Hydroxy aldehyde intramolecular cyclization

The intramolecular cyclization of diketo-enals and keto-enals was accomplished by the combination of a cationic Rh complex and fn(2-furyl)phos-phine (2 - Fur3P). The corresponding bicyclic hydroxy-aldehydes were produced in good to excellent yields, as demonstrated by the formation of 74,76 and 78 (Scheme 22) [36]. 

It is well known that in the cyclization of a y-hydroxy aldehyde to form the corresponding six-membered ring hemiacetal through intramolecular cyclization the hemiacetal form always predominates (48). This might account for the fact that no noticeable carbonyl absorption has been observed in the IR and NMR spectra of 54. However, the equilibrium between the hemiacetal and the aldehyde forms might shift in favor of the aldehyde form as the borane reduction proceeds until 54 is completely transformed to 55. 

Oxandrolone Oxandrolone, 17j3-hydroxy-17a-methyl-2-oxa-5-androstan-3-one (29.3.10), is made by oxidation of the C1-C2 double bond of 17j3-hydroxy-17a-methyl-l-androsten-3-one by a mixture of lead tetraacetate and osmium tetroxide with an opening of the A ring of the steroid system, which forms an aldehyde acid (29.3.9). Upon reducing the aldehyde group with sodium borohydride, intramolecular cyclization takes place, directly forming a lactone (29.3.10), which is the desired oxandrolone [31,32]. 

In a similar manner, intramolecular cyclization of the O-stannyl ketyl derivatives 201 and 206, generated from the oxazolyl aldehydes 200 and 205, provides a facile method for the chiral synthesis of 3-hydroxy-2-(hydroxymethyl)-5-substimted-pyrrolidines 202 and 203 and the piperidine analogues 207 and 208 that can be successfully transformed into naturally occurring amino alcohols, (+)-bulgecinine 204 and (—)-desoxoprosopinine 209, respectively (Fig. 

Intramolecular Marschalk reaction. Ai. intramolecular Marschalk reaction (9, 376) can be used to effect a synthesis of anthracvclinones from anthraquinones. Thus the oi-hydroxy aldehyde 2, formed on saponification of the a-hydroxydichloride 1, on reduction of the quinone group cyclizes in the alkaline medium to the tetracyclic tran.s- and ci/j-diols(3and4)inaboutequal amounts. Cyclization underphase-transfer conditions results in improved yields and, more importantly, can alter the stereoselectivity. Triton B is the most effective catalyst for stereoselective cyclization to the desired natural tran -diol. 

All hemiacetals are formed by nucleophilic addition of a hydroxy group to a carbonyl group. In the same way, cyclic hemiacetals are formed by intramolecular cyclization of hydroxy aldehydes. 

Problem 21.38 What lactol (cyclic hemiacetal) is formed from intramolecular cyclization of each hydroxy aldehyde ... 

Intramolecular cyclization of a hydroxy aldehyde forms a hemiacetal with a new stereogenic center, so that an equal amount of two enantiomers results. 

DCC-mediated condensation of hydroxy aldehyde 240 and acid 268 gave the aldehyde ester 269 (70%). An intramolecular olefination followed by chromatographic separation of the desired C-8 diastereomer led to the isolation of the 16-membered ring macrocycle 270 in 20% yield. Desilylation, oxidation, and cyclization then afforded a 47% yield of y-lactone 271. Acylation of the C-3 hydroxyl group was followed by reduction of the y-lactone and C-9 carbonyl. 

Aldol reactions involving aluminum species are considered to be of less synthetic value because of the ambiguous isomerization of the aldol products, under the influence of the Lewis-acidic aluminum species. Efforts have been made to generate an aluminum enolate in a regiospecific manner. Addition of dialkylchloroalane and zinc to a mixture of an a-halo ketone (126) and an aldehyde leads to the formation of enolate (127), which subsequently reacts with the aldehyde, as shown in Scheme 53.71 This method is applicable to the construction of medium to large rings by intramolecular aldol cyclization of various a-bromocarboxylates of u)-hydroxy aldehydes (e.g. BiCHRC02(CH2) CH0 where — 9, 11 or 12 and R = H or Me). The macrolactonization proceeds in reasonable yield, as shown in Scheme 53. 

Recently, Volodarskii and Sevast yanova160-163 have synthesized a number of N- (aroylalkyl) nitrones (73) (by the condensation of a-halo ketones with the sodium salt of anfo -benzaldoxime or of iV-hydroxy-a-amino ketones with aldehydes),160-162 which undergo intramolecular cyclization in acetic anhydride-sulfuric acid to give the corresponding oxazoles (74) in excellent yields.161-168... 

Yields of the cyclized product are in the range 49—69%. Cyclization of a-bromo-carboxylates of o>-hydroxy-aldehydes to macrolides by an intramolecular aldol addition has been carried out by formation of the aluminium enolate (Zn, Et2Al-Cl) yields vary between 35 and 68%. 

A new approach to Combretastatin D2 involves two independent Wittig steps. The starting material of the first one was 3-hydroxy-4-methoxybenzaldehyde. The methoxycarbonylethenyl-product was then converted in several steps to a phosphonium salt, also containing an aldehyde function, that underwent an intramolecular cyclization (Scheme 90). ... 

An intramolecular [2+2] photocycloaddition of allyl ethers with dioxinones followed by a base-induced fragmentation leads to substituted tetrahydropyran-4-ones <1997TL5579>. A one-pot scandium triflate catalyzed diastereoselec-tive cyclization between aldehydes and (3-hydroxy dioxinones 1046 followed by alkoxide addition to the resulting bicycles 1047 leads to 3-carboxy-substituted tetrahydropyran-4-ones 1048 with high levels of diastereoselectivity as a mixture of keto/enol tautomers (Scheme 268, Table 49) <20050L1113>. 

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