Boc protected form

Imines are, preferably, used in the N-Boc-protected form less electrophilic N-allyl and N-benzyl imines gave unsuccessful results [36], The tert-butyldimethyl-silyl ketene acetals are the most suitable silyl ketene acetal substrates. It should be added that a low temperature is required to suppress an undesired uncatalyzed reaction that leads to racemates. 

Formation of a 3-amino azetidinone and its N-Boc protected form from oxazolidinone precursors shows that various reactions can be performed with good yields (67-95%) without affecting the 7V-[bis(trimethylsilyl)methyl] group... 

More versatile are the lithiations of carbamates (N-Boc amines) - as with lithiation a to oxygen, the lack of electrophilicity in a carbamate C=0 group and its particularly electron-rich oxygen lone pairs conspire to facilitate lithiation. In their Boc protected form, even simple amines such as 45 may be lithiated.37... 

Let s consider the synthesis of Gly-Ala. First, the amino group of glycine must be protected. (Today, amino acids can be purchased in BOC protected form.)... 

G.R. Pettit and co-workers used a novel fefraA/s(triphenylphosphine)cobalt(0)-promoted Reformatsky reaction for the synthesis of a dolastatin 10 unit, dolaproine in a Boc-protected form. ... 

Electrophilic Amination. r-Butyl )V-lithio-)V-(/)-toluenesulfonyloxy)carbamate (1) is prepared from Abutyl W(/)-toluenesulfonyloxy)carbamate, which is easily obtained on a large scale by tosylation of the commercially available f-butyl )V-hydroxycarbamate. (1) is an electrophilic aminating reagent and a synthetic equivalent of +NHBoc . It reacts with alkyllithium reagents (eq 1) or arylcopper reagents (eq 2) to provide primary amines in their (V-Boc protected form. 

Although these Boc derivatives underwent methylation with poor selectivity (compared to 3-amino-N-benzoyl butanoates [106] and Z-protected methyl 4-phen-yl-3-aminobutanoate [107]), epimers were succesfully separated by preparative HPLC or by flash chromatography. However, saponification of the methyl ester caused partial epimerization of the a-stereocenter and a two-step (epimerization free) procedure involving titanate-mediated transesterification to the corresponding benzyl esters and hydrogenation was used instead to recover the required Boc-y9 -amino acids in enantiomerically pure form [104, 105]. N-Boc-protected amino acids 19 and 20 for incorporation into water-soluble /9-peptides were pre-... 

A somewhat unusual sequence to generate azepanones 80 involved the intramolecular addition of hydroxylamines to alkynes 76 to form cyclic nitrones 77. A vinyl magnesium bromide addition at low temperatures and a reduction with TiCls followed by N-Boc protection led to the azepane 78. Double bond bromination and subsequent RUO4 oxidation gave the lactam 79. Several further steps allowed the generation of the lactam structure 80 proposed for d,/-aca-cialactam, but the spectral data of the synthetic material differed from that of the natural product (Scheme 16)] [23 a, b]. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

The combination of PhSiH3 with a catalytic amount of bis(tri-n-butyltin) oxide reduces azides to primary amines in excellent yields (Eq. 3 33).556 The reducing agent is (n-Bu)3SnH formed in situ by the silane. Azides are converted into Boc-protected primary amines with the PMHS/Pd/C reagent (Eq. 3 34).557,558... 

Researchers at Merck Co. [35] who, together with scientists from Solvias, had developed the enantioselective hydrogenation of unprotected enamine amides and esters [36], reported a more recent example of product inhibition. The product amine amide or ester was found to be an inhibitor of the catalyst, and indeed instances of catalyst poisoning by amines have been reported several times (see later). The authors also found an excellent solution to this problem the addition of BOC-anhydride to the hydrogenation reaction neatly reacts away all the amine to form the BOC-protected amine, whereas the enamine was left unreacted (Scheme 44.4). This addition resulted in a remarkable rate enhancement [35]. 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

Due to its labile and diprotic nature, the hydroxamate is typically installed in its protected form at the end of the synthetic sequence. In general, only the alcohol proton is derivatized, and examples include 0-Bn , 0-f-Bu, 0-Bz ", 0-TMS " , 0-TBS °, and 0-SEM (2-(trimethylsilyl)ethoxymethyl). On rare occasions, both differentially protecting groups can be cleaved in a single operation iV,0-bis-(Boc), A-Boc-O-THP, and A-Boc-O-TBS 52. 

Since the thioester linkage is susceptible to nucleophilic attack but stable to TEA treatment during solid-phase peptide synthesis (using standard Boc protection), Weigel and colleagues " have envisioned that hydroxylamine derivatives could directly cleave resin-bound peptide thioesters 201 or 202 to form the corresponding peptide hydroxamates 203 (Scheme 88). 

A very elegant synthetic approach was reported a year later by Davies et al., leveraging asymmetric C-H activation chemistry to accomplish a one-pot synthesis of d-threo methyiphenidate (Scheme 17.10) (Davies et al., 1999). A-Boc piperidine (33) was selectively alkylated by the carbene formed by decomposition of diazoester 34 in a reaction mediated by 25 mol% of chiral Rh (II) catalyst 35, giving the A-Boc protected (2R,2 R) isomer in a single step. TFA was added to accomplish removal of the Boc group after the C-H insertion reaction was complete, affording (R,R)-methylphenidate (2) with an ee of 86% in 52% overall yield. 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

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