Chapter 3: Protecting Groups

I. Protecting Groups of Hydroxyl Groups Chapter 3: Protecting Groups Consider the stability and effect of anomeric group! Consider the solubility of starting material (the choice of solvent)! Consider the reactivity of different hydroxyl groups! * DCM is common for pyranoses with 2-3 H s. For pyranose with more than 4 H s, use DMF or pyridine. * Nucleophilicity of H groups on pyranoses (chair conformation) (Carbohydr. Res. 1987, 162, 159.) 1 H > 2 H Equatorial H > axial H Equatorial H with vicinal axial H (or R) > Equatorial H without vicinal axial H (or R) H H 4 6 3 H 2 H 1 Me Estimated order of nucleophilicity: 6-H > 2-H > 3-H ~ 4-H H 6 H H 4 3 2 H 1 Me Estimated order of nucleophilicity: 6-H > 3-H > 2-H > 4-H 1

(i) Alkyl ether type Sug H Sug R Advantages: * Relatively stable in harsh conditions (acidic, basic, reflux, etc.) * Enhance the reactivity of glycosylation due to electron-donating effect * More compatible to the conditions needed for deoxygenation or amino (azido) substitution * Selective protection is possible Disadvantages: * Relatively harder to remove (deprotect) * Conditions for protection and deprotection may not be compatible to other types of protecting groups (a) R = methyl (CH 3, Me) * Not commonly used due to the difficulty of deprotection * Methoxy group can be found in naturally occurring unusual sugars Protection Deprotection Reagent/Condition Reference MeI, NaH in THF or DMF Tetrahedron Lett. 1989, 30, 641. Me 3 + - BF 4 J. rg. Chem. 1972, 37, 912. MeTf, DCM, py., 80 C MeI, Ag 2 J. Am. Chem. Soc. 1980, 102, 7083. BBr 3, EtAc or DCM J. rg. Chem. 1979, 44, 4863. SiCl 4, NaH, DCM, CH 3 CN Synthesis 1982, 1048. AlCl 3, AlBr 3 Chem. Lett. 1979, 97. Ac 2, FeCl 3, 80 C J. rg. Chem. 1974, 39, 3728 H SPh 1) CH 3 I, NaH, THF 2) AcH, TFA, H 2 77% H H CH 3 SPh 2

(b) R = trityl, triphenylmethyl (Ph 3 C, Tr) * Excellent for selective protection of primary H * Stable in basic but very labile in acidic conditions * Easy to observe with TLC * Deprotection can be tricky Protection Deprotection Reagent/Condition Reference TrCl, 3 amines, DCM Tetrahedron Lett. 1989, 30, 641. TFA, t-buh Carbohydr. Res. 1978, 60, 206. HCl, CHCl 3, 0 C Carbohydr. Res. 1971, 17, 439. TsH, DCM, MeH Tetrahedron Lett. 1977, 18, 3473. BF 3, Et 2 Can. J. Chem. 1978, 56, 2700 3

(c) R = methoxymethyl (CH 3 CH 2, MM) * Can be incorporated at relatively weak basic conditions (3 amine) but needs relatively strong acid (TFA) to remove * Stable in basic conditions * The reagent, MMCl, is considered carcinogenic Protection Deprotection Reagent/Condition Reference MMCl, NaH in THF or J. Am. Chem. Soc. 1972, 94, 7827. DMF MMCl, DIPEA, 0 C or r.t. - Synthesis 1975, 276. CH 2 (Me) 2, TsH, LiBr, r.t. Synthesis 1985, 74. Conc. HCl, MeH Chem. Commun. 1974, 298. Me 2 BBr, DCM J. Am. Chem. Soc. 1981, 103, 3213. TFA, DCM J. Am. Chem. Soc. 1981, 103, 3210. LiBF 4, CH 3 CN, 80 C J. rg. Chem. 1986, 51, 635. 4

(d) R = benzyl (C 6 H 5 CH 2, Bn) * Can be traceless removed using hydrogenolysis * Stable in basic conditions * Relatively stable in acidic conditions * Quenching excess reagent (BrBr) with MeH can be tricky Protection Deprotection Reagent/Condition Reference BnCl, Bu 4 N + -HS - 4, KH Tetrahedron Lett. 1975, 16, 3251. BnBr, NaH, THF or DMF, Tetrahedron Lett. 1976, 17, 3535. TBAI BnBr, Ag 2, DMF, r.t. Bull. Korean Chem. Soc. 2003, 24, 163. J. rg. Chem. 1985, 50, 3940. BnBr, Bu 2 Sn or (Bu 3 Sn) 2, J. Am. Chem. Soc. 1994, 116, 5647 toluene, reflux BnC(NH)CCl 3, TfH J. Am. Chem. Soc. 1988, 110, 1624. Synthesis 1987, 568. H 2, Pd/C or Pd(H) 2 /C TMSI, DCM J. rg. Chem. 1977, 42, 3761. BF 3 -Et 2, NaI, CH 3 CN J. Chem. Res. Synop. 1985, 232. Ac 2, cat.c. H 2 S 4, 0 C J. rg. Chem. 2004, 69, 1513. FeCl3, DCM Tetrahedron: Asymmetry 1995, 857. Ph H H Me 1) (n-bu 3 Sn) 2 Ph 2) BnBr H Bn Me + Ph Bn H Me (Synthesis 1994, 1121) 10 : 1 Ph H H Me n - Bu 4 N + -HS 4 - BnBr, NaH, DCM Ph Bn H + Ph H 30% Me 50% Bn Me Ph H H Me n - Bu 4 N + -HS 4 - BnBr, NaH, DCM 50% Ph H Bn Me (rg. Lett. 2004, 6, 1365) 5

(e) R = p-methoxybenzyl (CH 3 C 6 H 4 CH 2, PMB) * More prone to oxidative cleavage than Bn but less prone to reductive cleavage than Bn * Stable in basic conditions * Relatively stable in acidic conditions Protection Deprotection Reagent/Condition Reference PMBCl, NaH, THF or DMF J. rg. Chem. 1984, 49, 51. PMBC(NH)CCl 3, TfH Tetrahedron Lett. 1988, 29, 4139. Tetrahedron Lett. 1983, 24, 5364. (NH 3 ) 2 Ce(N 2 ) 6, Ceric ammonium nitrate (CAN), CH 3 CN, H 2 DDQ, DCM J. Am. Chem. Soc. 1985, 107, 4586. 6

(f) R = tetrahydropyranyl (THP) * Stability similar to glycosidic bond * Stable in basic conditions Protection Deprotection Reagent/Condition Reference Dihydropyran, TsH, DCM J. rg. Chem. 1979, 44, 1438. Dihydropyran, PPTS, DCM J. rg. Chem. 1977, 42, 3772. HAc, THF, H 2 J. rg. Chem. 1979, 44, 1438. PPTS, EtH, 55 C J. rg. Chem. 1977, 42, 3772. TsH, MeH, r.t. J. Am. Chem. Soc. 1978, 100, 1942. MgBr 2, Et 2, r.t. Tetrahedron Lett. 1987, 28, 439. (ii) Silyl ether type Sug H + R 3 Si X + NR' 3 Sug SiR 3 + H NR' 3 X * Stability varies General reagents for protection: R 3 SiX with 3 amines (DIPEA, TEA, immidazole, lutidine, pyridine, etc) Common reagents for deprotection: TBAF, BF 3, KF, or pyridine-hf Trimethylsilyl (TMS) Triethylsilyl (TES) Triisopropylsilyl (TIPS) t-butyldimethylsilyl (TBS) t-butyldiphenylsilyl (TBDPS) Can be cleaved with K 2 C 3, MeH or citric acid Can be cleaved with HAc Possible for selective protection of 1 H Selective protection of 1 H Selective protection of 1 H Relatively stable in basic condition 7

(iii) Ester type Sug H + C R X Sug C R + HX (a) R = trifluoroacetyl (TFA) General reagent for protection: trifluoroacetic anhydride with 3 amines (DIPEA, TEA, immidazole, lutidine, pyridine etc), DMAP as catalyst Common reagent for deprotection: weak acids or bases (b) R = acetyl (Ac) General reagents for protection: Ac 2 with 3 amines (DIPEA, TEA, immidazole, lutidine, pyridine etc) or Ac 2 with cat. acids. Common reagents for deprotection: K 2 C 3, MeH, cat. NaMe in MeH, or LiH, THF, H 2 (J. rg. Chem. 2004, 69, 1513) * anomeric acetyl group can be selectively removed with H 2 NNH 2 -HAc or BnNH 2 8

(c) R = trimethylacetyl (Piv) * Can be used for selective protection General reagent for protection: pivaloyl chloride (PivCl) with 3 amines (DIPEA, TEA, pyridine etc) Deprotection Reagent/Condition Reference Bu 4 N + H -, r.t. Tetrahedron Lett. 1979, 20, 3561. NaH, EtH, H 2 Tetrahedron Lett. 1973, 14, 317. t-buk J. rg. Chem. 1977, 42, 918. DIBAL H H H H Me PivCl (2 equiv.) pyr. H H Piv Piv Me H H H H PivCl (2 equiv.) pyr. H Piv Piv H Me Me H H H H SPh (J. rg. Chem. 1998, 63, 6035) PivCl (2 equiv.) pyr. Piv H Piv H SPh 9

(d) R = Benzoyl (Bz) * Can be used for selective protection General reagent for protection: benzoyl chloride (BzCl) with 3 amines (DIPEA, TEA, pyridine etc) * Less common method for protection: Benzoic acid, DEAD, PPh 3 Deprotection Reagent/Condition Reference Cat. NaMe, MeH J. rg. Chem. 2004, 69, 1513. LiH, THF/H 2 (3/1) J. rg. Chem. 2004, 69, 1513. K 2 C 3, MeH DIBAL 10

II. Protecting Groups of 1,2- or 1,3-Dihydroxyl Groups Consider the formation of acetal (ketal) from diol and aldehyde (ketone)! Consider the solubility of ring or fused ring for selectivity! Six-membered ring: thermodynamically favored Five-membered ring: kinetically favored General Mechanism 11

(i) For selection between 1,3-diol and trans-1,2-diol R H vs. R H (ii) For selection between 1,3-diol and cis-1,2-diol R vs. R H H R R H vs. R R H (iii) For selection between trans-1,2-diol and cis-1,2-diol H H vs. H H 12

(iv) Acetonide (isopropylidene) Common reagents for protection: acetone or Me 2 C(Me) 2 and acids (TsH, PPTS, ZnCl 2 etc) with removal of water Common reagents for deprotection: acids (TsH, TFA, HCl etc) with addition of water 13

(v) Benzylidene Common reagents for protection: PhCH or PhCH(Me) 2 and acids (TsH, PPTS, ZnCl 2 etc) with removal of water Common reagents for deprotection: acids (TsH, TFA, HCl etc) with addition of water * Can be selectively converted into Bn or Bz Ph NBS, CCl 4 BaC 3, reflux H Br Bz H Ph H Me H Me Bz Br H NBS, CCl 4 BaC 3, reflux H H Me (J. rg. Chem. 1969, 34, 1035) H Me Me Bn R NPhth NaBH 3 CN TFA, DMF 90% PMB H Bn NPhth R (J. rg. Chem. 2000, 65, 2410) NaBH 3 CN TMSCl, MeCN 51% H PMB Bn R NPhth 14

(vi) Cyclohexane-1,2-diacetals (CDA) MeH, CH(Me) 3 cat. H 2 S 4, reflux Me Me Me Me H H H H Me CDA, MeH CH(Me) 3, cat. CSA reflux 48% (Angew. Chem. Int. Ed. Engl. 1994, 33, 2290) Me H Me H Me Similar reagent: CH 3 C(Me) 2 C(Me) 2 CH 3, or 2,3-butanedione (vii) Silyl-based protecting group Triisopropyldisilyl (TIPDS) H Z ipr ipr Si Z H H Si ipr ipr H 15

(viii) ther examples H H H H Cyclohexone dimethyl ketal, TsH-H 2, CH 3 CN H H 41% (rg. Lett. 2004, 3, 1381) 16

III. Protecting Groups of Amino Groups (i) Masking NH 2 (amino) as (azido) * rganoazides can be explosive ([C+]/N 3) ((a) P. A. S. Smith, pen-chain Nitrogen Compounds, vol. 2, Benjamin, New York, 1966, 211 256; (b) J. H. Boyer, R. Moriarty, B. de Darwent, P. A. S. Smith, Chem. Eng. News 1964, 42, 6.) H 2 N H 2 N H H H H 2 N NH 2 H H NH 2 NH 2 H H Tf, Et 3 N, CuS 4, MeH/H 2 /CH 2 Cl 2 H H (J. Am. Chem. Soc. 1999, 121, 6527-6541; Tetrahedron Lett. 1996, 37, 6029-6032) H H H H H 1) S 2 Cl 2, MeCN 2) imidazole Na S (rg. Lett. 2007, 9, 3797 3800) N N R NH 2 CuS 3, K 2 C 3 MeH R 17

The azido group can be converted (reduced) to amino group using the following methods: (1) H 2, Pd/C; (2) PR 3, THF, H 2 ; (3) LiAlH 4 ; (4) thiols (HSCH 2 CH 2 SH, HSCH 2 CH 2 H, H HS SH dithiothreitol H etc) * Hydrogenation can be * Mechanism of Staudinger reaction 18

* Staudinger reaction can be selective (J. Am. Chem. Soc. 2002, 124, 10773-10778; J. rg. Chem. 2007, 72, 4055-4066) 6' Bn I Bn 1' 2' N proton (ppm) 3 H-1 3.18 H-3 3.38 H-2' 3.51 H-6' 3.49/3.35 H II 1 Bn 6,3',4'-tri--benzyltetraazidoneamine 3 PMe 3 Bn Bn N 6' 3 I 1' 2' H 2 N H 3 II 1 Bn Bn 6' I 1' 2' 3 Bn proton (ppm) H-1 3.6 H-3 3.4 H-2' 3.00 H-6' 3.27/3.10 H-3" 3.78 II 1 1" Bn 2" 3" III Per-azido per-benzyl tobramycin Bn Bn Bn PMe 3 then Cbz-Cl 6' I 1' 2' 3 Bn II 1 1" Bn 2" HN III Bn Bn Cbz 6' Ac I Ac N N 4 3 3 Ac 5 1" III Ac 2"' Ac IV 6"' Ac II 1 Ac proton d (ppm) H-1 3.43 H-3 3.53 H-2' 3.16 H-6' 3.3 a H-2''' 3.3 a H-6''' 3.59/3.28 a : approximate value 1.0 M PMe 3 in toluene (1.1 eq.), Boc-N (2.4 eq.), toluene, -78 o C to 10 o C 45% Ac Ac Ac Ac Ac Ac Ac H N (mixed with minor N-3 Boc adduct) Boc 1) TFA/CH 2 Cl 2 2) EDC, HBt, Et 3 N, NMP, DMF H H 28% N H Z Ac Ac Ac Ac Ac Ac H N H N H Z Ac 19

N 6' 3 I Ac Ac 2' N 3 3 Ac 1" III II 1 Ac 1.0 M PMe 3 in toluene (1.1 eq.), Boc-N (2.4 eq.), toluene, -78 o C to 10 o C 31% Ac Ac Ac Ac H N Boc Ac Ac Ac Ac proton (ppm) H-1 3.4 H-3 3.5 H-2' 3.25 H-6' 3.3 Boc-N: CN N (ii) Phthalamide (intermediate involved in Gabriel amine synthesis) Common reagents for protection: phthalic anhydride Common reagents for deprotection: acids hydrazine, EtH, reflux Example: 20

(iii) Carbamate-type Cl R NH 2 + R' + B * Solvent selection is important. R H N + H B R' Cl (a) 9-Fluorenylmethoxycarbonyl chloride (Fmoc-Cl) * Stable in acidic and neutral conditions * Easy to observe with strong UV absorption Cl Common reagents for deprotection: amines (piperidine) (b) Di-tert-butyl dicarbonate, Boc anhydride (Boc 2 ) * Stable in basic and neutral conditions Common reagents for deprotection: acids (TFA) 21

(c) Benzyl chloroformate, Carbobenzoxy chloride (Cbz-Cl, Z-Cl) Cl * Stable in acidic, basic and neutral conditions Common reagents for deprotection: hydrogenolysis (H 2, Pd/C)) (d) Allyl chloroformate (Alloc-Cl) Cl * Stable in acidic, basic and neutral conditions Common reagents for deprotection: Pd(0) reagents 22