Mitsunobu carbamic acids

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). 

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. 

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.

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. 

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... 

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