A new entry to Amaryllidaceae alkaloids from carbohydrates: total synthesis of (+)-vittatine.

Article abstract of DOI:10.1039/b402762k

The stereoselective and chiral synthesis of the Amaryllidaceae alkaloid, (+)-vittatine 1, is described; the quaternary carbon in 1 was generated by Claisen rearrangement of a cyclohexenol derived from D-glucose by way of a Ferrier's carbocyclisation react

Full text of DOI:10.1039/b402762k

A new entry to Amaryllidaceae alkaloids from carbohydrates: total
synthesis of (+)-vittatine†
Masahiro Bohno, Hidetomo Imase and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan. E-mail: chida@applc.keio.ac.jp; Fax: 81 45 566 1573; Tel: 81 45 566 1573
Received (in Cambridge, UK) 23rd February 2004, Accepted 11th March 2004
First published as an Advance Article on the web 30th March 2004
The stereoselective and chiral synthesis of the Amaryllidaceae
alkaloid, (+)-vittatine 1, is described; the quaternary carbon in 1
was generated by Claisen rearrangement of a cyclohexenol
Reduction of the ester function in 7 with DIBAL-H gave primary
alcohol 8 (97% yield), to which was introduced an amino function
by Mitsunobu amination11 to afford 9 in 98% yield (Scheme 2).
Treatment of 9 with Na–naphthalene12 in THF at 240 °C removed
N-Ts as well as O-benzyl groups to give 10 in 77% yield. The
construction of the perhydroindole skeleton was successfully
achieved by intramolecular aminomercuration–demercuration10b,13
of 10 to provide 11 in 75% yield.§ The requisite carbon–carbon
double bond between C(1) and C(2) was introduced by Chugaev
reaction. Thus, the hydroxy group in 11 was transformed into
xanthate ester, and this was heated at 160 °C in the presence of
potassium carbonate to provide 12 in 80% yield. Deprotection of
the N-Boc group by the action of BF3·OEt2 gave 13 (78% yield,
starting material 12 was recovered in 14% yield). Exposure of 13 to
the conditions of the Pictet–Spengler reaction5b generated the
fourth ring between N(5) and C(14) and induced the deprotection of
derived from -glucose by way of a Ferrier’s carbocyclisation
D
reaction and a hexahydroindole skeleton was effectively con-
structed by intramolecular aminomercuration–demercuration,
followed by Chugaev reaction.
Ferrier’s carbocyclisation reaction is one of the most useful
transformations for the construction of optically pure cyclohex-
anone derivatives from aldohexoses.1 Chiral and highly function-
alized cyclohexanes obtained by this reaction are potentially
versatile chiral building blocks in natural product synthesis.2 Here
we report a stereoselective and chiral total synthesis of (+)-vittatine
1, an Amaryllidaceae alkaloid, starting from -glucose. (+)-Vitta-
D
tine3 is the enantiomer of (2)-crinine, a representative natural
product of the crinine class of alkaloids, and has a basic skeleton
with the same absolute configuration as that of the more
pharmacologically active crinane class of alkaloids such as
haemanthidine, pretazettine and tazettine.4 Although a number of
synthetic approaches towards crinine and the crinan class of
alkaloids have been developed,5 reports on chiral syntheses of these
natural products6 are limited. Since these alkaloids are known to
show a wide range of biological activities,4 it is still important to
establish a chiral and effective synthetic route to these compounds
from readily available materials.
1
the O-TBS group to furnish (+)-vittatine 1 in 51% yield. The H
NMR data (CDCl3)¶ were fully identical with those for (2)-crinine
reported by Pearson5c and physical properties of 1 showed good
22
agreement {mp 205–207 °C; [a]D +28 (c 0.20, CHCl3)} with
25
those reported for natural (+)-vittatine3b {mp 207–208 °C; [a]D
+26 (c 0.5, CHCl3)}.
Synthesis of 1 commenced from 3-deoxy-
prepared from commercially available methyl 4,6-O-benzylidene-
a- -glucopyranoside in two steps (75% overall yield). Compound
D
-glucose derivative7 2
D
2 was converted into the known chiral cyclohexenone 32a‡ by the
procedure developed in our laboratory using catalytic Ferrier’s
carbocyclisation reaction8 as the key transformation (total 5 steps,
50% overall yield) (Scheme 1). Reaction of 3 with 3,4-(methylene-
dioxy)phenylmagnesium bromide at 2100 °C gave 1,2-adduct 4 as
a diastereomeric mixture (ca. 3 : 1) in 92% yield. Oxidation of 4
with PCC afforded cyclohexenone 5, which was reduced under the
conditions of Luche9 at 278 °C to give allyl alcohol 6 and its
diastereomeric alcohol in 68 and 7% yields from 4, respectively.
The observed coupling constant in 6 (J1,2 = 7.8 Hz) supported the
assigned configuration. Claisen rearrangement of 6 with triethyl
orthoacetate in the presence of powdered molecular sieves 4A and
a catalytic amount of propionic acid10 at 130 °C successfully
constructed the quaternary carbon to provide the rearranged
product 7 in 60% yield (starting material 6 was recovered in 10%
yield).
Scheme 1 Bn = –CH2Ph, TBS = –SiMe2(t-Bu). Reagents and conditions:
i (1) diisobutylaluminium hydride (DIBAL-H), toluene, rt, (2) I2, Ph3P,
imidazole, toluene, (3) TBSCl, imidazole, DMF; (4) t-BuOK, THF; (5)
Hg(OCOCF3)2 (30 mol%), acetone–acetate buffer (1 : 1), rt, then MsCl,
Et3N, CH2Cl2 (see ref. 2a); ii 3,4-(methylenedioxy)phenyl bromide, Mg,
THF, 2100 °C; iii PCC, MS4A, CH2Cl2, rt; iv NaBH4, CeCl3·7H2O,
MeOH–CH2Cl2 (1 : 1), 278 °C; v CH3C(OEt)3, cat. EtCOOH, MS4A, 130
°C, 48 h, in a sealed tube.
† Electronic Supplementary Information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b4/b402762k/
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C h e m . C o m m u n . , 2 0 0 4 , 1 0 8 6 – 1 0 8 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

1 R. J. Ferrier and S. Middleton, Chem. Rev., 1993, 93, 2779; R. J. Ferrier
and S. Middleton, Top. Curr. Chem., 2001, 215, 277.
2 For recent application of Ferrier’s carbocyclisation reaction to natural
product synthesis, see (a) S. Imuta, S. Ochiai, M. Kuribayashi and N.
Chida, Tetrahedron Lett., 2003, 44, 5047; (b) T. Momose, M. Setoguchi,
T. Fujita, H. Tamura and N. Chida, Chem. Commun., 2000, 2237; (c) S.
Amano, N. Ogawa, M. Ohtsuka and N. Chida, Tetrahedron, 1999, 55,
2205; S. Amano, N. Takemura, M. Ohtsuka, S. Ogawa and N. Chida,
Tetrahedron, 1999, 55, 3855; H. Takahashi, H. Kittaka and S. Ikegami,
J. Org. Chem., 2001, 66, 2705; C. Taillefumier and Y. Chapleur, Can.
J. Chem., 2000, 78, 708.
3 Isolation of (+)-vittatine, see (a) H.-G. Boit, Chem. Ber., 1956, 89, 1129;
(b) H.-G. Boit and H. Ehmke, Chem. Ber., 1957, 90, 369; (c) Y. Uyeo,
K. Kotera, T. Okada, S. Takagi and Y. Tsuda, Chem. Pharm. Bull.,
1966, 14, 793.
4 S. F. Martin, in The Alkaloids, ed. A. Brossi, Academic Press, New
York, 1987, vol. 30, p. 251; O. Hoshino, in The Alkaloids, ed. G. A.
Cordell, Academic Press, New York, 1998, vol. 51, p. 323; J. R. Lewis,
Nat. Prod. Rep., 1998, 15, 107.
5 For total synthesis of racemic crinine, see (a) H. Muxfeldt, R. S.
Schneider and J. B. Mooberry, J. Am. Chem. Soc., 1966, 88, 3670; H. W.
Whitelock Jr. and G. L. Smith, J. Am. Chem. Soc., 1967, 89, 3600; L. E.
Overman, L. T. Mandelson and E. F. Jacobsen, J. Am. Chem. Soc., 1983,
105, 6629; (b) S. F. Martin and C. L. Campbell, Tetrahedron Lett., 1987,
28, 503; S. F. Martin and C. L. Campbell, J. Org. Chem., 1988, 53, 3184;
(c) W. H. Pearson and F. E. Lovering, J. Org. Chem., 1998, 63, 3607.
For synthetic efforts towards crinine and the crinan class of alkaloids,
see ref. 4.
6 For total synthesis of (2)-crinine, see L. E. Overman and S. Sugai, Helv.
Chim. Acta, 1985, 68, 745. (+)-Maritidine, see Y. Kita, T. Takeda, M.
Gyoten, H. Tohma, M. H. Zenk and J. Eichhorn, J. Org. Chem., 1991,
61, 5857. (2)-Amabiline and (2)-augustamine, see ref. 5(c). (+)-Crina-
mine, (2)-haemanthidine and (+)-pretazettine, see T. Nishimata and M.
Mori, J. Org. Chem., 1998, 63, 7586; T. Nishimata, Y. Sato and M.
Mori, J. Org. Chem., 2004, 69, 1837. (2)-Haemanthidine, (+)-pre-
tazettine and (+)-tazettine, see S. W. Baldwin and J. S. Debenham, Org.
Lett., 2000, 2, 99.
Scheme 2 Ts = –C6H4(p-Me), Boc = –C(O)OCMe3. Reagents and
conditions: i DIBAL-H, toluene, 278 °C; ii NH(Ts)Boc, PPh3, diethyl
azodicarboxylate. THF, rt; iii Na–naphthalene, THF, 240 °C, 90 min; iv
Hg(OCOCF3)2, THF, rt, then NaBH4, 0.5 M aq. NaOH–MeOH, rt; v NaH,
CS2, MeI, THF, then 1,2-dichlorobenzene, K2CO3, MS4A, 160 °C; vi
BF3·OEt2, MS4A, CH2Cl2, rt; vii formalin, 6 M aq. HCl–MeOH, 50 °C.
In summary, transformation of a readily available carbohydrate,
D-glucose, into the representative Amaryllidaceae alkaloid, (+)-vit-
tatine 1, has been achieved. This is the first asymmetric synthesis of
1 and further study on synthesis of structurally more complex
alkaloids in this class such as haemanthidine and tazettine based on
the same strategy is under investigation in our laboratory.
7 E. Vis and P. Karrer, Helv. Chim. Acta, 1954, 46, 378.
8 N. Chida, M. Ohtsuka, K. Ogura and S. Ogawa, Bull. Chem. Soc. Jpn.,
1991, 64, 2118.
9 A. L. Gemal and J.-L. Luche, J. Am. Chem. Soc., 1981, 103, 5454.
10 (a) S. Kano, T. Yokoyama, Y. Yuasa and S. Shibuya, Chem. Lett., 1982,
1915; H. F. Strauss and A. Wiechers, Tetrahedron Lett., 1979, 4495; H.
Fujioka, H. Annoura, K. Murano, Y. Kita and Y. Tamura, Chem. Pharm.
Bull., 1989, 37, 2047; S. Bauermeister, I. D. Gouws, H. F. Strauss and
E. M. M. Venter, J. Chem. Soc., Perkin Trans. 1, 1991, 561; (b) N.
Chida, K. Sugihara and S. Ogawa, J. Chem. Soc., Chem. Commun.,
1994, 901; N. Chida, K. Sugihara, S. Amano and S. Ogawa, J. Chem.
Soc., Perkin Trans. 1, 1997, 275.
11 J. R. Henry, L. R. Marcin, M. C. McIntosh, P. M. Scola, G. D. Harris Jr.
and S. M. Weinreb, Tetrahedron Lett., 1989, 30, 5709.
12 O. Yamada and K. Ogasawara, Org. Lett., 2000, 2, 2785.
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Notes and references
‡ Cyclohexenone 3 was used as the key intermediate for our total synthesis
of (2)-actinobolin. See ref. 2(a).
§ Similar aminomercuration gave no cyclised product when the correspond-
ing amine (with no Boc group) was employed as the substrate.
¶ In the 1H and 13C NMR of vittatine in CDCl3 (treated with alumina prior
to measuring to remove residual DCl), chemical shifts of some signals were
found to vary significantly by the concentration of the sample. Such
concentration dependence was not observed when spectra were measured in
pyridine-d5.
C h e m . C o m m u n . , 2 0 0 4 , 1 0 8 6 – 1 0 8 7
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