Total synthesis of (+)-phyllantidine

Article abstract of DOI:10.1002/anie.200602569

Three into one will go! A three-component coupling of a hydroxylamine, an aldehyde, and a cyclopropane diester provides the tetrahydro-1,2-oxazine scaffold necessary for completion of the first total synthesis of the natural product phyllantidine. (Figure

Full text of DOI:10.1002/anie.200602569

Communications
Total Synthesis
DOI: 10.1002/anie.200602569
Total Synthesis of (+)-Phyllantidine**
Cheryl A. Carson and Michael A. Kerr*
Dedicated to Professor K. C. Nicolaou
on the occasion of his 60th birthday
There exists a small group of alkaloids isolated from the
Euporbiaceae family of plants known as the securinega
alkaloids (Figure 1).[1] These compounds have an indolizidine
[*] C. A. Carson, Dr. M. A. Kerr
Department of Chemistry
The University of Western Ontario
London, ON, N6A5B7 (Canada)
Fax: (+1)519-661-3022
E-mail: makerr@uwo.ca
[**] We thank the Natural Sciences and Engineering Research Council
(NSERC) of Canada and Boehringer Ingelheim Canada for funding.
We are grateful to D. Hairsine for performing MS analyses. C.A.C. is
the recipient of an NSERC CGSM postgraduate scholarship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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adducts from this cycloaddition would fulfill the requirements
of a practical synthetic route to phyllantidine (Scheme 1).
Scheme 1. Retrosynthesis of phyllantidine. RCM=ring-closing olefin
metathesis.
Figure 1. The securinega alkaloids including (+)-phyllantidine (5).
core imbedded within an azabicyclo [3.2.1] ring system. This is
fused to a butenolide moiety forming a rather interesting and
structurally complex molecular framework. Securinine (1)
and its C2 epimer allosecurinine (2) are constituents of
Securinega suffruticosa,[2] and the antipodal compounds
virosecurinine (3) and viroallosecurinine (4) are found in
Securinega virosa.[3] While these compounds show interesting
activity in the central nervous system (CNS) in the form of
antagonism of the g-aminobutyric acid (GABA) receptor,[4]
the synthetic chemist is drawn to the compact and complex
architecture of the compounds. Indeed several syntheses of
the securinine series of compounds have been reported.[5] Of
interest to us are not the indolizidines 1–4 but a related and
much rarer alkaloid phyllantidine 5 (isolated from Phyllan-
thus discoides and Seurinega suffruticosa)[6] and its enantio-
mer (from Breynia coronata).[7]
To date, no syntheses of phyllantidine (or ent-phyllanti-
dine) have been reported, although phyllantidine is available
through the peroxide (or peracid) oxidation of virosecur-
inine.[8] This proceeds via the N-oxide which undergoes a
Meisenheimer rearrangement yielding phyllantidine. Since
the synthetic routes to the securinine alkaloids are quite
complex and lengthy, this route to phyllantidine is less than
appealing. Herein, we present a convenient and direct
synthesis of (+)-phyllantidine.
Perhaps the most significant structural feature of phyl-
lantidine is the tetrahydro-1,2-oxazine ring. This heterocyclic
motif is uncommon in natural products and is found in FR-
900482 (and a few related compounds)[9]. This structural
feature also makes phyllantidine an elusive target since there
are few ways to directly prepare tetrahydro-1,2-oxazines.
Recently, however, we reported that nitrones (either as
isolated compounds or generated in situ) react smoothly with
1,1-cyclopropane diesters under the influence of Lewis acids
to form tetrahydro-1,2-oxazines in what we have termed a
“homo-1,3-dipolar cycloaddition”.[10] The reactions are dia-
stereoselective and yield only 3,6-cis adducts. Both the
substitution pattern and relative stereochemistry of the
Initially, we envisioned a cycloaddition between a cyclic
nitrone 11 and cyclopropane 8 as a rapid access to an
advanced bicyclic intermediate such as 12 [Eq. (1)]. However,
we have not been able to obtain adducts from the cyclo-
addition reaction using nitrones such as 11 as the substrate.
Our synthesis of phyllantidine commenced with the three-
component coupling of hydroxylamine 13, aldehyde 14, and
cyclopropane 8[11] under the influence of catalytic ytterbium
triflate hydrate to give the tetrahydro-1,2-oxazine 15 in 86%
yield as a 12:1 mixture of diastereomers, in which the major
product bore the required cis relationship between the
oxazine vinyl substituent and the alkyl chain (Scheme 2).
Interestingly, we occasionally saw this slight loss of diaster-
eochemical integrity when the cycloaddition reaction mixture
was heated to reflux. However, perhaps more interesting and
surprising is that there was approximately 10% erosion of the
absolute stereochemistry, with the cis adduct isolated as a
90:10 mixture of enantiomers. This has mechanistic implica-
tions and a detailed study of the stereochemistry of these
cycloadditions is underway. Krapcho decarboxylation pro-
ceeded smoothly to produce 16 as a 1:1 mixture of diastereo-
mers in 85% yield. Treatment of 16 (mixture of epimers) with
KHMDS to generate the potassium enolate followed by
treatment with the Davis oxaziridine[12] gave the hydroxy
esters 17 and 18 as an inseparable mixture of diastereomers
(1:3 in favor of the desired isomer; Scheme 2).
We were delighted to find that our expectations of a
diastereoselective hydroxylation were born out, since this
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Scheme 2. Synthesis of advanced intermediate 23. a) Ytterbium(III) trifluoromethanesulfonate hydrate (5 mol%), MS (4 Š), toluene, heated at
reflux (86%); b) LiCl (5 equiv), DMSO, H2O, 1608C (85%); c) KHMDS, Davis oxaziridine, THF, À788C (80% as a 3:1 diasteromeric mixture of
18 and 17); d) LAH, THF, 08C (97%); e) 2,2-dimethoxypropane, p-toluenesulfonic acid, DMSO (74%); f) 6n HCl, THF (93% based on 20);
=
g) IBX, DMSO (64%); h) CH2 CHMgBr, THF, (76%); i) IBX, DMSO (79%). PMB=p-methoxybenzyl, Ts=toluene-4-sulfonyl, LAH=lithium
aluminum hydride, KHMDS=potassium bis(trimethylsilyl)amide, IBX=o-iodoxybenzoic acid.
transformation was the greatest concern to us at the outset of
the project. Our rationale for the predicted selectivity is
shown in Scheme 3. The enolate derived from 16 may be
envisaged as the chair conformers A or B. Whether one
invokes A or B, approach of the electrophilic oxidant should
be from the top face (bold arrow in Scheme 3) to avoid either
a 1,3-diaxial interaction with the vinyl group in A or a 1,2-
interaction with the alkyl chain in B. It is worth noting that in
a simpler model system, in which both the substituents on the
nitrogen atom and the alkyl chain were replaced by phenyl
moieties, there was complete selectivity for the desired
isomer.
and 20 as a 1:3 mixture as expected (Scheme 3). This mixture
was amenable to simple separation by flash column chroma-
tography giving, after acetonide removal (in 93% yield), 21 as
a single isomer. Oxidation of the primary hydroxy group gave
an aldehyde 22 (in 64% yield), which was treated with
vinylmagnesium bromide to give a diastereomeric mixture of
the allylic alcohols in 76% yield. Oxidation gave the enone
23, which we anticipated would be an appropriate substrate
for RCM.
While the sequence of reactions in Scheme 2 certainly
produced 23 in a relatively efficient way, this sequence of
protection through formation of acetonides, separation, and
deprotection seemed rather clumsy. This procedure was
necessary at the time to better understand the reaction
sequence. In addition, separation of the diols resulting from
the reduction of mixture 17/18 was not possible in a
preparative manner.
Reduction of this mixture with LAH afforded the diols (in
97% yield), which upon derivatization gave the acetonides 19
In order to circumvent the tedious protection/deprotec-
tion sequence, the diastereomeric mixture of 17/18 (ratio 1:3)
was subjected to a sequence of four reactions (Scheme 4),
namely, reduction using LAH, oxidation of the primary
alcohol to an aldehyde using IBX, addition of vinylmagne-
sium bromide, and finally oxidation of the allylic alcohol to
give the vinyl ketone 23. At this juncture, the unwanted
diastereomer was readily removed by flash column chroma-
tography. Enone 23 proved to be a suitable substrate for RCM
with Grubbs second-generation catalyst. In the event, ring
closure to give enone 24 proceeded in 74% yield. The O-
acetyl derivative of 24 was explored as a substrate for aldol-
type ring closure to form the butenolide, yet all attempts to
affect this cyclization failed. Fortunately, an alternative
acylation[13] using diethylphosphonoacetic acid afforded sub-
strate 25 (in 71% yield), which after an intramolecular
Horner–Emmons reaction, was converted into the desired 26
in quantitative yield.[14] The natural product 5 was ultimately
Scheme 3. Model for selective hydroxylation showing steric interac-
tions between oxidant and vinyl group in A and between oxidant and
alkyl chain in B.
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[2] For information on original isolation, see: a) V. I. Muravꢀeva,
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b) V. I. Muravꢀeva, A. I. Banꢀkovskii, Med. Prom-st. SSSR 1956,
10, 27 – 28; for structure determination of securinine and
isolation of allosecurinine, see: c) I. Satoda, M. Murayama, J.
Tsuji, E. Yoshii, Tetrahedron Lett. 1962, 1199 – 1206.
[3] a) For isolation of virosecurinine, see: T. Nakano, T. H. Yang, S.
Terao, Tetrahedron 1963, 609 – 619; b) for isolation of viroallo-
securinine, see: S. Saito, T. Iwamoto, T. Tanaka, C. Matsumura,
N. Sugimoto, Z. Horii, Y. Tamura, Chem. Ind. 1964, 28, 1263 –
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Chem. Pharm. Bull. 1966, 14, 313 – 314.
Scheme 4. Synthesis of (+)-phyllantidine. a) LAH, THF, 08C; b) IBX,
=
[6] a) Z. Horii, T. Imanishi, M. Yamauchi, M. Hanaoka, J. Parello, S.
Munavalli, Tetrahedron Lett. 1972, 1877 – 1880; b) J. Parello, S.
Munavalli, C. R. Hebd. Seances Acad. Sci. 1965, 260, 337 – 340.
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[8] T. Nakano, S. Terao, K. H. Lee, Y. Saeki, L. J. Durham, J. Org.
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[9] I. Uchida, S. Takase, H. Kayakiri, S. Kiyoto, M. Hashimoto, T.
Tada, S. Koda, Y. Morimoto, J. Am. Chem. Soc. 1987, 109, 4108 –
4109.
DMSO; c) CH2 CHMgBr, THF; d) IBX, DMSO (20% overall yield of
one diastereomer from a mixture of 17 and 18); e) second-generation
Grubbs catalyst (20 mol%), CH2Cl2, heated at reflux (74%); f) dieth-
ylphosphonoacetic acid, DCC, CH2Cl2 (71%); g) K2CO3, [18]crown-6,
toluene (quant.); h) DDQ/CH2Cl2, H2O (98%); i) Ph3P, DIAD, toluene
(98%). Mes=mesityl=2,4,6-trimethylphenyl, DCC=1,3-dicyclohexyl-
carbodiimide, DDQ=2,3-dichloro-4,6-dicyano-1,4-benzoquinone, DIA-
D=diisopropylazodicarboxylate.
[10] a) M. D. Ganton, M. A. Kerr, J. Org. Chem. 2004, 69, 8554 –
8557; b) I. S. Young, M. A. Kerr, Org. Lett. 2004, 6, 139 – 141;
I. S. Young, M. A. Kerr, Angew. Chem. 2003, 115, 3131 – 3134;
Angew. Chem. Int. Ed. 2003, 42, 3023 – 3026.
[11] These compounds are all readily prepared in short sequences
from commercial materials. Their preparation is included in the
Supporting Information.
[12] a) F. A. Davis, J. Lamendola, U. Nadir, E. W. Lluger, T. C.
Sedergran, T. W. Panunto, R. Billmers, R. Jenkins, Jr., I. J.
Turchi, W. H. Watson, J. S. Chen, M. Kimura, J. Am. Chem. Soc.
1980, 102, 2000 – 2005; b) F. A. Davis, L. C. Vishwakarma, J. M.
Billmers, J. Finn, J. Org. Chem. 1984, 49, 3243 – 3244.
[13] M. Nahmany, A. Melman, Org. Lett. 2001, 3, 3733 – 3735.
[14] This method was used in a similar butenolide formation for the
synthesis of related alkaloids norsecurinine and phyllanthine.
See: a) G. Han, M. G. LaPorte, J. J. Folmer, K. M. Werner, S. M.
Weinreb, Angew. Chem. 2000, 112, 243 – 246; Angew. Chem. Int.
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6306.
secured through oxidative removal of both the p-methoxy-
benzyl groups and ring closure under Mitsunobu conditions.
À
This method of piperidine formation is unusual for C N bond
formation, and we were pleasantly surprised at its efficiency.
However, there is ample precedent for such transforma-
tions.[15] The spectral data for synthetic (+)-phyllantidine
correspond to those reported in the literature, including the
sign of optical rotation. Analysis by HPLC on a chiral
stationary phase indicated no trace of the (À) isomer.
In summary, we have succeeded in preparing for the first
time the structurally unusual and demanding alkaloid
phyllantidine using a homo [3+2] dipolar cycloaddition. The
overall yield of the natural product is around 6% over 12
synthetic operations from the cycloaddition. Efforts to adapt
À
this protocol (through N O bond reduction and ring closure
to form a pyrrolidine) to other securinega alkaloids are in
progress.
[15] For examples of piperidine formation through Mitsunobu
cyclization, see: a) T. Tsunoda, F. Ozaki, N. Shirakata, Y.
Tamaoka, H. Yamamoto, S. Ito, Tetrahedron Lett. 1996, 37,
2463 – 2466; b) G. E. Keck, A. Palani, Tetrahedron Lett. 1993, 34,
3223 – 3224.
Received: June 27, 2006
Published online: September 13, 2006
Keywords: alkaloids · cycloaddition · nitrone · oxazine ·
.
total synthesis
[1] V. Snieckus, The Alkaloids, Vol. 14, Academic Press, New York,
1973, p. 425 – 506.
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