Cyanohydrin acetonides

Alkylations of 4-cyano-l,3-dioxanes (cyanohydrin acetonides) represent a highly practical approach to syn-l,3-diol synthesis. Herein we present a comprehensive summary of cyanohydrin acetonide chemistry, with particular emphasis on practical aspects of couplings, as well as their utility in natural product synthesis. Both 4-acetoxy-l,3-dioxanes and 4-lithio-1,3-dioxanes have emerged as interesting anri-l,3-diol synthons. The preparation and utility of these two synthons are described. 

Keywords Cyanohydrin acetonide alkylations. Reductive decyanations, Oxocarbenium ions. Reductive lithiation... 

Beau and Sinay described a method which laid the groundwork for cyanohydrin acetonide alkylations [1]. Their strategy involved alkylation and reductive desulfonylation of glucopyranosyl sulfones 4. In this one-pot procedure, low temperature alkylation and subsequent reductive desulfonylation with lithium naphthalenide generated -C-glycosides with good selectivity >10 1 j3 a) and in moderate to good yield (Eq. 1). 

A 1,3-diol sometimes represents a more convenient precursor to cyanohydrin acetonides. For these instances, an alternate procedure has been developed. Selective oxidation of a 1,3-diol with TEMPO/NaOCl generates a sensitive -hydroxy aldehyde (see also Sect. 3.2). The neat -hydroxy aldehyde is prone to dimerization, but can be handled in solution without significant dimerization. Conversion to the cyanohydrin acetonide is accomplished in a manner similar... 

Leahy demonstrated that unsaturation at the 5-position of a 4-cyano-l,3-dioxane can lead to a reversal in selectivity [12] (Eq. 6). Alkylation of cyanohydrin acetonide 19 with benzyl bromide generated a 9 1 mixture of 20 and 21, with the flufz-isomer 20 predominating, in 57% overall yield. An alkylithium intermediate in which overlap with the methylidene tt orbital favors the axial configuration could account for this anomalous selectivity. 

Rychnovsky demonstrated that the latter explanation is correct in reductive decyanations, the intermediate radical equilibrates to the most stable (axial) radical, and this equilibration determines the stereochemical outcome. Reductive decyanation of a 52 48 mixture of cyanohydrin acetonides 22 provided the 5yn-product 25 with 99 1 selectivity (Scheme 4). Ab initio calculations revealed a ca. 3.5 kcal/mol enthalpy difference between the axial and equatorial radical... 

Lithiated cyanohydrin acetonides are potent nucleophiles. Reactive electrophiles like butyl bromide work well (Eq. 8). Less reactive electrophiles like -alkoxy-and -silyloxy bromides (Eqs. 9 and 10) also smoothly participate in alkylations. Increased steric bulk near the reacting center of the cyanohydrin acetonide is well tolerated (Eq. 11) [21]. 

A range of amide bases can be employed. Typically LDA is used, but in certain complex cases, LiNEt2 was found to be more effective. One exceptional case involves the ostensibly simple alkylation of a cyanohydrin acetonide with allyl chloride (Eq. 12). Here, use of LDA gave essentially none of the desired product 39, whereas KHMDS or LHMDS gave excellent yields [5]. 

Most often, the application of cyanohydrin acetonide couplings to a natural product synthesis calls for coupling with a primary alkyl halide. This has proven successful in every instance. However, on occasion, alkylations of more hindered epoxides or hindered alkyl halides are desirable. These reactions are less dependable. 

The cyanohydrin acetonide method has been a valuable tool in natural product synthesis. The first reported demonstration of this strategy was the total synthesis of (-)-roxaticin [29]. In this approach, treatment of cyanohydrin 57 with an excess of the C2-symmetrical dibromide 58 provided 59, without overalkylation (Scheme 6). A second alkylation involving cyanohydrin 60 gave 61 in excellent yield. (-)-Roxaticin was accessed in ca. 10 steps from tetraacetonide 62. 

In another application of the cyanohydrin acetonide method, cyanohydrin acetonide 64 (Fig. 2) was developed as a common precursor to both the nucleophilic and electrophilic components of a convergent coupling [30]. Orthogonal... 

Scheme 9). Although cyanohydrin acetonide 64 could conceivably have been used, the silyl ether 75 was chosen. This compound is readily available from (l)-malic acid, and can undergo electrophilic activation under far more mild conditions than compound 64. Alkylation of the 1,3-diol synthon 75 with bromide 76 created the C11-C26 framework of roflamycoin, in 85% yield. A two-step conversion of the terminal siloxy group to the primary iodide (78) proceeded in 80% overall yield. 

Alkylation of cyanohydrin acetonide 79 with the iodide 78 proceeded smoothly to give pentaacetonide 80 in 70% yield (Scheme 10). This represents the entire polyol framework of roflamycoin. An eight-step sequence involving installation of the polyene, macrocyclization via Horner-Emmons reaction, and protecting group machinations, completed the first total synthesis of roflamycoin. 

The polyene macrolide filipin was isolated in 1955 from the cell culture filtrates of Sterptomyces filipinensis, and was later shown to be a mixture of four components [36]. Although too toxic for therapeutic use, the filipin complex has found widespread use as a histochemical stain for cholesterol and has even been used to quantitate cholesterol in cell membranes [37]. The flat structure of filipin III, the major component of the filipin complex, was assigned from a series of degradation studies [38]. Rychnovsky completed the structure determination by elucidating the relative and absolute stereochemistry [39]. The total synthesis plan for filipin III relied heavily on the cyanohydrin acetonide methodology discussed above. 

The final assembly of the polyol chain is shown below. Scheme 15. Alkylation of cyanohydrin acetonide 12 with the C6-C15 iodide 87 gave the coupled product 98. The anion of 12 suffered extensive decomposition under standard alky-... 

Axial addition to oxocarbenium ions derived from 1,3-dioxanes provides protected a f/-l,3-diols. Our group has developed 4-acetoxy-1,3-dioxanes as oxocarbenium ion precursors. This general strategy for the convergent preparation of anfz-l,3-diols complements cyanohydrin acetonide methodology, which gives access to sy -l,3-diol synthons (Sect. 2). 

New synthetic methods are the lifeblood of organic chemistry. Synthetic efforts toward natural products often provide the impetus for the development of novel methodology. Reactive synthons derived from 1,3-dioxanes have proven to be valuable intermediates for both syn- and anfz-1,3-diols found in many complex natural products. Coupling reactions at the 4-position of 1,3-dioxanes exploit anomeric effects to generate syu-1,3-diols (cyanohydrin acetonides), autz-1,3-diols (4-acetoxy-1,3-dioxanes), and either syn- or azztz-1,3-diols (4-lithio-1,3-dioxanes). In the future, as biologically active polyol-containing natural products continue to be discovered, the methods described above should see much use. 

Reductive decyanation. This reaction is a key step in a route to syn-l,3-diol acetonides from P-trimethylsilyloxy aldehydes (1). Reaction of 1 with trimethylsilyl cyanide followed by acetonation gives a 1 1 mixture of a protected cyanohydrin (2). This mixture is converted into a single isomer (3) on alkylation of the anion of the cyanohydrin acetonide. Reductive decyanation with Na-NH3 at -78° produces a syn-diol acetonide (4). The apparent retention of configuration in the reduction results from preferential formation of an intermediate axial anion. 

Rychnovsky and his group have recently developed new synthetic methods that lead to the total syntheses of the polyene macrolides roxaticin [2], roflamycoin [3], and filipin III [4]. The polyol chains of all three natural products were constructed by iterative, stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation, illustrated here by the synthesis of the polyol framework of filipin III (1) (Scheme I). The bifunctional cyanohydrin acetonide 2, prepared by ruthenium/BINAP catalyzed enantioselective hydrogenation of the corresponding ) -keto ester (BINAP = [ 1,1 -binaphthyl]-2,2 -diylbis(diphenylphosphane)), is deprotonated with LiNEt2 and alkylated with 2-benzyloxy-l-iodoethane. The alkylation product 3 is converted by a Finkelstein reaction into the iodide 4, which is used to alkylate a second... 

Scheme 2. Reductive decyanation of the cyanohydrin acetonide 9 according to Rychnovsky et al.

Rychnovsky has employed highly stereoselective reductive decyanations of cyanohydrin acetonides in the synthesis of vy -l,3-diols [9, 10]. In the reduction of a 52 48 mixture of cyanohydrin acetonides by lithium in ammonia at —78°C, the stereochemistry of the reduction is set during the rapid and non-selective electron transfer to the intermediate axial radical, which generates the configurationally stable axial alkyllithium. Subsequent protonation from the axial direction gives the yy -l,3-diol acetonide with >100 1 stereoselectivity (Scheme 4). The same syn-... 

An alkylation/reductive decyanation method was developed for the efficient synthesis of xjn-l,3-diols [9, 10]. Cyanohydrin acetonides are rapidly deprotonated by amide bases and alkylated with suitably reactive electrophiles to yield diaste-reomerically pure coupled products. Subsequent exposure to Li/NHa affords exclusively xy -l,3-diol acetonides (see above). Although the alkylation itself is stereoselective, it is noteworthy that the, 2>-syn stereochemistry is ultimately set in the reductive decyanation by virtue of the anomeric axial radical intermediate. This methodology was effectively applied in the total synthesis of the polyene macrolide roflamycoin (Scheme 15) [23]. Noteworthy is the formation of the entire protected polyol segment of roflamycoin by treatment of a late-stage intermediate with Li/ NHa to effect a simultaneous decyanation/debenzylation. 

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