An investigation into the total synthesis of clerocidin: Stereoselective synthesis of a clerodane intermediate

Article abstract of DOI:10.1016/S0957-4166(98)00349-8

A key clerodane intermediate was prepared during the investigation of the total synthesis of clerocidin. The diterpene backbone was synthesized by an enantioselective Robinson annulation followed by trapping of the enolate using allyl bromide. Selective hydrogenation conditions were developed to introduce the axial methyl group at the C₈ position. A palladium-mediated carbonylation reaction was employed to generate the key α,β-unsaturated dialdehyde.

Full text of DOI:10.1016/S0957-4166(98)00349-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3179–3183
An investigation into the total synthesis of clerocidin:
stereoselective synthesis of a clerodane intermediate
∗
Ji-In Kim Almstead, Thomas P. Demuth Jr. and Benoit Ledoussal
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA
Received 20 August 1998; accepted 20 August 1998
Abstract
A key clerodane intermediate was prepared during the investigation of the total synthesis of clerocidin. The
diterpene backbone was synthesized by an enantioselective Robinson annulation followed by trapping of the
enolate using allyl bromide. Selective hydrogenationconditions were developed to introduce the axial methyl group
at the C8 position. A palladium-mediated carbonylation reaction was employed to generate the key α,β-unsaturated
dialdehyde. © 1998 Elsevier Science Ltd. All rights reserved.
Recent interest in the synthesis of clerodane diterpenes has been stimulated by the potential anticancer
1
and antimicrobial activities displayed by this class of compounds. Clerocidin, a naturally occurring
antibiotic isolated from the fungus Oidiodendron truncatum, was subsequently identified as a topo-
2
isomerase inhibitor. Two additional compounds, terpentecin and UCT4B which have a high degree
3
of structural homology and a similar activity profile to clerocidin, contain several common features
which make their synthesis challenging. The unique trans configuration present between the C and
8
4
C methyl groups which is unlike most other clerodanes reported in the literature, and the highly
9
oxygenated side chain which can readily cyclize, hydrate, and dimerize, significantly complicate the
2
synthesis and isolation process of these molecules. The total syntheses of clerodanes possessing cis
5
dimethyl stereochemistry at the C and C positions have been reported (rac-ajugarin and rac-stephalic
8
9
6
acid ). However, the synthesis of clerodanes with trans methyl geometry is largely unreported with the
exception of Kobayashi’s recent effort towards the total synthesis of terpentecin.7
∗
Corresponding author. E-mail: Almstead.jk@pg.com
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00349-8

3180
J.-I. K. Almstead et al. / Tetrahedron: Asymmetry 9 (1998) 3179–3183
Herein, the synthesis of diterpenoid 1, a precursor to clerocidin is described. This target molecule
was also used as an intermediate in the synthesis of related clerodane analogs of biological interest. The
retrosynthetic analysis of clerocidin is shown in Scheme 1.
Scheme 1.
The synthesis begins with the optically pure Wieland–Miescher ketone 3 {[α]D25=+143 (c 1.65,
8
benzene)} which was prepared from triketone 2 in the presence of L-phenylalanine and (+)-
9
camphorsulfonic acid (77% yield) Selective protection of one carbonyl group as the dioxolane 4 was
accomplished in the presence of oxalic acid (70% yield). The optical purity of enone 3 was confirmed
by resolving the enantiomers of ketone 4 on a chiral cyclodextrin GC column (only a trace of the minor
enantiomer was detected).
10
The C substituent was introduced by reductive alkylation of 4 with various electrophiles. The yield
9
was observed to be highly dependent on the steric nature of the electrophile; the silyl ether (a) produced
only the protonated product 6, whereas allyl iodide (b) was prone to overalkylation (table in Scheme 2).
Both ethyl bromoacetate and allyl bromide proved to be good electrophiles, providing high isolated yields
of the desired products, 5c and 5d, respectively. The absolute configuration of the carbon centers C , C9
5
and C was independently confirmed by X-ray crystallography of intermediate 7 (generated by oxidation
1
0
11
of the aldehyde resulting from ozonolysis of 5d).
Scheme 2.
The introduction of the axial C methyl group on the diterpene ring was achieved by hydrogenation
8
of the C exocyclic double bond. The hydrogenation reaction of a model substrate was examined
8
in order to determine the optimal reaction conditions to provide the desired diastereomer in excess
(thermodynamically less favored, axial product). Model substrate 8 (Scheme 3) containing a gem-
dimethyl group at the C position was prepared in 59% yield via olefination of the C carbonyl using
9
8
11
salt-free Wittig conditions (methyltriphenylphosphonium bromide and n-BuLi in benzene at 60°C).
The hydrogenation of 8 was performed in the presence of various catalysts at atmospheric pressure.
1
The ratio of diastereomers 9a/9b was determined by GC analysis and H NMR (CDCl : C CH
3
8
3
axial=1.01 ppm and CH equatorial=0.91 ppm). When 5% Pd/C was used as a catalyst, the thermo-
3
dynamically more stable isomer 9b with an equatorial methyl group was formed in excess, whereas

J.-I. K. Almstead et al. / Tetrahedron: Asymmetry 9 (1998) 3179–3183
3181
Scheme 3.
9a was formed in excess in the presence of Pt black catalyst (Table 1). The rate of hydrogenation
increased in the following order: Pt/C<Ir black<Pd/C∼Pt. Polar, protic solvents such as methanol and
ethanol provided higher diastereoselectivity in favor of the desired product 9a, and increased the rate of
hydrogenation when compared to solvents such as benzene and dioxane. A small scale hydrogenation of
8
with Pt in methanol afforded the desired product 9a quantitatively, at atmospheric pressure in less than
2
h with a diastereoselectivity of almost 9 to 1.
Table 1
Hydrogenation results (NR=no reaction)
The hydrogenation results demonstrate that the less stable, axial methyl substrate may be formed in
excess, possibly under kinetically controlled conditions. In related systems, the thermodynamically more
stable product was obtained in excess.12 The possibility of the double bond isomerization during the
hydrogenation step was eliminated by examining the hydrogenation reaction of endocyclic substrate 10
(prepared by MeLi addition to the ketone, followed by dehydration in DMSO). Under the same reaction
conditions, only 15% of 10 was hydrogenated after 15 h (ratio of 9a to 9b undetermined). In conclusion,
the hydrogenation of the exocyclic olefin in 8 was responsible for the observed diastereoselectivity in
favor of the desired product, 9a.
The optimized hydrogenation conditions were applied to the olefin 13 which was prepared in four
steps (21% overall yield, Scheme 4). Ozonolysis followed by lithium aluminum hydride reduction of
6d afforded diol 11 which was selectively protected. Jones oxidation of the secondary alcohol afforded
ketone 12 which was subsequently converted to the desired olefin 13. The hydrogenation of 13 with Pt
in methanol gave rise to a mixture of diastereomers 14a and 14b in the ratio of 7 to 1 (according to GC
1
13
and NMR) in almost quantitative yield. The assignment of the stereochemistry by H and C NMR was
made on the mixture of diastereomers 14 since they were not separable by chromatography.11 However,
removal of the dioxolane group afforded silyl ethers 15a and 15b (88% yield) which were separable by
chromatography (Scheme 5).
Scheme 4.

3182
J.-I. K. Almstead et al. / Tetrahedron: Asymmetry 9 (1998) 3179–3183
There are several methods reported in the literature for introduction of α,β-unsaturation into cyclic
13
ketones. We were interested in a versatile yet direct conversion of 15 to either an α,β-unsaturated
aldehyde or an ester. This was achieved by a two-step process which successfully utilized a palladium-
catalyzed reaction. The ketone 15a was treated with LDA, and the resulting enolate was trapped in situ
with N-phenyl triflamide to provide the enol triflate 16 in 60% yield (Scheme 5). In order to ensure
complete enolate formation alpha to a neopentyl center, the reaction mixture was allowed to warm
to room temperature. Reaction of the enol triflate with a catalytic amount of tetrakis(triphenylphos-
phine)palladium and carbon monoxide in the presence of either methanol or n-Bu SnH provided the
3
CO insertion products, 17 or 18, respectively (55 or 67% yield). Following the removal of the silyl
protecting group from 18 with p-toluenesulfonic acid, the resulting alcohol was oxidized with pyridinium
chlorochormate to provide the target dialdehyde 1 in 90% yield.
Scheme 5.
The diastereoselective coupling of the dialdehyde with a clerocidin-like side chain can be achieved
through a chromium-mediated reaction which has been employed successfully with other systems.14 The
design, synthesis, and scope of the optically active side chain precursor of clerocidin will be described in
a separate communication.
In summary, the diterpene backbone was efficiently constructed using an asymmetric Robinson
annulation method. Two key reactions made the synthesis of optically active 1 feasible: first, the
stereoselective hydrogenation of the exocyclic double bond in 13 provided the less stable product
which was crucial to achieving trans C –C dimethyl stereochemistry and, second, the α,β-unsaturated
8
9
aldehyde 18 was prepared in two steps via the enol triflate 16 and palladium chemistry.
References
1. (a) Andersen, N. R.; Lorck, H. O. B; Rasmussen, P. R. J. Antibiotics 1983, 753. (b) McCullough, J. E.; Muller, M. T.;
Howells, A. J.; Maxwell, A.; O’Sullivan, J.; Summerill, R. S.; Parker, W. L.; Wells, J. S.; Bonner, D. P. J. Antibiotics 1993,
235.
2
3
. (a) Andersen, N. R.; Rasmussen, P. R. Tetrahedron Lett. 1984, 25(4) 465. (b) Ibid, Tetrahedron Lett. 1984, 25(4), 469.
. (a) Tamamura, T.; Sawa, T.; Isshiki, K.; Masuda, T.; Homma, Y.; Iinuma, H.; Naganawa, H.; Hamada, M.; Takeuchi, T.;
Umezawa, H. J. Antibiotics 1985, 1664. (b) Tamamura, T.; Tsuchiya, M.; Isshiki, K.; Sawa, T.; Takeuchi, T. J. Antibiotics
1988, 648. (c) Kawada, S.; Yamashita, Y.; Uosaki, Y.; Gomi, K.; Iwasaki, T.; Takiguchi, T.; Nakano, H. J. Antibiotics 1992,
1182.
4
. (a) (−)-Kolavenol and (−)-agelasine B: Piers, E.; Roberge, J. Y. Tetrahedron Lett. 1991, 32(39), 5219. (b) Ibid, Tetrahedron
Lett. 1992, 33(46), 6923. (c) trans-Maingayic acid: Tokoroyama, T.; Fujimori, K.; Shimizu, T.; Yamagiwa, Y.; Monden,
M.; Iio, H. Tetrahedron 1988, 44(21), 6607. (d) rac-Avarol: Sarma, A. S.; Chattopadhyay, P. J. Org. Chem. 1982, 47, 1727.
(e) rac-Annonene: Takahashi, S.; Kusumi, S.; Kakisawa, H. Chem. Lett. 1979, 515.
5. (a) rac-epi-Ajugarin I and rac-ajugarin I: Luteijn, J. M.; de Groot, A. Tetrahedron Lett. 1982, 3421. (b) rac-Ajugarin I:
Ley, S. V.; Simpkins, N. S.; Whittle, A. J. J. Chem. Soc., Chem. Commun. 1983, 503. (c) Ibid, Tetrahedron 1986, 42(23),
6519. (d) rac-Ajugarin IV: Kende, A. S.; Roth, B.; Kubo, I. Tetrahedron Lett. 1982, 1751.

J.-I. K. Almstead et al. / Tetrahedron: Asymmetry 9 (1998) 3179–3183
3183
6
7
8
9
. Pers, E.; Fleming, F. F. J. Chem. Soc., Chem. Commun. 1989, 1665.
. Takao, K.-I.; Kobayashi, S. Tetrahedron Lett. 1997, 38, 6685.
. Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53(10), 2308. Lit. [α]
28=+147.
D
. When L-proline was used in the cyclization step, the reaction afforded the desired product, albeit in lower optical purity;
Hajos, Z. G; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
10. (a) Smith III, A. B; Mewshar, R. J. Org. Chem. 1984, 49, 3685. (b) Stork, G.; Goldman, R. N.; Coombs, R. V.; Tsuji, J. J.
Am. Chem. Soc. 1965, 87, 275.
11. X-Ray data from Fred Wireko of Procter and Gamble Co.
12. (a) Sarma, A. S.; Chattopadhyay, P. J. Org. Chem. 1982, 47, 1727. (b) Sarma, A. S.; Chattopadhyay, P. Tetrahedron Lett.
1980, 21, 3719. (c) Hydrogenation Methods; Rylander, P. N.; Academic Press: London, 1985. (d) Lejeune, J.; Lallemand,
J. Y. Tetrahedron Lett. 1991, 32, 2621. (e) Sum, P.-E.; Weiler, L. Can. J. Chem. 1978, 56, 2700. (f) Watson, A. T.; Park,
K.; Wiemer, D. F. J. Org. Chem. 1995, 60, 5102.
1
1
3. Comprehensive Organic Transformations; Larock, R. C.; VCH Publishers: New York, 1989 and references therein.
4. (a) Chen, C.; Tagami, K.; Kishi, Y. J. Org. Chem. 1995, 60, 5386. (b) Queneau, Y.; Krol, W. J.; Bornmann, W. G.;
Danishefsky, S. J. Bull. Soc. Chim. Fr. 1993, 130, 358. (c) Takai, K.; Kimura, K.; Kurada, T.; Hiyama, T.; Nazaki, H.
Tetrahedron Lett. 1983, 24, 5281.