Absolute configuration of phytocassanes as proposed on the basis of the CD spectrum of synthetic (+)-2-deoxyphytocassane A

Article abstract of DOI:10.1016/S0040-4039(99)02060-2

Phytocassane A-E possess ent-cassane skeleton because synthetic (+)-2- deoxyphytocassane A with cassane skeleton showed the Cotton effects positive at 369 nm (due to the ring-C dienone chromophore) and negative at 289 nm (due to the ring-A carbonyl group), while the natural phytocassane A exhibited the opposite cotton effects.

Full text of DOI:10.1016/S0040-4039(99)02060-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 351–354
Absolute configuration of phytocassanes as proposed on the basis
of the CD spectrum of synthetic (+)-2-deoxyphytocassane A
Arata Yajima and Kenji Mori ∗
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku, Tokyo, 162-8601,
Japan
Received 5 October 1999; revised 25 October 1999; accepted 29 October 1999
Abstract
Phytocassane A–E possess ent-cassane skeleton because synthetic (+)-2-deoxyphytocassane A with cassane
skeleton showed the Cotton effects positive at 369 nm (due to the ring-C dienone chromophore) and negative at
289 nm (due to the ring-A carbonyl group), while the natural phytocassane A exhibited the opposite Cotton effects.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: circular dichroism; configuration; phytoalexins; terpenes; terpenoids.
Phytoalexins are antifungal and defensive metabolites playing an important role in plant chemical
ecology, and are biosynthesized in plant cells after their exposure to pathogens. Phytocassanes A–E were
isolated as the phytoalexins produced by rice plants (Oryza sativa) infected with Magnaporthe grisea (old
name: Pyricularia oryzae), Rhizoctonia solani and Phytophthora infesta.1,2 Their structures as cassane
diterpenes were proposed as 1–5 (Scheme 1) on the basis of extensive spectroscopic analysis.1,2 Their
absolute configuration, however, remained unknown even after their CD measurements.
This paper describes a synthesis of (+)-2-deoxyphytocassane A (6) with depicted absolute configura-
tion. Comparison of its CD spectrum in a longer wave length region (>300 nm) with those of phytocassans
enabled us to propose 10 as the absolute configuration of phytocassane A. Phytocassanes belong to ent-
series of diterpenoids like the gibberellins and (+)-oryzalexin A (7), another phytoalexin produced by
rice plants,3 whose synthesis was previously reported by Mori and Waku.4
Scheme 2 summarizes our synthesis of (+)-2-deoxyphytocassane A (6). (S)-(+)-Wieland–Miescher
ketone5 was selected as the starting material, because it gave enantiomerically pure 8 by simple yeast
reduction with Torulaspora delbrueckii IFO 10921.6 Conversion of 8 to 9 was executed according to
Smith and Mewshaw.7 Removal of the THP protective group of 9 was followed by acetalization of the
C-3 carbonyl group and Swern oxidation of the C-9 hydroxy group to give ketone 10.8 Formylation of
10 was followed by Robinson annelation (methyl vinyl ketone) with concomitant removal of the formyl
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02060-2
tetl 15988

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Scheme 1. Structures of phytoalexins produced by rice plants
group (cf. Ref. 9). Birch reduction of the resulting tricyclic enone yielded the saturated ketone 11 after
reoxidation with PCC. For the introduction of the axial methyl group at C-14, the ketone 11 was first
converted to the enone 12. Accordingly, 11 was thiophenylated by the method of Trost and Massiot,10 and
the resulting phenylthio ether was oxidized with dimethyldioxirane11 to give the corresponding phenyl
sulfoxide, whose thermolysis furnished 12. Conjugate addition of lithium dimethylcuprate to 12 afforded
13 as a mixture of the desired α- and axially methylated one at C-14 and its equatorial isomer. In the
1H NMR spectrum of 13, the axial methyl group at C-14 absorbed at δ=0.79 (d, J=7.4 Hz) due to the
shielding effect caused by the ring-C,9 while the equatorial one showed a doublet at δ=0.99 (d, J=6.4
Hz). The ratio of these two isomers was axial-methyl:equatorial-methyl=1:2. Different conditions for
the introduction of the methyl group were examined with no improved results. Unfortunately, the two
isomers could not be separated at this stage, and, therefore, the mixture 13 was employed as such in the
next step to attach a hydroxymethyl group at C-13 by the method of Corey and Smith.12 Protection of
the newly generated primary hydroxy group as TBDPS ether gave 14.
In order to introduce an oxygen function at C-11, the ketone 14 was subjected to the Shapiro olefination
reaction13 to give 15 after chromatographic purification. Fortunately at this stage, the undesired β-methyl
isomers at C-14 could be eliminated and what we obtained was a diastereomeric mixture (15) at C-13 with
the correct stereochemistry at C-14, exhibiting 1H NMR signals at δ=0.63 and 0.81 (d, J=7 Hz, total 3H).
The reason for this unexpected disappearance of the β-methyl isomers at C-14 was unclear. Deprotection
of the TBDPS protective group of 15 was followed by epoxidation of the resulting olefinic alcohol with
MCPBA to give 16. Dess–Martin oxidation of 16 afforded the corresponding epoxy aldehyde, which was
treated with pyrrolidine to give γ-hydroxy-α,β-unsaturated aldehyde 17. This aldehyde 17 was subjected
to Wittig methylenation, TPAP oxidation14 and deacetalization to give (+)-2-deoxyphytocassane A (6),
[α]D26=+5.8 (c 0.1, CHCl3).15 The overall yield of (+)-6 was 0.04% based on (S)-8 (27 steps).
The CD spectrum of (+)-6 showed a positive Cotton effect at 369 nm (∆ε=+1.63) due to the n→π*
transition of the ring-C carbonyl group,16 while all of the natural phytocassanes A–E showed negative
Cotton effects at the wave length between 345 and 369 nm [λext nm (∆ε): A, 369 (−2.78); B, 345
(−5.36); C, 349 (−5.17); D, 368 (−3.27); E, 348 (−4.47)]. The absolute configuration of the natural
phytocassane A was therefore proposed as depicted in 10.
To further support this conclusion, we decided to synthesize some model compounds 18–2117 with
different ring-A functionalities without any functional group on ring-C, and compared their CD with
those of the natural and synthetic phytocassanes (Scheme 3). As expected, the ketones 18–21 with no
ring-C functionality showed no CD absorption around 369 nm. Accordingly, the strong CD absorption
at 369 nm of (+)-2-deoxyphytocassane A (6) must be due to the chirality of the ring-C. The ketones
18–21 exhibited CD absorption around 290 nm due to the n→π* transition of the ring-A carbonyl group

353
Scheme 2. Reagents: (a) DHP, TsOH, CH2Cl2 (91%); (b) PhSH, HCHO aq., Et3N, EtOH, reflux (79%); (c) Li, H2O, liq. NH3,
THF then MeI, THF (79%); (d) TsOH, MeOH, H2O (99%); (e) ethylene glycol, PPTS, benzene, 80°C (94%); (f) DMSO,
(COCl)2, Et3N, CH2Cl2 (92%); (g) (1) HCO2Et, NaH, THF, toluene; (2) methyl vinyl ketone, Et3N; (3) MeONa, MeOH (76%,
three steps); (h) Li, EtOH, liq. NH3, THF; (i) PCC, MS 3A, CH2Cl2 (76%, two steps); (j) (1) LDA, PhSSO2Ph, THF, −78°C;
(2) dimethyldioxirane, CH2Cl2, −78°C; (3) CaCO3, toluene, 110°C (83%, three steps based on recovered 11); (k) Me2CuLi,
Et2O, 0°C (quant.); (l) (1) NaH, HCO2Et, MeOH; (2) NaH, Red-Al, THF, −30°C; (3) TBDPSCl, imidazole, DMF; (m) (1)
TsNHNH2, MgSO4, THF; (2) excess LDA, THF, quenched with NH4Cl aq. then SiO2 chromatog. (8%, from 13); (n) TBAF,
THF (74%); (o) MCPBA, NaHCO3, CHCl3 (72%); (p) (1) Dess–Martin periodinane, CH2Cl2; (2) pyrrolidine, Et2O (85%, two
steps); (q) Ph3P_CH2, THF (77%); (r) TPAP, MS 3A, CH2Cl2, MeCN (91%); (s) 1N HCl, THF (64%)
[λext nm (∆ε): 18, 309 (−0.38); 19, 284 (−0.61); 20, 288 (+0.97); 21, 289 (+0.04)]. The ketone 21
with the same ketol system as that of phytocassane A showed a positive Cotton effect at 289 nm, while
phytocassane A exhibited a negative Cotton effect at 289 nm (∆ε −8.74).1 The opposite signs of the CD
absorptions at 369 nm of 6 and also at 289 nm of 21 in comparison to those of phytocassane A led us to
the conclusion that phytocassanes possess ent-cassane skeleton, and belong to the same stereochemical
families of diterpenoids as the gibberellins and oryzalexins.
Scheme 3. Structures of the ring-A model compounds
Acknowledgements
This work was financially supported by the Plant Biological Defense System Laboratories (Niigata)
and also by a Grant-in-Aid for Scientific Research from the Government of Japan. A.Y. thanks the Japan
Society for Promotion of Science for a fellowship (DC-1, No. 8099). Thanks are due to Dr. M. Iwata

354
(Meiji Seika Kaisha Ltd, Tokyo) for copies of the various spectra of phytocassanes. We also thank Prof.
T. Sugai and Mr. K. Fuhshuku (Keio University, Yokohama) for their help in the preparation of (S)-(+)-8.
References
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8. All the new compounds gave satisfactory spectral and elemental analytical data (combustion and/or HRMS).
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15. (+)-2-Deoxyphytocassane A (6): colorless gum; CD (EtOH) λext: 369 nm (∆ε +1.63), 279 nm (∆ε −1.20); IR (CHCl3) νmax
(cm−1)=2980 (s, C–H), 2870 (m, C–H), 1700 (s, C_O), 1650 (s, C_O), 1460 (m), 1385 (m), 1230 (w), 1110 (m); 1H NMR
(500 MHz, CDCl3): δ 1.06 (s, 3H, 20-CH3), 1.08 (s, 3H, 18-CH3), 1.09 (d, J=7 Hz, 3H, 17-CH3), 1.11 (s, 3H, 19–CH3),
1.42 (br, dd, J=3, 12 Hz, 1H, 5-H), 1.52 (m, 2H, 6β,7α-H), 1.66 (m, 2H, 1α,6α-H), 1.77 (m, 1H, 7β-H), 1.97 (d, J=13.2
Hz, 1H, 9-H), 2.22 (m, 1H, 8-H), 2.38 (ddd, J=4, 5.8, 14 Hz, 1H, 2α-H), 2.64 (m, 2H, 1β,14-H), 3.23 (ddd, J=4, 6.5, 14 Hz,
1H, 2β-H), 5.49 (d, J=10.9 Hz, 1H, 16-CHH), 5.67 (d, J=17.7 Hz, 1H, 16-CHH), 5.76 (s, 1H, 12-H), 6.35 (dd, J=10.9, 17.7
Hz, 1H, 15-H); 13C NMR (125 MHz, CDCl3): δ 13.3 (C-17), 14.2 (C-18), 21.7 (C-20), 22.2 (C-6), 26.2 (C-19), 31.1 (C-7),
33.3 (C-14), 34.5 (C-1), 37.9 (C-8), 37.9 (C-8), 38.4 (C-2), 38.4 (C-10), 48.1 (C-4), 55.7 (C-5), 55.9 (C-9), 120.6 (C-16),
128.6 (C-15), 136.3 (C-12), 160.7 (C-13), 201.1 (C-11), 216.8 (C-3); HRMS: C20H28O2: calcd 300.2088; found: 300.2094.
The protons of C-17 methyl group attached at C-14 of 6 absorbed at δ=1.06, while the same methyl group at C-14 of 15
appeared at δ=0.63 and 0.81. This may be due to the fact that C-17 methyl group of 6 is located near the conjugated dienone
system and thereby much more deshielded in comparison to the methyl group of 15.
16. Crabbé, P. Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry: Holden-Day: San Francisco, 1965,
pp. 191–243.
17. Synthetic methods for 18–21 will be reported in the full paper.