Oxetanes intramolecular cyclization reactions

Scheme 7.1 Formation of oxetanes by intramolecular cyclization reactions.

Craig, D, Munasinghem, V R N, Stereoselective template-directed C-glycosidation. Synthesis of bicyclic keto oxetanes via intramolecular cyclization reactions of (2-pyridylthio)glycosidic silyl enol ethers, J. Chem. Soc., Chem. Commun., 901-903, 1993. 

Acetyl-17-hydroxysteroids on oxidation with IBD lead to the formation of spiro-oxetan-3-ones. The reaction proceeds through an intermediate of the type 31, which undergoes intramolecular cyclization involving participation of the C17-OH group (85S1129) (Scheme 12). 

In a new method of ring enlargement of oxiranes to oxetanes, the intramolecular Williamson reaction is the essential last step. Reaction of an oxirane with selenomethyl-lithium reagents, followed by bromination, gives y-bromo alcohols, which can be cyclized by base to oxetanes. Since the oxiranes can be prepared readily from ketones and the selenomethyllithium reagent, this is also a synthesis of oxetanes from ketones (80TL585). 

A rapid one-pot method for converting 1,3-diols into oxetanes by the intramolecular Williamson reaction has recently been described. The monolithium salt is generated by treatment of the diol with one equivalent of butyllithium in cold THF, followed by addition of one equivalent of tosyl chloride to give a monotosylate, which is cyclized by addition of a second equivalent of butyllithium (equation 83). Yields of 70-90% are reported for a variety of alkyl- and aryl-substituted oxetanes (81S550). Another simple method for converting 1,3-diols into oxetanes consists of converting them to cyclic carbonate esters by ester... 

Oxetanes have also been synthesized by the immobilization of 2,2 -disubstituted 1,3-diols with polymer-bound sulfonyl chloride, followed by intramolecular cyclization/cleavage from the solid support (Scheme 17) <2005TL643>. One percent divinylbenzene (DVB) cross-linked polystyrene and polyethylene glycol (PEG) (average Mn 3400) were used as polymer support in this reaction, and in both cases the properties of the polymer support allowed rapid purification of the intermediate. Intermediates on the insoluble cross-linked polystyrene support could be washed with a range of organic solvents to remove insoluble impurities, whereas the soluble PEG supported products could be purified by recrystallization from isopropanol. This is thought to represent the first reported polymer-supported synthesis of oxetanes. 

Irradiation of the enone (80) at 282 nm brings about the formation of the oxetane (81), and this process has been used as a key step in the development of a synthesis of 2,7,9-trimethylenetricyclo[4.3.0.0 ]non-4-ene. Such intramolecular additions are popular methods for the formation of polycyclic compounds that can be used as starting materials in syntheses. An efficient example of this from earlier years is the formation of the oxetane (82,90%) from the intramolecular cyclization of the enone (83). The oxetane formed is a key intermediate in a new efficient route to enrfo-hirsutene. ° A review of the application of the Diels-Alder/Patemo-Buchi reaction as an approach to di- and tri-quinanes has been published. ... 

In addition to alkenes and acetylenes, carbonyl-containing compounds also participate in [2+2] cycloaddition reactions with indoles. The first example of oxetane formation via the photoreaction of indoles with a carbonyl group (a type of Patemo-Biichi reaction) was reported by Machida and coworkers [34, 35] (Scheme 16), who carried out the intramolecular cyclization of iV-acetylindole with phthalimide tethered with appropriate linkers 67a-d. Interestingly, only the... 

Imides prepared from a-aminoacid esters with an extractable y-proton (with respect to the phthalimide nitrogen as a) have been reported to furnish benz[c]diazepine-2,5-diones in a Norrish Type II process with retention of stereochemistry of the aminoacid asymmetric centre <92CB2467, 94T3627). Similar results are reported in the intramolecular cyclization of iV-alkyl succinimides, in contrast to the reaction of such compounds with alkenes in an intermolecular reaction, when the usual product is an oxetane <84CPB950,85MI901-02). 

This methodology was then employed to constmct the C, D-ring portion of paclitaxel (581) [178]. In this case, reaction of 574 with DMAD in 5 M ethereal LiC104 produced mainly 575 in 83% yield (Scheme 13.115). This diastereomer 575 was then converted into bicyclic lactone 576 in several steps. Further transformations produced oxabicycle 577 wherein three of the five requisite stereocenters are set. Ring opening and manipulation of the oxidation states of 578 afforded 579. This was followed by an intramolecular cyclization to produce the oxetane ring present in 580. 

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). ... 

Resin-based chemistry has been used to construct 480 from 481 by use of boron trifluoride to mediate both the cyclization and cleavage steps <1999AGE1121 >. When the monosaccharide was bound to the polystyrene resin (Merrifield and MPP type) by an alkylsulfonyl linker 482 and cyclization was mediated by 2- r/-butylimino-2-diethylamino-l,3-dimethylperhydro-l,3,2-diazaphosphorine, the reaction had low stereoselectivity and the products included tricyclic oxetanes and oxiranes <2004EJ04177>. The Mitsunobu reaction was used to obtain intramolecular N-alkylation of 483 and formation of 484 <2005AGE3732>. 

Sakamoto et al. also demonstrated the absolute oxetane synthesis in the solid-state photolysis of N-(a, 3-unsaturated carbonyl)benzoylformamides 39 (Scheme 18) [25]. These compounds undergo intramolecular [2 + 2] cyclization to give bicyclic oxetanes 40 in homogeneous solution. The x-ray analysis of N-isopropyl substituted imide 39a revealed that the crystal system was monoclinic and the space group P2 (Table 7). Crystals of 39a were powdered and photolyzed at 0°C. The imide undergoes the [2 + 2] cycloaddition to afford the bicyclic oxetane 40a, which is a mixture of diastereomers, namely, syn- and anti isomers at the C-7 position. In this reaction optically active syn-oxetane 40a with 37% ee (84% chemical yield) and racemic anti-40a were obtained (Table 8). The solid-state photoreaction proceeded even at — 78°C, and optically active syn-40a, which showed ee value as high as > 95% ee (conv 100%, chemical yield 89%), was... 

It is also worthwhile comparing the intramolecular photochemical cycloaddition reactions of ethylenic aldehydes and ketones with free radical intramolecular additions. For instance, irradiation of 5-hexen-2-one (470) (Scheme 161) in the gas phase gives the oxetane 471 as only cyclized product, as expected from the known photochemical intermolecular reaction between olefins and ketones. If the irradiation is conducted in solution 470 gives 471 (26%) and 472 (18%). With other y,< -unsaturated ketones, the bicyclic compound analogous to 472 may become the major product. With 2-allylcyclanones such as 473 (Scheme 161) bicyclic compounds are obtained (80% yield) as a mixture of 474 and 475, with 475 being the major product, but such compounds are difficult to isolate. " In the same manner, selective irradiation of the carbonyl group of 2-acyl-2,3-dihydro-4/f-pyrans (476) leads exclusively (23% yield) to exo-brevicomin (477) (a sex attractant), neither oxetane formation nor Norrish type II reaction being observed. The formation of the compounds 472, 475, and 477 which was considered as unexpected... 

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