First synthesis of a rearranged neo-clerodane diterpenoid. Development of totally regioselective trisubstituted furan ring assembly and medium-ring alkylation tactics for efficient access to (-)-teubrevin G [15]

Full text of DOI:10.1021/ja002450x

9324
J. Am. Chem. Soc. 2000, 122, 9324-9325
Scheme 1
First Synthesis of a Rearranged neo-Clerodane
Diterpenoid. Development of Totally Regioselective
Trisubstituted Furan Ring Assembly and
Medium-Ring Alkylation Tactics for Efficient Access
to (-)-Teubrevin G
Ivan Efremov and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio
State UniVersity, Columbus Ohio 43210
ReceiVed July 6, 2000
The clerodane and neo-clerodane diterpenoids occupy a
uniquely important place in the natural product field because of
the widespread distribution, extensive structural variation, and
pronounced biological activity of these secondary metabolites.1
While the vast majority of the members of this family is
characterized by the presence of a decalin framework (e.g.,
teulepicin (1)),2 a small group of offspring seco analogues have
Scheme 2
recently been isolated from the aerial parts of Teucrium breVi-
folium.3 These structurally unique constituents exemplified by
teubrevin G (2) feature a cyclooctanone core substituted in unusual
fashion with fused and spirocyclic oxygen-containing rings, the
ensemble of which causes 2 to be an intriguing synthetic target.
The structural assignment to 2 was arrived at on the basis of
spectroscopic data, including COSY, HMQC, NOESY, NOE, and
HMBC NMR analysis. Here we report a direct enantioselective
route to 2. The central features of the approach are a fully
regiocontrolled cycloaddition-retrograde fragmentation to form
a 2,3,4-trisubstituted furan and the exploitation of a stereodefined
alkylation in a medium ring context for the purpose of establishing
the proper absolute configuration at C-9.4
Retrosynthetically, we envisioned the alkylation of â-keto ester
3 to be a means potentially well suited to assembly of the
γ-lactone (Scheme 1). Access to this advanced intermediate was
to be gained by ring-closing metathesis of 5, such that the
C-acylation of 4 would materialize exclusively at C-9. The
viability of this approach rested therefore on the availability of
an expeditious means for generating the monocyclic 2,3,4-
trisubstituted furans 6 and 7, a family of heterocycles recognized
not to be readily accessible.5
comparable regioselectivity and have therefore been little utilized
except with symmetrically substituted alkynes.7,8 In light of this
precedent, the conversion of 89 in low yield to an inseparable
5.3:1 mixture of 9 and 10 was anticipated (Scheme 2). However,
when we turned to the corresponding acetylenic aldehyde, 11 was
produced as a single, easily purified regioisomer. A maximized
yield of 52% was realized if the process was arrested at 90%
conversion. It is noteworthy that the second possible furan was
not detected under any circumstances, possibly indicative of
previously unappreciated stereoelectronic factors.
Aldehyde 11 was subsequently transformed in an efficient two-
step sequence10 to 12, from which 13 was obtained without event
(6) (a) Liu, B.; Padwa, A. Tetrahedron Lett. 1999, 40, 1645. (b) Jacobi, P.
A.; Craig, T. A.; Walker, D. G.; Arrick, B. A.; Frechette, R. F. J. Am. Chem.
Soc. 1984, 106, 5585. (c) Jacobi, P. A.; Walker, D. G. J. Am. Chem. Soc.
1981, 103, 4611. (d) Jacobi, P. A.; Walker, D. G.; Odeh, I. M. A. J. Org.
Chem. 1981, 46, 2065. (e) Iesce, M. R.; Cermola, F.; Giordano, F.; Scarpati,
R.; Graziano, M. L. J. Chem. Soc., Perkin Trans. 1 1994, 3295. (f) Selnick,
H. G.; Brookes, L. M. Tetrahedron Lett. 1989, 30, 6607.
(7) (a) Caesar, J. C.; Griffiths, D. V.; Griffiths, P. A.; Tebby, J. C. J. Chem.
Soc., Perkin Trans. 1 1990, 2329. (b) Van Aken, K.; Hoornaert, G. J. Chem.
Soc., Chem. Commun. 1992, 895. (c) Koenig, H.; Graf, F.; Weberndoerfer,
V. Liebigs Ann. Chem. 1981, 668.
A key feature of the intramolecular [4 + 2] cycloaddition-
retrofragmentation of alkyne-tethered oxazoles is the directed
formation of polycyclic furans.6 Intermolecular variants lack
(1) (a) Meritt, A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 243. (b) Hanson, J.
R. Nat. Prod. Rep. 1993, 10, 159; 1994, 11, 265. (c) Rodriguez-Hahn, L.;
Esquivel, B.; Cardenas, J. Prog. Chem. Org. Nat. Prod. 1994, 63, 107. (d)
Tokoroyama, T. Synthesis 2000, 611.
(2) Savona, G.; Piozzi, F.; Servettaz, O.; Rodriguez, B.; Hueso-Rodriguez,
J. A.; de la Torre, M. C. Phytochemistry 1986, 25, 2569.
(3) Rodriguez, B.; de la Torre, M. C.; Jimeno, M. L.; Bruno, M.; Fazio,
C.; Piozzi, F.; Savona, G.; Perales, A. Tetrahedron 1995, 51, 837.
(4) The numbering is that originally proposed by Rodriguez et al.3 and
appears unusual because an attempt has been made to track the relocation of
the carbon atoms during the ring-opening rearrangement.
(5) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P L.; Lo, T. H.; Tong,
S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(8) This process appears to have been applied only once to construction of
a 2,3,4- (Yadav, J. S.; Valluri, M.; Rao, A. V. R. Tetrahedron Lett. 1994, 35,
3609) and a 2,3,5-trisubstituted furan (Iesce, M. R.; Cermola, F.; Graziano,
M. L.; Scarpati, R. J. Chem. Soc., Perkin Trans. 1 1994, 147).
(9) Oxazole 8 was prepared by sequential reaction of the known acetal of
methyl acetoacetate (Zamir, L. O.; Sauriol, F.; Nguen, C.-D. Tetrahedron Lett.
1987, 28, 3059. Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203)
with ammonium hydroxide and then with phenacyl bromide in toluene at 100
°C.
(10) Profitt, J. A.; Watts, D. S.; Corey, E. J. J. Org. Chem. 1975, 40, 127.
10.1021/ja002450x CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9325
Scheme 3
Scheme 4
by desilylative oxidation. The availability of this aldehyde
permitted proper enantiocontrolled introduction of the C-3 hy-
droxyl group by application of Nagao’s chiral 1,3-thiazolidine-
2-thione technology11 (Scheme 3). The N-acetyl derivative 14
enters smoothly into aldol condensation with 13 to furnish 15 in
80% yield at a de level of 98%. The â-hydroxy amide was next
silylated and subjected to lithium borohydride reduction.12
Chemoselective Grieco dehydration13 of the resulting primary
carbinol 16 followed by Dibal-H reduction, treatment with
vinylmagnesium bromide, and Swern oxidation gave rise to
dienone 18, whose role it was to serve as the precursor to a 3,4-
cyclooctenofuran.
When recourse was made to Grubbs’ catalyst14 for the ring-
closing metathesis step, only very modest yields of 20 (20-35%)
were realized, and only after use was made of long reaction times
(>3 days) and high catalyst loadings (30-35 mol %). Use of
copper(I) salts15 increased the level of conversion to ∼50%, but
the requisite proportion of catalyst remained high. A very practical
resolution to this problem was uncovered in the form of 19.16
This ruthenium complex delivered 20 in 90% yield when
employed at the 10 mol % level in refluxing CH2Cl2 for 34 h.
With the eight-membered ring in place, we began installation
of the remaining eastern sector of 2. As anticipated,17 the
deprotonation of 20 with lithium hexamethyldisilazide was
directed away from the OTBS substituent, thereby allowing for
efficient conversion to the enolized â-keto ester 21 with Mander’s
reagent18 (Scheme 4). The superfluous double bond in 21 was
saturated cleanly without reducing the furan ring by conventional
hydrogenation over Pd/C. Considerable experimentation was
required to uncover reaction conditions that would cause the
enolate anion of 22 to be alkylated by iodide 23.19 The use of
cesium carbonate in warm DMSO uniquely afforded useful yields
of 24 (61%) and its easily separated diastereomer (15%). The
stereochemical course of this bond-forming protocol can be
rationalized in terms of the preferred adoption of conformer A in
the low-energy transition state as a consequence of the quasi-
equatorial projection of the distal OTBS substituent. In spatial
arrangement A, an unfavorable gauche interaction with the furan
ring is also operational. However, the significantly less sterically
encumbered top surface of A is particularly conducive to optimal
kinetic control.
Treatment of 24 with mineral acid in acetone induced the
selective hydrolysis of two protecting groups. The free hydroxyl
substituent in 25, although unusually sluggish toward acetylation,
was efficiently transformed into 26 when promoted by DMAP.
Arrival at (-)-teubrevin G (2) was ultimately achieved via
oxidative removal of the PMB group with DDQ and lactonization
under aqueous acidic conditions. The assembly required 21 steps
from 8 and proceeded in 5.2% overall yield. The synthetic product
was identical in all respects with the literature spectral data (1H
and 13C NMR, IR, HRMS) and chiroptical properties.20
In conclusion, a synthesis of (-)-teubrevin G has been achieved
by a series of regiocontrolled tactics including a one-step route
to a 2,3,4-trisubstituted furan, generation of a highly substituted
2-cyclooctenone by ring-closing metathesis, and reliance on
remote asymmetric induction to establish the absolute configu-
ration of the spirocyclic carbon.
(11) Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiani, M.; Inoue, T.;
Hasimoto, K.; Fujita, E. J. Org. Chem. 1986, 51, 2391.
(12) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. H.; Miyashiro,
J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307.
(13) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.
Supporting Information Available: Representative experimental
procedures and spectroscopic data (PDF). This information is available
free of charge via the Internet at http://pubs.acs.org.
(14) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202 and references
therein.
JA002450X
(15) (a) Dias, E. L.; Nguen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997,
119, 3887. (b) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (c) Schwab, P.; Grubbs, R. H.; Ziller,
J. W. J. Am. Chem. Soc. 1996, 118, 100.
(19) This reagent was prepared from 3-vinylfuran via asymmetric dihy-
droxylation by analogy to the 2-isomer (Harris, J. M.; Keranen, M. D.;
O’Doherty, G. A. J. Org. Chem. 1999, 64, 2982). The (2R)-diol of >90% ee
was condensed with p-methoxybenzaldehyde dimethylacetal, reduced with
Dibal-H, and exposed to triphenylphosphine diiodide.
(16) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(17) Paquette, L. A.; O’Neil, S. V.; Guillo, N.; Zeng, Q.; Young, D. G.
Synlett 1999, 1857.
22
(20) An [R]D of -69.6 (c 0.46, CHCl3) was measured for (-)-2. The
reported rotation of the natural substance is [R]D -64.1 (c 0.382, CHCl3).3
21
(18) Mander, L. N.; Sehti, S. P. Tetrahedron Lett. 1983, 24, 5425.