Alkylation of dithianes

Assembling a five-component coupling product in a single operation further extended this methodology. Following alkylation of dithiane 78 with epoxide (—)79 (2.6 equivalent each) to generate the unrearranged alkoxy dithiane 80, sequential addition of HMPA and (—)-epichlorohydrin 81 (1 equivalent) furnished the bis(silyloxy dithiane) carbinols (- -)82 in 66% yield (equation 29) . ... 

Finally, the synthesis of both attenols was accomplished by employing both electrophiles 106 and 112 as shown in Scheme 1.2.24. The alkylation of dithiane 113 with 106 proceeded cleanly in 96% yield. The second alkylation using 112 had to be carried out in the presence of HMPA and yielded 115 in 84% yield. Copper-mediated hydrolysis of the dithiane and p-toluenesulfonic acid catalyzed ketal formation finally gave a mixture of the title compounds 100 (57%) and 101 (9%), each over two steps. This synthesis is so far the shortest and most efficient one [60]. 

Alkylation of dithian itself 27 with the iodide 32 establishes the 1,4-diO relationship in 34 and this new dithian can be acylated with DMF (IV NCHO). The carbon skeleton of half pyreno-phorin 35 is completed by an -selective Wittig reaction with a stabilised ylid. 

The requisite dihydroxyketones are commonly assembled via iterative aldol coupling reactions [1], but other methods including Nef reactions [17,18], acetylide additions [19, 20], 1,3-dipolar nitrile oxide cycloadditions [21], iterative alkylation of dithianes [22-28], hydrazones [29], oximes [30], nitriles [31], or dihalomethylene species [32-34], cross-metathesis/hydroboration/oxidation [35], iterative substitution of a xanthate [36], dihydroxylation/desymmetrization of alkenes [37], Homer-Wadsworth-Emmons olehnations [38, 39], allylmetallations [40], and alkyne-alkyne cross-coupling [41] have also been reported. 

Similarly, in another example, alkylation of 111 with diepoxide (—)-115 (1 equiv.) in the presence of HMPA (1.3 equiv.) furnished diol (+)-117. Protection of (+)-117 to form the acetonide, removal of the silyl protecting groups (TBAF), and hydrolysis of the dithiane with Hg(Cl04)2 provided the diketone (+)-118. Hydroxy-directed syn-reduction of both carbonyl groups with NaBI U in the presence of Et2BOMe, and triacetonide formation, followed by hydrogenolysis and monosilylation, afforded the desired Schreiber subtarget (+)-119, which was employed in the synthesis of (+)-mycoticins A and B (Scheme 8.31) [56b]. 

Carlson and Helquist410 were the first to perform the alkylation of 2-lithio 1,3-dithian-S-oxide 323 (equation 180). The yields of this reaction appeared, however, to be low. In spite of the fact that dithian-S-oxides have been intensively investigated268-411, their synthetic applications are rather limited. 

Alkylation and hydrolysis of imines alkylation of aldehydes 10-107 Alkylation and hydrolysis of dithianes 10-108 Alkylation and hydrolysis of oxazines and similar compounds 10-109 Reaction of diazo aldehydes with boranes... 

Alkylation and hydrolysis of dithianes and similar compounds 10-108 Alkylation and hydrolysis of oxazines... 

C-Alkylation of ethyl l,3-dithiane-2-carboxylate (for preparation, see 4.1.6) under mild soliddiquid phase-transfer catalytic conditions [32, 33] provides a potentially useful route to a-ketoesters. 

Stable 2-metalo-l,3-dithianes, such as stannanes or silanes, have also been prepared and reacted with electrophiles. Sequential alkylation of a 2,2-bis-stannyl-l,3-dithiane (i, BuLi, oxirane ii, BuLi, alkyl bromide) furnished the 2,2-dialkylated products in 40% yield (Equation 40) <1997JA2058>. 

Alkylation at a Position a to a Hetero Atom. Alkylation of 1,3-Dithianes 2-(2-Alkyl-1,3-dithianyl)-de-halogenation... 

The most important use of 1,3-dithianes (792) stems from their ability to function as acyl anion equivalents (794 Scheme 184). Metallation of this heterocycle followed by alkylation of the anion and cleavage of the dithiane group produces a carbonyl compound. Since such aspects of dithiane chemistry have been extensively documented (69S17 75JOC231), only a few of the more current applications of these heterocycles are highlighted. We again note here that the application of heterocycles to the synthesis of carbonyl compounds has been the sole subject of an extensive review (77H(6)73l). 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

Diethyl-3,5-octadiene 174 Dithiane oxides alkylation of 84 carbanions of 84 Dithianes alkylation of 76,79 as acyl anion equivalents 75 carbanions of 76,79 cleavage of 14-18.76,79 desulfurization of 78 oxidation of 23... 

Dithioacetals (see also dithianes and dithiolanes) alkylation of 98 as acyl anion equivalents 75 carbanions of 87,97-102 cleavage of 14-18,98,102 desulfurization of 78 metal-catalysed coupling 127 reaction with Grignard reagents 127 reductive lithiation of 89 synthesis of 12-19,97-102 Dithioacids synthesis of 40... 

One hydrolytic method that is useful for the preparation of ketones is the hydrolysis of dithianes. 1.3-Dithiane can be alkylated by treatment with butyl lithium followed by an alkylating agent. The two sulfurs flanking the acetal carbon acidify the protons on that carbon such that butyl lithium can remove one giving a sulfur-stabilized anion. This anion reacts with alkyl halides or sulfonates to give alkylated products. This sequence can be repeated to give a bis-alkylated product. Hydrolysis then yields a ketone. Ditliioacetals are much more resistant to hydrolysis than acetals and thus Hg2+ is often used to promote efficient hydrolysis. 

The acidity difference of hydrogen atoms adjacent to divalent sulfur compared to oxygen stems from the greater polarizability of sulfur and the longer C-S-bond length d-orbitals are not involved. In most cases treatment of dithianes with w-BuLi at temperatures of -30 °C is sufficient for the preparation of the lithio-derivatives. With pKA values of approximately 30, lithiated dithianes can react with aldehydes or ketones, epoxides and acid derivatives, but also with alkyl halides without competing elimination reactions. 

The needed substituted dithiane could itself be prepared by a similar alkylation of the unsubstituted dithiane anion. The synthesis is shown in Figure 23.2. 

Table 4. Alkylation of Enolates of 2-Acyl-2-alkyl-1,3-dithiane 1 -Oxide Substrates...

For the fast ge/w-dialkylation of 1,3-dithiane dianion, tin-lithium transmetallation at the 2-position of dithiane is a much faster process than the corresponding deprotonation. 2,2-Bis[tri(n-butyl)stannyl]dithiane (175)223 can be alkylated sequentially it was trans-metallated with n-BuLi at —78 °C, after 5 minutes treated with the first alkyl halide and after 10 more minutes the process was repeated providing dialkylated products224. This strategy has been used in the total synthesis of (—)-perhydrohistrionicotoxin, namely preparing the key compound 178 employing successively iodides 176 and 177 as electrophiles (Scheme 50)224. 

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