Mitsunobu reaction total synthesis reactions

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

Jin and Weinreb reported the enantioselective total synthesis of 5,11-methano-morphanthridine Amaryllidaceae alkaloids via ethynylation of a chiral aldehyde followed by allenylsilane cyclization (Scheme 4.6) [10]. Addition of ethynylmagnesium bromide to 27 produced a 2 1 mixture of (S)- and (R)-propargyl alcohols 28. Both of these isomers were separately converted into the desired same acetate 28 by acetylation or Mitsunobu inversion reaction. After the reaction of 28 with a silyl cuprate, the resulting allene 29 was then converted into (-)-coccinine 31 via an allenylsilane cyclization. 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

Schkeryantz and Pearson (59) reported a total synthesis of ( )-crinane (298) using an intramolecular azide-alkene cycloaddition (Scheme 9.59). The allylic acetate 294 was first subjected to an Ireland-Claisen rearrangement followed by reduction to give alcohol 295, which was then converted into the azide 296 using Mitsunobu conditions. Intramolecular cycloaddition of the azide 296 in refluxing toluene followed by extrusion of nitrogen gave the imine 297 in quantitative yield. On reduction with sodium cyanoborohydride and subsequent reaction with... 

Smidt and Langner111"1 in their synthesis of the natural calcium blocker leualacin utilized the Mitsunobu reaction for the construction of the linear depsipeptide N-(tert-but oxycarbony I) -(3-alanyl-O-D-leucic acid benzyl ester in 69% yield. Higher yields (94-96%) were reported for two didepsipeptide units N-(/er/-butoxycarbonyl)-./V-methylleucyl-D-lactic acid diphen-ylmethyl ester and iV-(/er/-butoxycarbonyl)-yV-methylleucyl-D-phenyllactic acid diphe-nylmethyl ester in the course of the total synthesis of the anthelmintic cyclooctadepsipeptide PF1022A based on the Mitsunobu reaction.1102 ... 

For example, the fermentation of (2-bromoethyl)-benzene with recombinant E. coli furnished excellent yields of the corresponding c/.v-diol. enantiopure 3-(2-bromoethyl)-benzene-l,2-diol. The latter was used as a building block in the total synthesis of (+)-codeine (Fig. 29). Besides a Mitsunobu inversion of one of the stereogenic centers, two successive Heck cyclizations led to the enantiomer of the natural product [173]. Slight modifications of the reaction sequence, generating an epoxide intermediate, also furnished access to the naturally occurring enantiomer (—)-codeine [28]. 

In total syntheses of 3-lactam antibiotics, the formation of 2-azetidinones is crucial. In a biomimetic synthesis, the N—C4 bond is best closed by the open chain hydroxamate (equation 48), because, depending on the different pATa values of the three potentially ionizable positions, only the ring-forming amide is ionized. 3-halohydroxamates are cyclized by base treatment, whereas 3-hydroxyhydroxamates cyclize via the Mitsunobu reaction (diethyl azodicarboxylate, PhsP). More highly substituted precursors yield isomeric 3-lactams after rearrangement. ... 

The total synthesis of several amaryllidaceae alkaloids including that of narciclasine was accomplished in the laboratory of T. Hudlicky. The C2 stereochemistry was established by a two-step sequence Luche reduction of the a,(3-unsaturated cyclic ketone followed by a Mitsunobu reaction. The ketone was first mixed with over one equivalent of CeCIs in methanol and then the resulting solution was cooled to 0 °C, and the sodium borohydride was added. In 30 minutes the reaction was done, and the excess NaBH4 was quenched with AcOH. The delivery of the hydride occurred from the less hindered face of the ketone and the allylic alcohol was obtained as a single diastereomer. 

In the stereoselective total synthesis of ( )-14-deoxyisoamijiol by G. Majetich et al., the last step was the epimerization of the C2 secondary allylic alcohol functionality. The Mitsunobu reaction resulted only in a poor yield (30%) of the inverted product, so the well-established sulfoxide-sulfenate rearrangement was utilized. The allyic alcohol was first treated with benzenesulfenyl chloride, which afforded the thermodynamically more stable epimeric sulfenate ester via an allylic sulfoxide intermediate. The addition of trimethyl phosphite shifted the equilibrium to the right by consuming the desired epimeric sulfenate ester and produced the natural product. 

The enantioselective total synthesis of the complex bioactive indole alkaloid enf-WIN 64821 was accomplished by L.E. Overman and co-workers." This natural product is a representative member of the family of the C2-symmetric bispyrrolidinoindoline diketopiperazine alkaloids. The stereospecific incorporation of two C-N bonds was achieved using the Mitsunobu reaction to convert two secondary alcohol functionalities to the corresponding alkyl azides with inversion of configuration. The azides subsequently were reduced to the primary amines and cyclized to the desired ib/s-amidine functionality. 

In the laboratory of G.A. Molander, a general route for the synthesis of eunicellin diterpenes was developed and was applied for the asymmetric total synthesis of deacetoxyalcyonin acetate. One of the key steps was an inramolecular NHK coupling reaction between an enol triflate and an aldehyde. The cyclopentenol product was formed in high yield as a 2 1 mixture of diastereomers. The undesired diastereomer could be transformed to the desired one using a Mitsunobu reaction. 

A convergent total synthesis of 15-membered macrolactone, (-)-amphidinolide P was reported by D.R. Williams and coworkers.In their approach, they utilized the Sakurai aiiyiation to introduce the C7 hydroxyl group and the homoallylic side chain. The transformation was effected by BF3-OEt2 at -78 °C to provide the homoallylic alcohol as a 2 1 mixture of diastereomers. The desired alcohol proved to be the major diastereomer, as it resulted from the Felkin-Ahn controlled addition of the allylsilane to the aldehyde. The minor diastereomer was converted into the desired stereoisomer via a Mitsunobu reaction. 

A stepwise formal [3+3] cycloaddition reaction entailed the generation of the dianion of 168, transmetalation with MgBr2, and addition of aziridine 169 to give intermediate 170. A Mitsunobu reaction to give 171 completed the sequence with an overall yield of >90% <05OL2993> (Scheme 48). This strategy was applied to other aziridines in the preparation of 3-methylenepiperidine intermediates for the total synthesis of several Nuphar alkaloids <05JOC207>. 

The elegant formal total synthesis of morphine, accomplished by Parker, shows some similarities to that of Fuchs through analogous disconnections. In both syntheses, the core of the molecule was formed as a result of a tandem process in this case as a result of a radical cascade.79 80 The immediate cyclization precursor 191 was prepared via a Mitsunobu reaction between monoprotected cw-diol 189 (prepared in 8 steps from 2-((3-methoxyphenyl)ethylamine) in 47% overall yield) and phenol 188, followed by cleavage of the silyl ether, Scheme 21. The key step, homolytic cleavage of the Ci2-Br... 

Mitsunobu et al. [46] reported an efficient macrolactonization using diethyl azodicarboxylate (DEAD) and Ph3P. In the case of (o-hydroxy acids having a secondary alcohol, this cyclization takes place with inversion of the configuration of the alcohol. In the total synthesis of latrunculin A (82) and B, the Mitsunobu reaction was used for the macrolactonization of the seco-acid 81 with inversion of the secondary alcohol [47]. 

Intramolecular coupling of 120 having an aryl iodide group and a vinylstannane group accomplished the total synthesis of (-)-zealarenone (99) (Scheme 19) [77]. The first total synthesis of macrolactin A (124) was efficiently accomplished based on the Stille reaction of 122 for both stereospecific construction of the diene moieties and closure of the 24-membered macrocyclic ring [78]. The key precursor 122 was synthesized via two Stille couplings and Mitsunobu esterification. An alternative route to the dimethyl ether 125 was reported by cyclization of 123, which was prepared by the Stille and Suzuki couplings followed by DCC-DMAP esterification... 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

In the initial stage of the total synthesis of (-)-verrucarol (9) from 2, we utilized the above Knoevenagel-type intramolecular cyclization strategy for the construction of the A-ring as illustrated in Scheme 18. Hydride reduction of 2 followed by a modified Mitsunobu reaction [86] of the... 

For the total synthesis of baccharin B5 (379) six more steps were necessary. First, the alcohol group was protected and then the unconjugated double bonds could be epoxidized selectively to provide 477 as a single product. Subsequently, the epoxide of the macrocycle 477 was eliminated to an allylic double bond, which could be epoxidized again and gave the epimer of baccharin B5. Last, the epimer was converted into baccharin B5 (379) via a Mitsunobu reaction (Scheme 8.21). 

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