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Protecting Groups Are Attacked by the by Attacked Are Groups Protecting -Troc -Phthalimido), Benzylidene and Isopropyl- O N CO 2

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Protecting Groups Are Attacked by the by Attacked Are Groups Protecting -Troc -Phthalimido), Benzylidene and Isopropyl- O N CO 2 View Online / Journal Homepage / Table of Contents for this issue REVIEW Protecting groups Krzysztof Jarowicki and Philip Kocienski Department of Chemistry, University of Glasgow, Glasgow, UK G12 8QQ Covering: 1997 OBn H2N Previous review: Contemp. Org. Synth., 1997, 4, 454 NH NO RO O 2 3 RO SEt H2N 1 Introduction NH 3 (5 mmol) 2 Hydroxy protecting groups O 2.1 Esters O CCl3 MeONa (1 mmol) 2.2 Silyl ethers (in MeOH, 1 ml, 1 M) MeOH-CH2Cl2 2.3 Alkyl ethers 1 R = Ac 4 (6 ml) (50 ml, 9:1), rt 94% rt, 15 min 0.1 mmol scale 2.4 Alkoxyalkyl ethers 2 R = H 3 Thiol protecting groups G/GHNO3 4 Diol protecting groups 4 5 Carboxy protecting groups G = guanidine 6 Phosphate protecting groups Scheme 1 7 Carbonyl protecting groups 8 Amino protecting groups OTBS 9 Miscellaneous protecting groups 10 Reviews 11 References TESO O H OMe H 1 Introduction O O OMe The following review covers new developments in protecting OTES TBSO group methodology which appeared in 1997. As with our previ- O ous annual review, our coverage is a personal selection of OR methods which we deemed interesting or useful. Many of the O O references were selected through a Science Citation Index O search based on the root words block, protect and cleavage; AcO however, casual reading unearthed many facets of protecting OAc group chemistry which are beyond the pale of a typical key- word search. Inevitably our casual reading omits whole areas in OTES Downloaded by San Francisco State University on 14 September 2012 Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H which we lack expertise and so we cannot claim comprehensive coverage of the literature. The review is organised according to 5 R = COCH2OMe the functional groups protected with emphasis being placed on NH3, MeOH 82% 6 R = H deprotection conditions. A separate annual review on combin- atorial chemistry appeared earlier this year which incorporates 6 steps the related subject of solid phase linker chemistry. OTBS 2 Hydroxy protecting groups 2.1 Esters HO O Attempts to use standard basic reagents to cleave the O-acetyl H OMe H groups in aminosugar derivative 1 (e.g. MeONa in MeOH; NH3 O O ff OMe in MeOH; K2CO3 in MeOH–H2O) also a ected the N-Troc 1 O HO (2,2,2-trichloroethoxycarbonyl) group (Scheme 1). The goal O was finally achieved with a MeOH–CH Cl solution of a mix- 2 2 HO O ture of guanidine and guanidine nitrate (4) [obtained by the O reaction of guanidine nitrate (3) with 0.2 equivalents of sodium O methoxide]. Both S- and O-glycosides are stable under the O reaction conditions as are some standard protecting groups HO OAc like NPhth (N-phthalimido), benzylidene and isopropyl- t idene acetals, BnO, and Ph2Bu SiO but tetrachlorophthalimido, OH N-Fmoc, and O-Troc protecting groups are attacked by the guanidine–guanidine nitrate reagent. 7 In the closing stages of an impressive synthesis of the marine Scheme 2 antitumour agent altohyrtin C (7, Scheme 2), Evans and co- workers 2 exploited the higher base lability of methoxyacetates The penultimate step in a recent synthesis of the antitumour to achieve a selective deprotection in the presence of two macrolides cryptophycin 1 (11) required a mild method for the secondary acetate functions in intermediate 5. introduction of the epoxide ring in the side chain 3 (Scheme 3). J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 4005 View Online OH Ph O O Ph O OH OOHN Cl N3(CH2)3C(OMe)3 MeO O OOHN Cl Me3SiCl 63% O HN O OMe O HN O OMe N3 O O 8 9 –Me3SiOMe Cl O O O Ph Ph (a) Ph P, H O (63%) OOHN Cl 3 2 O O OOHN Cl (b) K2CO3, Me2C=O (98%) O HN O OMe O HN O OMe O N3 O 11 10 Scheme 3 A variant of a direct method for the conversion of diols to 3-yloxycarbonyl (Doc) group can be used for protecting the epoxides developed by Sharpless 4 was cleverly adapted to the hydroxy group of tyrosine.6 The protection is achieved in the case at hand. Thus diol 8 was treated with the 4-azido-1,1,1- reaction of tyrosine derivative 14 with 2,4-dimethylpentan-3-yl trimethoxybutane in the presence of chlorotrimethylsilane chloroformate and ethyldiisopropylamine (Scheme 5). The Doc to give the cyclic orthoester 9 which decomposed under the group is 1000-fold more stable towards nucleophilic piperidine reaction conditions with loss of Me3SiOMe to give the chloro- than the commonly used 2-bromobenzyloxycarbonyl (2-BrCbz) hydrin ester 10 (inversion). Selective reduction of the azide group and it is completely cleaved by hydrogen fluoride. How- under Staudinger conditions produced an intermediate amino ever the 2-BrCbz group is superior in terms of acid stability (the ester which underwent intramolecular lactamisation to release loss of protection after 20 min in 50% trifluoroacetic acid– a hydroxy group. In the last step, the resultant chlorohydrin CH2Cl2 is 0.01% for 2-BrCbz group and 0.04% for Doc group). was converted to the cryptophycin 1 (11) on treatment with base. The Hasan group 5 tested o-nitrobenzyloxycarbonyl (NBOC) O OH and related groups as photolabile protectors of nucleoside i (a) Pr 2CHOC(O)Cl O O 5Ј-hydroxy groups (Scheme 4). Generally the rates of photo- i EtNPr 2 removal of 2-(o-nitrophenyl)ethoxycarbonyl (NPEOC) deriv- MeCN Downloaded by San Francisco State University on 14 September 2012 atives (12, n = 1) were faster than the corresponding NBOC- Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H = (b) Pd/H2 protected compounds (12, n 0). Also substitution at the COOBn α-carbon had an enhancing effect. The most reactive com- COOH = pound had a methyl group and ethyl chain (t1/2 0.66 min) and NHBoc = NHBoc the order of reactivity of 12 was found to be: R Me, 14 n = 1>R= o-nitrophenyl, n = 1>R= o-nitrophenyl, n = 0. 15 Unden and co-workers reported that the 2,4-dimethylpentan- Scheme 5 O NO2 R 2.2 Silyl ethers NH In the final steps of an elegant synthesis of dynemicin A (19, (CH2)nO O N O Scheme 6), Myers and co-workers 7 needed to deprotect the O O hydroquinone in Diels–Alder adduct 18 before cleavage of the sensitive bicyclic acetal followed by in situ oxidation to the 12 HO anthraquinone in the target. This required the use of an iso- hν (365 nm, 200 W Hg lamp) benzofuran (16) with highly labile protecting groups for which MeOH-H2O (1:1) the trimethylsilyl ether was ideally suited. Thus, brief treatment of Diels–Alder adduct 18 with excess activated manganese fl O dioxide and triethylamine trihydro uoride (1:1 molar ratio, ca. 70 equiv.) led to cleavage of the three trimethylsilyl ethers NH together with the triisopropylsilyl ester and the resultant ff HO product oxidised in situ to a ord dynemicin A (19) in 53% yield. N O N-Silylpyridinium triflates are powerful silylating agents O which have been used in the preparation of enol silanes and for the silylation of carboxylic acids.8 Olah and Klumpp report a HO new method for their preparation as well as their use in the 13 silylation of alcohols 9 (Scheme 7). The salts 21a–c were pre- Scheme 4 pared by reaction of an allylsilane 20 with triflic acid followed 4006 J. Chem. Soc., Perkin Trans. 1, 1998, 4005–4037 View Online O – + O PPh Br PPh3 (1.5 mmol) 3 Br Br MeCN (3 ml) Br Br i CO2Si(Pr )3 TMSO N CaCO3 (0.9 mmol) O 0 °C Br Br OMe 23 Br O + H 1.5 mmol 24 R OTMS TMSO O OTBDPS 16 17 75% THF, –20 → 55 °C, 5 min 25 R = OTES 24, THF (1 ml), rt, 6 h 75% (0.5 mmol scale) 26 R = Br Scheme 8 butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS) ethers. i CO2Si(Pr )3 TMSO N This allows the selective bromination of 25 to give 26 in 75% O yield. OMe Maiti and Roy 12 reported a selective method for deprotection O H of primary allylic, benzylic, homoallylic and aryl TBS ethers using aqueous DMSO at 90 ЊC (Scheme 9). All other TBS- TMSOO O protected groups as well as THP ethers, methylenedioxy ethers, TMS 18 benzyl ethers, methyl ethers and aldehyde functionalities remain unaffected. Also a benzyl TBS ether can be selectively MnO2, Et3N•3HF 53% THF, 23 °C, 9 min deprotected in the presence of an aryl TBS ether. OTBS 27 R = TBS CO2H DMSO (10 ml) OH O HN 82% H O (2 ml), 90 °C, 8 h O RO 28 R = H 2 OMe OMe H Scheme 9 OH OOH Full details of Fraser-Reid’s synthesis of the bacterial nodu- 19 lation factor 30 NodRf-III (C18:2, MeFuc) have been pub- Scheme 6 lished.13 The final step of the synthesis required removal of three TBS ethers, one of which was protecting the anomeric (a) CF3SO3H (1 equiv.) position in 29 (Scheme 10). Anomeric deprotections using CH2Cl2, 0 °C, 2 h TBAF are complicated by Lobry de Bruyn–Alberda van SiR3 – (b) pyridine (1 equiv.) CF3SO3 Eckenstein rearrangements and other base catalysed degrad- rt, 2 h N 20 ations and mildly acidic methods (e.g. PPTS in MeOH at 55 ЊC) Downloaded by San Francisco State University on 14 September 2012 SiR3 Published on 01 January 1998 http://pubs.rsc.org | doi:10.1039/A803688H were fruitless even after extended reaction times.
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