The synthesis of (+)-nemorensic acid

Article abstract of DOI:10.1039/b000565g

The synthesis of (+)-nemorensic acid in nine steps is described; key steps in the route were the stereoselective Birch reduction of a substituted furan, and addition of allyltrimethylsilane to an oxonium ion at C-5; an X- ray crystal structure of (-)-nemorensic acid provided proof of the relative stereochemistry of the target.

Full text of DOI:10.1039/b000565g

The synthesis of (+)-nemorensic acid
Timothy J. Donohoe,*a Jean-Baptiste Guillermin,a Christopher Framptonb† and Daryl S. Walterb
a Department of Chemistry, The University of Manchester, Oxford Road, Manchester, UK M13 9PL.
E-mail: t.j.donohoe@man.ac.uk
b Department of Chemistry, Roche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Herts, UK AL7 3AY
Received (in Liverpool, UK) 19th January 2000, Accepted 8th February 2000,
Published on the Web, 2nd March 2000
The synthesis of (+)-nemorensic acid in nine steps is
described; key steps in the route were the stereoselective
Birch reduction of a substituted furan, and addition of
allyltrimethylsilane to an oxonium ion at C-5; an X-ray
crystal structure of (2)-nemorensic acid provided proof of
the relative stereochemistry of the target.
We have recently initiated a research programme aimed at
synthesising the pyrrolizidine alkaloids.1 These alkaloids are a
diverse series of compounds, isolated from the Senecio family
of plants, which display a wide range of biological activities
such as hepatotoxicity and carcinogenic activity; some of these
alkaloids have the ability to cross-link DNA at specific points.2
In particular we were drawn to pyrrolizidine alkaloids contain-
ing a macrocyclic bislactone. Hydrolysis of these bislactone
alkaloids yields a diol (necine base) and a diacid (necic acid).
Scheme 2 Reagents and conditions: i, SOCl2, then (R,R)-bismethoxy-
While the synthesis of necine bases is well established, the necic
methylpyrrolidine, NaOH, 95%; ii, Na, NH3, THF, 278 °C then MeI, 93%;
acid moiety has received relatively little attention; indeed it is
iii, CrO3, H2SO4, 89%; iv, H2, Pd-C, EtOH, AcOH, 87% (pure cis).
variation in this part of the molecule that is responsible for much
of the diversity of these plant alkaloids. We now report our
studies on the synthesis of nemorensic acid, which is obtained
from hydrolysis of nemorensine (Scheme 1).3 A survey of the
literature reveals that nemorensic acid has been synthesised by
the groups of Klein (±),4 White (+),5 Mascareñas (±)6 and
Honda (+).7 Our retrosynthetic analysis of nemorensic acid
identified the lactone 1 as a viable precursor for the target; we
know from previous studies that 1 can be prepared from the
commercially available 3-methyl-2-furoic acid via a Birch
reduction on a chiral auxiliary (Xc) laden furan.8
Our synthesis began with 2, which was coupled to (R,R)-
(2)-bismethoxymethylpyrrolidine in excellent yield. We have
already reported that the reductive methylation of 3 proceeds in
high yield and with !30+1 diastereoselectivity.8 Subsequent
Jones (allylic) oxidation gave 5 and hydrogenation with
palladium provided 6 in good overall yield, and with high
selectivity for the isomer shown (Scheme 2).9
The lactone 6 (structure proven by X-ray crystallography)
was treated with ‘Cp2TiMe2’ which was freshly prepared from
Cp2TiCl2 and MeLi, according to Petasis (Scheme 3).10 The
resulting enol ether 7 was rather sensitive to hydrolysis and was,
therefore, converted immediately into the acetal 8 (1+1 mixture
of epimers) with acidic methanol (72% overall yield). Introduc-
tion of carbon functionality at C-5 was accomplished by
Scheme 3 Reagents and conditions: i, Cp2TiCl2, MeLi; ii, MeOH, HCl,
72% (two steps); iii, allyltrimethylsilane, TiCl4, CH2Cl2, 278 °C, 79%.
reaction of the epimeric mixture of acetals with titanium
tetrachloride and allyltrimethylsilane. The allylated compound
9 that resulted from this reaction was formed as a single
1
diastereoisomer according to H NMR analysis of the crude
reaction mixture. We could assign the stereochemistry of the
product with the aid of NOE experiments which showed a
strong (and reciprocal) enhancement between the allylic
methylene protons and the (cis) methine proton at C-3 (Fig. 1).
Scheme 1
† Author to whom correspondence on the X-ray crystal structure should be
addressed.
Fig. 1
DOI: 10.1039/b000565g
Chem. Commun., 2000, 465–466
This journal is © The Royal Society of Chemistry 2000
465

reported in the literature. Its melting point was 171–173 °C (lit.3
174–177 °C) and its optical rotation was [a]D +84 (c 0.18,
EtOH) (lit.3 [a]D +87 (c 0.84, EtOH)).
To conclude, we have prepared (+)-nemorensic acid in nine
steps and 25% overall yield using the Birch reduction of furan
as the key step. This synthesis is particularly efficient and is
amenable to the preparation of ample amounts of material.
We thank the EPSRC and Roche Pharmaceuticals for
financial support. Clare Stevenson is thanked for some
preliminary experiments.
Notes and references
‡ In the initial phase of our studies we prepared the unnatural (2)
enantiomer of nemorensic acid and obtained X-ray crystallographic analysis
on this material. Crystal data for (2)-nemorensic acid: C10H16O5, M =
216.23, orthorhombic, a = 8.4556(2), b = 11.4227(2), c = 11.4637(2) Å,
U = 1107.23(4) Å3, T = 123(1) K, space group P212121 (no. 19), Z = 4,
Dc = 1.297 g cm21, m(Mo-Ka) = 0.104 mm21. Data collected on a Bruker
AXS SMART CCD diffractometer, 9403 reflections measured, data
truncated to 0.80 Å (qmax 26.37°, 99.8% complete), 2269 reflections unique
Scheme 4 Reagents and conditions: i, RuCl3 (cat.) NaIO4; ii, 6 M HCl, D,
65% (two steps).
(Rint = 0.0182). Final agreement factors for 161 parameters gave R1
0.0274, wR2 = 0.0773 and GOF = 1.001 based on all 2269 data, absolute
structure not determined, final difference map +0.21 and 20.15 e Å23
Programs used: Bruker AXS SMART and SAINT control and integration
software, SHELXTL Structure solution and refinement (G. M. Sheldrick,
University of Göttingen, Germany). CCDC 182/1540. See http://
www.rsc.org/suppdata/cc/b0/b000565g/ for crystallographic data in .cif
format.
=
The sense of diastereoselectivity displayed during the allylsi-
lane addition to acetal 8 is interesting and is consistent with a
recent observation by Woerpel et al. on related systems.11
According to this model, geminal substitution at C-2 is crucial
for high levels of selectivity, and the main reason for addition to
the lower face of the oxonium ion derived from 8 is steric
interaction with the pseudoaxial methyl group at C-2 (Fig. 1).
The synthesis was completed by oxidative cleavage of the
alkene unit with catalytic ruthenium tetroxide; the acid 10 was
immediately treated with aqueous acid to cleave the auxiliary
and liberate nemorensic acid, (65% yield from 9) (Scheme 4).
The relative stereochemistry of the product was confirmed by
X-ray crystallographic analysis (Fig. 2).‡
.
1 For a review see: D. J. Robins, Nat. Prod. Rep., 1995, 12, 413 and
references therein..
2 See J. J. Tepe and R. M. Williams, J. Am. Chem. Soc., 1999, 121, 2951
and references therein..
3 A. Klásek, P. Sedmera, A. Boeva and F. Santavy´, Collect. Czech. Chem.
Commun., 1973, 38, 2504.
4 L. L. Klein, J. Am. Chem. Soc., 1985, 107, 257.
5 M. P. Dillon, N. C. Lee, F. Stappenbeck and J. D. White, J. Chem. Soc.,
Chem. Commun., 1995, 1645.
Nemorensic acid produced by this sequence had spectro-
scopic data (1H, 13C NMR) that were identical with those
6 J. R. Rodríguez, A. Rumbo, L. Castedo and J. L. Mascareñas, J. Org.
Chem., 1999, 64, 4560.
7 T. Honda and F. Ishikawa, J. Org. Chem., 1999, 64, 5542.
8 T. J. Donohoe, M. Helliwell, C. A. Stevenson and T. Ladduwahetty,
Tetrahedron Lett., 1998, 39, 3071.
9 T. J. Donohoe, C. A. Stevenson M. Helliwell, R. Irshad and T.
Ladduwahetty, Tetrahedron: Asymmetry, 1999, 10, 1315.
10 N. A. Petasis and E. I. Bzowej, J. Am. Chem. Soc., 1990, 112, 6392.
11 J. T. Shaw and K. A. Woerpel, Tetrahedron, 1999, 55, 8747; see also C.
Brückner, H. Lorey and H.-U. Reissig, Angew. Chem., Int. Ed. Engl.,
1986, 25, 556.
Fig. 2 Nemorensic acid.
Communication b000565g
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Chem. Commun., 2000, 465–466