Dithiane, Brook 1,5-rearrangement

Smith et al. have developed a very elegant route to complex polyol structures by sequential dithiane-epoxide coupling reactions (Scheme 7) [16]. Following the work of Tietze [17], 2-silyl-1,3-dithianes 42 are deprotonated with /BuLi in ether and converted into the stable lithium alk-oxides 43 with enantiomerically pure epoxides. A fast 1,4-Brook rearrangement occurs only after the addition of 0.3 equivalents of hexamethyl-phosphoramide (HMPA) or 1,3-dimethylhexahy-dro-2-pyrimidone (DMPU) to the reaction mixture. A new lithiated dithiane 44 that can undergo... 

A one-pot five-component dithiane linchpin coupiing was applied as the key synthetic transformation in A.B. Smith s approach to Schreiber s C16-C28 trisacetonide subtarget for mycoticins A and B. To prevent a premature Brook rearrangement, ether was used instead of THF as a solvent for the initial deprotonation of 2-TBS-1,3-dithiane. The third component in the iinchpin coupiing was (S,S)-diepoxypentane that was added to the reaction mixture along with HMPA in THF. 

Smith, A. B., iii, Boidi, A. M. Muiticomponent Linchpin Coupiings of Siiyi Dithianes via Soivent-Controiied Brook Rearrangement. J. Am. Chem. Soc. 1997, 119, 6925-6926. 

The syntheses of the C1-C12 AB and C13-C28 CD segments, 528 and 535, are summarized in Scheme 75. The syntheses of the two segments are based on a one-pot unsymmetric bisalkylation of 2-TBS-l,3-dithiane (525) with Brook rearrangement. Epoxides 521, 522, 523, and 524 were synthesized as coupling partners. 

Conditions have been optimised to allow successful sequential bisalkylation of the 2-substituted 1,3-dithiane anion. An interfering Brook rearrangement is controlled by the choice of solvent. The methodology has potential in the synthesis of macrolides <97JA6925>. 

The third section of the chapter describes recently developed anion relay chemistry (ARC) involving threefold domino Sj -Brook rearrangement/ reactions, discovered by Tietze and extensively explored by Amos Smith 111 and his group. These reactions are also initiated by nucleophihc ring opening of epoxides, usually by silyl-substituted dithiane anions, and find useful apphcation in natural product synthesis. 

A highly useful threefold domino Brook rearrangement/Sjj reaction of silyl-1,3-dithiane with epoxides was first reported by Tietze and coworkers [47] (Scheme 4.28). Thus, treatment of 2.2equiv of enantiopure epoxides (k)-139a... 

Addition of an aUcyllithium to the aldehyde of 132, followed by cation exchange to the potassium alkoxide, led to 1,5-Brook rearrangement. The resulting potassium dithiane 133 was allylated, providing masked y-hydroxyketone 134 in good overall yield. 

The three-component process with 2-t-butyldimethylsilyl-l,3-dithiane has been further optimized to incorporate two different epoxides, employing solvent as a means to control the 1,4-Brook rearrangement (eq 9). In this protocol, lithiation and alkylation of the first epoxide are conducted in Et20 rather than THF to prevent premature silyl migration. Introduction of HMPA (or DMPU) with the second epoxide in Et20 initiates the Brook process subsequently leading to the desired unsymmetrical, three-component adducts. 

Silicon-Induced Domino Reactions. In a series of papers, Schaumann et al. disclosed the synthesis of various cyclic compounds utilizing a silicon-induced reaction cascade. Treatment of an epoxyalkyl tosylate with 2-lithio-2-TMS-l,3-dithiane leads to the corresponding lithium alkoxide. Subsequent 1,4-Brook rearrangement and displacement of the tosylates affords cyclopen-tanols in good yield (eq 24). ... 

Additionally, Schaumann demonstrated that this approach can be used in the S3Uithesis of pyrrolidine- and piperidine-2,3-diones. Treatment of bromoalkyl isocyanates with 2-lithio-2-TMS-l,3-dithiane provides, after Brook rearrangement and nucleophilic displacement of bromide, the corresponding lactams with moderate to good yields. Protection of the nitrogen followed by a two-step dithiane hydrolysis affords pyrrolidine- and piperidine-2,3-diones (eq 25) ... 

Multicomponent Linchpin Reactions. 2-Lithio-2-TMS-1,3-dithiane has also been employed as a bi-directional nucleophile or linchpin in epoxide opening reactions where both openings occur in an intermolecular fashion. The dithiane anion first attacks the less hindered carbon of the epoxide then, in the presence of THF and 12-crown-4,1,4-Brook rearrangement occurs with transfer of the TMS group to reveal a new dithiane anion that can react with an additional equivalent of epoxide (eq 27). This reaction, first reported by Tietze et al. in 1994, suffered from a lack of control over the rearrangement step, thus limiting the use to the formation of symmetric 1,5-diols. ... 

Sn2 VersusSN2 Reactionof2-TMS-l,3-Dithiane With Vinyl Epoxides. In 2002 Smith et al. demonstrated that 2-lithio-2-TMS-1,3-dithiane reacts with vinyl epoxides in an Sn2 fashion exclusively, while other, larger silyl dithianes afford mixtures of Sn2 and Sn2 products. Particularly useful, the large 2-lithio-2-triisopropyl-1,3-dithiane provides solely the Sn2 product. Furthermore, it was found that trans epoxides furnish syn products and cis epoxides produced anti products, albeit in modest yields (eq 28). However, under the reaction conditions (THF, HMPA) the TMS group underwent a 1,4-Brook rearrangement to afford a 1 1 mixture of the anticipated homoaUyhc alcohol and the rearranged silyl ether. 

One of the most used sequential component reactions in the asymmetric construction of chiral compounds is the so-called anion relay chemistry (ARC) [2], This linchpin coupling protocol consists in the alkylation of an anion, generally a silyl lithium dithiane derivative, by an epoxide or an aziridine, resulting in an oxy- or aza-anion, which in the presence of hexamethylphosphoramide (HMPA) or other polar solvent gives a 1,4-Brook rearrangement, thereby leading to a new reactive dithiane anion that is capable of reacting with a second electrophile E+ (Scheme 11.1). 

A short synthesis of (5 ,9 )-(—)-indolizidine 223AB (1806) by Smith and Kim used the silylated dithiane 1847 as a linchpin for the one-pot tandem alkylation with epoxide (- -)-1848 and the N-tosylaziridine (—)-1849 (Scheme 233). The first intermediate is presumably alkoxide 1850, which undergoes a 1,4-Brook rearrangement to 1851 before reaction with the aziridine. The bis-alkylated dithiane (—)-1852 was isolated in... 

The Brook 1,4-rearrangement is useful in cyclopentanol synthesis. For example, Schaumann and co-workers demonstrated that lithiated or-silyl dithiane 112 was useful for construction of cyclopentanol 115. Addition to epoxytosylate 113 followed by 1,4-silyl migration provided lithiodithiane 114 for closure of the five-membered ring. ... 

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