Hydroxy aldehyde 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. 

The construction of the C2-C3 bond of the 1-hydroxyethylene moiety by the addition of a two-carbon fragment to aminoalkyl epoxides, amino ketones, p-amino-a-hydroxy aldehydes, or 4-amino-3-oxo phosphonates was also studied. As summarized in Scheme 14, Evans et al.[28] added a malonate to an aminoalkyl epoxide and the product spontaneously cyclized, leading to a lactone.— Then, the second side chain was incorporated into the a-carbon of the lactone, providing a mixture of C2 epimers. The final compound was obtained by hydrolysis and decarboxylation. The lack of diastereoselectivity of this method is offset by the small number of steps and the accessibility to all eight possible stereoisomers. Biihlmayer et al.[30] also used a similar method, but they transformed the epoxide into the apparently more reactive iodide. Then, the iodide compound was treated with an enolate. 

Peptide aldehydes can be synthesized via hydrolysis of thiazolidine precursors with mercury or copper salts (Scheme 10). 56 The Phe-thiazolidine derivative 27 was prepared from reduction of dihydrothiazole ring in 26, which was formed from a (5-hydroxy thioamide cyclization of 25 using the Mitsunobu reaction. N-Terminal Boc and Z groups on thiazolidine pseudopeptides such as Boc-Ala-Phe-thiazolidine and Z-Phe-Tyr-thiazolidine are stable to hydrolysis that affords Boc-Ala-Phe-H and Z-Phe-Tyr-H. 56 ... 

B. Helferich [Ber64, 104 (1931)] had noted the tendency of 7-hydroxy aldehydes to cyclize. 

Hydroxy aldehydes or ketones normally exist in equilibrium with the corresponding 2-hydroxytetrahydrofurans, which afford 2,3-dihydrofurans on dehydration. Similarly, 7-aminoketones spontaneously yield pyrrolines. From a mechanistic viewpoint the-initial cyclizations may be regarded as being initiated by nucleophilic attack of the heteroatom upon the carbonyl group. While such reactions occur with facility, their synthetic applicability is largely determined by the accessibility of appropriate precursors. A selection of examples of this type of ring closure is provided in Scheme 12. 

The aldehyde substrates may be used as racemic mixtures in many cases, as the aldolase catalyzed reactions can concomitantly accomplish kinetic resolution. For example, when DHAP was combined with d- and L-glyceraldehyde in the presence of FDP aldolase, the reaction proceeded 20 times faster with the D-enantiomer. Fuc 1-P aldolase and Rha 1-P aldolase show kinetic preferences (greater than 19/1) for the L-enantiomer of 2-hydroxy-aldehydes. Alternatively, these reactions may be allowed to equilibrate to the more thermodynamically favored products. This thermodynamic approach is particularly useful when the aldol products can cyclize to the pyranose form. Since the reaction is reversible under thermodynamic conditions, the product with the fewest 1,3-diaxial interactions will predominate. This was demonstrated in the formation of 5-deoxy-5-methyl-fructose-l-phosphate as a minor product (Scheme 5.5).20a 25 The major product, which is thermodynamically more stable, arises from the kinetically less reaction acceptor. 

The hydroxy aldehyde 108 was converted into lactone 109 (a 1 1 diastereomeric mixture) by a samarium-mediated cyclization reaction (Scheme 23) <1997TL8245>. 

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. 

Hemiacetals are formed from hydroxy aldehydes " or ketones which are usually first in a protected form and are deblocked prior to cyclization. Ozonolysis of cyclohexene derivative 5 and reductive workup, followed by hydrolysis of the acid chloride formed in situ and borane reduction of the carboxylic acid, leads to the six-membered hemiacetal 6. a precursor for fluo-rinated sugars that are potentially versatile as molecular probes in the elucidation of biochemical processes. ... 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

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. 

Hemiacetals in sugars are formed in the same way that other hemiacetals are formed—that is. by cyclization of hydroxy aldehydes. Thus, the hemiacetal of glucose is formed by cyclization of an acyclic po/yhydroxy aldehyde (A), as shown in the accompanying equation. This process illustrates two important features. 

Cyclization forms a new stereogenic center, exactly analogous to the cyclization of the simpler hydroxy aldehyde (5-hydroxypentanal) in Section 21.16A. The new OH group of the hemiacetal can occupy either the equatorial or axial position. 

Hydroxy aldehydes A and B readily cyclize to form hemiacetals. Draw the stereoisomers formed in this reaction from both A and B. Explain why this process gives an optically inactive product mixture from A, and an optically active product mixture from B. 

With the necessary carbons present in (49), it can be seen that the scheme of oxidation of the allylic methyl group to the aldehyde level (selenium dioxide), and a reduction of the coumarin with concommitant hydrolysis (zinc/acetic acid), afforded the hydroxy-aldehyde-acid intermediate (57), which expectedly and spontaneously cyclized to the tricyclic lactone (55) under the conditions of the reaction. 

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. 

Chlorosulphonyl isocyanate (reviews [324, 3147a, 3340] cyclizes 2-hydroxy-aldehydes and -acetophenones in good yields the corresponding benzophenones are not cyclized in this way. Methyl isocyanate in alkaline solution also reacts with salicylaldehyde to give a high yield of a fused oxazinone. 

Nakane and Hutchinson have further shown that the aldol step in this cyclization is stereoselective as well as regioselective. Treatment of (39) with Hunig s base, acetic anhydride and 4-(A, A -dimethyl-amino)pyridine (DMAP), followed by sodium borohydride reduction of the intermediate P-hydroxy aldehyde, gives diol (40) in 48% yield no diastereomeric diols were detected (equation 102). 2i... 

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