1.2- Carbonyl transposition

The next steps of the synthesis, which formally involves a 1,2-carbonyl transposition from C(3) to C(2) and its conversion to the desired endo-N group, followed by a Mannich condensation, are outlined in Schemes 13.2.4 -13.2.6. 

The 1,2-carbonyl transposition takes place through the enJo-epoxide 18 easily prepared through the tosylhydrazone 16, followed by regioselective cleavage to the less substituted double bond (17) with 2 equivalents of methyllithium [4] and epoxidation with MCPBA in chloroform from the more accesible convex face of the decalin system. 

Ikegami has devised an interesting approach based upon 1,3-cyclooctadiene monoepoxide as starting material (Scheme LX) Transannular cyclization, Sharpless epoxidation, and silylation leads to 638 which is opened with reasonable regioselec-tivity upon reaction with l,3-bis(methylthio)allyllithium. Once aldehyde 639 had been accessed, -amyllithium addition was found to be stereoselective, perhaps because of the location of the te -butyldimethylsilyloxy group. Nevertheless, 640 is ultimately produced in low overall yield. This situation is rectified in part by the initial formation of 641 and eventual decarboxylative elimination of 642 to arrive at 643. An additional improvement has appeared in the form of a 1,2-carbonyl transposition sequence which successfully transforms 641 into 644... 

Ikegami s successful synthesis of racemic 720 materialized by initial conversion of 701 to 725 via a 1,2-carbonyl transposition sequence (Scheme LXXVIII) Treatment of 725 with methoxycarbene, deprotection, and oxidation provided 72 6. Acid-promoted cyclopropane ring cleavage and added functional group manipulation led to 727 which could be allylated stereoselectively. The tricyclic enone 724 was subsequently produced conventionally. 

An expeditious stereospecific synthesis of the protoilludane skeleton has been actively pursued by Matsumoto s group. In his first approach (Scheme 42),307 bicyclooctanone 274 was smoothly elaborated in classical fashion. Using a five-step sequence to effect a 1,2-carbonyl transposition with retention of a hydroxyl group at the original carbonyl site, these workers then prepared 275. Oxidation of this intermediate followed by end acetylation afforded 276. When this enone was irradiated... 

A 1,2-carbonyl transposition sequence based on the Woodward dithioacetalisa-tion reaction was used to relocate a carbonyl group in 95.1 [Scheme 2.95] to the adjacent position in 95 6.190 A total of 6 steps were required in which the key step was the dithioacetalisation of the a-hydroxymethylene derivative 95 2. After reduction of the carbonyl group, the dithiane was hydrolysed to the a-acetoxy ketone whence dissolving metal reduction removed the acetate function. 

Carbonyl transposition. Yee and Schultz have used a modification of the method of Trost (8, 392) for this transposition. The first step also involves bissul-fenylation with this reagent, but more satisfactory results were obtained when the lithium enolate was generated with lithium tetramethylpiperidide. The remaining steps are formulated in equation (I). It is also possible to convert the intermediate hydroxy thioketal to the ketol, which is then mesylated and reduced to the trans-... 

In contrast to these results, it has been demonstrated that a-(methylthio)tosylhydrazone monoanions, formed by reaction of an initially formed dianion with dimethyl disulfide, undergo in situ dianion formation rather than elimination, to give vinyl sulfides (Scheme 71 ). Since vinyl sulfides can be hydrolyzed to ketones, this sequence constitutes a very effective 1,2-carbonyl transposition. 

The aprotic Bamford-Stevens reaction has been utilized for the development of a methodology towards 1,2-carbonyl transposition in natural product synthesis. The example in Scheme 8 illustrates the regiocontrolled alkene formation for the synthesis of hirsutic acid. ... 

Many other 1,2-carbonyl transpositions with skeletal rearrangement are known. In general, aldehydes react more rapidly than ketones the rearrangement of a ketone to form an aldehyde appears to be unknown, but ketones can be converted to other ketones. A few examples from the early work of Venus-Danilova ° are illustrated. Thus cyclobutane- and cyclopentane-carbaldehyde both gave the simple ring-expanded ketones as shown in equations (5) and (6), upon treatment with concentrated sulfuric acid. 

In general, 1,2-carbonyl transpositions require more vigorous conditions (stronger acid, higher temperatures) than pinacol rearrangements in which the same carbenium ion intermediates may be generated. However, harsher conditions than actually required have frequently been used to carry out pinacol rearrangements, and care must be taken to avoid over-interpretation of the mechanism from examination of the products. 

The overall reaction corresponds to a 1,2-carbonyl transposition. A critical prerequisite for success is the presence of the substituent R, which must be capable of thermodynamically stabilizing the ring-expanded radical by electron delocalization. In this way, ester or phenyl substituents tip the balance of the equilibrium in favor of inter-ring bond cleavage in the bicyclic cyclopropanoxyl radical, and thus promote the ring expansion. If this substituent is absent, straightforward reduction to afford 2-methylcycloalkanones occurs, e.g. 57. ... 

The conversion of (3i )-(+)-citronellal into (—)-isopulegol is well known (Vol. 4, p. 28), although this and related (Vol. 7, p. 30) work is not cited in an examination of Lewis acid catalysis in which ZnBt2 gives optimum results [70% yield, 94% (—) -isopulegol]. Another 1,2-carbonyl transposition procedure (Scheme 3) converts menthone via the tosylhydrazone (134) into carvomenthone (135) although in lower yield (48%) than the epoxysilane route reported... 

A new procedure for regioselective 1,2-carbonyl transposition using arenesulfonylhy-drazones is reported. Thus, when the dianion derived from the tosylhydrazone of 127 is treated with dimethyl disulfide, the sulfide 128 is obtained regioselectively. The latter, upon treatment with BuLi, produces a deep-red solution of the dianion, which on aqueous workup gives the vinyl sulfide 129. From this, ketone 130 is obtained by treatment with mercuric chloride in hot aqueous acetonitrile (equation 73)61. A similar example is shown in equation 74. 

Finally, since phenyl vinyl sulfides can be hydrolyzed to carbonyl compounds, the methodology provides a new 1,2-carbonyl transposition route. For example, 3-cholestanone... 

In the first of these syntheses, described by Fujimoto and coworkers (Scheme 32) [42], the acetoxy derivative 248, prepared from tetrahydrosantonin 3b, afforded ketoacetate 249 on treatment with tetramethyl ammonium acetate via a 1,2-carbonyl transposition reaction. Irradiation of this compound in the presence of HgO/l2 led to the oxidation of the C(14) methyl group of compound 250 to give compound 251,... 

Carbonyl transposition. The last steps in a total synthesis of dl- y-coramine (5) required a 1,2-transposition of the carbonyl group of 2. This was accomplished by bissulfenylation of the lithium enolate of 2 with phenyl ben-zenethiosulfonate (1). The carbonyl group of the product was reduced and the... 

Tsuda Y, Hosoi S, Nakai A, Sakai Y, Abe T, Ishi Y, Kiuchi F, Sano T (1991) Synthesis of Erythrina and Related Alkaloids. XXIV. Total Synthesis of Erysotrine from 1,7-Cycloerythrinan Derivatives by the Use of a New 1,2-Carbonyl Transposition... 

An alkylative 1,2-carbonyl transposition in cyclohex-2-enones can be accomplished in fair to good yield as described in Scheme 70. ... 

A soln. of startg. ketal and PPh3 in benzene treated with iodine at room temp., and stirred for 15 h product. Y 88%. This is part of a multistep 1,2-carbonyl transposition in a-oxyketones. F.e.s. H.R. Sonawane et al.. Tetrahedron 44, 7319-24 (1988). 

S-Phenylthio chlorides, tosylates, and mesylates undergo p-elimination to vinyl sulfides in high yield upon treatment with f-BuOK/DMSO (eq 3). This type of reaction is an important step in a synthetically useful 1,2-carbonyl transposition sequence. ... 

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