Cyclization of diols

The environmentally benign synthesis of lactones has attracted attention because of their importance in natural product chemistry. The oxidative cyclization of diols via carbon-oxygen bond formation is the most well-known approach for the synthesis of lactones [70]. 

Simultaneous deprotection and cyclization of diols 60a and 60b with 3 M HCl in MeOH followed by acetylation yielded the 2,3-trans- ( 50%) (61a and 61b) and for the first time 2,3-cw-flavan-3-ol methylether acetate derivatives ( 20%) (62a and 62b) in excellent enantiomeric excesses (>99%). The optical purity was assessed by H NMR using [Eu(hfc)3] as chiral shift reagent. The absolute configuration of the derivatives of the tram- and cii-flavan-3-ol derivatives was assigned by comparison of CD data with those of authentic samples in the catechin or epicatechin series flavan-3-ols. Thus, the absolute configuration of the flavan-3-ol methyl ether acetates confirms the assigned configuration of the diols as derived from the Sharpless model. 

Simultaneous deprotection and cyclization of diols (43a) and (43b), and subsequent acetylation gave the 2, i-trans ( 50%) (44a and 44b), and uniquely also the 2,3-a j -flavan-3-ol methyl ether acetate derivatives... 

Preparation of Aziridines by Cyclization. A most useful general method for the high-yield syntheses of a variety of O or N heterocyclic systems from the cyclization of diols or amino-alcohols, respectively, has been reported. Treatment of diols with a mixture of Et02CN= NC02Et and PPhs causes cyclization to three- or seven-membered rings. In the case of 2-amino-2-methyl-propane (206), a quantitative yield of 2,2-dimethylaziridine (208) is obtained via the intermediate (207) (Scheme 11). It has been suggested that intermediates of this type are general for such cyclizations. 

Oxathiocins obviously remain exceedingly scarce. Cyclization routes provide access, in modest yields, to the ring system, but may be limited by the inaccessibility of appropriate precursors. The use of sulfur atom transfer reagents to effect the cyclization of diols may represent a more general entry to the 1,2-oxathiocin ring system, but the synthetic potential of this route clearly has scarcely been examined. 

Lipshutz reported the first gold-catalyzed dehydrative cyclization of diols and triols in aqueous medium to the corresponding heterocycles 6 in good to excellent yield at room temperature. The reactions occur in nanoparticle micelles (TPGS-750-M) where the hydrophobic effect drives the dehydration reaction. The addition of salts was also shown to decrease reaction times (140L724). 

Table 8. Comparison of the Thermodynamic Properties for the Cyclization of Diols (298°K) ...

Cyclization. A new approach to the synthesis of oxaziridines involves the reaction of tosyl chloride in aqueous alkaline solution with a cyclic nitrone this reaction appears to be mechanistically similar to the cyclization of diol monotosylates in epoxide synthesis. This method has been applied to heterocyclic steroidal nitrones (276). ° Photo-oxidation of cyclohexylamine may... 

Nucleophiles other than water may be used. If an alcohol is used as the nucleophile, the initial product is an enol ether, which can then add a second alcohol molecule to form a ketal (Scheme 6.9). This reaction has often been used effectively in an intramolecular sense to form bicyclic acetals unsaturated diols cyclize to ketals. The formation of the second C-O bond may be either H+ catalysed, via oxonium ion 6.21, or Pd(II) catalysed via if-complex 6.22 and -complex 6.23. This reaction has been employed in a synthesis of frontalin 6.17 and in a synthesis of saliniketals A and B by cyclization of diol 6.24 (Scheme 6.10). ... 

The acid-catalyzed cyclodehydration of ( )- and meso-2,5-hexanediol has been shown to proceed with inversion of configuration in most cases, affording cis- and rra/if-2,S-dimethyltetrahydrofuran, respectively. However, various extents of racemization are observed in the actions of certain Lewis acids and H2S04. The stereospecific cyclization of diols to tetrahydrofurans occurs if phenylthio participation is involved. The reactions of 2-phenylthio-l,4-diols such as (118) with dimethyl sulfate afford (119) with net retention of configuration, whereas acid-catalyzed cyclizations of 4-phenylthio-l,3-diols such as (120) take place with PhS migration and hence inversion at both the migration origin and terminus (Scheme 50). °°... 

Example 3.6 Mayers et al. prepared chiral oxazoline 27 from propionic acid and easily available optically pure alcohol (lS,2S)-l-phenyl-2-aminopropan-l,3-diole 25 as a convenient substrate for stereoselective a-alkylation (Scheme 3.11) [15,16]. It is interesting to note the selective cyclization of diol 25 to oxazoline 26 by the more nucleophilic benzylic OH group in the presence of the primary OH group. 

This was nicely shown to be true in the Pauson-Khand cyclization of diol 438. 

Reaction with Di- and Polyols. Although intermolecular dehydration between two molecules of alcohols to afford acyclic ethers usually does not occur with the DEAD-TPP system, intramolecular cyclization of diols to produce three to seven-membered ethers is a common and high yielding reaction. Contrary to an early report, 1,3-propanediol does not form oxetane. Oxetanes can be formed, however, using the trimethyl phosphite modification of the Mitsunobu reaction. The reaction of (5)-1,2-propanediol and ( )-l,4-pentanediol with DEAD and TPP affords the corresponding cyclic ethers with 80-87% retention of stereochemistry at the chiral carbon, while (5)-phenyl-1,2-ethanediol affords racemic styrene oxide. In contrast to the reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphos-phonium salts (25a) and (25b) have been postulated as key intermediates in the present reaction (eq 20). ... 

A-Nor-B-homo steroids with different substitution patterns than those described above may be prepared by acid catalyzed cyclization of 3)3-hydroxy-5(10)-seco-cholest-tra/w-l(l0)-en-5-one acetate (134a) formed in 30-40% yield by mercuric oxide-iodine sensitized irradiation of cholestane-3j3,5a-diol... 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

An easy, silica gel-promoted 6-endo cyclization of y-epoxy alcohol 32 to pyran 33, followed by acid-catalyzed spiroketalization of the keto diol 34, afforded the common tricyclic spiroketal fragment 35 of lituarines A, B, and C (Scheme 8.8) [20b],... 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

An alternative new synthetic approach to chrysene 1,2-dihydro-diol based on Method IV has recently been developed (60). This method (Figure 12) entails synthesis of 2-chrysenol via alkylation of 1-1ithio-2,5-dimethoxy-1,4-cyclohexadiene with 2-(1-naphthyl) e-thyl bromide followed by mild acid treatment to ge nerate the diketone 12. Acid-catalyzed cyclization of 12 gave the unsaturated tetracyclic ketone 13 which was transformed to 2-chrysenol via dehydrogenation of its enol acetate with o-chloranil followed by hydrolysis. Oxidation of 2-chrysenol with Fremy s salt gave chrysene... 

The cyclization of y -hydroxy ketones is useful for the formation of pyrans,306,403 both directly and via rearrangement, as illustrated in Eq. 231.153 As with their acyclic counterparts, these cyclizations also occur with the silyl ethers of the hydroxy ketones where Et3SiH/BiBr3 is used with the TBS and TES ethers.342,404 A methyl thiomethyl ether is also capable of undergoing the reductive cyclization 405 In like manner, 1,4-diols and e-hydroxy ketones provide oxepanes, with I ds Si H or PhMe2SiH/TMSOTf being especially effective (Eqs. 232 and 233).336,406 The trimethylsilyl ether of the alcohol also provides the oxepane.306... 

A number of novel crown ether analogs 203-205 incorporating the azofurazan subunit have been synthesized by oxidative cyclization of bis(aminofurazanylic)ethers of 1,2-diols by dibromoisocyanurate (Scheme 46) and base-promoted coupling of bis[(nitrofurazanyl)azo]compounds (Scheme 47). This reaction provides a new and versatile... 

Disubstituted- and 2,3,4-trisubstituted-furans are provided by oxidation or oxidation/acid-induced cyclization of the corresponding 2-butene-l,4-diols. These methods have been successfully employed for the synthesis of hibiscone C <00SL363> and cristatic acid . 

Iodocyclization to hydroxy tetrahydrofurans. Cyclization of y,8-unsaturated alcohols to tetrahydrofurans (12, 254-256) can be directed by an allylic oxygen substituent, which also can increase the rate of cyclization. Thus derivatives of 4-pentene-l,3-diol undergo iodocyclization mainly to dr-3-hydroxy-2-iodomethylte-trahydrofurans. 

The stereospecific reduction of a 2-butyne-l, 4-diol derivative and silver( I)-mediated cyclization of the resulting allene were successively applied to a short total synthesis of (+)-furanomycin 165 (Scheme 4.42) [68], Stereoselective addition of lithium acetylide 161 to Garner s aldehyde in the presence of zinc bromide afforded 162 in 77% yield. The hydroxyl group-directed reduction of 162 with LiAlH4 in Et20 produced the allene 163 stereospecifically. Cyclization followed by subsequent functional group manipulations afforded (+)-furanomycin 165. 

Intramolecular coupling Some aromatic diketones have been stereoselectively cy-clized under various electrolysis conditions, which, together with the substrate structure, strongly influence the stereochemistry of the formed cyclic diol. Reductive cyclization of 1,8-diaroylnaphthalenes led to trans-diols, 2,2 -diaroylbiphenyls and a, )-diaroylalkanes yielded cis-diols with different stereoselectivities depending on substrate structure and electrolysis conditions (pH, cosolvent) (Fig. 57) [310-312]. 

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