Stereospecific cis- and trans -ring fusions arising from common intermediates

Abstract

Highly concise and stereospecific routes to cis and trans fusion, carrying various functionality at one of the bridgehead carbons, have been accomplished. Diels-Alder cycloaddition | cyclobutenone | angular methylation | mechanistic studies O ur group has been studying the synthetic utility of the DielsAlder (DA) reaction of the parent cyclobutenone, 2 (1). Recently reported results demonstrate that 2 is a highly reactive, endo-selective dienophile (Fig. 1, Eq. 1) (2). We have also developed a series of intramolecular Diels-Alder (IMDA) reactions, wherein the cyclobutenone component is tethered to various conjugated dienes (compare 4); cycloaddition of these substrates delivers adducts of the type 5, which can be readily converted to trans-fused systems bearing iso-DA patterns (Fig. 1, Eq. 2, 5→6) (3). Additionally, we have described the synthesis and DA cycloaddition of an even more powerful dienophile, 2-bromocyclobutenone (Fig. 1, Eq. 3, 7) (4). The direct adducts of this [4+2] reaction (compare 8) are readily converted to norcarane carboxylic acids (9) through exposure to hydroxide base. The research described herein was initially focused on efforts to add carbon-based nucleophiles to DA cycloadducts of the type 8. It might well have been expected that such reactions would give rise to products such as 10, wherein a ketone is appended to the junction of the norcarane system (Fig. 1, Eq. 4). Results and DiscussionWith a view toward accomplishing the transformation envisioned in Fig. 1, Eq. 4, compounds of the type 8 were exposed to methyllithium as described in Fig. 2. Interestingly, exposure of substrate 8a to the conditions shown led to an 81% yield of the angularly methylated product 11a, apparently unaccompanied by any part of the corresponding trans-fused diastereomer (Fig. 2, entry 1). Reactions conducted with related DA adducts 8b and 8c resulted in quite similar outcomes (Fig. 2, entries 2 and 3). Although we were confident that the products obtained were cisfused (Fig. 2, 11a-c), it was the synthesis of the rigorously assignable trans-fused product (vide infra) and its nonidentity with 11a that served to allow for sound assignment of the cisring fusion.An obvious mechanistic proposal to account for the formation of this structure envisions lithium-halogen exchange (5-8) leading to 12a and methyl bromide (Fig. 3). This step is followed by angular methylation (9-11) of 12a. It would not be surprising for such a reaction to have a very high preference for producing cis fusion. Clearly, a great deal of ring strain would be introduced in any transition state en route to trans-fused products.Whereas the enolate alkylation proposal is presumptive, several alternate formulations merited consideration. In principle, one can envision the possibility that lithium enolate 12a is not actually produced (perhaps due to ring strain). Rather, 11 (Fig. 3) arises from the merger of otherwise high-energy species en route to 12a and 12b. For instance, "radicaloid" (5) character could be generated at both the bridgehead ...

Diastereoselective Addition of PhSCF2SiMe3 to Chiral N-tert-Butanesulfinyl Ketimines Derived from Isatins: Synthesis of Enantioenriched gem-Difluoromethylenated Spiro-pyrrolidinyl and Spiro-piperidinyl Oxindoles

“…In the presence of BF 3 ·OEt 2 , the iminium intermediate X with angle strain was formed via intermediate IX . Finally, the approach of hydride from the upper face of the iminium group of X provided 9 , possessing a cis -fused bicyclic skeleton between lactam and indoline rings while product 10 was not observed …”

A Direct Organocatalytic Enantioselective Route to Functionalizedtrans‐Diels–Alder Products Having the Norcarane Scaffold

“…Intrigued by these results, we decided to test the α‐brominated enones employed by Danishefsky et al. using the optimized reaction conditions [3a–g] . Pleasingly, 2‐bromocyclopent‐2‐en‐1‐one and 2‐bromocyclohex‐2‐en‐1‐one delivered the trans ‐Diels–Alder products 3 q and 3 r in high yields (72–80 %), excellent diastereoselectivities (>20:1 d.r.…”

“…Synthetic methodologies to obtain trans-Diels-Alder products have been of interest for decades with only few efficient limited strategies currently present. [3,4] Danishefsky et al developed two methodologies to obtain the trans-Diels-Alder scaffold by post-reaction modifications with substrate-dependent selectivity (Scheme 1b). [3] These strategies utilize the a-halogenated enones as dienenophiles to obtain atertiary halogenated carbon center as ah andle for subsequent transformations.T he first strategy proceeds through ar adical dehalogenation to form the thermodynamically more stable trans-decalin structure (Scheme 1b left).…”

“…[3,4] Danishefsky et al developed two methodologies to obtain the trans-Diels-Alder scaffold by post-reaction modifications with substrate-dependent selectivity (Scheme 1b). [3] These strategies utilize the a-halogenated enones as dienenophiles to obtain atertiary halogenated carbon center as ah andle for subsequent transformations.T he first strategy proceeds through ar adical dehalogenation to form the thermodynamically more stable trans-decalin structure (Scheme 1b left). Theo ther strategy relies on transforming the halogen into am ethyl-sulfide-or methyl-sulfone intermediate,followed by reductive cleavage, to afford the trans-decalin scaffold with amethyl group at the ring junction (Scheme 1b right).…”

Naturally Occurring Norsteroids and Their Design and Pharmaceutical Application

“…Calvatianone (259), a sterol with a 6/5/6/5-fused ring system and a contracted tetrahydrofuran B ring, was detected in Calvatia nipponica Spiro-astraodoric acid (264), a lanostane-type triterpenoid with a spirocyclic structure, was discovered in Astraeus odoratus, exhibiting cytotoxicity against various cancer cell lines [181]. Spirosacraoic acid A (265), with a rearranged tirucallane skeleton, was isolated from Boswellia sacra [182].…”