Mitsunobu carbamates

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Some carbamates can be cleanly N-alkylated on insoluble supports, either by treatment with strong bases and alkylating agents, or by reaction with aliphatic alcohols under Mitsunobu conditions (Table 14.9). Alkylation under Mitsunobu conditions... 

Dinsmore and Mercer further investigated this reaction using DBU as a base and n-Bu3P/DBAD (di-tert-butyl azodicarboxylate) as Mitsunobu s reactants, and found an unexpected steroselectivity in the Mitsunobu transformation [75b], In fact, the stereochemical course of the Mitsunobu reaction (Scheme 6.11) depended on whether the carbamic acid intermediate was N-substituted with hydrogen (retention) or with carbon (inversion). 

N-Acyl or N-alkoxycarbonyl amidines or guanidines can be deprotonated and then alkylated [120]. The scope and limitations of these reactions are similar to those of the N-alkylation of amides or carbamates. N,N -Bis(tert-butyloxycarbonyl)guan-idine is sufficiently acidic to undergo clean N-alkylation under the conditions of the Mitsunobu reaction [121]. 

Figure 2.34 shows the mechanism of this reaction. A key intermediate is the alkylated phosphine oxide A, with which the carboxylate ion reacts to displace the leaving group 0=PPh3. Figure 2.34 also shows that this carboxylate ion results from the deprotonation of the carboxylic acid used by the intermediate carbamate anion B. Nucleophiles that can be deproto-nated by B analogously, i.e., quantitatively, are also alkylated under Mitsunobu-like conditions (see Figure 2.36). In contrast, nucleophiles that are too weakly acidic cannot undergo Mitsunobu alkylation. Thus, for example, there are Mitsunobu etherifications of phenols, but not of alcohols.

Diimide reduction of 96, obtained by the enzymatic oxidation of 95 (96% ee) [67], followed by O-acetylation afforded cyclohexene-diol 97 in 47% yield (Scheme 19). Compound 97 was converted into carbamate 98 by S 2 reaction with methylamine and subsequent urethane formation. Regioselective protection of the diol in 98 with TBSC1 afforded 99, which was coupled with bromoisovanillin 54 under the conditions of Mitsunobu to provide 100 (see Sect. 2.2.2). The intramolecular Heck reaction of 100 constructed the benzofuran ring including a quaternary center to afford 101 in 82% yield. Wittig reaction of 101 with Ph3P=CHBr generated vinyl bromide 102 in 49% yield as a mixture of E- and Z-isomers (E Z = ca. 1 2). 

Amino-l-hydroxyethyl)phosphonic acid occurs in the plasma membrane of Acanthamoeba castellani and the 2R isomer is formed, in that organism, by the hydroxy-lation of (2-aminoethvl)phosphonic acid This biosynthesis step in vitro has been studied by Hammerschmidt" who synthesized various chiral deuterium-labelled derivatives of both compounds using the isotopically labelled 2-benzyloxyethanal in Abramov reactions to obtain, initially, the dimethyl (2-benzyloxy-l-hydroxyethyl)phosphonate (362). This ester was resolved through the diastereoisomeric carbamates 363 the separated carbamates were sequentially de-l-O-protected, silylated at the a-HO group, debenzylat-ed and, by means of the Mitsunobu reaction, converted into dimethyl [2-eizido- -(tert-butyldimethylsilyloxy)ethyl]phosphonates. Subsequently, standard reactions were used to transform the latter into the diastereoisomeric, isotopically labelled (2-amino-1-hydroxy-ethyl)phosphonic acid. 

The Mitsunobu reaction can be used in the preparation of carbamate esters as well (e.g., 234). The reaction proceeds via an in-situ carboxylation of an alkylamine with CO2, followed by an 0-alkylation with an alcohol in the presence of TPP/DEAD. Yields are typically in the 80-90% range. A solid-supported version in which Fmoc-(I)-phenylalanine is tethered to Wang resin via an ester has also been reported. In situ deprotection with a tertiary amine to yield an 0-ammonium carbamate intermediate in the presence of primary aliphatic alcohols and PBuj/ADDP leads to the formation of the corresponding carbamates the carbamates are typically obtained in 40-80% yield with variable purity after TEA cleavage from the resin. 

The resulting carbamate salts 235 were then reacted with a freshly prepared solution of the activated betaine of TPP or TBP and DIAD to provide the isocyanates 236. After completion of the reaction, as monitored by the IR stretch of the isocyanate, the desired products were obtained by fractional distillation or flash chromatography. Aniline, benzylamine and 2,6-diisopropylaniline gave no or very poor yields of the desired isocyanates under these reaction conditions. The poor yields in these reactions are due to formation of nonreactive intermediate carbamoylhydrazines or competing triazolinone formation the latter arises from reaction of an activated arylisocyanate and the Mitsunobu betaine. 

Fot the use of SESCl in the synthesis of f-butyl [[2-(trimethylsilyl) ethyl]sulfonyl]carbamate, a useftil reagent in Mitsunobu reactions, see JV-(t-butoxycarbonyl)- >-toluenesulfonamide Campbell, J. A. Hart, D. J., J. Org. Chem. 1993,58, 2900. 

In the synthesis of (—)-lupinine (926) by Santos et al., (lR,2S,5R)-8-phenyhnenthol was used as the chiral auxiliary in controlling the stereochemical outcome of the reaction of the piperidine-containing carbamate 1042 with the 2-silyloxyfuran 1043 (Scheme 130). With trimethylsilyl triflate as Lewis acid catalyst and butyhnethylimidazolinium tetrafluorobo-rate as additive, an 80% yield was obtained as a 9.7 1 mixture in favor of threo-product (—)-1044. After hydrogenation of the double bond, treatment of the intermediate (—)-1045 with sodium methoxide effected rearrangement to the (R,R)-(- -)-l-hydroxyquinolizidin-4-one (- -)-1046 in 93% overall yield. Mitsunobu inversion of the alcohol to the (lS)-epimer (—)-1047 followed by alane reduction of the lactam afforded the quinolizi-din-l-ol (—)-1048. A second inversion at C-1 with cyanide produced the... 

C.J. Dinsmore, S.P. Mercer, Carboxylation and Mitsunobu reaction of amines to give carbamates retention vs inversion of configuration is substituent-dependent, Org. Lett. 6 (2004) 2885-2888. 

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