First Asymmetric Total Syntheses of (+)-Crinamine, (-)-Haemanthidine, and (+)-Pretazettine

Full text of DOI:10.1021/jo9815249

7586
J . Org. Chem. 1998, 63, 7586-7587
Sch em e 1
F ir st Asym m etr ic Tota l Syn th eses of
(+)-Cr in a m in e, (-)-Ha em a n th id in e, a n d
(+)-P r eta zettin e
Toyoki Nishimata and Miwako Mori*
Graduate School of Pharmaceutical Sciences,
Hokkaido University, Sapporo 060-0812, J apan
Received J uly 31, 1998
Sch em e 2
The Amaryllidaceae alkaloids have been of interest as
synthetic targets due to the wide range of biological activities
they exhibit.1 Over 100 alkaloids have been isolated from
members of the Amaryllidaceae, and most of these com-
pounds may be classified into eight skeletally homogeneous
subgroups. Here, we report the first asymmetric total
syntheses2 of the crinane-type alkaloid, (+)-crinamine (1),3
(-)-haemanthidine (2), and (+)-pretazettine (3)4,5 in a few
efficient steps (Scheme 1).
Our plan is shown in Scheme 2. We have already reported
the asymmetric synthesis of 2-arylcyclohexenylamine de-
rivatives via π-allylpalldium complex generated from 4, Pd-
(0), and (S)-BINAPO.7 There are many alkaloids containing
the hexahydroindole skeleton that have an aryl group at the
ring junction. We were stimulated to synthesize some of
these alkaloids in optically pure form. If aldehyde (S)-6 is
obtained using this asymmetric amination procedure, the
intramolecular carbonyl-ene reaction8 of 6 would construct
the quaternary carbon center of 7 in a stereoselective
manner via I. From this compound, the target alkaloids
would be synthesized in an optically pure form in short steps.
Initially, we tried to synthesize cyclohexenylamine deriva-
tive 9 from 49 and 8 (Scheme 3).10 When a THF solution of
4a (1 equiv), acetal 8 (1.1 equiv), Pd2dba3‚CHCl3 (2.5 mol
Sch em e 3
Ta ble 1.
Rea ction of 4 w ith 8 in th e P r esen ce of
P a lla d iu m Com p lex
temp
(°C)
time
(h)
yield
(%)a
ee
(%)
run
X
solv
(1) (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, p 251. (b) Hoshino, O. Ibid. 1998; Vol. 51, p 323.
(c) Lewis, J . R. Nat. Prod. Rep. 1998, 15, 107.
(2) Asymmetric total syntheses of crinine-type alkaloids: (a) (+)-Mar-
itidine: Yamada, S.-I.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1976, 57.
(b) (-)-Crinine: Overman, L. E.; Sugai, S. Helv. Chem. Acta 1985, 68, 745.
(c) (-)-Amabiline and (-)-augustamine: Pearson, W. H.; Lovering, F. E. J .
Am. Chem. Soc. 1995, 117, 12336. (d) Formal total synthesis of (+)-
Maritidine: Kita, Y.; Takeda, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.;
Eichhorn, J . J . Org. Chem. 1996, 61, 5857.
1
2
3
4
CO2Me (4a )
THF
rt
0
0
-20
-20
-20
rt
18
106
4
48
91
68
31 (38)
73
80
65
60
68
69
74
67
68
75
b
PO(OEt)2 (4b) THF
THF
DMF
EtCN
THF
5
6
310
160
48 (21)
43 (28)
7c
(3) Isolations of (+)-crinamine: (a) Mason, L. H.; Puschett, E. R.;
Wildman, W. C. J . Am. Chem. Soc. 1955, 77, 1253. (b) Kobayashi, S.;
Tokumoto, T.; Kihara, M.; Imakura, Y.; Shingu, T.; Taira, Z. Chem. Pharm.
Bull. 1984, 32, 3015. Total synthesis of (()-crinamine: (c) Isobe, K.; Taga,
J .; Tsuda, Y. Tetrahedron Lett. 1976, 2331.
a
The number in parenthesis shows the yield of recovered
starting material. b NaH was used as a base. c (S)-BINAP was used
as a ligand.
(4) Isolations of (-)-haemanthidine: (a) Boit, H. G. Chem. Ber. 1954,
87, 1339. (b) Takagi, S.; Yamaki, M. Yakugaku Zasshi 1974, 94, 617. Chem.
Abstr. 81, 74924y. Isolation of (+)-pretazettine: (c) Wildman, W. C.; Bailey,
D. T. J . Org. Chem. 1968, 33, 3749. Total syntheses of (()-haemanthidine
and (()-pretazettine: (d) Hendrickson, J . B.; Bogard, T. L.; Fisch, M. E. J .
Am. Chem. Soc. 1970, 92, 5538. (e) Tsuda, Y.; Ukai, A.; Isobe, K. Tetrahedron
Lett. 1972, 3153. (f) Martin, S. F.; Davidsen, S. K. J . Am. Chem. Soc. 1984,
106, 6431. Formal total synthesis of (()-haemanthidine and (()-pretazet-
tine: (g) Ishibashi, H.; Nakatani, H.; Iwatani, S.; Sato, T.; Nakamura, N.;
Ikeda, M. J . Chem. Soc., Chem. Commun. 1989, 1767.
(5) Total syntheses of (()-tazettine and/or (()-6a-epipretazettine (syn-
thetic compound by Wildman6): (a) Danishefsky, S.; Morris, J .; Mullen, G.;
Gammill, R.; J . Am. Chem. Soc. 1980, 102, 2838. (b) White, J . D.; Chong,
W. K. M.; Thirring, K. J . Org. Chem. 1983, 48, 2300. (c) Abelman, M. M.;
Overman, L. E.; Tran, V. D. J . Am. Chem. Soc. 1990, 112, 6959. (d) Rigby,
J . H.; Cavezza, A.; Heeg, M. J . J . Am. Chem. Soc. 1998, 120, 3664. Formal
total synthesis of (()-6a-epipretazettine: (e) Overman, L. E.; Wild, H.
Tetrahedron Lett. 1989, 30, 647.
(6) Wildman, W. C.; Bailey, D. T. J . Am. Chem. Soc. 1969, 91, 150.
(7) Mori, M.; Kuroda, S.; Zhang, C.-S.; Sato, Y. J . Org. Chem. 1997, 62,
3263.
(8) Recent review; Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.
(9) Substrate 4a and 4b were synthesized by the same procedure as that
previously reported.7 For experimental details, see Supporting Information.
(10) Hall, R. J .; Dharmasena, P.; Marchant, J .; Oliveira-Campos, A.-M.
F.; Queiroz, M.-J . R. P.; Raposo, M. M.; Shannon, P. V. R. J . Chem. Soc.,
Perkin Trans. 1 1993, 1879.
%), and (S)-BINAPO11 (5.0 mol %) was stirred at room
temperature for 18 h, cyclohexenylamine derivative 9 was
obtained in 68% yield with 60% ee as a crystalline product
(Table 1, run 1).12 The ee of 9 was slightly increased when
the reaction was carried out at a low temperature, although
the reaction time was long and the yield was moderate (run
2). Then the leaving group was changed to phosphonate,
and the reaction of 4b with 8 was carried out in the presence
of NaH. At a low temperature, the reaction proceeded
smoothly, and the desired product 9 was obtained in 80%
yield with 74% ee (run 4). As a solvent, THF was the most
suitable (runs 4-6), and with (S)-BINAP as the ligand the
reaction gave 9 with a high ee, although the yield was only
moderate (run 7).
Surprisingly, when compound 9 with 74% ee was recrys-
talyzed from MeOH, racemic 9 was obtained as colorless
(11) Grubbs, R. H.; DeVries, R. A. Tetrahedron Lett. 1977, 26, 1879.
(12) The ee value of 9 was determined by HPLC analysis (DAICEL
CHIRALPAK AS, hexane/2-propanol 9/1).
10.1021/jo9815249 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/01/1998

Communications
J . Org. Chem., Vol. 63, No. 22, 1998 7587
Sch em e 4
Sch em e 5
Sch em e 6
crystals, and the concentration of the mother liquor gave
the oily (-)-9 with 99% ee.
Next the intramolecular carbonyl-ene reaction of enantio
pure 9 was carried out. Deacetalization of 9 with FeCl3‚
SiO213 gave the aldehyde 6 in high yield. As expected, when
a toluene solution of 6 was heated at 230-240 °C in the
presence of 4 Å molecular sieves for several hours, the
desired hexahydroindole 7 was obtained in 51-59% yield
(68-72% conversion) as a sole product. The NOE experi-
ment with acetylated compound 10 indicates that the ring
junction of the five- and six-membered ring is cis and that
the acetoxy group is trans to the aryl group. The stereo-
chemistry of this compound is consistent with that of the
target alkaloids. On the other hand, the SnCl4-catalyzed
(10 mol %) carbonyl-ene reaction of 6 in CH2Cl2 at 0 °C for
3 h gave an unusual rearrangement product 11 in 82%
yield.14 From the spectral data, the structure of this
compound was assigned to be 11, as shown in Scheme 4.15
Presumably, the six-membered ring formation is promoted
by the coordination of SnCl4 to the carbonyl group, and the
generated cation II is stabilized by an adjacent aryl group.
Carbon-carbon bond fission of II is accelerated by the
formation of an imminium cation, and then oxygen attacks
III to give cyclic ether 11.16
The alkaloids 1-3 were synthesized from the key inter-
mediate 10 (Scheme 5). Allylic oxidation of 10 with SeO2
gave alcohol 12 in a highly stereoselective manner as the
sole product because SeO2 approached the olefin from the
face opposite of the large phenyl group. It is quite interest-
ing that the reaction of Ms2O with 12 in the presence of
NEt3, followed by treatment with MeOH, gave 13 as the
main product (13:14, 6.0:1).17 Detosylation of 13 followed
by methylenation and deacetylation smoothly proceeded to
give (+)-crinamine, whose [R]D value, melting point, and
spectral data agreed with those reported in the literature.3a,b
Thus, the asymmetric total synthesis of (+)-crinamine was
achieved in nine steps from 4b in 20% overall yield, and this
establishes the absolute confuguration of C-3 in (-)-9 to be
S.
(13) Fadel, A.; Yefsah, R.; Salau¨n, J . Synthesis 1987, 37.
(14) The ee of 11 was determined by HPLC (DAICEL CHIRALCEL OD)
to be 70% ee. Probably, compound 6 was partially racemized by coordination
of SnCl4 to the tosyl amide group.
(15) When compound 16 was treated with 100 mol % of SnCl4 at -5 °C,
unusual rearrangement products were obtained in 19% yield as a mixture
of 17 and 18 along with 19.
Ta ble 2 Sn Cl4-P r om oted Ca r bon yl-en e Rea ction of 16
For the synthesis of (-)-haemanthidine (2) and (+)-
pretazettine (3), the Mitsunobu reaction of 12 with formic
acid, followed by hydrolysis, was carried out to give the
epimeric alcohol of 12 in 94% yield. However, treatment of
epi-12 with MeI in the presence of KH or NaH gave 14 in
low yield. After various attempts, and it was found that
treatment of 12 with HC(OMe)3 in the presence of Mont-
morillonite K-1018 gave 14 in high yield (14:13, 4.0:1)
(Scheme 6). Detosylation of 14, followed by formylation,19
gave compound 15. Treatment of 15 with POCl3, followed
by deacetylation, gave (-)-haemanthidine (2), which could
be converted into (+)-pretazettine (3) by a known method.4c,f
The [R]D value, melting point, and spectral data of synthetic
2 and 3, respectively, agreed with those reported in the
literature.4a-c Further studies are in progress.
yield (%)
SnCl4
temp
(°C)
(mol %)
17
18
19
100
10
-5
rt
13
89
6
0
29
0
However, this reaction was carried out using 10 mol % of SnCl4 to give 17
in 89% yield as a single product. By comparing with the spectral data of 17
and 18 and the spectra of the NOE experiments on them, the stereochem-
istry of these compounds could be determined. The stereochemistry of 11
was confirmed by a comparison with the above data.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research (No. 09470478) from
Ministry of Education, Science, Sports and Culture, J apan,
which is gratefully acknowledged.
(16) A similar rearrangement has been reported: cf. Csuzdi, E.; Pallagi,
I.; J erkovich, G.; So´lyom, S. Synlett 1994, 429.
(17) In previous reports,4f,5a,b compounds having the methyl group on
nitrogen (in our case, tosyl group) were treated under the same reaction
conditions to give only R-methoxylated product.
Su p p or tin g In for m a tion Ava ila ble: The experimental pro-
cedures for the synthesis of 1-3 and spectral data (9 pages).
(18) Kumar, H. M. S.; Reddy, B. V. S.; Mohanty, J . S.; Yadav, J . S.
Tetrahedron Lett. 1997, 38, 3619.
(19) Schmidhammer, H.; Brossi, A. Can. J . Chem. 1982, 60, 3055.
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