Facile construction of the lathyrane-type framework via Cr-Ni-mediated cyclization as a key step

Article abstract of DOI:10.1016/S0040-4039(00)00133-7

A tricyclic compound (1) that has a lathyrane-type framework was designed as a model compound of the key intermediate of some diterpenes from Euphorbiacea and Thymeleacea. Two fragments 2 and 3 were derived from commercially available methyl cyclopentanone-2-carboxylate and (+)-3-carene, respectively. These fragments were coupled by a Cr(II)-Ni(II)-mediated reaction, followed by cyclization under the same conditions to afford 1 in moderate yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00133-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2189–2192
Facile construction of the lathyrane-type framework via
Cr–Ni-mediated cyclization as a key step
Tomoo Matsuura,a Shosuke Yamamura a,∗ and Yukimasa Terada b
aDepartment of Chemistry, Faculty of Science and Technology, Keio University, Yokohama, 223-8522, Japan
bFaculty of Pharmacy, Meijo University, Nagoya, 468-8503, Japan
Received 17 December 1999; revised 11 January 2000; accepted 14 January 2000
Abstract
A tricyclic compound (1) that has a lathyrane-type framework was designed as a model compound of the key
intermediate of some diterpenes from Euphorbiacea and Thymeleacea. Two fragments 2 and 3 were derived from
commercially available methyl cyclopentanone-2-carboxylate and (+)-3-carene, respectively. These fragments
were coupled by a Cr(II)–Ni(II)-mediated reaction, followed by cyclization under the same conditions to afford
1 in moderate yield. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cyclization; terpenes and terpenoids; medium-ring carbocycles.
A variety of diterpenes with a unique structure have been isolated from the plants of Euphorbiacea and
Thymeleacea species. The key intermediate of these skeletons is a lathyrane-type skeleton.1 Some other
skeletons, jatrophane, jatrapholane and tigliane seem to be derived from this framework2 as shown in
Scheme 1. Therefore, development of a facile, convenient route for the synthesis of the lathyrane skeleton
provides us with a new strategy for other diterpenes via framework transformation. We have reported
some transformation reactions to tigliane and jatrapholane frameworks from the lathyrane skeleton.3
We report herein a new route to the construction of the lathyrane-type framework. We designed a
model compound 1, which has functional groups necessary for skeletal transformation.
The retrosynthetic route is shown in Scheme 2. Compound 1 seems to be derived from 2 containing
a five-membered ring and 3 containing a three-membered ring. Both 2 and 3 could be derived from
commercially available methyl cyclopentanone-2-carboxylate, and (+)-3-carene, respectively.
Synthesis of 2 is shown in Scheme 3. Methyl cyclopentanone-2-carboxylate was converted to triflate
4,4 followed by Sonogashira coupling reaction with methyl acetylene to give 6.5 This compound was
further derived to 9 in three steps and subjected to cis-specific stannylcupration under Oehlschlager’s
conditions to give dienyl stannane 10.6 Under these conditions, regioselectivity of this reaction was
approximately 3:1 for the desired product. The byproduct via trans addition was not observed.
∗
Corresponding author. Tel: +00 81 45 563 1141; fax: +00 81 45 563 5967; e-mail: yamamura@chem.keio.ac.jp (S.
Yamamura)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00133-7
tetl 16409

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Scheme 1. Adolf–Hecker postulate of biosynthesis of diterpenes from Euphorbiacea
Scheme 2. Synthetic plan of model compound 1
Scheme 3. Reagents and conditions: (a) Tf2O (1.0 equiv.), Et3N (1.0 equiv.), CH2Cl2, −78°C, 0.5 h, 95%; (b) Pd(PPh3)4 (0.3
mol%), CuI (5 mol%), MeCCH (10 equiv.), tol., rt, 2.5 h, 97%; (c) DIBAL-H (2.1 equiv.), tol., −78°C, 1.5 h, 95%; (d) Swern
oxd., 88%; (e) HOCH2CH2OH (8.0 equiv.), PPTS (1 mol%), PhH, reflux, 4.5 h, 82%; (f) nBu3SnCu(nBu)CNLi2 (3.0 equiv.),
THF, −78°C, 0.5 h, then MeOH, 78% (3:1); (g) I2 (1.0 equiv.), Et2O, 0°C, 30 min quant.
The synthesis of the fragment 3 is shown in Scheme 4. Ozonolysis of (+)-3-carene gave the known
ketone 11.7 This compound was derived to aldehyde 3 in seven steps. (8% overall yield from (+)-3-
carene.)
Compounds 2 and 3 were coupled with a Cr(II)–Ni(II) reagent8 to give 13 (Scheme 5). The stereo-
selectivity of this step was not observed (1:1). The methyl acetylene moiety was treated with Schwaltz’s
reagent followed by treatment with iodine,9 then by deprotection to afford 14. Retreatment of 14 with
the Cr(II)–Ni(II) reagent for cyclization afforded 11-membered ring compound 15. Nevertheless, this
compound seems to have significant transannular interaction; Cr(II)–Ni(II) coupling was effective for the

2191
Scheme 4. Reagents and conditions: (a) O3, MeOH, −78°C then Me2S, TsOH, 81%; (b) TsNHNH2, PhH:MeOH (1:1), rt, 30
min; (c) nBuLi (2.1 equiv.), Et2O, 0°C, overnight; (d) HClO4, THF–H2O, rt, 4 h, 53% in three steps; (e) PCl5 (2.0 equiv.),
n-hexane, 0°C, 15 min; (f) O3, MeOH, −78°C, then Me2S, TsOH, 40% in two steps; (g) nBuLi (3.2 equiv.), THF:Et2O (1:1),
−78°C to rt then MeI, 68%; (h) HClO4, (cat.), THF–H2O, rt, 1 day, 70%
construction of the lathyrane-type framework. Compound 15 was treated with IBX10 to give rise to the
target compound (1).11
Scheme 5. Reagents and conditions: (a) CrCl2 (4.0 equiv.), NiCl2 (5 mol%), DMF, rt, 3 h, 48%; (b) LiEt3BH (1.0 equiv.)
followed by Cp2Zr(H)Cl (2.1 equiv.), 50°C, 1 h, then I2, 68%; (c) Et2O–10% HCl aq., 0°C, 15 min, quant.; (d) CrCl2 (10
equiv.), NiCl2 (1 mol%), DMSO, rt, overnight, 43%; (e) IBX (1.0 M solution in DMSO, 2.0 equiv.), CH2Cl2, 2 h, 82%
The conformation of 1 is determined by observation of NOE as shown in Fig. 1. Molecular mechanics
calculation of 1a indicated that this conformer is much stabilized as compared with the other conformer
(1b).12 Conformer 1a is the same as that of the lathyrane-type natural product.
As a result, we were able to establish a new synthetic route to the lathyrane framework using
Cr(II)–Ni(II) coupling reaction as the key-step. Compound 1 is a versatile intermediate of jatrapholane
and tigliane frameworks via transannular cyclization and we are developing transformation reactions for
syntheses of diterpenes including phorbol, ingenol and others.
References
1. Total synthesis of a natural product with lathyrane skeleton, see; Smith III, A. B.; Dorsey, B. D.; Visnick, M.; Maeda, T.;
Malamas, M. S. J. Am. Chem. Soc. 1986, 108, 3110.
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3. Shizuri, Y.; Ohtsuka, J.; Kosemura, S.; Terada, Y.; Yamamura, S. Tetrahedron Lett. 1984, 48, 5547–5550.
4. Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.
5. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467–4470.

2192
Fig. 1. Two conformers of cyclization product 1
6. (a) Aksela, R.; Oelschlager, A. C. Tetrahedron 1991, 47, 1163–1176. (b) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.;
Reuter, D. C. Tetrahedron Lett. 1989, 16, 2065–2068.
7. (a) Shigeno, J.; Ohne, K.; Yamaguchi, T.; Sasaki, H.; Shibasaki, M. Heterocycles 1992, 33, 161–171. (b) Verbrugge, P. A.;
Kramer, P. A.; van Berkel, J.; Kelderman, H. C. Eur. Pat. 1979, 2850, Shell Int. Res.
8. (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644–5646. (b) Takai, K.; Tagashira, M.;
Kuroda, T.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048–6050. (c) Kres, M. H.; Miller, W. H.; Kishi, Y.
Tetrahedron Lett. 1993, 34, 6003–6006. (c) Fürstner, A. Chem. Rev. 1999, 99, 991–1045.
9. (a) Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett. 1990, 31, 7257–7260. (b) Schwartz, J.; Labinger, J. A.
Angew. Chem., Int. Ed. Engl. 1976, 15, 333–340.
10. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–8022.
11. Spectral data for 1: 1H NMR (CDCl3 400 MHz) δ 7.02 (1H, br s), 5.71 (1H, dd, J=1.5, 9.8 Hz), 0.31 (1H, dd, J=11.7, 12.2
Hz), 2.80–2.65 (3H, complex), 2.59 (1H, m), 2.46 (1H, dd, J=4.4, 12.2 Hz), 1.93 (2H, m), 1.67 (3H, d, J=1.5 Hz), 1.66 (3H,
d, J=2.0 Hz), 1.31 (1H, dd, J=9.3, 9.8 Hz), 1.11 (3H, s), 1.06 (1H, ddd, J=4.4, 9.3, 11.7 Hz). 13C NMR (CDCl3, 100 MHz)
δ 202.0, 197.5, 148.3, 142.3, 140.8, 138.8, 137.3, 131.3, 38.3, 34.6, 33.7, 28.4, 28.3, 26.1, 22.2, 20.7, 15.7, 14.6, 13.2. IR
(NaCl, neat) 2951, 1651, 1613 cm−1. HRMS calcd for C19H24O2: 284.1775. Found 284.1795. [α]D21 (CHCl3, c=1.0) −479°.
12. Molecular mechanics calculations were carried out using the MM2/MMP2 molecular modeling program. The effect of
conjugated π-orbital systems was taken into consideration. The starting geometry of 1a and 1b conformers of each
compound was generated by using the program COORD with bond length, bond angles, and torsional angles obtainable
from Dreiding molecular models. Iterative calculations were made to minimize the steric energy of each conformer until the
energy converged within 0.0039 kcal/mol Å. Subsequently, the torsion angle C15–C4–C5–C6 was driven from 40° to 180°
(1a conformer) or −40° to −180° (1b conformer) at a 10° step using the Tortional Driver option of MM2. The activation
energy of the inversion of the C5_C6 bond was estimated by the energy difference between the maximum and the minimum.
All calculations were performed on a FACOM M-180 at Nagoya University Computation Center: MM2/MMP2: Burkert, U.;
Allinger, N. L. Molecular Mechanics, ACS Monograph 177, American Chemical Society: Washington, DC, 1982; QCPE
#691. COORD: Rhee, J., COORD program, QCPE, #226.