Cyclization Mitsunobu

Unfortunately, only two attempts were made to use this approach in the synthesis of five-membered cyclic nitronates (5), and only one of them could be considered as successful. In the latter case, isomeric nitrocyclopropane was obtained as the major product. Only a-functionalized nitro alcohols are readily involved in the Mitsunobu cyclization. However, the possibility of isomerization of by-products, nitrocyclopropanes, which was mentioned in the discussion of Scheme 3.16, caused the revision of this process as a procedure for the synthesis of five-membered cyclic nitronates. (A new approach to the synthesis of initial y-nitro alcohols from readily available AN was documented in Reference 64)... 

A similar scaffold for the preparation of peptidomimetics was prepared by Mitsunobu cyclization of the molecule coming from the coupling of 4-benzylprolinol and iV-nosyl(o-nitrobenzensulfonyl) tryptophan 316 (Scheme 41). A Mitsunobu cyclization occurred easily due to the acidity of the NH of the nosyl group that could be further selectively deprotected under very mild conditions. The so-formed bicyclic amine 317 can be further coupled with different amino acids to give compounds 318, employed in the search of a new somatostatin pharmacophore <2005BML4033>. 

A new method for the preparation of pyrrolo[2,l-c][l,4]benzothiazepine 292 starting from aldehyde 291 with an intramolecular Mitsunobu cyclization in the last step has been reported (Scheme 63 (1999T1479)). A disadvantage of this procedure is the redox nature of the Mitsunobu reaction, which is responsible for a side oxidation of the thiol group and poor isolated yields of the product. 

Several stereoselective syntheses of 4-(ribofuranosyl)imidazole nucleosides were reported. Imidazole 53 was obtained from 50 by a Mitsunobu cyclization [95TL3165]. Treatment of a suitably protected ribofuranosyl chloride with two equivalents of a lithioimidazole afforded the 1-(5-imidazolyl)ribofuranoid glycal (54) directly which undergoes elimination to the furylimidazole (55) [95CPB152]. 

Mitsunobu cyclization of sulfonamides 215 produced substituted heteronines 216 in moderate yield (Equation 20) <1999JME4547>. 

Synthesis of (-I-) calanolide A (Scheme 8-11) was achieved by enzyme catalyzed resolution of the aldol products ( )-53. Compound 7 with acetaldehyde by aldol reaction in the presence of LDA/TiCU stereoselectively produced a mixmre of ( )-53 and ( )-54 (94% yield), the ratio of which was 96 4. ( )-53 was then resolved by lipase AK-catalyzed acylation reaction in the presence of tert-butyl methyl ether and vinyl acetate at 40 °C to obtain 41% yield of (+)-55 and 54% yield of the acetate (—)-56. Mitsunobu cyclization of (+)-55 in the presence of tri-phenylphosphine and dielthyl azodicarboxylate afforded 63% yield of (-l-)-43 with 94% ee as determined by chiral HPLC. Luche reaction on (+)-43 with CeCla 7H2O and triphenyl phosphine oxide and NaBH4 in the presence of ethanol at 30 °C gave the crude product. It was purified by column chromatography on silica gel to give 78% yield of a mixture containing 90% of (+)-calanolide A and 10% (+)-calanohde B, which were further separated by HPLC. 

A short, asymmetric total synthesis of an important 3-(hydroxymethyl)carbacephalosporin antibiotic was achieved by M.J. Miller and co-workers. ° The p-lactam ring was formed via a Mitsunobu cyclization, while the six-membered unsaturated ring was constructed by a HWE cyclization. This intramolecular olefination afforded a single diastereomer in 85% yield. 

The Mitsunobu cyclizations of 3-(co-hydroxyalkyl)-l,2,4-thiadiazine 1,1-dioxides to the angular, rather than to the linear fused thiadiazine systems (see Section 6.14.7.5), are cited as chemical evidence in support of the earlier theoretical and spectroscopic data for the AH- rather than the 2H-tautomeric form of these heterocycles <91PS(59)529,91S159>. 

Alternatively, 848 can be prepared sequentially by first treating 822 with triphenylphosphine in benzene at room temperature to provide the aminoalcohol 846. This is then tosylated to 847 followed by an intramolecular Mitsunobu cyclization to provide 848 in an overall yield of 61% (Scheme 185). 

A different approach for the synthesis of racemic /rans-pterocarpans was also developed. A frans-fused 2-3-disubstituted dihydrobenzofuran was produced by AgBF,-promoted intramolecular cyclization, and after reduction of an ester function the six-membered oxygen ring was formed by Mitsunobu cyclization <01T7113>. 

In yet another useful modification of this chemistry, Squibb chemists [34] devised a method for cyclization of 3-hydroxyvaline as required for the synthesis of the orally active monosulfactam tigemonam. Cyclization of the tertiary alcohol under typically employed conditions was problematic. Mitsunobu cyclization of 44 gave lactam 45 in poor yield along with an unprecedented rearrangement product 46 [35]. Mesylation was nonselective, but 0-sulfonation with picoline S03 complex followed by base treatment afforded 45 in 58% yield after recrystallization via the intermediacy of the derived sulfate. 

Taddei and coworkers [49] also reported an MW-promoted solid-phase synthesis of 3,6-disubstituted perhydro-diazepin-2,5-dione 70 (Scheme 10) involving a Mitsunobu cyclization of a hydroxamic acid derivative anchored to PS-DVB 2-chlorotrityl resin (69). The prepared compound was proved to be useful as constrained peptidomimetics. 

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