Total synthesis of the lycorenine-type amaryllidaceae alkaloid (±)-Clivonine via a biomimetic ring-switch from a lycorine-type progenitor

Article abstract of DOI:10.1021/ja910184j

A fully diastereoselective total synthesis of the lycorenine-type Amaryllidaceae alkaloid (±)-clivonine (19) is reported via a route that employs for the first time a biomimetic ring-switch from a lycorine-type progenitor, thereby corroborating experimentally the biogenetic hypothesis first expounded for these compounds by Barton in 1960.

Full text of DOI:10.1021/ja910184j

Published on Web 03/17/2010
Total Synthesis of the Lycorenine-Type Amaryllidaceae
Alkaloid (()-Clivonine via a Biomimetic Ring-Switch from a
Lycorine-Type Progenitor
Carles Giro´ Man˜as,‡ Victoria L. Paddock,‡ Christian G. Bochet,§,|
Alan C. Spivey,*,‡,| Andrew J. P. White,‡ Inderjit Mann,⊥ and Wolfgang Oppolzer|,†
Department of Chemistry, South Kensington Campus, Imperial College London, London SW7
2AZ, U.K., Department of Chemistry, UniVersity of Fribourg, 9 Ch. du Musee, CH-1700
Fribourg, Switzerland, Department of Organic Chemistry, UniVersity of GeneVa, 30, quai Ernest
Ansermet, CH-1211 GeneVa 4, Switzerland, and GSK Tonbridge, Old Powder Mills, Leigh,
Tonbridge, Kent TN11 9AN, U.K.
Received December 9, 2009; E-mail: a.c.spivey@imperial.ac.uk
Abstract: A fully diastereoselective total synthesis of the lycorenine-type Amaryllidaceae alkaloid (()-
clivonine (19) is reported via a route that employs for the first time a biomimetic ring-switch from a lycorine-
type progenitor, thereby corroborating experimentally the biogenetic hypothesis first expounded for these
compounds by Barton in 1960.
Scheme 1. Outline Biosynthesis of Tazettine and Lycorenine-Type
Alkaloids from Norbelladine (1) via “Ring-Switching” a
Introduction
The Amaryllidaceae alkaloids are a large class of naturally
occurring bases isolated from herbaceous perennials such as
daffodils that can mostly be classified as belonging to one of
eight skeletally distinct subclasses.1 All these alkaloids derive
from a common bisphenol biosynthetic precursor, norbelladine
(1, itself derived from Phe and Tyr).2 This biogenetic scheme
was first enunciated by Barton in 1957.3 He used the Amaryl-
lidaceae alkaloids to illustrate his thesis that intramolecular
phenolic oxidative coupling constituted a critical diversifying
step in alkaloid biosynthesis, an idea that proved correct and
revolutionized our understanding of alkaloid biogenesis.2 Ini-
tially, Barton was unable to account for the tazettine4 and
lycorenine subclasses within this regime, proposing that these
compounds were possibly derived from intermolecular phenolic
coupling,3 but in 1960 he revised his proposal to encompass
their formation by rearrangement of haemeanthamine (2) and
lycorine-type (I) progenitors, respectively.5 Interconversion was
proposed to involve benzylic oxidation (f lactamols 3 and II)
and then ring-opening/bond rotation/ring closure/N-methylation
‡ Imperial College London.
§ University of Fribourg.
| University of Geneva.
⊥ GSK Tonbridge.
† Deceased March 15, 1996.
a Precise structures and non-essential stereochemistry are omitted from
I-IV. (a) p,p-Phenolic coupling; (b) o,p-phenolic coupling; (c) benzylic
oxidation; (d) ring-switching (including N-methylation); (e) Cannizzaro
redox process (during isolation); (f) lactol oxidation.
(1) (a) Jin, Z. Nat. Prod. Rep. 2009, 26, 363–381, and previous reviews
in this series. (b) Hoshino, O. The Alkaloids 1998, 51, 323–424. (c)
Martin, S. F. The Alkaloids 1987, 30, 251–376.
(2) Herbert, R. B. The Biosynthesis of Secondary Metabolites, 2nd ed.;
Springer: Berlin, 1989.
(3) Barton, D. R. H. Festshrift Arthur Stoll; Birkhauser: Basel, Switzerland,
1957; pp126-129.
(4) In 1957, tazettine was thought to be a natural product. Later, Wildman
showed it to be an artifact of isolation during which an intramolecular
crossed-Cannizzaro rearrangement takes place; pretazettine is the
natural product6,7c
(5) (a) Barton, D. R. H. Welch Foundation J. 1960, 165–180. (b) Barton,
D. R. H. Proc. Chem. Soc. 1963, 293–298. (c) Battersby, A. R. Proc.
Chem. Soc. 1963, 189–200.
(f lactols 4 and III), a process we will refer to as “ring-
switching”. An intramolecular crossed-Cannizzaro rearrange-
ment (during isolation)6,7c accounts for the conversion of
pretazettine (4) to tazettine (5), whereas lactol III to lactone
IV oxidation occurs in the lycorenine series (Scheme 1).
Wildman subsequently corroborated these hypotheses by
tritium feeding experiments in Sprekelia formosissima for
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10.1021/ja910184j  2010 American Chemical Society

Total Synthesis of Alkaloid (()-Clivonine
A R T I C L E S
tazettine (5)8 and in Narcissus ‘King Alfred’ for lycorenine.9
Moreover, Wildman developed a biomimetic protocol for the
synthesis of pretazettine (4) from haemeanthidine (3)6 which
has been employed in all but two10 subsequent total syntheses
of tazettine7 and pretazettine.11 However, Wildman was unable
to develop a corresponding protocol for biomimetic conversion
of lycorine to lycorenine-type ring systems (I f IV), noting
that this conversion requires a ∼180° rotation and minimal relief
of strain, as compared to a ∼90° rotation accompanied by
significant relief of strain in the haemeanthidine/pretazettine
series (3 f 4).6,7c,9 Consequently, although Mizukami and
Kotera have developed a multistep, nonbiomimetic synthetic
sequence for this type of interconversion based on the von Braun
reaction,12 Barton’s original hypothesis remains synthetically
unverified. Herein we describe a concise, fully diastereoselective
total synthesis of the lycorenine-type Amaryllidaceae alkaloid
(()-clivonine (19) from a lycorine-type progenitor 17 in which
this key transformation has finally been accomplished.
Scheme 2. Synthesis of Clivonine Progenitor 15
Results and Discussion
Clivonine (19) was isolated and characterized from CliVia
miniata Regel in 1956 by Wildman,13 and its relative and
absolute stereochemistry was established by Jeffs et al. in
1971.14,15 To date, the only synthesis of (()-clivonine has been
that reported by Irie in 1973 (17 steps, 0.43% overall yield from
piperonal).16
The synthesis of (()-clivonine progenitor 15 parallels our
previous synthesis of (+)-trianthine (16), employing a retro-
Cope elimination17 (11 f 12) as the key step (Scheme 2).18
Although trianthine (16) and clivonine progenitor 15 both
have trans B-C/cis C-D ring-junctions, they are diastereomeric
with respect to the ring C cis-diol motif. Consequently, following
1,2-addition of aryllithium reagent to the convex face of bicyclic
enone (()-619,20 and trapping as acetate 7 (92% yield), a one-
pot Ireland-Claisen rearrangement/CH2N2 esterification was
employed to relay the stereochemistry at C11b to C3a with
retention of configuration (f 8, 85% yield; cf. the vinyl cuprate
SN2′ displacement with inVersion of configuration employed for
trianthine).18a Ester to aldehyde reduction (DIBAL-H) and then
oximation (NH2OH·HCl, 82% yield, 2 steps) and oxime
reduction (NaCNBH3) then afforded retro-Cope elimination
substrate 11 (83% yield). Hydroxylamine 11 cyclized smoothly
upon heating as a 0.014 M solution in degassed toluene at
80 °C for 17 h to provide N-hydroxyhydrindole 12 as a single
stereoisomer in 98% yield.18a Hydrogenolysis of the N-O bond
(Raney-Ni, 94% yield), N-formylation (HCO2COMe, 93%
yield), and then Bischler-Napieralski ring B closure with
concomitant acetonide deprotection (POCl3) gave water-soluble
iminium salt 15 after purification by ion-exchange and then C18
reverse-phase solid-phase extraction (SPE) (42% yield).
Prior studies in which we had been unable to obtain lactamol
17 cleanly, via lactam half-reduction (LiEtBH3) or via Polonovs-
ki reactions from the amine-N-oxide (Ac2O or TFAA), had
taught us that lactamol 17 was extremely sensitive to Cannizzaro
disproportionation to give a 1:1 mixture of the corresponding
amine and lactam, particularly under basic conditions. Attempts
to transform iminium salt 15 into the corresponding N-methyl
aldehyde according to a procedure developed by Rozwadowska
for hydrastinine using MeI in MeOH,21,22 and into lactamol 17
according to procedures developed by Dosta´l for sanguinarine
using NaOD in d3-MeCN/D2O)23 or Na2CO3/D2O,24 also
induced substantial disproportionation. However, treatment of
a solution of iminium salt 15 in d6-DMSO/D2O (5:1 v/v) with
(6) Wildman, W. C.; Bailey, D. T. J. Am. Chem. Soc. 1969, 91, 150–
157, and references therein.
(7) (a) Hendrickson, J. B.; Bogard, T. L.; Fisch, M. E.; Grossert, S.;
Yoshimura, N. J. Am. Chem. Soc. 1974, 96, 7781–7789. (b) Tsuda,
Y.; Ukai, A.; Isobe, K. Tetrahedron Lett. 1972, 13, 3153–3156. (c)
Danishefsky, S.; Morris, J.; Mullen, G.; Gammill, R. J. Am. Chem.
Soc. 1982, 104, 7591–7599.
(8) Fales, H. M.; Wildman, W. C. J. Am. Chem. Soc. 1964, 86, 294–295.
(9) Harken, R. D.; Christensen, C. P.; Wildman, W. C. J. Org. Chem.
1976, 41, 2450–2454.
(10) (a) Abelman, M. M.; Overman, L. E.; Tran, V. D. J. Am. Chem. Soc.
1990, 112, 6959–6964. (b) Rigby, J. H.; Cavezza, A.; Heeg, M. J.
J. Am. Chem. Soc. 1998, 120, 3664–3670.
(11) (a) Martin, S. F.; Davidsen, S. K.; Puckette, T. A. J. Org. Chem. 1987,
52, 1962–1972. (b) Baldwin, S. W.; Debenham, J. S. Org. Lett. 2000,
2, 99–102. (c) Nishimata, T.; Sato, Y.; Mori, M. J. Org. Chem. 2004,
69, 1837–1843. (d) Zhang, F.-M.; Tu, Y.-Q.; Liu, J.-D.; Fan, X.-H.;
Shi, L.; Hu, X.-D.; Wang, S.-H.; Zhang, Y.-Q. Tetrahedron 2006,
62, 9446–9455.
(19) Prepared by a telescoped variant of the method described by Hudlicky,
T.; Fan, R. L.; Tsunoda, T.; Luna, H.; Andersen, C.; Price, J. D. Isr.
J. Chem. 1991, 31, 229–238. Ramesh, K.; Wolfe, M. S.; Lee, Y.;
Velde, D. V.; Borchardt, R. T. J. Org. Chem. 1992, 57, 5861–5868.
See Supporting Information.
(20) Enone 6 can also be prepared in enantiomerically pure form [(5S, 6S)-
(+)-6] via Pseudomonas putida microbial oxidation of chlorobenzene,
see: (a) Spivey, A. C.; Giro´ Man˜as, C.; Mann, I. Chem. Commun.
2005, 4426–4428. (b) Reference 18a.
(12) (a) Mizukami, S. Tetrahedron 1960, 11, 89–95. (b) Kotera, K.;
Hamada, Y.; Nakane, R. Tetrahedron 1968, 24, 759–770.
(13) Briggs, C. K.; Highet, R. J.; Highet, P. F.; Wildman, W. C. J. Am.
Chem. Soc. 1956, 78, 2899–2904.
(14) Dopke, W.; Bienert, M.; Burlingame, A. L.; Jeffs, P. W.; Farrier, D. S.
Tetrahedron Lett. 1967, 451–457.
(15) Jeffs, P. W.; Hansen, J. F.; Dopke, W.; Bienert, M. Tetrahedron 1971,
27, 5065–5079.
(21) Rozwadowska, M. D. Bull. Acad. Pol. Sci., Sci. Chim. 1971, 19, 673–
679.
(16) (a) Irie, H.; Nagai, Y.; Tamoto, K.; Tanaka, H. J. Chem. Soc., Chem.
Commun. 1973, 302–303. (b) Tanaka, H.; Irie, H.; Babu, S.; Uyeo,
S.; Kuno, A.; Ishiguro, Y. J. Chem. Soc., Perkin Trans. 1 1979, 535–
538.
(22) Gluszynska, A.; Mackowska, I.; Rozwadowska, M. D.; Sienniak, W.
Tetrahedron: Asymmetry 2004, 15, 2499–2505.
(23) Dosta´l, J.; Pota´e`ek, M.; Nechva´tal, M. Collect. Czech. Chem. Commun.
1993, 58, 395–403.
(17) Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243–269.
(18) (a) Oppolzer, W.; Spivey, A. C.; Bochet, C. B. J. Am. Chem. Soc.
1994, 116, 3139–3140. (b) Spivey, A. C. Chimia 2009, 63, 864–866.
(24) See`ka´øova´, P.; Marek, R.; Dosta´l, J.; Dommisse, R.; Esmans, E. L.
Magn. Reson. Chem. 2002, 40, 147–152.
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A R T I C L E S
Giro´ Man˜as et al.
Scheme 3. Biomimetic Ring-Switch of Lycorine-Type Progenitor 17
into Clivonine (19) and the Molecular Structure of 19·HCl (X-ray)
tion of just 1 equiv of a dilute solution of MeI in d6-DMSO to
freshly prepared solution of lactamol 17/Cs2CO3 (in d6-DMSO/
D2O) afforded a mixture of species, of which the major
component was tentatively assigned as N-methyl aldehyde 18
by 1H NMR spectroscopy (aldehyde proton, s at δ ∼9.67 ppm;
N-Me, s at δ ∼2.35 ppm). Further optimization was confounded
by the formation of what appeared to be quaternized salts, which
were also formed to a greater extent when employing alternative
methylating agents (e.g., Me2SO4, MeOTf). However, freeze-
drying of this mixture, suspension of the residue in toluene,
and treatment with Fetizon’s reagent reproducibly afforded (()-
clivonine (19) in 32% yield after chromatography from iminium
salt 15 (12 steps, 6.1% overall yield from enone 6). All
spectroscopic data matched those reported for the natural
material,14,25 and its molecular structure was confirmed by a
single-crystal X-ray structure determination on its hydrochloride
(Scheme 3).
a solution of Cs2CO3 in D2O (0.77 M, 1.3 equiv) reproducibly
gave clean conversion to a single, unassigned epimer of lactamol
Conclusion
In conclusion, we have reported the total synthesis of the
lycorenine-type Amaryllidaceae alkaloid (()-clivonine (19) via
a route that employs, for the first time, a biomimetic ring-switch
from a lycorine-type progenitor, thereby finally corroborating
experimentally the biogenetic hypothesis first expounded for
these compounds by Barton 50 years ago.
We are currently exploring this approach for the synthesis
of hippeastrine from lycorine1 and investigating whether there
is a causal relationship between ring-switching and the life-
cycle of the herbaceous perennials in which these alkaloids are
found.26
1
17 in ∼5 min, as evidenced by H NMR spectroscopy (15
iminium methine, s at δ ∼9.07 ppm f 17 lactamol methine, s
at δ ∼4.92 ppm) (Scheme 3).
Next, we explored N-methylation. Wildman6 described two
protocols for conversion of haemeanthidine (3) to pretazettine
(4): N-methiodide salt formation (MeI in MeOH) and then
careful basification of an aqueous acidic solution of this salt
with K2CO3 and extraction into CHCl3 was the method adopted
(with modifications)7,11 in subsequent syntheses, but Esch-
weiler-Clarke reductive methylation (HCO2H/H2CO) and then
basification and extraction was reportedly equally efficient. In
our hands, the Eschweiler-Clarke method returned only the
corresponding amine when applied to lactamol 17, whereas
treatment with methanolic MeI gave a complex mixture of
Acknowledgment. We gratefully acknowledge the Swiss Na-
tional Science Foundation, the EPSRC, and GSK for financial
support for this work.
1
products containing methyl ether/acetal signals by H NMR
Supporting Information Available: Full experimental details,
NMR spectra, and details of the crystallographic analysis,
including CIF file, of structure 19·HCl. This material is available
free of charge via the Internet at http://pubs.acs.org.
spectroscopy. Extensive experimentation established that addi-
(25) Zetta, L.; Gatti, G.; Fuganti, C. J. Chem. Soc., Perkin Trans. 2 1973,
1180–1184.
(26) The isolated yields of these alkaloid constituents show strong seasonal
dependence (e.g., ref 8).
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