation and dihydroxylation to give the diol 11
as a 6:1 mixture of diastereomers. Allylation of the ketone,
oxidative cleavage of the diol, and methyl acetal formation
produced a single diastereomer of 12, whose structure was verified
by X-ray crystallography. The minor amino ketone 10 from the
Smalley cyclization could also be transformed into 12, except
that the benzyloxy-bearing stereocenter had the opposite config-
uration.21 Ozonolysis of 12, reduction, and silylation gave 13,
which was debenzylated and oxidized22 to afford the pivotal
ketone 14. Condensation of a solution of 14 in toluene with
(aminomethyl)tributylstannane23 in the presence of trimethyl-
aluminum9b generated a solution of the (2-azaallyl)stannane 15,
which was diluted with THF and treated sequentially with phenyl
vinyl sulfide and n-BuLi at -78 °C. The spirocyclic pyrrolidine
16 was isolated as a mixture of regio- and stereoisomers (or amide
rotamers)24 in 75% yield based on the ketone 14. Protection of
16 as its Teoc derivative followed by oxidation of the sulfide to
the sulfoxide and elimination gave the 3-pyrroline 17 in good
overall yield.24 Hydrolysis of the methyl acetal with aqueous acid
was problematic, but demethylation with boron trichloride
provided the lactol, which was oxidized to a lactone with PCC.
Deprotection of the alcohol and mesylation afforded 18. Finally,
Teoc removal with CF3CO2H followed by heating the trifluoro-
acetate salt with Hu¨nig’s base gave (()-lapidilectine B (1), which
exhibited physical data identical to those of the natural alkaloid,
spectra of which were kindly provided by Dr. Khalijah Awang
of the University of Malaya.25
In summary, the first total synthesis of (()-lapidilectine B has
been accomplished, which also represents the first synthesis of a
member of the 5,6,12,13-tetrahydro-11a,13a-ethano-3H-pyrrolo-
[1′,2′:1,8]azocino[5,4-b]indole class of alkaloids. The pivotal
2-azaallyl anion cycloaddition proceeded in good yield and facial
selectivity to produce the spirocyclic pyrrolidine substructure.
Other key steps include the first implementation of Smalley’s
method for 1,2-dihydro-3H-indol-3-one (indoxyl) synthesis in a
natural product setting, and a successful intramolecular N-
alkylation to generate the perhydroazocine nucleus of this alkaloid.
Further studies on the use of these methods for the synthesis of
related Kopsia alkaloids are underway.
(8) For recent synthetic work on other Kopsia alkaloids, see: (a) Magnus,
P.; Hobson, L. A.; Westlund, N.; Lynch, V. Tetrahedron Lett. 2001, 42, 993-
997. (b) Magnus, P.; Westlund, N. Tetrahedron Lett. 2000, 41, 9369-9372.
(c) Kuehne, M. E.; Li, Y.-L.; Wei, C.-Q. J. Org. Chem. 2000, 65, 6434-
6440. (d) Magnus, P.; Payne, A. H.; Hobson, L. Tetrahedron Lett. 2000, 41,
2077-2081. (e) Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.; Lynch,
V. Tetrahedron Lett. 1999, 40, 5135-5138.
Acknowledgment. We thank the National Institutes of Health (GM-
52491), the Petroleum Research Fund, administered by the American
Chemical Society, and the Korea Science and Engineering Foundation
(KOSEF fellowship to I.Y.L.) for financial support of this research. We
thank Dr. Khalijah Awang of the University of Malaya for providing
spectra of natural lapidilectine B, and Dr. Jeff W. Kampf of the University
of Michigan (Department of Chemistry) for the X-ray crystallographic
determination of the structure of 12.
(9) See the following recent papers and the earlier work cited therein: (a)
Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607-3617. (b)
Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688-689.
(10) Ardakani, M. A.; Smalley, R. K. Tetrahedron Lett. 1979, 4769-4772.
(11) Azadi-Ardakani, M.; Alkhader, M. A.; Lippiatt, J. H.; Patel, D. I.;
Smalley, R. K.; Higson, S. J. Chem. Soc., Perkin Trans I 1986, 1107-1111.
(12) Young, R. C.; Downes, C. P.; Jones, M.; Milliner, K. J.; Rana, K. K.;
Ward, J. G. Eur. J. Med. Chem. 1994, 29, 537-550. Sequence used: PhCH2-
Br, NaH, DMF, 60 °C, 12 h (37%); PCC, Celite, CH2Cl2, rt, 3 h (80%).
(13) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
(14) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K.
L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org.
Chem. 1986, 51, 279-280.
Supporting Information Available: Experimental procedures and
characterization data for 1, 6, 9, 10, and 16; photocopies of spectra of
synthetic and natural lapidilectine B; variable temperature 1H NMR spectra
of lapidilectine B (PDF). Crystallographic data for 12 (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.
1995, 117, 5776-5788.
(16) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C. J.
Org. Chem. 1990, 55, 5833-5847.
JA016007D
1
(17) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987,
28, 945-948.
(24) The mixture 16, which showed nine acetal methine protons in its H
NMR spectrum, could be separated by chromatography on silica gel into two
fractions. The first fraction, which contained one-third of the product, was
found to be the 4-(phenylthio)pyrrolidine as either a mixture of two
diastereomers or two amide rotamers. The second fraction, accounting for
two-thirds of the material, was found to be the 3-(phenylthio)pyrrolidine, again
as either two diastereomers or two amide rotamers. This fraction also contained
less than 10% of other isomers. It was not necessary to separate the isomers
of 16 to proceed further. Examination of the alkenes 17 and 18 showed that
they were 4:1 and 7:1 mixtures of diastereomers at the spiro carbon C(13a),
respectively, providing evidence that the diastereofacial selectivity in the
2-azaallyl anion cycloaddition (producing 16) was reasonable.
(18) Lipshutz, B. H.; Parker, D. A.; Kozlowski, J. A.; Nguyen, S. L.
Tetrahedron Lett. 1984, 25, 5959-5962.
(19) Fukuyama, T.; Xu, L.; Goto, S. J. Am. Chem. Soc. 1992, 114, 383-
385.
(20) Duclos, R. I., Jr.; Tung, J. S.; Rapoport, H. J. Org. Chem. 1984, 49,
5243-5246.
(21) Methyl carbamate formation, osmylation, bis(trimethylsilyl) ether
formation, allylmagnesium bromide addition, desilylation, and periodate
cleavage gave an aldehyde that spontaneously epimerized and formed a cyclic
hemiacetal, which was converted to the methyl acetal 12 (but epimeric at the
benzyloxy group). See: Mi, Y. Ph.D. Thesis, University of Michigan, 1999.
(22) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639-666.
(25) In the original work on the isolation of lapidilectine B, several
impurities in the 1H NMR spectrum were noted. We also observed these peaks
but were able to show that they were due to carbamate rotamers by variable
1
(23) Pearson, W. H.; Postich, M. J. J. Org. Chem. 1992, 57, 6354-6357.
temperature H NMR spectroscopy. See the Supporting Information.