Formal Asymmetric Synthesis of Pentalenolactone E and Pentalenolactone F-1. Retrosynthesis and π-Facial Differentiation in Palladium-Catalyzed and Dipolar [3 + 2]-Cycloaddition Reactions of Bicyclic Alkenes: Evidence for Electrostatic Control of Stereoselectivity

Abstract

A successful new strategy for the asymmetric synthesis of pentalenolactone E (2a) and pentalenolactone F (2b) has been developed. This strategy involves the assembly of ring A of 2a and 2b through a Binger‐type Pd‐catalyzed [3 + 2]‐cycloaddition reaction of diquinene 7 with the diphenyl‐substituted methylenecyclopropane 18. Diquinene 7 is available in an enantiomerically pure state in 8 steps from diester 8 by using a pig liver esterase catalyzed enantioselective hydrolysis as the key step. Unexpected facial selectivities of 1,3‐dipolar and Pd‐catalyzed [3 + 2]‐cycloaddition reactions as well Michael reactions of 7 have been observed. Thus, 7 reacted with CH2N2 with a stereoselectivity of 98% or greater in favour of reaction at the concave side, with formation of the cisoid triquinane 27. A Trost‐type Pd‐catalyzed reaction of 7 with 11 gave the transoid triquinane 6 and the cisoid triquinane 12 in ratios of 1:1.7 to 1:5.3 depending on the polarity of the solvent. Binger‐type Pd‐catalyzed cycloaddition reactions of 7 with methylenecyclopropane (13) in toluene afforded a mixture of 6 and 12 in a ratio of 1:7. In the Pd‐catalyzed reaction of 7 with the phenyl‐substituted methylenecyclopropanes 14a/b the cisoid triquinane 15 was obtained with a selectivity of 6.7:1 or above. Pd‐catalyzed reactions of 7 with the disubstituted methylenecyclopropanes 16 and 18 gave, however, the transoid triquinanes 17 and 19, respectively, with selectivities of 23:1 and 7:1, respectively. Nakamura‐type cycloaddition of 7 to the methylenecyclopropanone ketal 20 led to the quantitative formation of the transoid triquinane 21a and the cisoid triquinane 22a in a ratio of 1:2. The structures of cycloadducts 12, 15, 19 and 27 were determined by X‐ray analyses. The π‐facial differentiation may be ascribed mainly to a stabilization of the concave transition states by an electrostatic interaction between the lactone carbonyl group and the nucleophilic reagents. The stereoselectivity model proposed has been substantiated by a study of the analogous cycloaddition reactions of diquinenes 29a−c, which exhibited only a low π‐facial stereoselectivity, and by an X‐ray structure analysis of 7, which revealed a slight concave pyramidalization of the double bond. X‐ray structure analysis and NMR spectroscopy of diquinane 28a showed the 5E‐conformation, in which the hydroxy group occupies the pseudoaxial position, to be the more stable one. According to force‐field calculations, the 5E‐conformation seems to be stabilized by an intramolecular electrostatic interaction between the hydroxylic oxygen atom and the lactone carbonyl group, corresponding to the initial step of an intermolecular nucleophilic attack at the carbonyl group. The O−C1 distance and the O−C1−O angle found in the crystal structure of 28a support this notion.

Inductive and Resonance Effects of Substituents on π-Face Selection

“…The presence of the carbonyl group was shown to be crucial for the syn preference in additions to related alkenes, see Scheme , , although it is not a sufficient factor per se, cf. OsO 4 oxidation of bicyclo(3.2.0)hept-2-en-6-one, section 2.3.2.3, Scheme .…”

Benzylidenecyclopropane

“…22 Diquinene reacts with benzylidenecyclopropane in the presence of (Cp)Pd(allyl)/P(iPr) 3 (1:1) as catalyst to give the cisoid triquinane in moderate isolated yield (eq 13). 23 Ph + (dba) 2 1,3-Dipolar cycloadditions of benzylidenecyclopropane are scarce and employ the methylenecyclopropane (MCP) unit as a two-carbon component. Benzylidenecyclopropane reacts with phthalhydrazide in the presence of iodobenzene diacetate to form the corresponding dihydrooxazole derivative (eq 14).…”

Dearomatization applications of I(III) reagents and some unusual reactivity amongst resorcinol derived cyclohexadienones

“…For example, compound 5a undergoes a selective [3+2] cycloaddition with diazomethane at 0 °C in diethyl ether to afford the tetrahydro-3 H -indazole 16a (76% yield, Scheme 5). 18 On the other hand, the enone 5g proceeds in a [4+2] cycloaddition at 155 °C in a sealed tube containing toluene and the masked Durst–Charlton dimethide 19 to afford the tricyclic ring system 17g as a single diastereomer. 17 Type 5 enones can also participate in 1,4-conjugate additions.…”