Synthesis of Diquinane Natural Products

The Nazarov cyclization has been featured in a variety of synthetic endeavors involving both natural and unnatural products. In the area of polyquinane natural products ( )-hirsutene (88), ( )-mod-hephene (89), ( )-silphinene (90), ( )-A 2)-capnellene (91) and ( )-cedrene, have all been prepared (Scheme 37). The synthesis of (91) is noteworthy in the iterative use of the silicon-directed Nazarov cyclization. TIk divinyl ketones were constructed by the carbonylation-coupling of enol triflates (92) and (95) with the -silylvinylstannane (Scheme 38). llie diquinane (94), obtained from Nazarov cyclization of (93), was transformed into enol triflate (95) which was coupled with the -silylvinylstaimane as before. Silicon-directed Nazarov cyclization of (96) was highly diastereoselective to provide the cis,anti,cis isomer of (16). The synthesis was completed by routine manipulations. 

The [(PhjP)2PdCl2-Et3Al]-catalyzed reaction of butadiene with Af -dimethylallylamine is a particularly intriguing linear dimerization reactionJ It appears to involve a carbon electrophile (allyl cation or an equivalent). The reaction affords a 1 9 mixture of 1-(1V -dimethylamino)-2,7-octadiene (211) and 212 in 79% yield (Scheme 66). The formation of 211 requires dimethylamine and hence requires that Al -dimethylallylamine must decompose under the reaction conditions. Its decomposition could liberate allyl cation or an equivalent (e.g., a 7r-allylpalladium). The formation of 212 could arise via addition of the allyl electrophile to the paUadacycle 213 in an Se fashion to afford 214 and be completed by subsequent addition of dimethylamine. The adduct 212 has been used as an intermediate in the synthesis of the diquinane 215 and the natural product (+)-sativene (216).P26]... 

The use of carbanionic nucleophiles in the Mizoroki-Heck cyclization-/ -allyl nucleophilic trapping sequence allowed for streamlined access to the triquinane core common to various members of the capnellene family of natural products. For example, Shibasaki and coworkers obtained diquinane 57 in 77% yield and 87% ee by Mizoroki-Heck cy-clization of trienyl triflate 47 in the presence of malonate nucleophile 56 Scheme 16.14). It is notable that two new C-C bonds and three stereocentres are generated in this reaction. Eleven additional steps were used to convert intermediate 57 to ( )-A ( Ecapnellene (58). This first catalytic asymmetric total synthesis ( )-A d2). j pjjgjjgjjg achieved in 19 steps and 20% overall yield from commercially available materials. A related approach has recently been employed to prepare intermediates en route to capnellenols 53 and 54 (Scheme 16.12) [41]. 

A prototypical exanple of the ODPM rearrangement reaction is the conversion of the bicyclo[2.2.2]oct-5-en-2-one 21 into the isomeric and cyclopropa-fused diquinane 22 fScheme This conversion proceeds in 81% yield, and many variants of it have been used to great effect in the synthesis of polyquinane-containing natural products,exanples of which are presented in Section 9.4. 

In cyclic systems, the constraints of the frameworks bearing the reacting n-systems tend to limit the stereochemical outcomes of the reaction in a synthetically beneficial manner. The preservation of enantiomeric purity associated with the ODPM rearrangement of the (+)- and (-)-forms of compound 21 into the corresponding enantiomers of cyclopropa-fused diquinane 22 fScheme 9.4 is particularly significant because of the extensive application of this basic process in the synthesis of a range of polyquinane-containing natural products (see Section M). 

D.i.d. Diquinanes. The successful execution of AHRs for the formation of 6,6- and 6,5-ring systems from prochiral substrates clearly suggested an extension of the method to the formation of 5,5-systems, which form the backbone of a large number of natural products. The use of prochiral cyclopentadienyl systems, however, involves the generation of a rr-allylpalladium species, which must then be trapped with a suitable nucleophile. " The greater reactivity of the 1,3-diene substrate toward the silver salts used in the reactions and the propensity for undesirable side reactions such as Diels-Alder cycloadditions must also be borne in mind. The former problem, in fact, figures prominently in the first example of an AHR-based diquinane synthesis to be published (Scheme... 

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