Aldol-type cyclization reaction synthesis

Next, we examined the synthesis of a 4a,8a-/rans-fused ring system such as 49 using the same aldol-type cyclization reaction of 48. The methyl ketone 9 was converted to alcohol 46, which was treated with sodium hydride to afford the oxazolizinone 47. The terminal olefin in 47 was cleaved oxidatively to give rise to the keto aldehyde 48. However, the aldol-type cyclization reaction of 48 under the same reaction conditions as for 42 or 43 was very messy and no cyclized product was isolated. 

We have described (88TL4855) a simple synthesis of pyridin-2-ones by a two-step annulation of 2 with aliphatic acid chlorides (Scheme 27). The acylation of aminoazadienes 2 in pyridine furnished 4-amidoyl-l-azabutadienes 107 in high yields (85JOC802) lithium diisopropylamide-catalyzed aldol-type cyclization of 107 afforded pyridin-2-ones 108 in 83-94% yield. Extension of this reaction to methanesulfonyl chloride permitted preparation of open-chain derivatives 109 in 88-90% yield, which in turn cyclized in the presence of lithium diisopropylamide to 2//-l,2-thiazines 110 in 82-92% yield (89TL4705). Earlier work by the Komatsu-Ohshiro group showed that the reaction of simple 1-azadienes... 

Induction of Asymmetry by Amino Acids. No fewer than sis types of reactions can be carried out with yields of 75—100% usiag amino acid catalysts, ie, catalytic hydrogenation, iatramolecular aldol cyclizations, cyanhydrin synthesis, alkylation of carbonyl compounds, hydrosdylation, and epoxidations (91). 

A trifold anionic/pericyclic domino reaction was used for the synthesis of the dioxapyrrolizidine 2-655 combining a nitro aldol condensation, SN-type cyclization, SN-type etherification, and an intramolecular 1,3-dipolar cyclization as described by Rosini and coworkers (Scheme 2.148) [339]. 

Stereoselectivity. See Asymmetric induction Axial/equatorial-, Cis/trans-, Enantio-, Endo/exo- or Erythro/threo-Selectivity Inversion Retention definition (e.e.), 107 footnote Steric hindrance, overcoming of in acylations, 145 in aldol type reactions, 55-56 in corrin synthesis, 261-262 in Diels-Alder cyclizations, 86 in Michael type additions, 90 in oiefinations Barton olefination, 34-35 McMurry olefination, 41 Peterson olefination, 33 in syntheses of ce-hydrdoxy ketones, 52 Steric strain, due to bridges (Bredt s rule) effect on enolization, 276, 277, 296, 299 effect on f3-lactam stability, 311-315 —, due to crowding, release of in chlorophyll synthesis, 258-259 in metc-cyclophane rearrangement, 38, 338 in dodecahedrane synthesis, 336-337 in prismane synthesis, 330 in tetrahedrane synthesis, 330 —, due to small angles, release of, 79-80, 330-333, 337... 

The reaction between amino group (-NH2) and a carbonyl group (C=0) elsewhere in the same molecule has been used in the synthesis of many heterocyclic compounds. For example as shown in Equation 9.53, substituted quinolines can be produced by acid-catalyzed cyclization of the appropriate aminoketones (formed during the Friedlander synthesis, in this instance between propanone and ortho-aminobenzaldehyde, in an aldol-type reaction with loss of water this chapter, vide infra), and even more than one reaction can be induced to occur. Thus, in Equation 9.54,1,2-benzenediamine (ort/io-aminoaniline) undergoes acid-catalyzed addition to 2,3-butane-dione to produce 2,3-dimethyl-13-benzopyrazine (23-dime thy Iquinoxaline). ... 

Interest in the synthesis of the mitomycins has resulted in a variety of procedures for the preparation of pyrrolo-indoles and related structures. Now Ban and his colleagues have reported a biomimetic route to the mitosane skeleton which involves a novel retro-aldol type of ring-opening reaction followed by a trans-annular cyclization (Scheme 102). A mitosane-like compound is available via... 

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

With a synthesis of 58 completed, the key intramolecular diketone aldol cyclization was investigated. Precedent for this type of 1,8-dicarbonyl aldol reaction is rare, although an aldol reaction has been proposed in the biosynthetic pathway to the hypocrellins. The only reported examples of such diketone aldol cyclizations involve multicyclic or bridged bicyclic systems, and of these no examples exist for 1,8-diketones forming 7-membered rings. MM2 calculations indicated that a... 

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