Academic literature on the topic 'Acetonides - Deprotection'

Investigations of the metabolic conversion of the phytohormone 24-epicastasterone (1) in the cockroach Periplaneta americana (L.) required the synthesis of 2,24-diepicastasterone (4), 3,24-diepicastasterone (7b) and 2-dehydro-3,24-diepicastasterone (9) as reference standards. 2,24-Diepicastasterone (4) was synthesized from 2α,3α-epoxy derivative 2 as well as from the 2β,3β-epoxy-22,23-diol 3 by acid-catalyzed water addition to the epoxy function leading to the desired 2β,3α-trans functionality. 3,24-Diepicastasterone (7b) was prepared by NaBH4-reduction of the 3-oxo derivative 6. Upon deprotection conditions from the ketol acetonides 6 and 8 in both cases 2-dehydro-3,24-diepicastasterone (9) was obtained. The structure of 2,24-diepicastasterone (4) was confirmed by X-ray analysis.

The thesis entitled ‘Chemistry of molybdenum xanthate (MoO2[Et2NCS2]2): Applications in organic synthesis’ is presented in 4 chapters. Molybdenum (IV and VI) oxo-complexes are the subject of significant interest due to their functional and structural similarities with several molybdo-enzymes.1 Literature survey suggests that, molybdenum (VI as well as IV) xanthate2 1 resembles the active sites of various molybdo-enzymes. Therefore, in the present thesis, we are presenting our attempts directed towards exploiting molybdenum xanthate 1 in developing various useful methodologies. Figure 1: Molybdenum xanthate Chapter 1 discloses the utility of molybdenum xanthate (1) in catalytic, aerobic oxidation of organic azides and alcohols as presented in part A and B. Part A: A mild molybdenum xanthate catalyzed, chemoselective oxidation of benzylic azides to the corresponding aldehydes3 under aerobic condition is described. This oxidation turned out to be a general method and a variety of benzylic azides were oxidized to the corresponding aldehydes. This oxidation protocol tolerates a variety of functional groups including alcohols, esters, ketones, halides and olefins. More importantly, the oxidation of azides stops at corresponding aldehyde stage without further oxidation to the corresponding carboxylic acids. A few examples are presented in scheme 1. Part B: As our attempts to oxidize alcohols with molybdenum xanthate 1 were unsuccessful (Chapter 1, Part A), we have attempted supporting the reagent 1 and investigated its utility in the oxidation of alcohols. As a consequence, polyaniline supported molybdenum xanthate (MoO2[Et2NCS2]2) is designed and used in an aerobic and mild chemoselective oxidation of alcohols4 to the corresponding aldehydes and ketones. The scheme to use polyaniline as the support for molybdenum xanthate was derived from the fact that polyaniline is known to increase the redox activity of various metal complexes by coordinating to the metal centre.5 The present oxidation strategy tolerates a variety of functional groups such as olefin, ketones, sulfides, tertiary amines, propargyl group etc. This oxidation strategy also works very well for the oxidation of secondary benzylic alcohols. Interestingly, the supported catalyst can be filtered after the reaction and reused for further oxidation without loss of its activity. Some representative examples are presented in Scheme 2. Chapter 2 describes the chemoselective and efficient reduction of azides to the corresponding amines. In this chapter, we have shown that a catalytic amount of molybdenum xanthate (1, MoO2[S2CNEt2]2) with PhSiH3 is an effective catalyst for the reduction of azides to the corresponding amines.6 This reduction of azides by 1, was inspired by the reductive silylation of aldehydes through the activation of silanes.7 This reduction tolerates a variety of reducible functional groups such as olefin, aldehydes, ketones, esters, amides and ethers, acetals etc. This strategy was also extended to various aliphatic azides to synthesize amine and their N-Boc derivatives in good yields. Scheme 3 illustrates few examples. Chapter 3 discloses convenient methods for the synthesis of substituted thiourea derivatives as presented in part A and B. Part A: A convenient method for the synthesis of tri-substituted thiourea derivatives by the reaction of primary amines with molybdenum dialkyl dithiocarbamates is presented in Part A.8 Primary amines on reaction with molybdenum xanthate produce corresponding thioureas in moderate to good yields. Similar reactions with propargylamine and 2-aminoethanol produce cyclic thiaoxazolidine and oxazolidine derivatives respectively. This methodology has been successfully adopted for the synthesis of amino acids derived chiral thioureas. Some examples are presented in Scheme 4. Scheme 4: Molybdenum xanthate mediated synthesis of thioureas Part B: An efficient method for the synthesis of symmetrical and unsymmetrical substituted thiourea9 derivatives by simple condensation of amine and carbon disulfide in aqueous medium is extensively studied. Present method describes the involvement of amino dithiol moiety as an intermediate. Though this method is not successful with secondary amines and aryl amines, it works smoothly with aliphatic primary amines to afford various di- and tri-substituted thiourea derivatives. The present method is also useful in synthesizing various substituted 2-mercapto imidazole heterocycles in moderate yields. A few examples are seen in Scheme 5. Scheme 5: Synthesis of thiourea derivatives in aqueous medium Chapter 4 describes a chemoselective deprotection10 of terminal acetonides (isopropylidines) by using aqueous TBHP (70%). A variety of acetonide derivatives on reaction with aq. TBHP in water:t-BuOH (1:1) as solvent mixtures furnish the corresponding acetonide deprotected diol products in good yields. This unprecedented deprotection strategy, tolerates a variety of acid sensitive functional groups such as silyl ether, trityl, olefin, propargyl, methoxymethyl ether, N-Boc, lactones, esters etc. A few examples are documented in Scheme 6. Scheme 6: Chemoselective deprotection of acetonides (For structural formula pl see the pdf file)

The thesis entitled ‘Chemistry of molybdenum xanthate (MoO2[Et2NCS2]2): Applications in organic synthesis’ is presented in 4 chapters. Molybdenum (IV and VI) oxo-complexes are the subject of significant interest due to their functional and structural similarities with several molybdo-enzymes.1 Literature survey suggests that, molybdenum (VI as well as IV) xanthate2 1 resembles the active sites of various molybdo-enzymes. Therefore, in the present thesis, we are presenting our attempts directed towards exploiting molybdenum xanthate 1 in developing various useful methodologies. Figure 1: Molybdenum xanthate Chapter 1 discloses the utility of molybdenum xanthate (1) in catalytic, aerobic oxidation of organic azides and alcohols as presented in part A and B. Part A: A mild molybdenum xanthate catalyzed, chemoselective oxidation of benzylic azides to the corresponding aldehydes3 under aerobic condition is described. This oxidation turned out to be a general method and a variety of benzylic azides were oxidized to the corresponding aldehydes. This oxidation protocol tolerates a variety of functional groups including alcohols, esters, ketones, halides and olefins. More importantly, the oxidation of azides stops at corresponding aldehyde stage without further oxidation to the corresponding carboxylic acids. A few examples are presented in scheme 1. Part B: As our attempts to oxidize alcohols with molybdenum xanthate 1 were unsuccessful (Chapter 1, Part A), we have attempted supporting the reagent 1 and investigated its utility in the oxidation of alcohols. As a consequence, polyaniline supported molybdenum xanthate (MoO2[Et2NCS2]2) is designed and used in an aerobic and mild chemoselective oxidation of alcohols4 to the corresponding aldehydes and ketones. The scheme to use polyaniline as the support for molybdenum xanthate was derived from the fact that polyaniline is known to increase the redox activity of various metal complexes by coordinating to the metal centre.5 The present oxidation strategy tolerates a variety of functional groups such as olefin, ketones, sulfides, tertiary amines, propargyl group etc. This oxidation strategy also works very well for the oxidation of secondary benzylic alcohols. Interestingly, the supported catalyst can be filtered after the reaction and reused for further oxidation without loss of its activity. Some representative examples are presented in Scheme 2. Chapter 2 describes the chemoselective and efficient reduction of azides to the corresponding amines. In this chapter, we have shown that a catalytic amount of molybdenum xanthate (1, MoO2[S2CNEt2]2) with PhSiH3 is an effective catalyst for the reduction of azides to the corresponding amines.6 This reduction of azides by 1, was inspired by the reductive silylation of aldehydes through the activation of silanes.7 This reduction tolerates a variety of reducible functional groups such as olefin, aldehydes, ketones, esters, amides and ethers, acetals etc. This strategy was also extended to various aliphatic azides to synthesize amine and their N-Boc derivatives in good yields. Scheme 3 illustrates few examples. Chapter 3 discloses convenient methods for the synthesis of substituted thiourea derivatives as presented in part A and B. Part A: A convenient method for the synthesis of tri-substituted thiourea derivatives by the reaction of primary amines with molybdenum dialkyl dithiocarbamates is presented in Part A.8 Primary amines on reaction with molybdenum xanthate produce corresponding thioureas in moderate to good yields. Similar reactions with propargylamine and 2-aminoethanol produce cyclic thiaoxazolidine and oxazolidine derivatives respectively. This methodology has been successfully adopted for the synthesis of amino acids derived chiral thioureas. Some examples are presented in Scheme 4. Scheme 4: Molybdenum xanthate mediated synthesis of thioureas Part B: An efficient method for the synthesis of symmetrical and unsymmetrical substituted thiourea9 derivatives by simple condensation of amine and carbon disulfide in aqueous medium is extensively studied. Present method describes the involvement of amino dithiol moiety as an intermediate. Though this method is not successful with secondary amines and aryl amines, it works smoothly with aliphatic primary amines to afford various di- and tri-substituted thiourea derivatives. The present method is also useful in synthesizing various substituted 2-mercapto imidazole heterocycles in moderate yields. A few examples are seen in Scheme 5. Scheme 5: Synthesis of thiourea derivatives in aqueous medium Chapter 4 describes a chemoselective deprotection10 of terminal acetonides (isopropylidines) by using aqueous TBHP (70%). A variety of acetonide derivatives on reaction with aq. TBHP in water:t-BuOH (1:1) as solvent mixtures furnish the corresponding acetonide deprotected diol products in good yields. This unprecedented deprotection strategy, tolerates a variety of acid sensitive functional groups such as silyl ether, trityl, olefin, propargyl, methoxymethyl ether, N-Boc, lactones, esters etc. A few examples are documented in Scheme 6. Scheme 6: Chemoselective deprotection of acetonides (For structural formula pl see the pdf file)

(−)-Lasonolide A 4, isolated from the Caribbean sponge Forcepia sp., showed remarkable anticancer activity in the NIH 60-cell screen. The central step in the syn­thesis of 4 reported (J. Am. Chem. Soc. 2014, 136, 88) by Barry M. Trost of Stanford University was the remarkably selective, convergent Ru-mediated coupling of 1 with 2 to give 3. To prepare 1, the authors took advantage of the underutilized Cu-mediated addi­tion of a Grignard reagent 6 to propargyl alcohol 5, to give 7. Coupling with the ace­tonide 8 followed by deprotection led to the phosphonium salt 9. The other half of 1 was prepared from the acetonide 10 of the commodity chemical 1,1,1-tris(hydroxymethyl)ethane. Oxidation followed by Zn-catalyzed aldol addition of the ketone 11 led to the alcohol 12. Diastereoselective reduction followed by protection gave 13. Condensation with benzaldehyde proceeded with remarkable diastereoselection, setting the quaternary center of 14. Spontaneous intramolecular Michael addition proceeded under the conditions of the subse­quent Horner-Emmons reaction, leading to the aldehyde 15. Wittig reaction with the phosphonium salt 9 followed by deprotection completed the preparation of the alkyne 1. The β-ketoester 18 prepared by the addition of 17 to 16 was prone to unwanted conjugation, and the terminal alkene was easily reduced under hydrogenation con­ditions. Enzymatic conditions were found to effect dynamic kinetic resolution and reduction, to give 19. The derived ketone 21, from coupling with 20 was reduced using the Corey organocatalyst, then hydrosilated, leading to 22. Under metathesis with 23, the product unsaturated aldehyde cyclized to 24. Homologation followed by allylation then completed the construction of 2. Acetone was the solvent of choice for the coupling of 1 with 2. This led to the acetonide 3, that was hydrolyzed and protected to give 25. Yamaguchi macrolac­tonization followed by deprotection then delivered (−)-lasonolide A 4. It is instruc­tive to compare this work to the four previous total syntheses of 4, one of which (Org. Highlights November 26, 2007) we have previously highlighted.

The polyene macrolide RK-397 3, isolated from soil bacteria, has antifungal, antibacterial and anti-tumor activity. Tarek Sammakia of the University of Colorado has described (Angew. Chem. Int. Ed. 2007, 46, 1066) the highly convergent coupling of 1 with 2, leading to 3. The preparation of 1 depended on the powerful methods that have been developed for acyclic stereocontrol. Beginning with the allylic alcohol 4, Sharpless asymmetric epoxidation established the absolute configuration of 5. Following the Jung “non-aldol aldol” protocol, exposure of 5 to TMSOTf delivered the aldehyde 6 in high de. Condensation of 6 with the lithium enolate of acetone also proceeded with high de. The resulting alcohol was protected as the MOM ether, to direct the stereoselectivity of the subsequent aldol condensation with 8. Selective β-elimination followed by reduction and protecting group exchange then gave 1. The preparation of 2 took advantage of the power of Brown asymmetric allylation. Allylation of the symmetrical 11 led to the diol 12. This was desymmetrized by selective acetonide formation, to give 13. Ozonolysis, reductive work-up, and protection of the newly-formed 1,3-diol gave 14, setting the stage for oxidation and asymmetric allylation to give 15. Reductive deprotection and oxidation then delivered the acetonide 2. The tris acetonide 16 was assembled by addition of the enolate derived from 1 to the aldehyde 2, followed by reduction and protection. Kinetically-controlled metathesis with 17 established the triene 18. Phosphonate-mediated homologation to the pentaene 19 followed by hydrolysis and Yamaguchi macrolactonization then completed the synthesis of the macrolide RK-397 3.

Welwitindolinone A Isonitrile 3 is the first of a family of oxindole natural products isolated from the cyanobacteria Hapalosiphon welwischii and Westiella intricate on the basis of their activity for reversing multiple drug resistance (MDR). A key transformation in the total synthesis of 3 reported (J. Am. Chem. Soc. 2008, 130, 2087) by John L. Wood, now at Colorado State University, was the chlorination of 1, that in one step established both the axial secondary chloro substituent and the flanking chiral quaternary center. The starting material for the synthesis of 3 was the diene acetonide 5, readily prepared from the Birch reduction product 4. Intermolecular ketene cycloaddition proceeded with high regio- and diastereoselectivity, to give the bicyclooctenone 6. The triazene-bearing Grignard reagent 7 added to the ketone 6 with the anticipated high diastereocontrol, to give, after reduction and protection, the cyclic urethane 8. Selective oxidation of the diol derived from 8 followed by silylation delivered the enone 9. Conjugate addition of hydride followed by enolate trapping gave the trifl ate 10. Pd-catalyzed meth-oxycarbonylation established the methyl ester 11. Addition of CH3MgBr to 11 gave 1, setting the stage for the establishment of the two key stereogenic centers of 2 and so of 3. The transformation of 1 to 2 was envisioned as being initiated by formation of a bridging chloronium ion. Pinacol-like 1,2-methyl migration then proceeded to form the trans diaxial product, moving the ketone-bearing branch equatorial. In addition to being an elegant solution of the problem of how to establish the axial chloro substituent of 3, this strategy might have some generality for the stereocontrolled construction of other alkylated cyclic quaternary centers. Reduction of the ketone 2 and dehydration of the resulting alcohol led, after deprotection and oxidation, to the ketone 12. Protection followed by β-elimination gave the enone 13. Direct reductive amination of 13 failed, but reduction of the methoxime was successful, giving, after acylation, the formamide 14. Reductive N-O bond cleavage followed by deprotection and isonitrile formation then set the stage for the planned intramolecular acylation to complete the synthesis of Welwitindolinone A Isonitrile 3.

The tetracyclic alkaloid (–)-dendrobine 3 has at its core a cyclohexane that is substituted at each of its six positions, including one quaternary center. Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2012, 51, 3436) to assemble this ring by the Ireland-Claisen rearrangement of the lactone 1. The absolute configuration of the final product stemmed from the commercial enantiomerically pure acetonide 4, which was selectively converted to the Z-ester 5. Following the precedent of Costa, TBAF-mediated conjugate addition of 2-nitropropane to 5 proceeded with high diastereocontrol, to give, after free radical reduction, the ester 6, which was carried on the aldehyde 7. Exposure of the alkyne 9 to an in situ-generated Schwartz reagent followed by iodination gave 10 with 10:1 regioselectivity. It was possible to separate 10 from its regioisomer by careful silica gel chromatography. Metalation followed by the addition to 7 gave an intermediate that was conveniently debenzoylated with excess ethyl magnesium bromide to deliver the diol 11. Selective oxidation led to the lactone 1. Exposure of 1 to LDA and TMS-Cl induced rearrangement to the cyclohexene acid, which was esterified to give 2. Deprotection and oxidation then gave the enone 12. Cyclohexene construction by tethered Claisen rearrangement is a powerful transformation that has been little used in target-directed synthesis. Selective addition of pyrrolidine to the aldehyde of 12 generated an enamine, leading to an intramolecular Michael addition to the enone. This selectively gave the cis ring fusion, as expected, but the product was a mixture of epimers at the other newly formed stereogenic center. This difficulty was overcome by forming the enamine from N-methylbenzylamine. After cyclization, hydrogenation set the additional center with the expected clean stereocontrol, and also effected debenzylation to give 14. To close the last ring, the ketone 14 was brominated with the reagent 15, which was developed (Can. J. Chem. 1969, 47, 706) for the kinetic bromination of ketones. Exposure of the crude α-bromo ketone to 4-dimethylaminopyridine then effected cyclization to 16. Following the literature precedent, reduction of the ketone of 16 with NaBH4 followed by gentle warming led to (–)-dendrobine 3.