Alkylation of cyanohydrin

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. 

While alkylation of terminal epoxides is reliable, attempted alkylations of 1,2-disubstituted epoxides have proved capricious. An unsuccessful approach to the swinholides, which called for the alkylation of cyanohydrin 47 with epoxide 48, is one such example. In the event, alkylation cleanly produced imidate 49, rather than the expected product 50 [27] (Eq. 14). 

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. 

Schemes 14 and 15 outline the polyol chain assembly. Alkylation of cyanohydrin 93 with iodide 94 provided the chlorocyanohydrin 95, which was converted to the required iodide (96). A second alkylation of 93, this time with 96, provided bisacetonide 97 in 70-80% yield. Conversion of 97 to iodide 87 completed the synthesis of the C6-C15 fragment.

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-... 

Higher substituted cyanohydrines e.g. 303 for insecticidally inactive esters may be obtained by a-alkylation of cyanohydrine ethers 302 [656] (Reaction scheme 214). 

Nitrile groups m cyanohydrins are hydrolyzed under conditions similar to those of alkyl cyanides Cyanohydrin formation followed by hydrolysis provides a route to the preparation of a hydroxy carboxylic acids... 

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. 

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. 

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. 

Our group has also reported that the alkylation products of 4-cyano-l,3-diox-anes can serve as substrates for radical atom transfer reactions [41]. One such example is shown below (Eq. 17). Slow addition of tributyltin hydride/AIBN to a refluxing solution of cyanohydrin 115 generated the radical nitrile transfer product 116. This method, though somewhat limited in scope, can provide access to syn-l,3-diols which maybe unstable to the vigorous Li/NHg reduction conditions. 

A range of l,3-oxazolidin-4-ones (93) have been prepared by cyclocondensation of cyanohydrins, R R C(OH)CN, with aldehydes or ketones, R COR, under anhydrous strong acid conditions. The R groups used are mainly simple alkyl and aryl moieties, and the mechanism is discussed. 

While the addition-oxidation and the addition-protonation procedures are successful with ester enol-ates as well as more reactive carbon nucleophiles, the addition-acylation procedure requires more reactive anions and the addition of a polar aptotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion) but cyanohydrin acetal anions are successful. The addition of the cyanohydrin acetal anion (71) to [(l,4-dimethoxynaphthalene)Cr(CO)3] occurs by kinetic control at C-P in THF-HMPA and leads to the a,p-diacetyl derivative (72) after methyl iodide addition, and hydrolysis of the cyanohydrin acetal (equation 50).84,124-126... 

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

In the optical resolution of cyanohydrins, it was first found that brucine (4) is a suitable host for the cyanohydrins which substituted with one aromatic group and one bulky alkyl group. In this case, not only a simple enantiomer separation of rac-cyanohydrin but also its transformation to one enantiomer occurred and one pure enantiomer was obtained in a yield of more than 100%. For example, when a solution of rac-l-cyano-2,2-dimethyl-l-phenylpropanol (61a) (1.0 g, 5.3 mmol) and 4 (2.1 g, 5.3 mmol) in MeOH (2 ml) was kept in a capped flask for 12 h, a 1 1 brucine complex of (+)-61a (2.08 g, 134%, mp 112-114 °C) separated out as colorless prisms. Decomposition of the complex with dil HC1 gave (+)-61a of 97% ee (0.67 g, 134%). From the filtrate, rac-61a (0.33 g, 33%) was obtained.273 The... 

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. 

Formaldehyde reacts quickly and quantitatively with HCN. Most other aldehydes have equilibrium constants that favor cyanohydrin formation. Reactions of HCN with ketones have equilibrium constants that may favor either the ketones or the cyanohydrins, depending on the structure. Ketones that are hindered by large alkyl groups react slowly with HCN and give poor yields of cyanohydrins. 

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... 

OL-Keto esters. The cyanohydrin silyl ether < 1) of methyl glyoxylate (4, 542-543 5, 720) can be converted by alkylation of the anion into the enol acetate (2) of a-keto esters. 

Macrocyclic ketones. A recent method for synthesis of macrocyclic ketones involves intramolecular alkylation of protected cyanohydrins. Sodium hexamethyidisilazide... 

The use of a C-enriched building block anchored to a resin makes the gel-phase spectrum selective for the appearance of the new C signal, and the enrichment allows much shorter acquisition times (133, 134) a real-time kinetic was reported for the alkylation of amines with C-enriched bromoacetic acid (135). An example from our laboratories (136) shows the formation of a cyanohydrin on SP is monitored by C-enriched gel-phase NMR using C-benzaldehyde. The appearance of the cyanohydrin signal (63.2 ppm) and its increase at different reaction times is easily monitored by comparison with the constant signals of the solvent (deuterated benzene, 133-126 ppm. Fig. 1.19, spectra A-D). A major drawback of this technique is the cost and the limited availability of C-enriched building blocks, which currently severely limits its application. 

---