Deprotection acetals

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

Copper-based Lewis acids have some advantages for hydrolysis reactions they are mild, nonacidic, and can control reactions due to chelation by the substrate to achieve high selectivity. CuS04 is effective for acetal deprotection (Scheme 47).197 Thioacetals198,199 and selenoacetals200-202 are also hydrolyzed by copper Lewis acids, and dehydration is accelerated by Cu11 Lewis acids under mild conditions.203... 

Marchand and co-workers ° synthesis of 5,5,9,9-tetranitropentacyclo[5.3.0.0 .0 °.0 ] decane (52) reqnired the dioxime of pentacyclo[5.3.0.0 .0 °.0 ]decane-5,9-dione (49) for the incorporation of the four nitro groups. Synthesis of the diketone precursor (48) was achieved in only five steps from cyclopentanone. Thus, acetal protection of cyclopentanone with ethylene glycol, followed by a-bromination, and dehydrobromination with sodium in methanol, yielded the reactive intermediate (45), which underwent a spontaneous Diels-Alder cycloaddition to give (46). Selective acetal deprotection of (46) was followed by a photo-initiated intramolecular cyclization and final acetal deprotection with aqueous mineral acid to give the diketone (48). Derivatization of the diketone (48) to the corresponding dioxime (49) was followed by conversion of the oxime groups to gem-dinitro functionality using standard literature procedures. 

Application of the AA [103] resulted in an even shorter synthesis of 88. The aminohydroxy-lation was carried out with a slightly higher catalyst loading [1 mol % of Os, 2.5 mol % of (DHQ)2PHAL] compared with the dihydroxylation sequence and furnished tosyl protected phenylisoserine ester 87 with 82% ee in 69% yield. The enantiomeric excess of 87 was further raised to 92% ee by trituration with ethyl acetate. Deprotection and conversion into benzamide 88 afforded the C-13 side chain in a total of three steps. 

Cycle Used with Glycosyl Trichloroacetimidate Activation and Acetate Deprotection... 

Deprotonation of chromone 369 with lithium 2,2,6,6-tetramethylpiperidide followed by addition to aldehydes provided substrates which were converted directly to furo[3,4- ][l]benzopyran-9-ones (e.g., 371) upon acetal deprotection (Scheme 57) <2002S2341>. 

RCH2NH2 —> RCONH2The transformation of primary amines to amides can be effected by oxidation of N-Boc alkylamines with ruthenium tetroxide, generated in situ from Ru02 (catalytic) and NaI04 (excess) in aqueous ethyl acetate. Deprotection is effected with TFA in CH2C12. 

The synthesis of the derivatives (339)-(346) was carried out as shown in Scheme 28. Metalation of the acetal (336), followed by thiolation and alkylation, gave the ester derivative (337). Acetal deprotection to form (338) and subsequent treatment under Knoevenagel conditions with piper-idinium acetate in benzene afforded the desired ester (339). Reduction of compound (339) gave alcohol (340), which was converted to aldehyde (341) and protected as its acetal (342) under standard conditions. Deprotonation was effected by Bu"Li in THF at — 78 °C and subsequent conversion to the sulfonyl chloride was carried out by sequential treatment with sulfur dioxide and A-chloro-succinimide. Treatment of the sulfonyl chloride (343) with concentrated NH4OH in acetone provided the sulfonamide (344), which was deprotected (345) and subjected to reductive amination to provide compounds in the aminomethyl sulfonamide series (346). 

The mixture of anomers of 3, 5 -dibenzyl-2 -deoxy-2, 2 -difluorocytidine 76 obtained has been separated by crystallization from ethyl acetate. Deprotection with methanolic ammonia yielded 71b containing, after radio-HPLC, 99.8% of the desired / -isomer of >99.4% radiochemical purity. The overall radiochemical yield was 10.2%. 

The alkylation of sulfur with reactive alkylating agents, such as Mel, Me30Bp4 Et30Bp4, or MeOSOjCHj, results in 5,5-acetal deprotection without using Reductive removal of the sulfur of thioacetals with Raney-nickel (Ra-Ni) provides a frequently used procedure for deoxygenation of aldehydes or ketones. 

Having demonstrated the preparation of an array of small organic compounds in high purity and yield, multistep reactions were then conducted by spatially incorporating two supported reagents into a continuous flow reactor. As Fig. 14.11 illustrates, the first step of the reaction consists of an acid-catalyzed acetal deprotection to afford the respective aldehyde and the second step involves the base-catalyzed condensation of the aldehyde with an activated methylene. Using this approach, 100% deprotection of the acetal to aldehyde was observed and 99% conversion of the aldehyde to the desired unsaturated product was observed to an give analytically pure product in 99.6% yield. 

A new synthesis of three sex pheromones, (171), (172) and (173), of the Winter moth Operophtera brumata involves the use of the ylide (174) which acts as a homologating agent and allows further Wittig reactions of the products after acetal deprotection.Standard methods of phosphonate-based olefination have been applied to the synthesis of new retinals, e.g. (175) and (176), with modified methyl substitution patterns. ... 

A variety of other acid-catalysed transformations have also been performed in ILs such as polyesterifications, Boc amine protection, aiyl alleviation,pinacol rearrangements, acetal deprotection, the Hantzsch reaction and Beckmann rearrangements. ... 

Once in place, both isopropylidene and benzylidene functionality survive many routine synthetic operations and, when no longer required, may be readily removed by hydrolysis. Two aspects of acetal deprotection are of interest here (1) partial hydrolysis of bis-acetals, particularly bis(isopropylidenes) and (2) protecting group interchange, particularly of benzylidenes. 

Classical Zemplen acetate deprotection under these conditions all acetate groups and most other esters are cleaved. 

Figure 9 Proposed catalytic cycle for acid-catalyzed acetal deprotection inside a self-assembled tetrahedral host in basic media. For structural details of the tetrahedral host, see Figure 6(a) and (b). (Reproduced with permission from Ref. 41. American Chemical Society, 2009.)...

A vast number of aldehydes have so far been used as substrates of this set of aldolases in preparative experiments [20, 24, 25, 190). With the exception of generic aldehydes, acceptor components must be prepared by chemical synthesis. In general, ozonolysis of suitable olefins (with appropriate removal of the second fragment if this also is a substrate) or acidotalyzed acetal deprotection are convenient routes for generation of aldehyde substrates under mild conditions. Chiral aldehydes require either asymmetric synthesis of the respective enantiomer or separation of diastereomeric products produced from racemic material. In specific cases racemate resolution can be effected by the enantiomer selectivity of an aldolase (kinetic resolution Figure 5.27) or when isomeric products have significantly different stability (thermodynamic resolution vide infra). 

The general concept of the t-BOC and acetal deprotection schemes may be implemented in a large variety of ways using quite different monomeric or po eric components. A collection of such approaches is given in Scheme I for t-BOC deprotecdon, and in Scheme II for acetal cleavage systems. While some of the above tystems have been developed for DUV applications, it is evident from their chemistiy that they will be just as well suited for, e.g.. X-ray applications. 

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