Oxocene

Scheme 31 Efficient RCM to A4-oxocene 167 in Crimmins total syntheses of the marine natural products laurallene (168) and prelaureatin (169) [86]...

Cyclization of mixed acetals (13,300).4 This reaction is a particularly useful route to eight-membered cyclic ethers (oxocanes) and provides the first practical route to a natural oxocene, (- )-laurenyne (3), from an optically active mixed acetal 1. Thus cyclization of 1 followed by O-desilylation affords 2 as the only cyclic product. Remaining steps to 3 involved C-desilylation, for which only HF/pyridine is useful, introduction of unsaturation into the C2-side chain, and extension of the C8-side chain. Exploratory studies showed that unsaturation at the p- or y-positions to the cite of cyclization of 1 prevent or retard cyclization with a wide variety of Lewis acids. The cyclization is apparently more tolerant of substitution in the terminator position, C3-Q, of the oxocene. 

One year after the total synthesis of (-l-)-laurencin, Crimmins disclosed total syntheses of (-l-)-prelaureatin 232 and (-f)-laurallene 233, applying a similar strategy (Scheme 43). The critical RCM reaction was undertaken with precursor 230, anticipating that the gauche effect of the C6 and C7 oxygens would accelerate the ring closure. Exposure of 230 (0.005 M in dichloromethane) to catalyst B proceeded smoothly to provide the key A -oxocene 231 in 95% yield with no detectable dimerization. 

Oxocenes.1 A general route to these unsaturated eight-membered cyclic ethers involves an intramolecular cyclization of a hydroxyl group with a sulfonium ion, generated from a dithioketal by NCS-AgN03 (4,216) and a base (2,6-lutidine). Example ... 

Cyclization of hydroxy dithioketals. Nicolaou et al.1 have used this reaction for construction of oxocenes. The most satisfactory method involves activation of the sulfur of the starting material (1) with AgC104 to produce an oxocene derivative (2), followed by C-S cleavage. This second step can be effected with (C6H5)3SnH (AIBN) or by oxidation to the corresponding sulfoxide or sulfone, which then is cleaved with... 

C2H5)jSiH/BF3- 0(C2H5)2. The presence of a c/r-double bond is an essential for this cyclization. Another limitation is that yields are low when extended to synthesis of a nine-membered oxocene. 

Eight-membered rings with one oxygen atom are named as oxocanes, oxocenes, or oxocines. The name A"-oxocene is frequently used for compounds with one double bond n = 2-4 indicates the position of the double bond. Oxocenes, however, are preferentially named as dihydo- or tetrahydrooxocines. The names of some selected oxocane and oxocine compounds are shown. 

Oxocane (A2-Oxocene) 3,4-Dihydro-2H-oxocine 5,6-Dihydro-4H-oxocine... 

The intramolecular allylboration of an aldehyde function leads selectively to cir-disubstituted cyclic ethers. It has been shown that both the reactive aldehyde and the allylboronate moiety can be initially generated in situ in a masked form and then liberated simultaneously by hydrolysis of the precursor functions <1997JA7499>. This methodology was successfully applied to the one-pot synthesis of the oxocene 82, a precursor of (-l-)-laurencin (Scheme 13). A DIBAL reduction of the Weinreb amide 80, metalation with r f-butyllithium, borylation with the pinacol borate ester, and, finally, liberation of both the aldehyde and the allylboronate function by aqueous pH 7 buffer solution generated the reactive 81, which cyclized in 38% overall yield to the oxocene 82. Only the all-cis-diastereomer is formed, which means that the cyclization proceeds under high asymmetric induction from the resident stereogenic center present in 80. 

Acyclic ethers having an aldehyde and a /3-alkoxyacrylate group undergo Sml2-induced reductive cyclization to afford oxocanes or oxocenes in moderate yield but with low stereoselectivity (Scheme 16) <2002CL148>. 

Hydroxy epoxides, in the presence of La(OTf)3, undergo selective rr/o-cyclization <1998TL393>. Epoxide 99, for instance, under the conditions indicated in Scheme 18, affords oxocene 100 and a small amount of 7- w-cyclization product 101. When the reaction is conducted in DCM, for 8 days at 25 °C, only the %-endo-pmduct 100 is formed, albeit in lower yield (55%). 

Treatment of the allenyl sulfones 112 with KO Bu in BuOH at room temperature provides the oxocenes 113 or 114 in high yields (Scheme 25) <20010L3385>. 

Reaction of 3-hydroxy-oxonene 103 with the complex of bromine and l,2-bis(diphenylphosphino)ethane resulted in an expected mixture of brominated compounds 105 and 106, along with single stereoisomer of oxocene 107, probably due to the formation of the bridged oxonium cation and its two different directions of the reaction with bromide anion (Scheme 17, Section 14.10.5.5.3) <1995TL8263>. 

As discussed at the beginning of Sect. 4.1, a masked carbonyl, such as acetal, is more suitable for macrocyclization than the carbonyl itself b ause the nucleophilic substitution reaction on the former is irreversible. Overman and coworkers [111] developed a C—C bond-forming cyclization approach to 8-membered ethers by Lewis acid-promoted alkene substitution of mixed acetals. Thus, oxocenes with... 

A -oxocenes increase as the 5-substituent of a 5-hexenyl acetal is varied from H to SiMej to SPh. As shown in Scheme 62, the Cjs-nonisoprenoid metabolite ( )-laurenyne 190) was synthesized using this method [111b]. Thus, mixed acetal precursor 188 was treated with 2 equiv of stannic chloride in dichloromethane at 0 °C for 1.5 h followed by 0-desilylation to produce oxocene 189 as the sole cyclic ether product in 37% yield. 

In the synthetic studies of the marine natural products brevetoxins A and B, Nicolaou and coworkers [157] developed a highly efficient cyclization reaction of hydroxy dithioketals leading to oxocenes. As shown in Scheme 88, exposure of the hydroxy dithioketal 261 to 1.1 equiv of AT-chlorosuccinimide (NCS) in CH3CN in the presence of 2 equiv of 2,6-lutidine, 1.1 equiv of AgNOj, molecular sieves and silica gel at 25 °C for 5 min led to the oxocene 262 in 95% yield. 

As discussed earlier (Section 6.3.4), acyclic (pentadi-enyl)iron cations are intermediates in reactions involving protonation or Lewis acid activation of iron dienol or dienol acetate complexes. With appropriate functionalization, these cations may also be trapped intramolecularly (Scheme 81). In the case of the formation of tetrahydrofinans (278) and (279), equilibration of the transoid and cisoid cations is observed. However, this equilibration is not observed in the stereoselective cyclization to provide (racemic) oxocene (280). Analogous intramolecular cyclizations of sullur and nitrogen... 

The vinylsilane-terminated cyclization strategy has been extended to the preparation of eight-membered cyclic ethers. Oxocenes (Scheme 17) with AAunsaturation (3,6,7,8-tetrahydro-2//-oxocins) were prepared efficiently by the SnCU-catalyzed cyclization of the mixed acetals (39) with complete re-giochemical control. Electrophilic addition on the 2-(trimethylsilyl)-l-alkene occurs predominanfiy at the terminal position of the alkene to form a tertiary a-silyl, rather than a primary 3-silyl, carbocation. The... 

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