Advanced bicyclic intermediate

Dysidiolide is the first compound found to be a natural inhibitor of protein phosphatase cdc25A that is essential for cell proliferation. Y. Yamada et al. develcyed a novel total synthesis of this natural product using an intramolecular Diels-Alder cycloaddition as the key step. Deoxygenation of the advanced bicyclic intermediate at the C24 position was achieved under Woiff-Kishner reduction conditions to afford the C24 methyl group. 

With this bicyclic intermediate available in sizeable amounts, ready advance to 111 could be conveniently accomplished prior to annulation of the second five-membered ring (Scheme XIV). 1,3-Carbonyl transposition was realized by complete eradication of the original carbonyl by Ireland s method [60] followed by allylic oxidation. Application of the Piers cyclopentannulation protocol [61] to 111 made 113 conveniently available. Introduction of a methyl group into ring B was brought about by treatment of the kinetically derived enol triflate [62] with lithium dimethylcuprate [63], Hydrolysis of 114 gave the dienone, which was directly transformed into 115 by oxidation of its silyl enol ether with palladium acetate in acetonitrile [64],... 

This result should be compared to the cydization of the more advanced intermediate 49 (4 1 mixture of isomers at the acetal position Scheme 9.25), which afforded the bicyclic oxepane 50 as the sole product in excellent yield. It was suggested that this result was due to the presence of a trans-fused five-membered ring, which restricts the rotation around the C7-C8 bond and thus promotes the 7-endo cydization. 

One notable advance in this chemistry since the publication of CHEC-II(1996) is the use of enantiomerically enriched 3,6-dihydro-l,2-thiazine 1-oxides in the rearrangement sequence. For instance, iV-Cbz-protected bicyclic 1,2-dihydrothiazine 44 undergoes ring opening upon treatment with phenylmagnesium bromide (Scheme 16). The synthesis of allylic amino alcohol 129 is completed in excellent yield upon exposure of the intermediate sulfoxide 130 to trimethyl phosphite and methanol at 80 °C <2002TA2407, 2000TL3743>. 

This methodology has been applied to the synthesis of the bicyclic system (157),133 an advanced intermediate previously used in the synthesis of confertin.138 Reaction of the diazo compound (158) with rho-dium(II) mandelate gave an equilibrating mixture of the norcaradiene (159) and the fused cycloheptatriene (160) in essentially quantitative yield (Scheme 35). The mixture of (159) and (160) was converted to (157) in six steps in 20% overall yield. 

Recent advances in the synthesis of trans-iused polycyclic ethers by hydroxy epoxide cyclization reactions via monocyclic epoxonium ion intermediates and ether ring expansion reactions via bicyclic epoxonium ion intermediates are described in a review by Fujiwara and Murai. Natural trans-iu eA polycyclic ethers (e.g., brevetoxin A and ciguatoxin), produced by marine sources such as dinoflagellates, are hypothesized to be constructed from the corresponding polyepoxide precursors by a cascade of ring-closure reactions, which has prompted much work in the development of new methods for the construction of cyclic ethers from epoxides <2004BCJ2129>. 

Aryl ethers were also coupled intramolecularly with enol ethers when vinylsulfide was used as initiator of the coupling reaction the selectivity could be improved considerably [172e]. Additionally, the coupling to furan rings was studied, which led to advanced intermediates for the synthesis of bicyclic furan-containing natural products [172e],... 

The total synthesis of the antimicrobial drimane-type sesquiterpene (-)-pereniporin A was achieved by the research team of K. Mori. The advanced intermediate bicyclic primary alcohol was first oxidized to the corresponding aldehyde using the Moffatt oxidation. Interestingly, the sensitive a-hydroxy aldehyde moiety in the product remained unchanged. The final step was a global deprotection followed by a spontaneous lactol formation. 

Inspired by these results, Nicolaou et al. used a temporary boronate tether to overcome the undesired regiochemical bias in the intermolecular Diels-Alder reaction of diene 56 and dienophile 57, required for their approach to the C-ring of taxol 58 [21a, b, 24], Thermolysis of a benzene solution of 56 and 57 in the presence of PhB(OH)2 under dehydrating conditions provided the cycloadduct 59 in 79% yield (77% conversion) after transacetalization of the boron tether with 2,2-dimethylpropane-l,3-diol and intramolecular acyl transfer to the less strained [4.3.0]bicyclic system. This was further elaborated to an advanced intermediate in the ultimately successful synthesis of taxol (Scheme 10-21) [21c]. 

The enthusiasm for the pharmaceutical potential of the monocyclic P-lactams was matched by renewed interest in the chemistry of these compounds both in industry and academe. This review will focus on recent developments in the chemistry of monocyclic P-lactam antibiotics, emphasizing new or improved methods for construction of the azetidinone ring as opposed to a discussion of the functional group manipulation of preformed P-lactams and the structure-activity relationships of the ultimate products. Emphasis will be placed on key advances in the preparation of true monocyclic antibiotics and intermediates for their synthesis and not on the voluminous chemistry dealing with the preparation of azetidinone intermediates for the synthesis of bicyclic compounds such as penems. The latter topic is covered elsewhere in this volume. The review is intended to cover the period from 1983 through early 1989 with an emphasis on more recent developments. Attention is drawn to previous reviews [4-14] which deal with the early phases of development of the monocyclic p-lactam antibiotics as well as those aspects of their chemistry not discussed in this work. 

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