1,2-Propanediol substitution reactions

The synthesis of the mesoionic thiazolopyrimidine acyclonucleosides 97 incorporating the 2,3-dihydroxypropyl moiety was carried out starting by reaction of 2-bromothiazole with excess l-amino-2,3-propanediol acetonide via an aromatic nucleophilic substitution reaction to yield l-(2-thiazolylamino)-... 

Smith °" have demonstrated asymmetric interactions in stereospecific substitution reactions. An estimate of the magnitude of the asymmetric interaction in the case of the d and / form of d.s-[CoCl2(en)2] with the solvent (—)-2,3-butanedioF °, from solubility product measurements, suggests that antiracemisationin systems where solvolytic interference is less important (perhaps with m-[Co(N02)2(en)2] ), will lead to interesting kinetics. In this solvent, as well as 1,2-propanediol, such studies, when compared with the racemisation rates of the resolved complexes in the racemic or meso forms of the solvents, must lead to a greater understanding of the role of the solvent in a class of reactions whose precise mechanism has proved difficult to define. 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

Of the seven hydroxyl-containing peroxides listed in Table 2, six are rert-butylperoxy derivatives. Although the tert-butyl group kinetically stabilizes the peroxide so that its combustion enthalpy can be measured, its presence makes finding suitable reference compounds such as hydrocarbons and ethers to compare in reactions 2-9 more difficult. Reaction 6 is the only reaction for which there are enthalpy of formation data for the requisite comparison compounds. Three hydroxy peroxides, all from the same source26, have remarkably consistent enthalpies of reaction 6 in both the liquid and gas phases. The mean values derived from the vicinal-dioxygen substituted alcohols, 2-tert-butylperoxyethanol, 2-tert-pentylperoxyethanol and 3-terr-butylperoxy-1,2-propanediol, are —304.0 4.1 kJmol-1 (lq) and —257.1 6.0 kJmol-1 (g). However, these values... 

J. F. Duncan and K. R. Lynn, J. Chem. Soc., 3512, 3519 (1956) J. B. Ley and C. A. Vernon, Chem. Ini. (London), 146 (1956).] That the rate-determining step can be the migration when the first-formed carbocation is particularly stable has been shown by Schubert and LeFevre [note 18(b)]. These workers subjected 1,1-diphenyl-2-methyl- 1,2-propanediol to the pinacol rearrangement and found that deuterium substitution in the migrating methyls caused the reaction to slow down. 

By reacting 2-aminopyridine and epichlorohydrin, Knunjanz187 obtained the hydrochloride of 3-hydroxy-3,4-dihydro-2H-pyrido[l,2-a]pyrimidine (131 R = OH). Analogous products from 4-methyl-, 5-methyl-, 5-halo- and 3,5-dibromo-substituted 2-aminopyridines have been prepared by Soviet workers.188,189 The same products arose from the reaction of 2-aminopyridines and l,3-dichloro-2-propanol.188 189 Klusis and Kuthevicius190 reacted 2-aminopyridine with 3-chloro-1,2-propanediol (127) or 2,3-... 

Fukuzawa et al.245 used 2-phenyl- 1,3-dioxane to benzylate a variety of arenes [Eq. (5.91)]. Similar observations were made when substituted benzaldehydes were treated in the presence of 1,3-propanediol under identical conditions. Although 2-phenyl-1,3-dioxane gave similar results, benzaldehyde dialkylacetals in general were unreactive under similar conditions. Mechanistic studies including reaction of a labeled dioxane indicate the involvement of the alkylated intermediate 65 and product formation was interpreted via an 1,3-hydride shift. 

In a similar respect, ionization of 2,4-dichloro-2,4-dimethylpentane (6) does not give the 1,3-carbodication (7, eq 3).3 Despite the superacidic conditions, deprotonation occurs to give the allylic cation (8). Even substitution by phenyl groups is not enough to stabilize the 1,3-dication. For example 1,1,3,3-tetraphenyl-l,3-propanediol (9) also undergoes the deprotonaton or disproportionation reactions (eq 4).3... 

The ratio of 33A and 33B proved to be slightly solvent-dependent (Table V). The reactions of 3-amino-l,2-propanediol with substituted aromatic aldehydes in CDC13 resulted in five-component ring-chain tautomeric equilibria. Besides the open-chain form 34A, two epimeric oxazolidines (34B and 34B ) and two epimeric tetrahydro-l,3-oxazines (34C and 34C ) were identified in the tautomeric mixture. The proportions of the tautomers in the equilibrium for X = p-NC)2 were [34A] [34B] [34B ] [34C] [34C ] = 40.7 7.0 5.9 9.7 36.7 (94MI1, 94MI2). 

Prochiral Compounds. The enantiodifferentiation of prochi-ral compounds by lipase-catalyzed hydrolysis and transesterification reactions is fairly common, with prochiral 1,3-diols most frequently employed as substrates. Recent reports of asymmetric hydrolysis include diesters of 2-substituted 1,3-propanediols and 2-0-protected glycerol derivatives. The asymmetric transesterification of prochiral diols such as 2-0-benzylglycerol and various other 2-substituted 1,3-propanediol derivatives is also fairly common, most frequently with Vinyl Acetate as an irreversible acyl transfer agent. 

The cyclization in Step B is an improvement of Butler s procedure for the synthesis of which employs less convenient reagents, KNH and l-bromo-3-chloroacetone acetal. Beside the acetals derived from neopentyl glycol, those derived from ethanol, 1,3-propanediol and 2,4-pentanediol have been synthesized by the present method. The second part of Step B involves the formation and the electrophilic trapping of cyclopropenyl anion 2, which is the key element of the present preparations. Step B provides a simple route to substituted cyclopropenones, but the reaction is limited to alkylation with alkyl halides. The use of lithiated and zincated cyclopropenone acetal, on the other hand, is more general and permits the reaction with a variety of electrophiles alkyl, aryl and vinyl halides, Me3SiCl, Bu3SnCl, aldehydes, ketones, and epoxides. Repetition of the lithiation/alkylation sequence provides disubstituted cyclopropenone acetals. 

Phenmenthol monomalonates 1.20 are transformed by LDA into dilithiated anions, which also suffer diastereoselective alkylations on their least hindered face [166, 1008, 1034], After UAIH4 reduction, enantioenriched 2,2-dialkyl-l,3-propanediols are obtained. Alternatively, Curtius reaction followed by hydrolysis gives rise to nonracemic a-substituted aminoacids (Figure 5.16). The most interesting selectivities are observed when R and R are PhCH-j and Me. The highly stereoselective alkylation of the menthyl monoester of (1R, 2R)-cydopen-tanedicarboxylic add by methaliyl bromide is the first step of the total synthesis of (-)-ptaquilosin [1035]. 

Optically active 2-substituted- 1,3-propanediol derivatives were prepared as shown in equation 45. The bis-trimethylsilylated 1,3-diols were condensed with /-menthone in the presence of trimethylsilyl triflate to give the corresponding diastereomeric ketals, which were separated and subjected to further transformations. For example, the cleavage was carried out via a Mukaiyama reaction to generate the a-alkoxy ketone, which could be protected and then cleaved to the optically active, unsymmetrical, monoprotected 1,3-diol52. 

The importance of these side-reactions was corroborated by results from the Ni-catalyzed amination of 1,3-propanediols differently substituted at the C2-position... 

Dihydrooxazolcs, derived from (S,S)-2-amino-l-phenyl-1,3-propanediol, are readily alkylated and acylated in position 2 and have found many applications in selective carbanionic reactions. For their preparation, derivatives of carboxylic acids, such as imino ethers, are treated with the amino alcohol or its methyl ether (Section 2.3.2.)10, u. A typical example of such a procedure is given in Section 2.3.1., in connection with the synthesis of (/ )-phenylalaninol methyl ether. The 2-methyl-substituted intermediates in this synthesis are also commercially available. 

Like their amine analogues (Section 20.4.2.1) thiol-substituted alcohols may act as bidentates with chelation often leading to polymeric products. The stability constants of the Cd" complexes of both 2-mercaptoethanol (mel) and 3-mercapto-1,2-propanediol (mpd) have been determined, with polymeric structures being concluded similar to those of the previously determined Ni and Zn compounds. Similar data for the Pb" complexes showed polymer formation with mpd and gave evidence for Pb-mel species with at least five different metal ligand ratios. Reaction of the pertechnetate(VII) ion [Tc04] with sodium dithionite and 2-mercaptoethanol results in the... 

---