Chiral protected amines

The [2,3]- or [3,3]-sigmatropic rearrangements (Scheme 24) provide a means to introduce either the protected amine or the carbon atom which will become the carboxylic acid, while also positioning the double bond in the correct position for the alkene isosteres. Moreover, when starting from homochiral allyl alcohols, a very effective chirality transfer assures the stereospecific construction of the R1 and R2 side-chain stereochemistries. 

Extensive optimization studies identified highly electron-deficient 2,4-dinitrobenzyl-substituted aziridines as the most reactive substrates, chromium as the metal of choice, and indanol-derived Schiff bases as the most effective ligands. In this ring-opening process, catalyst 61 provided the highest selectivities. Using these optimized conditions, a variety of aziridines were selectively opened in a very efficient manner (Scheme 17.21).51 This reaction can provide an easy access to C2-symmetric 1,2-diamines, a valuable class of chiral auxiliaries, and even to less accessible non-C2-symmetric 1,2-diamines because of the differentially protected amines of the ring-opened products. 

Amino Alcohols and Mono-Protected 1,2-Diols 302 a-Chiral Primary Amines 306 Type I Acylative ASD of Achiral/meso-Diols 307 Type I Asymmetric Acyl Addition to 7r-Nucleophiles ... 

An enantioselective aryloxylation of aldehydes is based on their prior conversion to an enamine through reaction with a chiral secondary amine catalyst. A subsequent inverse HDA reaction with o-quinones leads to 3-alkyl-2-hydroxy-l,4-benzodioxins with ee ca. 80% (Scheme 47). Manipulation allows the synthesis of (S)-2-alkyl-2,3-dihydro-l,4-benzodioxins <07TL1605>. In like manner, racemic nitidanin, which possesses antimalarial properties, has been synthesised through a regioselective cycloaddition of an o-quinone with a protected 3-arylpropen-l-ol <07TL771>. 

For the preparation of aspartic proteinase inhibitors, Jones et al. [7] needed epimeric A -protected alcohols (see Table 1, entry 2). In this stereocontrolled synthesis of hydroxyethylene dipeptide isoteres, a chiral Grignard reagent was used in a reaction with a protected aminoaldehyde [7]. In this reaction, a 6 1 ratio of diastomers 4SAR) was obtained. The stereochemistry of the products was controlled by the complexation of the reagent with the protected amine the S-epimer predominates because of a chelation-controlled addition of the Grignard. 

Aminals, compounds having two amino groups bound to the same carbon atom, are represented in many medicinal agents having versatile therapeutic action, such as proteinase inhibitors and neurotensins. Antilla and coworkers developed an en antioselective synthesis of protected aminals from the amidation reaction of N Boc imines with a series of sulfonamides catalyzed by chiral phosphoric acids (Scheme 3.54a) [111]. In this novel enantioselective transformation, phosphoric acid 9 exhibited excellent catalytic activity and enantioselectivity in addition to N Boc aromatic imines. The enantioenriched aminal products were stable upon storage neither decomposition nor racemization was observed in solution over several days. The same research group reported the enantioselective amidation reaction of N Boc aromatic imines with phthalimide or its derivatives (Scheme 3.54b) [112]. 

The synthetic utility of this enantioselective alkylation of an arylimine rehes on a practical method for the dearylation of the resulting chiral amine. A two-step procedure was illustrated for amine 3a (R =Me), which begins with a protection step (n-BuLi/ClC02CH2Ph) followed by oxidative cleavage of the aryl moiety (ceric ammonium nitrate CAN). The N-protected amine 4a was isolated in only 58% overall yield without significant loss of enantiomeric purity (Scheme 3). 

Asymmetric oxidative alkylation of free tetrahydroisoquinolines 9 was recently described by Sodeoka and co-workers (Scheme 6) [22, 23]. Through the use of a chiral cationic palladium(II) species 10, The enantiopure alkylated BOC protected amines 11 were obtained with good yields and enantioselectivity. The alkylation is believed to occur through the initial protection of the amine with (Boc O, followed... 

Coupling of TV-protected amine 124 and thiazole carboxylic acid (125) is accomplished using the coupling agent DEPC to provide intermediate 126, which is further cyclized to give dolastatin 3 (127), a unique cyclic pentapeptide containing three common amino acids, Pro, Leu, and Val, and two unusual heterocyclic amino acids, the achiral (Gly)Thz and the chiral (GIn)Thz53... 

For synthesis of the trans N-Boc enantiomer 70, use was made of the chiral ketone 66, which is readily available by enzymatic resolution [91]. The ketone moiety was protected as the thioketal, and selective monohydrolysis then gave the monoacid 68. Curtius rearrangement of 68 with diphenylphosphorylazide (DPPA) and triethylamine (TEA) in tert-butanol gave the Boc-protected amine. Desulfurization with Raney nickel furnished the methyl ester 70 (Scheme 10). The (15,25) trans enantiomer was prepared analogously, starting from the enantiomer of ketone 66 [91]. 

Protection and activation of amines. Chiral borane-amine complexes, such as... 

A similar approach was reported by Wang et al. [60] a year later, consisting of a double Michael reaction of simple oxindoles with dienones. The reaction was simply catalyzed by a cinchona-based primary amine catalyst (XIII). The reaction afforded the final spirocyclic oxindoles in good yields and excellent enantioselectivities when diaryldienones were used. The only limitation of the reaction was the need to use carbamate-protected oxindoles thus, the use of unprotected or benzylated oxindoles is ineffective for this transformation. In 2010, the same research group proposed a similar approach [61]. They performed a reaction with an oxindole derivative decorated with a ketone in position 3 of the oxindole and acyclic enones. This reaction was catalyzed by chiral primary amines, affording the final spirooxindoles in good yields and enantioselectivities. 

The iminium activation strategy with the trifunctional chiral primary amine 28, which was used in the y-selective conjugate addition of y-butenolides (Scheme 28), also proved highly effective for promoting reaction with the y-butyrolactam (Scheme 32, first line) [52]. Although various chiral diamines, amino thioureas, and amino sulfonamides were evaluated during the optimization study, none of these catalysts gave rise to impressive levels of diastereoselectivity. Eventually, a bulky acid additive, such as the protected tryptophan derivative (V-Boc-L-Trp-OH),... 

Aryl Grignards add to chiral A-alkyl (or A-aryl) benzenesulflnylimines, PhCH=NSOR/PhCH=NSOAr, in high yield and de, to give chiral diaryl amines (in protected sulfinyl form). A comparative smdy of the use of the familiar f-butane or p-toluene groups at sulfur with 2,4,6-triisopropylbenzene finds that the latter is significantly superior in yield and de and that results are somewhat better at room temperature versus -40 °C (g)... 

Figure 3.7 General structures of anticancer chiral ferrocenes functionalized in the cyclopenta-dienyl-derived ligand with (a) a nucleobase (R, =side chain Nb = nucleobase) and (b) an amino acid (R2 = Fmoc-protected amine group) [52,54].

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