Stork annelation

The reaction of a,/3-unsaturated carbonyl compounds with enamines also leads to dihydropyrans, although it is not always possible to isolate these since they react further to give either ring-opened by-products or bicyclic derivatives arising from a Stork annelation. There has been considerable discussion on the mechanism of this reaction, although the initial nucleophilic attack of the enamine on the /3-carbon of the diene is not in doubt (63JA207). It is possible that a zwitterionic species is involved, either as an intermediate or merely in equilibrium with the dihydropyran (67JCS(C)226). 

When an oc,/)-unsaturated ketone is the acceptor, subsequent ring closure to yield a six-membered ring can occur, in two modes. As shown in Scheme 3, the initially formed enolate oxygen can add to the immonium ion of the dipolar intermediate to generate a dihydropyran (e.g., 3.2, Y = 0, X = C). Alternatively, proton transfer from the initially formed enolate and subsequent carbon-carbon bond construction between the enolate and the immonium ion can produce a new cyclohexanone ring. Elimination of the amine usually ensues to generate the corresponding cyclohexenone. This amine-promoted Robinson annelation is commonly referred to as a Stork annelation (3, 22). 

Under conditions not favoring dehydration alternative hydrolytic pathways predominate.233 Thus, if the carbinolamine derived from compound (101) is treated with aqueous base, the main product is the octalone (102).234 This annelation clearly has great potential in synthesis, and it has already been exploited in, for example, the construction of the AB ring system of steroids (Stork and McMurry235 see also Ohashi236). 

Snider, B. B., Shi, B. A novel extension of the Stork-Jung vinylsilane Robinson annelation procedure for the introduction of the cyciohexene of guanacastepene. Tetrahedron Lett. 2001, 42, 9123-9126. 

A fuller account of Stork s synthesis of the unsaturated tricyclic diketone [see (7) on 1, 277] is given in a communication of 1967.3 Another communication4 discusses the mechanism of the isoxazole annelation. 

A new and highly stereoselective total synthesis of the 13 -ethyl gonane (448) which used a Stork isoxazole annelation sequence on the diene (449) has been intimated. 

The Stork-Dolfini synthesis of the amino ketone 458 requires some 11 steps clearly, this is an area for improvement. One method used has been that of methyl vinyl ketone annelation (237). This procedure had been used previously in a synthesis of mesembrine (238) involving 2- -rolines. Stevens hoped to extend this technique to endocyclic enamines to give compounds in the octahydroquinolone series. 3-Ethylpiperid-2-one (549) was prepared from the y-lactone 550 according to standard procedures (239). N-Benzylation followed by reduction with diisobutyl-aluminum hydride (DIBAL) gave enamine 473. Addition of the enamine to methyl vinyl ketone (551) gave an almost quantitative yield of a hydroquinoline 552, which could be readily debenzylated to the known amino ketone 458. As with the Stork method of synthesis, this route to the Aspidosperma nucleus is efficient for the parent compounds but appears to lack the potential for diversification required to synthesize the more complex alkaloids such as vindoline (101) or even tabersonine (28). 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

An elegant synthesis of Warburganal (12) from the ketone (2) was reported by Kende and Blacklock [8] as depicted in Tig (1)". The ketone (2), prepared [3] by Robinson annelation of the 2-methyl-1,3-cyclohexanedione with ethyl vinyl ketone, on ketalization afforded (3) which was converted to the trans-decalone (4) by the reductive methylation procedure of Stork [9]. Wolff-Kishner reduction of (4) produced the ketal (5), which without purification was hydrolyzed with acid to obtain the trans-decalone (6) [10] in excellent yield. The present method for the synthesis of the decalone (6) appears more efficient and convenient than the methods previously reported [11,12], considering the overall yield and the stereoselectivity. 

Sandmeyer synthesis (isatin) 145 Schmidt-Druey synthesis (pyridazine) 461 Schollkopf synthesis (oxazole) 173 Sharpless-Katsuki epoxidation 24 Shaw synthesis (pyrimidine) 468 Skraup-Doebner-Miller synthesis (quinoline) 400 Smiles rearrangement 446 Sommelet-Hauser rearrangement 136 Staudinger reaction 53 Steglich reagent (DMAP) 348 Stork isoxazole annelation 191... 

Camptothecin, the potent antitumor and antileukemic agent isolated from the stem wood of the Chinese tree Camptotheca acuminata Nyssaceae, has been the target of numerous chemical syntheses. The first successful synthesis of this unusual alkaloid, characterized by an a-hydroxy-lactone and a pyridone system fused to a five-membered ring, was reported by Stork and Schultz in 1971. A key feature of this synthesis is construction of ring E by a novel lactone annelation involving addition-cyclization of the carbonate of an 0 -hydroxy ester to the tetracyclic Q ,/3-unsaturated lactam (B). 

This useful annelation procedure for fusion of 2-carboxy-A -cyclohexenone systems to a preexisting ring was previously marred by the difficult accessibility of 3-oxo-4-pentenoic acid ester. An efficient synthesis of this compound has now been devised by G. Stork and R. N. Guthikonda, Tetrahedron Lett, 2755 (1972). 

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