Cyano epimerization

Steroids possessing an epoxide grouping in the side chain have likewise been converted to fluorohydrins. Thus, 20-cyano-17,20-epoxides of structure (19) furnish the 17a-fluoro-20-ketones (20) after treatment of the intermediate cyanohydrins with boiling collidine. The epimeric 5a,6a 20,21-oxides (21) afford the expected bis-fluorohydrins (22). The reaction of the allylic... 

While both possible epimeric cyanohydrins are formed (with the 17a-cyano-17/9-hydroxy compound predominating) the mixture can be used in the dehydration step, which destroys the asymmetry. 

Enantiopure 3-phenyl-2-cyanoazetidines (S)-238 and (K)-238, which are epimeric at C2, are prepared in high yields from (K)-phenylglycinol. A one-pot sequence, including addition of organohthium or allyhnagne-sium bromide to the cyano group and in situ reduction of the resulting imine with sodium borohydride, allowed for the preparation of 2-(l-aminoalkyl)azetidines, which were then protected as N-Boc derivatives (R,S)-239 and (S,it)-239 [112] (Scheme 36). Complete anti diastereoselectivity (dr more than 95 5 by NMR) was observed in both cases. The same sequence... 

The cyano-, carbomethoxy- and phenylsulfonyl-substituted cyclopropanes [54] (Cram and Ratajczak, 1968), [55] (Yankee and Cram, 1970a Yankee et al., 1973a) and [56] (Yankee and Cram, 1970b,c Howe etal., 1973 Yankee et al., 1973b) were epimerized or were solvolysed to give an open-chain methyl ether a carbocation-carbanion zwitterion was proposed as the intermediate. 

The first asymmetric synthesis of (-)-monomorine I, an enantiomer of the natural alkaloid, by Husson and co-workers starts with the chiral 2-cyano-6-oxazolopiperidine synthon (385) prepared from (-)-phenylglycinol (384), glu-taraldehyde (383), and KCN (443). Alkylation of 385 with an iodo ketal led to the formation of a single product (386). The cyano acetal (386) was treated with silver tetrafluoroborate and then zinc borohydride to afford a 3 2 mixture of C-6 epimeric oxazolidine (387) having the (2S) configuration. Reaction of 387 with... 

The reaction of 3/3-acetoxy-5a-cholest-8(14)-en-7-one with EtjAlCN was the key reaction in a synthesis of cholestanes containing an oxygenated 14a-substi-tuent. Cholest-4-en-3-one reacted smoothly with KCN-acetone cyanohydrin in benzene or acetonitrile containing 18-crown-6 to give the epimeric 5-cyano-cholestan-3-ones. An 11 -hydroxy-group increased the proportion of a-epox-ide produced in the reaction of 3-oxo-A -steroids with H202-0H . A 9a-fluorine substituent also influenced the stereochemistry of the reaction products and a... 

X = O, CH2, or NS02Me. In each case, the only products detected were the cis-fused cycloadducts, whereas replacement of the phosphate group with a cyano functionality gave rise to traces of the tmns product. Subsequent oxidative removal of the epimeric phosphate group provided the lactams shown (Scheme 3.96). 

Kinetic studies by Doering and his collaborators at Harvard150-154 based on five sets of chiral 1,2-disubstituted cyclopropanes, with 1-cyano, 2-(phenyl or propen-2 -yl or -(E)-propenyl or phenylethynyl) (3) and 1 -phenyl-2-(propen-2 -yl) (4) substitution, established the ralative rotational propensities of these substituents and tested the proposition that they might be related to substituent moments of inertia. In all of these cases, the balance between one-center and two-center epimerizations from a trans isomer, reflected in (kt + k2) kl2, was fairly constant, ranging from 1.4 1 to 2.1 1. The kinetic advantages for one-center epimerizations at cyano-substituted carbons for the four cases studied were modest and not especially system-dependent the k, k2 ratios were 2.5,2.2,2.4 and 1.8, thus establishing that rotational propensities are not dictated by some simple function of the moments of inertia of substituents. 

Another exploitation of stereochemically specific deuterium labeling at C(3) was exemplified in an approach to determine the relative one-center epimerization rate constants in a cis-1 -cyano-2-isobutenylcyclopropane. Thanks to the deuterium labeling (equation 3) the distinction could be made without resort to chiral compounds, and the k. k2 ratio was found to be (3.9 0.5) 1 at 206.7 °Cl6tl. 

The synthesis continued with the formation of the 2-azabicyclo[3.3.1]nonane ring (D, E-rings), and epimerization of the cyano group at C-20 to an axial position. Closure of the C ring using a Bischler-Napieralski cyclization gave the quaternary indole alkaloid, ( )-melinonine-E (159). A closely related analog, ( )-strychnoxanthine, was also synthesized by a similar method [67]. 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

C, but was negligible at 180 °C or when on-column GC injection was used [96]. Cypermethrin [96] and cyfluthrin [96,330] also isomerized slowly (half-life ca. 160 days) at the asymmetric a-carbon atom in sterile water, as does deltametrin, which also has a cyano substituent at the asymmetric a-carbon atom in polar solvents [331, 332]. Cypermethrin isomerized rapidly in isopropanol (half-life of 3-7 days) and methanol (half-life of 2-3 days), as well as in organic solvent-water mixtures depending on water content and temperature [333]. Photolytic epimerization was observed for deltamethrin [331, 334] and for cyhalothrin, another cyano-bearing pyrethroid [335]. No isomerization by any means was observed for bifenthrin [96] and permethrin [96, 333], both of which lack cyano substituents. Thus, caution should be applied to cyano-bearing pyrethroids to avoid exposure to light and use of incompatible solvents (e.g. HPLC mobile phases), and in interpretation of enantiomer composition from environmental data to account for abiotic isomerization. 

Ethyl cyano(hydroxyimino)acetate (17) leads to less racenoization than HOBt when Ac-Ile-OH is coupled with H-Gly-OEt HCl in the presence of triethylanoine. Epimerization to Ac-D-alle-Gly-OEt was only 1.8%, as opposed to 2.7% with HOSu and 8.8% with HOBt.t Further detailed studies exemplifying the versatility of this additive have not been reported. 

The use of the oxime 2-cyano-2-hydroximinoethyl acetate as the A-hydroxy component led to the development of TOTU (21)t l and the corresponding hexafluorophosphate HOTU (20).P l TOTU results in less epimerization in segment couplings than BOP or TBTU (9).t l... 

This cycloaddition methodology utilizing N-lithiated azomethine ylides has some advantages. (1) The ylides can be generated in situ concurrently with or prior to cycloaddition. (2) The ylides are highly reactive toward a number of carbonyl-activated olefins. (3) Wide structural modification of ylides is possible. (4) The cycloadditions are perfectly diastereoselective. (5) No demetallation procedure is necessary. (6) No critical epimerization occurs even in the reactions of cyano-stabilized ylides 144. 

Chain extension by way of cyanohydrin formation (Section 25.20) The Kiliani-Fischer synthesis proceeds by nucleophilic addition of HCN to an aldose, followed by conversion of the cyano group to an aldehyde. A mixture of stereoisomers results the two aldoses are epimeric at C-2. Section 25.20 describes the modern version of the Kiliani-Fischer synthesis. The example at the right illustrates the classical version. 

The latest synthesis21 of ( )-epilupinine utilizes the Michael addition of acrylonitrile to 2-cyanomethylenepiperidine, which affords l-cyano-4-oxo-l,10-dehydroquinolizidine (15). Diborane reduction of this lactam-nitrile gave an epimeric mixture of cyanoquinolizidines (16), which was converted into the equatorial isomer and simultaneously hydrolysed by heating with potassium hydroxide in aqueous diethylene glycol. The product (17) was esterified and reduced (LiAlH4), with formation of ( )-epilupinine (18).21... 

---