Synthesis of (dl)-trichodiene using novel ring transformation reaction

Article abstract of DOI:10.1016/0040-4039(91)80089-O

Synthesis of (dl)-trichodiene has been completed via novel ring transformation reaction using TsOH/ethylene glycol.

Full text of DOI:10.1016/0040-4039(91)80089-O

Tet~ahedron Letters, Vol.32, No 40, pp 5581-5584. 1991
Printed in Great Britain
0040-4039/91 $3 00 +
Pergamon Press plc
Synthesis of (d/)-Trichodiene Using
Novel Ring Transformation Reaction
Masakazu Tanaka and Kiyoshi Sakai*
Faculty ofPharmaceutacal Sciences. Kyushu Umverstty. Fukuoka 812. Japan
Key Words (dl)-trtchodiene, fragmentatmn reacuon, ethylene glycol, nng cleavage, quaternary center
Abstract: Syntheszs of (dl)-trtchodtene has been completed wa novel ring transforraatton reactton using TsOH /
ethylene glycol
Ring transformation reaction is one of the most important tools to construct a synthetically difficult skeleton,
because this reaction provides a new route to prepare the target molecule from another readily prepared
compound.
Recently, we reported the novel ring cleavage and reconstruction reacuonsI of cyclic ketones. By treatment
with BF3 ] ethylene glycol (acetalization conditions), cyclopentanones and cyclohexanones with the carbonyl
function at the C3- or C4-position of the ct- and (]-side chains underwent ring cleavage to build up new five, six,
and/or seven-membered rings. The reaction process involving aldol condensation, acetalizat~on and Grob
fragmentation2 was tentatively proposed. These novel ring transformation reactions were apphed to the syntheses
of natural products such as bulnesollb and acorenone Blf.
In this communication, we wish to describe the new applicauon of this novel ring transformation reaction to
the synthesis of (d/)-trichodiene (1). Trichodiene 1 is a bicyclic sesquiterpene, and is an important biosynthetic
precursor of trichoteeenes3, which possess antifungal, antitumor and cytotoxic biological actwities. Up to now,
extensive effort has been directed to the synthesis of trichodiene4, because of xts synthetically attractive structure
associated with the presence of two adjacent quartemary centers in the molecule, and because trichodiene is found
only in minute amount in fungus Trichothecium r o s e u m . The approach (Scheme 3) employing novel ring
transformation reaction as the key step seems to be syntheucally advantageous for the introduction of the two
adjacent quaternary centers.
Commercially available, the 1,3-diketone (2)5 could be readdy converted to the enone (3) via a two-step
sequence [ i) s e c - B u O H , H+; ii) butenyl magnesium bromide ]. Treatment of 3 with MeCu-BF3 / Et20 (-78 °C -
r.t.)6,7 afforded the expected 1,4-adduct (4). The adduct 4 was converted to the ester (6) with two adjacent
quaternary centers via three sequences8 [ i) TMSC1 / Et3N, 130 °C; ix) LxNH2; iii) methyl 4-iodocrotonate, -60
°C]. The 1H NMR spectrum of 6 indicated the presence of two methyl ester protons (8: 3.733, 3.731),
suggesting a mixture of stereoisomers of 2,3-trans-and cis-cyclopentanones in the ratao of 2 (trans) to 1 (cis). The
cyclopentanone (6) could then be converted to the diketone (8) with the two quaternary centers required for ring
transformation reaction via Wacker oxidation to the unsaturated-daketone (7) followed by H2 / Pd-C reduction of
olefinic function9 (Scheme 1).
5581

1582
0
0
0
0
o
.
.
.
.
.
cooc.
47%
~
7
3
%
~ 79%
2
3
4
=
6
O
o
OOCH3
~
OOCH3
95%
88%
7
O
8
0
(a) 1) sec-BuOH, H+; 11) butenyl magnesium bromide (b) MeCu-BF3 / Et20
(c) 1) TMSC1 /Et3N, 130°C; n) L/NH2, m) methyl 4-10docrotonate
(d) PdCl2, CuCI, H20, 02 (e) He / Pd-C
Scheme 1
The I~aslbahty of-nng transformanon reacnbn was prehmmanfy examined by using a model compound
(14)10 w/th two adjacent quaternary centers (Scheme 2). By treatment w/th BF3 (7eq) / ethylene glycol (5eq) m
CH2C12 at room temperature 11, th/s substrate underwent facile nng transformation to afford the products
(15a,b). The structure of each product was determined by the analysis of spectroscopic data The IR and 1H
NMR spectrum of 15a indicated the ex/stence of OH (3450 cm"1), ester (1720 cm-1 ) function, and allyhc-CH 3
[& 1.63 (3H, s)], COOCH2CH20 [8- 3 70-3.90 (2H, m) and 4 10-4.20 (2H, re)l, oleflmc proton [8" 5.25 (1H,
m)], respectively, in addition to MS spectrum [m/z 222 (M+-H20), 205, 178, 107]. The 1H NMR spectrum of
15b showed the presence of COOCH2CH2OCH2CH20 [8. 3 50-3.70 (6H, m) and 4 15-4 25 (2H, m)]
0
E O 7 q
HOCH2CH2Ot t
OO--~'-OH +
COO-J'--O-~--OH
(5eq)
0
15a 44%
15b 23%
14
Scheme 2
With the success of the model study, we turned our attention to the synthesis of tnchodmne I (Scheme 3).
The dlketone 8 was subjected to fragmentanon condmons using BF3 / ethylene glycol. However, no
fragmentation product was obtained, and only aldol condensation product (9) was obtained m 56% yield This
result may be ascribed to the bulky subsntuents at the ~-posltlon of cyclopentanone; that is to say, the employed
reaction conditions are too weak for the acetahzanon of a hindered carbonyl funcnon.
The difficulties in ring transformanon using BF3 / ethylene glycol could be overcome by employing the
reacnon condmons of TsOH-H20 (2eq) / ethylene glycol (5eq) m refluxmg benzene. Accor&ng to thxs procedure,
the ring transformanon products (10a, b) were obtained m 42% and 8% yields, m addmon to the aldol
condensation product (9) (21%). The structures of these products were detemlmed by 1H NMR, 1R and MS
spectroscopic data. The 1H NMR spectrum of 10a indicated the pIesence ofp-tolyl funcuon [& 2 46 (3H, s);
7.34 (2H, d, J=10 Hz); 7.78 (2H, d, J=10 Hz)], oleflnic proton 18 5 23 (1H, m)l, ethylene glycol ester [8. 4 23

5583
(4H, s)], methyl ester [6:3.66 (3H, s)], and allylic methyl proton [5:1.63 (3H, br s)]. The IR spectrum [
carbonyl (1705 cm'l)] and MS spectrum [m/z: 480 (M+)] also supported the proposed structure.
Scheme
3
O_ ~ ~ cOOcHa
a
COOCH a
cool-
+
*"~ N , / N v , C O O C H 3 . _ . d ~ " " # 9 (21%)
lOa: El = TS (42%)
8
O
10b: R= CH2CH2OH (8%)
c
99% from lOa
57% from lOb
~
-
COOCHz
trichoenone 12
Trichodiene 1
II
(a) TsOH-H20 (2eq.) / HOCH2CH2OH (5eq.) (b) NaN(SiMe3)2 (4eq.)
(c) DBU, 2,4,6-collidine (d) ref. 4b,c
Each product was converted to the 13-ketoester (11) (99% yield from 10a, 57% yield from 10b) by
treatment with NaN(SiMe3)2 (4eq, r.t.). According to the Welch procedure4b (DBU in 2,4,6-collidine at 180 °C
for 3h), the [3-keto ester 11 was transformed into trichoenone (12) in 78% yxeld12. Spectroscopic data of
trichoenone were identical with those reported by Welch et al4b. The 1H NMR spectrum of 12 indicated that this
material is a 2:1 mixture of trichoenone and its diastereomer, bazzanenone4b [8: 0.894, 0.907 (total-3H, each s);
1.009, 1.019 (total-3H, each s)]. In the synthesis4b of trichodiene 1 from 12 by Wittig reacuon using
methylenetriphenylphosphorane, it is already known that bazzanenone was not converted to bazzanene under the
same conditions4b. Furthermore, trichodiene I can be separated4c from its dlastereomer, bazzanene, by AgNO3
impregnated silica gel chromatography. Thus, a formal synthesis of (d/)-trichodiene 1 was achieved.
Acknowledgment: This work was partially supported by Grants-in-Aid for Scientific Research (No.
02453142, 03771687) from the Ministry of Education, Science and Culture of Japan.
References and Notes
1.
a: H. Suemune, K. Oda and K. Sakai, Tetrahedron Lett., 1987, 28, 3373. b: M. Tanaka, H. Suemune
and K. Sakai, Tetrahedron Lett., 1988, 29, 1733. c: S. Nagumo, H. Suemune and K. Sakai, Tetrahedron
Lett., 1988, 29, 6927. d: Y. Miyao, M. Tanaka, H. Suemune and K. Sakai, J. Chem. Soc., Chem.
Commun., 1989, 1535. e: S. Nagumo, A. Matsukuma, F. Inoue, T. Yamamoto, H. Suemune and K.
Sakal, J. Chem. Soc., Chem. Commun., 1990, 1538. f: S. Nagumo, H. Suemune and K. Sakai, J.
Chem. Soc., Chem. Commun., 1990, 1778. g: T. Yamamoto, T. Eki, S. Nagumo, H. Suemune and K.
Sakai, Tetrahedron Lett., 1991, 32, 515.
2.
3.
C.A. Grob, Angew. Chem.Jn_t~Ed,,1967, 6, 1 and 1969, 8, 535.
a: S. Nozoe and Y. Machida, Tetrahedron, 1972, 28, 5105.
b: J. W. ApSimon et al., IUPAC; Pure and Applied Chemistry, 1990, 1339.
a: K. Yamakawa, R. Sakaguchi, T. Nakamura and K. Watanabe, Chemistry Letters, 1976, 991. b: S. C.
Welch, A. S. C. P. Rao, C. G. Gibbs and R. Y. Wong, J. Org. Chem, 1980, 45, 4077. c: M. Suda,
Tetrahedron Lett., 1982, 23, 427. d: R. H. Schlessinger and J. A. Schultz, J. Org. Chem, 1983, 48,
407. e: K. E. Harding and K. S. Clement, J. Org Chem., 1984, 49, 3870. f: J. C. Gilbert and B. E.
4.

584
Wlechman, J. Org. Chem, 1986, 51,258. g: G. A. Kraus and P. J. Thomas, J Org Chem, 1986, 51,
503. h: J. C. Gilbert and T. A. Kelly, J Org. Chem, 1986, 51, 4485.1: F. L. VanMlddlesworth, J. Org
Chem, 1986, 51, 5019. j: F. E. Ziegler, A. Nangla and G. Schulte, J. Am. Chem Soc, 1987, 109,
3987. k" K. E. Harding, K. S Clement and C Y. Tseng, J Org Chem, 1990, 55, 4403.1. R. L.
Snowden, R. Brauchh and P. Sonnay, Helv Chtm Acta, 1989, 72, 570. m: A J Pearson and M.
K. O'Brien, J. Org. Chem., 1989, 54, 4663.
1,3-Dlketone 2; 2-Methyl-1,3-cyclopentanedione is available from Aldrich Chemical Company.
1,4-Addition by Gilman reagents or Gngnard reagent an the presence of Cul and/or CuBr resulted in
failure.
5
6.
Y. Yamamoto and K. Maruyama, J Am. Chem Soc., 1987, 109, 3240.
H. O. House, L. J. Czuba, M. Gall and H D. Olmstead, J. Org Chem, 1969, 34, 2324.
Selected spectroscopic data of each compound. All compounds were obtained as colorless oil.
7
8.
9.
4" 1R' 1735, 1640 cm-t. IH NMR (CDC13) 8" 5 60-6 00 (1H, m), 4.85-5 10 (2H, m), 0.80-1.15 (6H, m)
MS m/z. 166 (M+), 94. bp 90-100 °C (bath temp.) / 0.3 mmHg
6: IR: 1720, 1650 cm 1. 1H NMR (CDCI3) 5' 6.85-7 15 (1H, m), 5 75-5.95 (2H, m), 4.95-5 10 (2H, m),
3.731, 3.733 (total-3H, each s), 0 92, 0.95 (total-6H, each s). MS m/z 264 (M+), 178, 43
8: IR: 1710 cm-l. 1H NMR (CDCI3) ~5: 3.657, 3.664 (total-3H, each s), 2 179, 2.192 (total-3H, each s),
0.842, 0.903, 0.932, 0.960 (total-6H, each s). MS m/z: 282 (M+), 264, I 11.
10. Substrate was synthesized as follows
O
OTMS
0
89%
71%
(a) i) LiNH2, I1) MeI, (b) PdC12, CuC1, H20, 02
Selected spectroscopic data of prehmmary experimental products. All compounds were
obtained as colorless o11.
11.
14: IR: 1735, 1715 cm -l. IH NMR (CDCI3) 8' 2 91 (3H, s), 2.10-2 50 (4H, m), 0.94 (6H, s), 0.86 (
3H, s). MS m/z: 196 (M+), 178, 43
15a: IR: 3450, 1720 cm-1 1H NMR (CDCI3) 8:5 25 (1H, m), 4.10-4.20 (2H, m), 3.70-3.90 (2H, m),
1.63 (3H, br s), 1.18 (3H, s), 1.15 (3H, s), 0.89 (3H, s). MS m/z- 222 (M+-H20), 205, 178, 107.15b.
IR: 3450, 1720 cm-1. 1H NMR (CDC13) 8:5.25 (1H, m), 4.15-4.25 (2H, m), 3 50-3.70 (6H, m), 1 63
(3H, br s), 1.17 (3H, s), 1.14 (3H, s), 0.88 (3H, s). MS m/z. 222 (M+), 205, 178, 107
12. Spectroscopic data of compounds. All compounds were obtained as colorless oil
9: IR" 1_730 crn-1 IH NMR (CDCJ_3) ~ 5 30-5 38 (!1~ m), 3 6.57, 3.663 (totat-3H, each s), 2 60 (1H,
m), 1.70 (3H, br s), 1.006, 1.023, 1.057, 1 094 (total-6H, each s) MS m/z. 264 (M+), 107.
10a: IR: 1705 1590 cm-1. IH NMR (CDC13) 8. 7.78 (2H, d, J=10 Hz), 7.34 (2H, d, J=10 Hz), 5.23 (1H,
m), 4.23 (4H, s), 3.66 (3H, s), 2 46 (3H, s), 1 63 (3H, br s), 0 819, 1 046, 1 096 (total-6H, s). MS m/z:
480 (M+), 448, 172 10b IR. 3500, 1740, 1720 cm 1. IH NMR (CDCI3) 8. 5.25 (1H, m), 4.10-4 30
(2H, m), 3.66 (3H, s), 3.50-3.75 (6H, m), 1.62 (3tt, br s), 0.87, 1.11, 1 15 (total-6H, each s) MS re~z.
371 (M++I).
11: IR: 1750, 1725, 1660, 1620 cm-l. 1H NMR (CDCI3) 8" 5.27 (1H, m), 3.73, 3.75 (total-3H, each s),
1.63 (3H, br s), 1.09 (3H, s), 091 (3H, s). MS m/z 264 (M+), 164
12. IR: 1725 cm"1 1H NMR (CDCI3) 8. 5.28 (1H, m), 1 63 (3H, br s), 1.009, 1.019 (total-3H, each s),
0.894, 0.907 (total-3H, each s) MS m/z 206 (M÷)
(Received in Japan 22 May 1991)