Myers Protective Groups – -Based Protection of the Hydroxyl Group Chem 115

General Reference: • In general, the stability of silyl towards acidic media increases as indicated: TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000) Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd4th ed. John Wiley & Sons: • In general, stability towards basic media increases in the following order: New Jersey,York, 1991 2007. . TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)

Important Silyl Protective Groups: Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd ed. John Wiley & Sons: New York, 1991. Half Half Life CH3 Et CH3 (5% NaOH–95% MeOH) (1% HCl–MeOH, 25 °C) RO Si CH3 RO Si Et RO Si i-Pr n-C6H13OTMS ”1 min ”1 min CH3 Et CH3

n-C6H13OSi-i-Bu(CH3)2 2.5 min ”1 min (TMS) Triethylsilyl (TES) DimethylisopropylsilylIsopropyldimethylsilyl (IPDMS) n-C6H13OTBS Stable for 24 h ”1 min

n-C6H13OSiCH3Ph2 ”1 min 14 min

Et CH3 Ph n-C6H13OTIPS Stable for 24 h 55 min RO Si i-Pr RO Si t-Bu RO Si t-Bu n-C6H13OTBDPS Stable for 24 h 225 min Et CH3 Ph Davies, J. S.; Higginbotham, L. C. L.; Tremeer, E. J.; Brown, C.; Treadgold, J. Diethylisopropylsilyl (DEIPS) t-Butyldimethylsilyl (TBS) t-Butyldiphenylsilyl (TBDPS) Chem. Soc., Perkin Trans . 1 1992, 3043. • A study comparing alkoxysilyl . trialkylsilyl groups has also been done: i-Pr R Half Life Half Life i-Pr R O Si i-Pr O + – t-Bu Silyl Ether Bu4N F (0.06 M, 6 equiv) HClO4 (0.01 M) RO Si i-Pr O Si t-Bu n-C12H25OTBS 140 h 1.4 h i-Pr R O Si i-Pr O i-Pr R n-C12H25OTBDPS 375 h > 200 h n-C H OSiPh (Oi-Pr) Triisopropylsilyl (TIPS) TetraisopropyldisiloxanylideneTetraisopropyldisilylene (TIPDS) (TIPDS)Di-t-butyldimethylsilyleneDi-t-butylsilylene (DTBS) (DTBS) 12 25 2 <0.03 h 0.7 h

n-C12H25OSiPh2(Ot-Bu) 5.8 h 17.5 h

n-C12H25OPh(OSiPh(t-Bu)(OCHt-Bu)(OCH3) 3) 22 h 200h General methods for the formation of silyl ethers: Gillard, J.W.; Fortin, R.; Morton, H. E.; Yoakim, C.; Quesnell, C. A.; Daignault, S.; Guindon, Y. J. Org. Chem. 1988, 53, 2602. R'3SiCl ROH ROSiR'3 • Silyl groups are typically deprotected with a source of . The Si–F bond stength is , DMF about 30 kcal/mol stronger than the Si–O bond. Fluoride sources: Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190. + – Tetrabutylammonium fluoride, Bu4N F (TBAF) •(HF)x R'3SiOTf ROH ROSiR'3 trihydrofluoride, Et3N•3HF 2,6-lutidine,2,6 lutidine, CH2Cl2 Hydrofluoric (dimethylamino)sulfonium difluorotrimethylsilicate (TASF) + – Corey, E. J.; Cho, H.; Rücker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, 3455. fluoride, H4N F P. Hogan

1 • Monosilylation of symmetrical is possible, and useful. • Selective Selective deprotection deprotection of of silyl silyl ethers ethers is isalso also important, important, and and is isalso also subject subject to to NaH, TBSCl, THF HO OH TBSO OH empirical determination. n 75-97% n n = 2-6,10 TESOTESO HOHO H C McDougal, P.G.; Rico, J.G.; Oh, Y.; Condon, B. D. J. Org. Chem. 1986, 51, 3388. H3C 3 CH CH3 CH3OBOM CH CHOBOM3 CH3 3 OBOM 3 OBOM TBDPSCl, i-Pr2NEt, DMF, 23 °C TBSO HO OH TBSO pyr•HF, CH3CN CHCH TBDPSO OH CHCH33 33 n 75-86% n 0 °C, 11 h, quant. O O H H n = 2,3,5,7,9 O O O AcO OO AcO O O Hu, L.; Liu, B.; Yu, C. Tetrahedron Lett. 2000, 41, 4281. O CH3 CH3 AcO OHOH BuLi, THF; TBSCl OTBS OTBS O Ph O H3C O HO HO HOHO CH CH 3 99%88% 3 3 OH CH3 CH3 N O H CH3 Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. J. Org. Chem. 19831984, 49, 4674. OH 3 • Selective protection of is of great importance in synthesis. Conditions often must be HO H determined empirically. BzOBzOAcO OTIPS Taxol O O H

OTIPS Holton, R. A., et al. J. Am. Chem. Soc., 1994, 116, 1599. H N O H CH O H O 3 H TESCl, 2,6-lutidine O H N H3C H N O H OH CH3 CH2Cl2, –78 °C O H CH3 H 97% H O H Cl CHCO H H3C O H 2 2 CH2 OH ONO N 2 AcO OAc AcO OAc HO CH 90% OAc CH3 H OAc TBSO OTES O TBSO O CH2 H OH • TESCl/imidazole and ONO N H O O H TESCl/imidazole and HO O TESOTf,• 2,6-lutidine both O CH3 OTES O CH3 gaveTESOTf, the bis-silylated 2,6-lutidine product. both O HO HO OTES OTBS OH OCH3 gave the bis-silylated product. H


H N O H O OH CH OAc O 3 H HO C H C O O H 2 O 3 HO C O O 2 CH CO2H 3 CH3 H HO CH ONO N 2 Zaragozic acid OH CH OH H 3 O Br Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106. OCH3

OCH3 Phorboxazole B • Selective deprotections in organic synthesis have been reviewed: Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1065. Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. Engl. 2000, 39, 2536. P. Hogan

2 Myers Protective Groups – Protection of Hydroxyl Groups, , and Chem 115

Esters and Carbonates General methods used to form esters and carbonates:

O pyr, DMAP O O O O O ROH RO RO RO RO Cl R' RO R' CH3 Cl Cl Cl Cl Cl Cl

Acetate (Ac) Chloroacetate Dichloroacetate Trichloroacetate O O pyr, DMAP O ROH R' O R' RO R'


OCH3 R O Trifluoroacetate (TFA) Pivaloate (Piv) Benzoate (Bz) p-Methoxybenzoate N N X– O DMAP = 4-Dimethylaminopyridine: O RO RO O O O N N RO RO H3C CH3 H3C CH3 OCH3 O • Proposed intermediate Br

p-Bromobenzoate Methyl 9-(Fluorenylmethyl) Carbonate Allyl Carbonate (Fmoc) (Alloc) DMAP is used to accelerate reactions between and activated esters. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.

O O O • In general, the susceptibility of esters to -catalyzed increases with the RO RO acidity of the product acid. RO O O O O RO CH Cl 3 Si(CH ) O CH Cl Cl 3 3 3 CH3 O O O H3C < OCH < < 2,2,2-Trichloroethyl Carbonate 2-(Trimethylsilyl)ethyl Carbonate Benzyl Carbonate t-Butyl Carbonate OCH 3 OCH3 H C 3 3 CH (Troc) (Teoc) (Cbz) (Boc) 3 CH3O

S O O RO O O N CH3 < < Cl < F Cl OCH3 OCH3 H3C H3C OCH3 OCH3 Cl F Cl F Dimethylthiocarbamate (DMTC)

P. Hogan/Seth B. Herzon

3 Esters:

• Several methods for forming and cleaving acetate esters have been developed. can often • Good selectivity can often be achieved in the selective deprotection of different esters. be used for the enantioselective hydrolysis of acetate esters. The enantioselective hydrolysis of meso diesters is an important synthetic transformation and racemic esters have been kinetically resolved using lipases.

OAc O OH O H3C H C O O 3 O Acetyl PCC H C 3 O H3C O 94%, 99% ee OAc OAc O OAc HO Cl HO O OH O O n-PrNH2 Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986, O O O O 27, 1255. 71% CH O OH 3 CH3O OH

• Lipases can also be effective for deprotection under very mild conditions, as in the case shown below, where conventional methods were unsuccessful. CH 3 CH3

O O O OAc O MY OH O 0.1 M pH 7.2 buffer Cl CH O Cl CH3 O 3 O O CH OH CH3 28 °C, 4 days 3 O O O Sakaki, J.; Sakoda, H.; Sugita, Y.; Sato, M.; Kaneto, C. Tetrahedron: Asymmetry, 1991, 2, 343. CH3 O OCH 3 O CH3 • A potentially general method for selectively acylating the primary hydroxyl group of a 1,2- N makesmakes useuse ofof stannylenestannylene acetalsacetals asas intermediates:intermediates: CH3 HO H OH

Bu2SnO, AcCl, Neocarzinostatin Chromophore HO OBn O OBn AcO OBn , 100 °C HO O CH2Cl2, 0 °C HO Myers, A. G.; Liang, J.; Hammond, M.; Wu, Y.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120, Bu Sn 5319. Bu

Review: Hannessian,Hanessian, S.; S.; David, David, S. S. Tetrahedron Tetrahedron 1985, 1985, 41, 41, 643., 643.

P. Hogan

4 • When one protective group is stable to conditions that cleave another and the converse is also true, these groups are often said to an orthogonal relationship. This concept is illustrated well in the Allyl Carbonate: context of carbonates (and ). O Pd2(dba)3, dppe, Et2NH, THF Summary of methods for deprotecting carbonates: RO ROH O Methyl Carbonate:

O Genet, J.P.; Blart E.; Savignac, M.; Lemeune, S.; Lemaire-Audoire, S.; Bernard, J. Synlett 1993, K2CO3, MeOH RO ROH 680. OCH3 2-(Trimethylsilyl)ethyl Carbonate:

Meyers, A. I.; Tomioka, K.; Roland, D. M.; Comins, D. Tetrahedron Lett. 1978, 19, 1375. O TBAF, THF RO ROH O 9-Fluorenylmethyl Carbonate: Si(CH3)3

• The pKa of fluorene is ≈ 10.3 O Gioeli, C.; Balgobin, S.; Josephson, S.; Chattopadhyaya, J. B. Tetrahedron Lett. 1981, 22, 969. RO H Et3N, pyr O ROH H fluorene = Benzyl Carbonate:

O H2, Pd–C, EtOH RO ROH O Chattopadhyaya, J. B.; Gioeli, C. J. Chem. Soc., Chem. Comm. 1982, 672.

Trichloroethyl Carbonate: Daubert, B. F.; King, G. C. J. Am. Chem. Soc. 1939, 61, 3328.

O Zn, AcOH Dimethylthiocarbamate (DMTC): RO ROH O S NaIO4 or Cl RO ROH Cl Cl N CH3 H2O2, NaOH H3C

Windholz, T. B.; Johnston, D. B. R. Tetrahedron Lett. 1988, 29, 2227. • The DMTC group is stable to a variety of reagents and reaction conditions (PCC oxidations, Swern oxidations, chromium reagents, Grignard and alkyllithium reagents, phosphorous , LAH, HF, TBAF, and borane).

• The is introduced using thiocarbonyldiimidazole followed by treatment with , or by reaction with commercially available ClCSN(CH3)2.

Barma, D. K.; Bandyopadhyay, A.; Capdevilla, J. H.; Falck, J. R. Org. Lett. 2003, 5, 4755. P. Hogan/Seth B. Herzon

5 Myers Protective Groups – Protection of Hydroxyl Groups, Chem 115

Cleavage of protective groups: Acetals as Protective Groups:

RO OCH3 RO O RO O CCl3 Methoxymethyl Ethers:

ROH RO OCH3 Methoxymethyl Ether Benzyloxymethyl Ether 2,2,2-Trichloroethoxymethyl Ether

(MOM) (BOM) 1. Conc. HCl, MeOH. Weinreb, S.; Auerbach, J. J. Chem. Soc., Chem. Comm. 1974, 889. OCH3 RO SCH RO O RO O 3 2. Bromocatechol borane. This reagent cleaves a number of protective groups in approximately the following order: MOMOR ʜ MEMOR > t-BuO CNHR > BnO CNHR ʜ OCH3 2 2 t-BuOR > BnOR > allylOR > t-BuO2CR ʜ 2° alkylOR > BnO2CR > 1° alkylOR >> 2-Methoxyethoxymethyl Ether Methylthiomethyl Ether p-Methoxybenzyloxymethylp-Methoxybenzyl Ether Ether alkylO2CR. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

(MEM) (MTM) (PMBM) 3. LiBF4, CH3CN, H2O. Ireland, R. E.; Varney, M. D. J. Org. Chem. 1986, 51, 635.

H C 3 CH Si 3 Benzyloxymethyl Ethers: RO O CH3 O OR

RO O ROH 2-(Trimethylsilyl)ethoxymethyl Ether Tetrahydropyranyl Ether


1. Na, NH3. Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 6260. General methods for forming acyclic, mixed acetals: 2. H2, Pd–C. D. Tanner, D.; Somfai, P. Tetrahedron 1987, 43, 4395.

3. Dowex 50W–X8, acidic . Roush, W. R.; Michaelidies, M. R.; Tai, D. F.; Base, Chong, W. K. M. J. Am. Chem. Soc. 1987, 109, 7575. ROH R'OCH2X RO OR'

Base-solvent combinations are often diisopropylethylamine-CH2Cl2, NaH-THF, or NaH-DMF. 4-Methoxybenzyloxymethyl Ether: Sometimes a source of iodide ion is added to enhance the reactivity of the alkylating reagent. Typical + –– sources include Bu4N FI , ,LiI, LiI, or or NaI. NaI. RO O ROH

General methods for introducing 2-tetrahydropyranyl ethers: OCH3

TsOH 1. DDQ, H O. Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1987, 28, 5125. ROH 2 O or O OR PPTS

PPTS = PyridiniumPryidinium p-toluenesulfonate

Grieco, P. A.; Yoshikoshi, A.; Miyashita, M. J. Org. Chem. 1977, 42, 3772, and references cited therein. P. Hogan

6 2,2,2-Trichloroethoxymethyl Ether: Tetrahydropyranyl Ether:


ROH O OR 1. Zn–Cu or Zn–Ag, MeOH. Jacobson, R. M.; Clader, J. W. Synth. Commun. 1979, 9, 57.

2. 6% Na(Hg), MeOH, THF. Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T.J.T. J. J. Am. Chem. Soc. 1990, 112, 7001. 1. PPTS, EtOH, 55 °C. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem., 1977, 44, 1438.

2. TsOH, MeOH, 25 °C. Corey, E. J.; Niwa, H.; Knolle, J. J. Am. Chem. Soc. 1978, 100, 1942. 2-Methoxyethoxymethyl Ether:

OCH Methylthiomethyl Ether: RO O 3 ROH

1. ZnBr2, CH2Cl2. Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett. 1976, 809. RO SCH3 ROH 2. Bromocatechol borane. Refer to the section on MOM ethers.

3. PPTS, t-BuOH, heat. Monti, H.; Leandri, G.; Klos-Ringuet, M.; Corriol, C. Synth. Comm. 1983, 13, 1021. 1. HgCl2, CH3CN, H2O. Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1976, 17, 3269.

2. AgNO3, THF, H2O, 2,6-lutidine. Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1976, 17, 3269.

2-(Trimethylsilyl)ethoxymethyl Ether: 3. MgBr2, n-BuSH, Et2O. Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett, 1992, 183.

H C 3 CH Si 3 ROH RO O CH3

+ – 1. n-Bu4N F , THF. Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.

2. TFA, CH2Cl2. Jansson, K.; Frejd, J.; Kihlberg, J.; Magnusson, G. Tetrahedron Lett. 1988, 29, 361.


7 Myers Protective Groups – Protection of Hydroxyl Groups, Ethers Chem 115

Formation of trityl ethers:

Ethers as Protective Groups: HO TrO O OCH3 O OCH Ph3CCl, DMAP 3


Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 19, 95. In general, selective protection of primary alcohols can be achieved.

Allyl Ether Trityl of trityl ethers:

RO 1. Amberlyst 15-H, MeOH. Malanga, C. Chem. Ind. 1987, 856. RO 2. CF3CO2H, t-BuOH. MacCross, M.; Cameron, D. J. Carbohydr. Res. 1978, 60, 206.

OCH3 Formation of benzyl ethers:

Benzyl Ether p-Methoxybenzyl Ether RO


R' Allylallyl ether formation: R' = H or OCH3

1. NaH, benzyl , THF. Czernecki, Czernecki, S.; S.; Georgoulis, Georgoulis, C.; C.; Provelenghiou, Provelenghiou, C. C. ROH RO Tetrahedron Lett. 1976,, 1717,, 3535.3535.

+ 2. p-CH3OC6H4CH2OC(=NH)CCl3, H . TheseThese areare usefuluseful conditionsconditions forfor base-sensitivebase-sensitive 1. NaH, allyl bromide, . Corey, E. J.; Suggs, W. J.; J. Org. Chem. 1973, 38, 3224. substrates.substrates. Horita, K.; Abe, R.; Yonemitsu, O.O. TetrahedronTetrahedron LettLett.. 19881988,, 2929,, 4139.4139. SimilarSimilar conditionsconditions havehave beenbeen developeddeveloped forfor benzylbenzyl ethers:ethers: White, J. D.; Reddy, G. N.; + 2. CH2=CHCH2OC(=NH)CCl3, H . This procedure is useful for base-sensitive substrates. Spessard,Spessard, G.G. O.O. J. J. Am. Am. Chem.Chem. Soc.Soc. 19881988,, 110110,, 1624.1624. Wessel, H.-P.; Iverson, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985, 2247.

3. p-CH3OC6H4CH2Cl, NaH, THF. Marco, Marco, J. J. L.; L.; Hueso-Rodriguez, Hueso-Rodriguez, J. J. A. A. Tetrahedron Tetrahedron Lett.Lett. 1988 1988, ,29 29, ,2459. 2459. Allylallyl ether cleavage: Cleavage of benzyl ethers:

1. The use of allyl ether protective groups in synthesis has been reviewed: Guibe, F. Tetrahedron 1998, 1. H / Pd-C, EtOH. Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746. 54, 2967. 2 Ammonium is often used as a source of H2: Bieg, T.; Szeja, W. Synthesis 1985, 76. 2. Pd(Ph3P)4, RSO2Na, CH2Cl2. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932. Cleavage of 4-methoxybenzyl ethers:

1. DDQ, CH2Cl2. Benzyl ethers are stable to these conditions. Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y. Yonemitsu, O. Tetrahedron 1986, 42, 3021.

P. Hogan

8 Myers Protective Groups – Protection of 1,2- and 1,3-Diols Chem 115

Protection of 1,2- and 1,3- Diols: The relative rates of hydrolysis of 1,2-O-alkylidene-_-glucofuranoses have been studied.

CH3 H3C CH3 HO H O O HO H O O CH3 CH OO OO OOOO OOOO HO O HO O 3 HOOH HOOH R' R R'nnn R R'R'R R'R'R n n n t1/2 = 8 h HO H O O t1/2 = 20 h HO H O O Ethylidene Acetal Cyclopentylidene Ketal Cyclohexylidene Ketal Acetonide HO O HO O HOOH HOOH t = 10 h t1/2 = 124 h OCH3 OCH3 1/2 OCH3 Van Heeswijk, W. A. R.; Goedhart, J. B.; Vliegenthart, J. F. G. Carbohydr. Res. 1977, 58, 337. O

OO OO OO OO General methods of cleavage:

R' R R' R R' R R'n R nn n R' R'' + HO OH Benzylidene Acetal 4-Methoxybenzylidene 3,4-Dimethoxybenzylidene Cyclic Carbonate OO H , H2O (ROH) Acetal Acetal R'n R R'n R • Generally, n = 0 or 1. R' R'' R' R'' R R'' Lewis acid plus donor OO H O OH OH O H General methods used to form acetals and ketals (illustrated for acetonides): R' R R' R R'n R n n H C CH 3 3 R'' H O O HO OH OO [O] O H+ OO R'' O OH OH O R'' R' R R' R H3C CH3 n n R' R n R'nn R R' R

Selective protection of : H3C CH3 • In general, acetonide formation with 1,2-diols occurs in preference protectionto 1,3-diols; to 1,3-diols; CH O OCH HO OH OO 3 3 H+ benzylidene acetals display reversed selectivity. ItIt isis oftenoften possiblepossible toto discriminatediscriminate between 1,2-between and 1,3-diols1,2- and of1,3-diols a triol group. of a triol group. H C CH 3 3 R'n R R'n R H3C CH3 OH OH CH3 HO , TsOH H3C O OH O O H3CH C CH3CH3 3 O HO CH OCH3 HO OH + OOO O 3 H CH CH3 3 H3C CH2 R' R 5 : 1 R'n R R'nn R Williams, D.D. R.; R.; Sit, Sit, S.-Y. S.-Y. J. J.Am. Am. Chem. Chem. Soc. Soc. 1984 1984, 106, 206, 2949., 2949.

P. Hogan

9 O O S CSA, H2O; 1) (CH ) CO, CuSO , TsOH S S H H S OH OH 3 2 4 O SOH p p-(CH-(CHO)CO)CHHCH(OCH(OCH ) ) H C 33 66 44 3 23 2 Cl 2) NaOH, EtOH 3 O OH CH2 O 67% over two steps O HOHO S O OTBDPS O OTBDPS 3) CuI, HH33CC CH OH O OH 2 MgBr H C O CSA = camphorsulfonic acid 82% 3 CH3 H3C

CH O Mortlock, S. V.; Stacey, N. A.; Thomas, E. J. J. Chem. Soc., Chem. Comm. 1987, 880. CH3O H CHC O H 3 3 SO H CH3 3 O O • In the case of a 1,2,3-triol, careful analysis must be performed to accurately predict the site of H3C acetonide formation. The more substituted acetonide will be favored in cases where the substiuents HH H3C on the resultant five-membered ring will be trans. If the substituents on the five-membered ring would H 3 H be oriented cis, then the alternative, less substituted acetonide may be favored. BzO HO HO HO OH OH HOOH OH Ingenol analog Ingenol

H HC3C CH3 3 H C CHCH Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 3 TsOH OO 3 3 O CH3 HH 121, 296. O HOHO OO HH OH 1:10 H3HC3C OH OH OO H ZnCl2, PhCHO H N OH N OH 71% N OBn N OBn

H3C Frankowski, A.; Deredas, D.; Le Noen, D.; Tschamber, T.; Strieth, J. CH3 O OH OTBS Helv. Chim. Acta. 1995, 78, 1837. H H O CH3CN, PPTS O CH3 CH3 H 83% H CH CH O CH OH 3 OH 3 HO OTBS 3 H3C TrO N p-(CH3O)C6H4CH(OCH3)2, TrO N OH OH N OO N PPTS, DMF, 23 °C, 96% MP OON HO CH3 O N O H H OH CH3 OH MP = p-methoxyphenyl HOHO O O N OH OH N Roush, W. R.; Coe, J. W. J. Org. Chem. 1989, 54, 915. See also, Mukai, C.; Miyakawa, M.; Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1997, 913. OON H Lampteroflavin, a source of bioluminescence. Isobe, M.; Takahashi, H.; Goto, T. Tetrahedron Lett. 1990, 31, 717. P. Hogan

10 Myers Protective Groups – Selective Protection of Chem 115

OCH • Selective protection methods are central to . The most common protective HO 3 groups in are acetonides, benzylidene acetals, and substituted benzylidene p-TsOH H O OH H C CH O OH acetals. ThisThis subjectsubject hashas beenbeen reviewed:reviewed: Calinaud,Calinaud, P.;P.; Gelas, Gelas, J. J. in in Preparative Preparative Carbohydrate Carbohydrate 2 3 O Chemistry.Chemistry. Hanessian, S. Ed. Marcel Dekker, Inc.: New York, 19971997.. H C HO OH 3 O OH 67% H3C H OH OH Selective Protection: thermodynamic control D-galactose

Gelas, J.; Horton, D. Carbohydr. Res. 1979, 71, 103. HO H3C 1 H C • Note that under kinetic control the most sterically accessible 6 5 O OH 3 O H4 acetone, H2SO4 O 1 (primary)(primary) alcoholalcohol preferentially is preferentially reacted. attacked. O 4 5 O CH • This reaction can be applied to many , including mannose, allose, and tallose HO 3 2 OH 55% 6 3 3 2 O Kinetic vs. thermodynamic control with a OH HO CH3 D- 1,2:5,6-Di-O-isopropylidene-D-glucopyranose Thermodynamic control HO HO O OH O OH acetone, MeOH Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318. H H 2-methoxypropene, HCl HO OH 70% O O

H3C CH3 OCH3 H OCH O OCH3 D-ribose HO 3 O OCHOCH3 Leonard, N. J.; Carraway, K. L. J. Heterocycl. Chem. 1966, 3, 485. O OCH 3 3 p-TsOH, O OH H Kinetic control DMF, 64% OH HO HO OH 2-methoxypropene O OH O OH OH p-TsOH, DMF, 50% H methyl-_-D-glucopyranoside HO OH OH O O H O O O Evans, M. E. Carbohydr. Res. 1972, 21, 473. HO H3C HO slow CH3 OCH3 O OH • Note the preference for 1,3-diol protection with the methyl 4,6-benzylidene-_-D-glucopyranoside benzylidene acetal. The is oriented fast exclusively as shown, in an equatorial orientation. HO OH OH The major in is the pyranose form (ʜ 80%). Under Selective Protection: kinetic control conditions that favor kinetic control, the least sterically encumbered in this form reacts preferentially. Isomerization is proposed to be slower than acetonide formation. This procedure also works well HO OCH3 with arabinose: H O OH H C CH O OH 2 3 O O OH 2-methoxypropene O OH H3C H HO OH p-TsOH O OH H3C H HO OH p-TsOH, DMF, 60-70% OH OH 95% OH O H OH O H3C D-glucose D-arabinose CH3

Gelas, J.; Horton, D. Carbohydr. Res. 1975, 45, 181. Wolfrom, M. L.; Diwadkar, A. B.; Gelas, J.; Horton, D. Carbohydr. Res. 1974, 35, 87. P. Hogan

11 HO O O OCH Protection of cis-vicinal diols: 3 (2,3-butanedione, OCH CH3 commercially 3 OH AcOOAc H3C HO available) H3C O O O OCH3 HO OH O O AcO H3C H OH O OCH _,_'-dichlorotoluene, CSA, CH(OCH3)3, MeOH, reflux. OCH3 OCH3 3 OH methyl-_-D-mannopyranoside O H 95% pyr, reflux, 58% O HO OH BF3•OEt2 is also an effective catalyst at 23 °C. OH AcOOAc Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, R. D.; Poisson, J.-F.; Warriner, S. L.; OOCH 3 Wesson., K. E. J. Chem. Soc., Perkins Trans. 1 1997, 2023. H X Generalities concerning the selective removal of acetals and ketals: HO O H O • Hydrolysis of the less substituted dioxane or ring occurs preferentially in • In general, cis-fused 5,6-systems substrates bearing two such groups. are formed faster than trans-fused 5,6-systems. OH O H H OH H H O O O AcOH, H2O Garegg, P. J.; Maron, L.; Swahn, C. G. Acta. Chem. Scand. 1972, 26, 518. O 80 °C, 85% H O O O O Formation of dispiroacetals as a protective group for vicinal trans diequatorial diols: H O CH3OO CH3OO

O OH O Kishi, Y.; Stamos, D.P. Tetrahedron Lett. 1996, 37, 8643 O HO CH3 OCH3 H3C dl-camphorsulfonic acid O CH H C O 3 3 O H H HO O O O H H HO HO O pH = 2, 40 °C O 76% O O HO O OCH3 CH3 CH3 methyl-_-L-fucopyranoside O 4 h HO H CH3 55% from O (derived from L-fucose) HO H CH3 glucose

Ley, S. V.; Leslie, R.; Tiffin, P. D.; Woods, M. Tetrahedron Lett. 1992, 4767. Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318. • 2,2-disubstituted2,2-disubstittued 1,3-dioxanes (6-membered rings) are generally hydrolyzed faster than the A cheaper alternative has also also been been developed: developed: corresponding (5-membered rings).

OH H O OAc O OH 1) 2-methoxypropene O HO CH3O OCH3 H C O OCH CH3 p-TsOH 3 O O 3 H3C OCH HO OH 3 OH 2) Ac2O, py CH3 H CH3O OCH3 HO OH O H3C O CH3 HO OH OO H C H3C D-mannose 3 OH CSA, CH(OCH3)3, MeOH, reflux OCH3 OCH3 methyl-_-D-mannopyranoside O OAc AcOH HO CH 91% 3 H2O HO O H3C O O 74% over O O O O Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org. Chem. 1996, 61, 3897. CH3 three steps H3C OAc H3C CH3 Horton, D.; Gelas, J. Carbohydr. Res. 1978, 45, 181. P. Hogan

12 H O OCH3 Lewis acid O OCH3 O OCH3 O BnO HO Special properties of benzylidene and substituted benzylidene acetals: hydride donor O OR' HO OR' BnO OR' H • In general, substitution of the ring of a benzylidene acetal with a p-methoxy OR OR increases the rate of hydrolysis by about an order of magnitude. OR A B

R' R' Lewis acid hydride donor (regioisomer) OCH3 Ac Ac TFA Et3SiH 95% (A)

Bn Bn TFA Et3SiH 80% (A) is more rapidly hydrolyzedhyrolyzed than than Bn Bn Bu2BOTf BH3•THF 87% (B) OO OO Bn Bn AlCl3 BH3•N(CH3)3 72% (A) R' R R'n R n Bn Bn HCl, THF NaBH3CN 82% (A)

Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G. J. Am. Chem. Soc. 1962, 84, 430. • The trifluroacetictrifluoroacetic acid/triethylsilane acid/triethylsilane reagent reagent was was ineffective ineffective with with a agalactose galactose derivative, derivative, howeverhowever thethe othersothers appearapperar to to be be general general methods. methods. Acetonides Acetonides and and other other ketals ketals and and acetals acetals • Benzylidene acetals can can also be cleaved from the diol reductively. Benzylidene acetals can also be cleaved from the diol reductively. cancan alsoalso bebe reduced,reduced, soso carecare inin syntheticsynthetic planningplanning mustmust bebe exercised.exercised.

Trifluoroacetic acid, triethylsilane : DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron Lett. 1995, 5, 669.

Dibutylboron triflate, borane: H , Pd-C, AcOH OO 2 HO OH Chan, T. H.; Lu, J. Tetrahedron Lett., 1998, 39, 355. or Aluminum trichloride, borane complex; R' R R'n R n NH3, Na () Garegg, P. J. Pure. Appl. Chem. 1984, 56, 845.

HCl, cyanoborohydride: OCH3 Qiao, L.; Vederas, J. C. J. Org. Chem. 1993, 58, 3480. TfOH, Kiessling, L. L.; Pohl, N. L. Tetrahedron Lett. 1997, 38, 6985.

Pd(OH)2, 25 °C, H2 Diisobutyl aluminum hydride is also an effective reagent for regioselective reduction of OO HO OH benzylidene acetals. This reagent gives the more hindered ether. R' R R'n R n Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.

Oxidation of benzylidene and substituted benzylidene acetals:

• Methods have also been developed to cleave only one - bond resulting inin • Acetals containing a may be oxidized at that position resulting in the formation thethe formationformation ofof aa benzylbenzyl ether.ether. ThisThis reactionreaction hashas beenbeen extensivelyextensively studiedstudied inin thethe contextcontext ofof of ahydroxy hydroxy esters. esters. carbohydrate chemistry. carbohydrate chemistry. R' R' [O] OO O OX


• This transformation can be effected under a variety of condtions, and someand some variants variants can becan be used to further functionalize a substrate. P. Hogan

13 General Reactions: Proposed Mechanism:

H H O OCH OO NBS O O Br OO NBS O O OH OOCH 3 3 O 3 NBS O • RR RRRRH2O RR nnnnO OH O OH H H OH OH In the methyl 4,6-O-benzylidenehexopyranoside series, the oxidative formation of bromo benzoates is a general reaction: H Br2 O OCH O OCH O 3 NBS, BaCO3 Br 3

O OH CCl4, 100% O OH H Br OH OH H O H O OCH3 O OCH O O 3 O OH H Br H O OCH 3 O OCH3 O OH O 3 NBS, BaCO Br H OH 3 OH O OH CCl , 67% O OH H 4 OH OH O

O OCH3 Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035, 1045, and 1053. Br

• This reaction has also been used to generate glycosylating reagents O OH OH H O H H O Br O O O Br O NBS, bromotrichloro- , then O CHH C O O CHH3C3 O O 3 3 H H H O O tetrabutylammonium O O O AcO AcO O H bromide H (anomerization) AcO OAc CH AcO OAc H C 3 • also cleaves acetals to hydroxy esters efficiently. This reaction has been OAc 3 OAc reviewed: Deslongchamps, P.; Atlani, P.; Frehel, D.; Malaval, A.; Moreau, C. O H O H Can. J. Chem. 1974, 52, 3651. O CH H 3 O CH3 O R' H H Hg(CN)2 CH O O O O H C 3 O 3 79% O H OO O3 R' O OH OH O R' over two steps O H OBz O CHH3C3 O OBz CH RR–78 °C H H 3 n RRnnRR O O CH AcO O O 3 H H HOOH AcO OAc OAc Collins, J. M.; Manro, A.; Opara-Mottah, E. C.; Ali, M. H. J. Chem. Soc., Chem. Comm. 1988, 272. P. Hogan

14 H OOO O + – OO O TMSDDQ, CuCl2, Bu4NClNCl X TMS

O OBz or PMPCOMBzO OBz • Hydroxy benzoates are obtained in the presence of . H OBz DDQ, CuBr , Bu +NBrNBr– OBz • The axial benzoate is usually obtained. CH O 2 4 33 X = Cl , 96% Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J. Org. Chem. 1984, 49, 992 O X = Br, 93% NC Cl PMP = p-methoxyphenyl OCH3 OCH3 DDQ = CH O NC Cl CH3 O OPiv NBS, BaCO3 3 OPiv O O OH O H2O, 72% O O Zhang, Z.; Magnusson, G. J. Org. Chem. 1996, 61, 2394. • 2-2-electron electron oxidationoxidation ofof 4-methoxybenzyl4-methoxybenzyl groupsgroups withwith DDQDDQ isis aa generalgeneral reaction.reaction.

• This has been used extensively to remove 4-methoxybenzyl ethers, and also to form 4-methoxybenzylidene acetals.

OCH3 OCH3 OCH CH O 3 3 OPiv OCH3 O O CH3 O OPv DDQ O H2O attacks exo face O TBSO O OH TBSO O OH HO H H OCH3 OCH3


OCH3 –H+

• Only this is available for donation into the other C-O m* orbital. TBSOTBSO O O H OCH3


Jones, A. B.; Yamaguchi, M.; Patten, S.; Danishefsky, S. J.; Ragan, J. A.; Smith, D. B.; King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754. Schreiber, S. L. J. Org. Chem. 1989, 54, 17. • Oxidation of 4-methoxybenzylidene acetals has also been studied: A useful extension of this reaction has been developed to protect diols directly:

H OOOO OCH3 O TMS OO CH CH DDQ, AcOH, H2O HO TMS 3 3 OCOPh CH3O OCOPh O OBz CH CH H MBzO OBz 3 OH 3 O OBz HO 2.2 equiv DDQ O CH3O OBz 71% MP H 79% (19% of regioisomer) Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983, 24, 4037. P. Hogan

15 Myers Protective Groups – Protection of Chem 115

Phenolic Protective Groups: t-Butyl Ether Formation:


Methyl Ether t-Butyl Ether Benzyl Ether Allyl Ether 1. , CF3SO3H, CH2Cl2, –78 °C. Holcombe, J. L.; Livinghouse, T. J. Org. Chem. 1986, 51, 11.

O O 2. t-Butyl , pyr. Masada, H.; Oishi, Y. Chem. Lett. 1978, 57. SiR O 3 O R O OR O OR

t-Butyl Ether Cleavage: Silyl Ethers Phenyl Esters Phenyl Carbonates Acetals

1. CF3CO2H, 25 °C. Beyerman, H. C.; Bontekoe, J. S. Recl. Trav. Chim. Pays-Bas. 1962, 81, 691. Ph Ph Si O t-Bu • For the other protective groups, the sections describing these groups in the context of alcohols should be consulted. Most of the preparations used for alcohols are applicable to t-Butyldiphenylsilylethyl Ether phenols. Hydroxyl protective groups that are cleaved with base are generally more labile with phenols.

Methyl Ether Formation: t-Butyldiphenylsilylethyl (TBDPSE) ether formation:

DIAD, PPh 3 Ph Ph Si OH O t-Bu OH OCH3 Ph Ph Si HO t-Bu

1. MeI, K2CO3, acetone. Vyas, G. N.; Shah, N. M. Org Synth., Collect. Vol. IV 1963, 836. • The TBDPSE group is stable to 5% TFA–CH2Cl2, 20% –CH2Cl2, catalytic 2. , Et2O. Bracher, F.; Schulte, B. J. Chem. Soc., Perkin Trans. 1 1996, 2619. , n-BuLi, and lead tetraacetate.

• The TBDPSE group has been cleaved using TBAF (2.0 equiv, 40 °C, overnight) or 50% TFA– Methyl Ether Cleavage: CH2Cl2.

Gerstenberger, B. S.; Konopelski, J. P. J. Org. Chem. 2005, 70, 1467. 1. Me3SiI, CHCl3, 25-50 °C. This reagent also cleaves benzyl, trityl, and t-butyl ethers rapidly. Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761.

2. EtSNa, DMF, reflux. Ahmad, R.; Saa, J. M.; Cava, M. P. J. Org. Chem. 1977, 42, 1228.

3. 9-Bromo-9-borabicyclo[3.3.0]nonane, CH2Cl2. Bhatt, M. V. J. Organomet. Chem. 1978, 156, 221. P. Hogan/Seth B. Herzon

16 Myers Protective Groups – Protection of the Chem 115

Carbonyl protective groups: Preparation of dimethyl acetals and ketals:

OCH3 O O R R R O CH3O OCH3 R' OCH R' O R' O 3 R R' R R'

dimethyl acetal 1,3-dioxane 1,3-dioxolane 1. MeOH, dry HCl. Cameron, A. F. B.; Hunt, J. S.; Oughton, J. F.; Wilkinson, P. A.; Wilson, B. M. J. Chem. Soc. 1953, 3864. SCH S S 3 O 2. MeOH, LaCl3, (MeO)3CH. Acetals are formed efficiently, but ketalization is unpredictable. R R R R Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1979, 44, 4187. R' SCH3 R' S R' S R' S 3. Me3SiOCH3, Me3SiOTf, CH2Cl2, –78 °C. Lipshutz, B. H.; Burgess-Henry, J.; Roth, G. P. S,S'-dimethylthioacetal 1,3-dithiane 1,3-dithiolane 1,3-oxathiolane Tetrahedron Lett. 1993, 34, 995.

General order of reactivity of carbonyl groups towards nucleophiles: 4. Sc(OTf)3, (MeO)3CH, toluene, 0 °C. Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett 1996, 839. (aliphatic > aromatic) > acylic ʜ cyclohexanones > cyclopentanones > _!`-unsaturated ketones ʜ _!_"disubstituted ketones >> aromatic ketones. • Other dialkyl acetals are formed similarly.

Cleavage of dimethyl acetals and ketals: Approximate rates (L mol –1s–1 at 25-30 °C) for proton-catalyzed (HCl, water or dioxane-water) cleavage of acetals and ketals. 1. TFA, CHCl3, H2O. These conditions cleaved a dimethyl acetal in the presence of a 1,3-dithiane and a dioxolane acetal. Ellison, R. A.; Lukenbach, E. R.; Chiu, C.-W. H3C OEt H OEt H OEt H OPh Tetrahedron Lett. 1975, 499.

OEt OEt OEt OEt 2. TsOH, acetone. Colvin, E. W.; Raphael, R. A.; Roberts, J. S. J. Chem. Soc., Chem. Commun. 1971, 858. CH3O 3. 70% H O , Cl CCO H, CH Cl , t-BuOH; dimethyl . Myers, A. G.; Fundy, M. A. 6 X 103 3 41 2 2 3 2 2 2 5 X 10 160 M.; Lindstrom, Jr. P. A. Tetrahedron Lett. 1988, 29, 5609.

O O O O H OEt H OEt H CH 3 O O O H3COEt H OEt O PvO PvO PvOPvO 70% H2O2 PvO H 5 1.2 1.6 –4 H H Me2S 1.5 X 10 Cl3CCO2H O H H MeOH O • In general, cyclic acetals are cleaved more slowly than their open chain analogs TBSOTBSO OCH3 TBSO OOH TBSOTBSO t-BuOH, CH2Cl2 TBSO 80% • In general, dithio acetals are not cleaved by Brønsted . OCH3 H 3 OCH3 Rates of acid-catalyzed cleavage of mono and acetals have been determined:

• Other methods resulted in cleavage of the . H OEt H SEt H SEt H SEt


160 41 1.3 3.5 X 10–4

Satchell, D. P. N.; Satchell, R. S. Chem. Soc. Rev. 1990, 19, 55.

P. Hogan

17 Cyclic acetals and ketals: • When protecting _,ß-unsaturated ketones, olefin isomerization is common.

Relative rates of ketalization with common diols: CH3 OH CH3 CH3 HO + O O H3C CH3 > OH > HOOH OH O acid HO OH HO O O A B

Cleavage of 1,3-dioxolanes vs. 1,3-dioxanes: Strong acids (pKa ʜ 1) tend to favor isomerization, while weaker acids (pKa • 3) favor isomerization much less so, or not at all.

O acid pK %A %B % conversion RR R O a > R' 100 0 90 R' O R' O 3.03 phthalic acid 2.89 70 30 90

Relative rates of cleavage for 1,3-dioxolanes: 1.23 80 20 93 0 100 100 TsOH < 1.0 CH3 CH3 R O CH R O R O 3 > > De Leeuw, J. W.; De Waard, E. R.; Beetz, T.; Huisman, H. O. Recl. Trav. Chim. Pays-Bas. R' O R' O R' O 1973, 92, 1047.

50,000 5000 1 • Generally, methods used for formation of 1,3-dioxolanes are also useful for formation of 1,3-dioxanes. Okawara, H.; Nakai, H.; Ohno, M. Tetrahedron Lett. 1982, 23, 1087.

Cleavage of 1,3-dioxanes and 1,3-dioxolanes: • In general, saturated ketones can be selectively protected in the presence of _!`-unsaturated ketones. 1. PPTS, acetone, H2O, heat. Hagiwara, H.; Uda, H. J. Chem. Soc., Chem. Commun. O 1987, 1351. O CH3 O O H3C H3C O Et 2. 1M HCl, THF. Grieco, P. A.; Nishizawa, M.; Oguri, T. Burke, S. D.; Marinovic, N. J. Am. Chem. Soc. 1977, 43, 4178. OH O HO O 3. Me2BBr, CH2Cl2, –78 °C. This reagent also cleaves MEM and MOM ethers. p-TsOH•H2O, 95% Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983, 24, 3969. Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, T.; Tatsuoka, T.; Meinwald, J. 4. NaI, CeCl3•7H2O, CH3CN. Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.; J. Org. Chem. 1986, 51, 773. Sambri, L. J. Org. Chem. 1997, 62, 4183. This method is selective for cleavage of ketals in the presence of acetals. It is also selective for ketals • Conditions have been developed to protect _!`-unsaturated ketones selectively. of _,ß-unsaturated ketones over ketals of saturated ketones. O O H C H C 3 OTMS 3 O O TMSO CH3 CH3 O H3C NaI, CeCl 7H O H3C TMSOTf, CH Cl O 3• 2 O O 2 2 CH CN –78 °C, 92% O H C H 3 H C H 3 23 °C, 2h 3

Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357. O H H 88% H H O O P. Hogan

18 Dithioacetals: InIn additionaddition toto servingserving asas aa protectiveprotective group,group, S,S, SS''-dialkyl-dialkyl acetalsacetals serveserve asas anan umpolungumpolung synthon in the construction theof carbon-carbon of carbon-carbon bonds. bonds. General methods of formation of S,S''-dialkyl acetals:

O SR = O see below S SR S R R SR R R R RR R' S R' SR R' S

1. RSH, HCl, 20 °C. Zinner, H. Chem. Ber. 1950, 83, 275. CH3O O CH3 Li CH CH3O O CH3 O 3 O SS 2. RSSi(CH3)3, ZnI2, Et2O. Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J. Am. O O Chem. Soc. 1977, 99, 5009. CH3O CH2 CH3O CH2 3. RSH, BF •Et O, CH Cl . Marshall, J. A.; Belletire, J. L. Tetrahedron Lett. 1971, 871. See also S 3 2 2 2 Cl Hatch, R. P.; Shringarpure, J.; Weinreb, S. M. J. Org. Chem. 1978, 43, 4172. _!`-Unsaturated 60% CH3 ketones are reported not to isomerize under these conditions. However, with any of the above S mentioned conditions conjugate addition is a concern.

• A variety of methods has been developed for the cleavage of S,S''-dialkyl acetals, largely CH3O O CH3 due to the fact that these functional groups are often difficult to remove. O O

CH3O O Cl General methods of cleavage of S,S''-dialkyl acetals:


1. Hg(ClO4)2, MeOH, CHCl3. Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron Lett. 1989, 30, 15, and references therein. Garbaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000, 2, 3127. 2. CuCl2, CuO, acetone, reflux. Stutz, P.; Stadler, P. A. Org. Synth. Collect. Vol. 1988, 6, 109.

3. m-CPBA; Et3N Ac2O, H2O. Kishi, Y.; Fukuyama, T.; Natatsuka, S. J. Am. Chem. Soc. 1973, 95, 6490.

4. (CF3CO2)2IPh, H2O, CH3CN. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.

P. Hogan

19 Myers Protective Groups – Protection of the Carboxyl Group Chem 115

Carboxyl Protective Groups: O BOPCl, Et3N, O R'OH R OH R OR' O CH CH2Cl2 O 3 O O CH3 CH CH3 3 R OCH3 R O CH3 R O R O Cl O N N O BOPCl = Methyl t-Butyl Ester Allyl Ester 1,1-Dimethylallyl Ester P O O O

Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.; Zugaza-Bilbao, A. O O O O Synthesis, 1980, 547.

R O CF3 R O R O R O Methyl esters: OCH3 Formation: 2,2,2-Trifluoroethyl Ester Phenyl Ester Benzyl Ester 4-Methoxybenzyl Ester O O

R OH R OCH3 OR O R' O R' O R' OR SiR 1. TMSCHN , MeOH, benzene. Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. 3 O O 2 R O OR O O Bull. 1981, 29, 1475. This is considered a safe alternative to using diazomethane. R'' 2. MeOH, H2SO4. Danishefsky, S.; Hirama, M.; Gombatz, K.; Harayama, T.; Berman, E.; R'' Schuda, P. J. Am. Chem. Soc. 1978, 100, 6536. Silyl Ester Ortho Ester 1,3-Dioxalone 1,3-Dioxanone Cleavage: Specific to !- and "-hydroxy acids 1. LiOH, MeOH, 5 °C. Corey, E. J.; Szekely, I.; Shiner, C. S. Tetrahedron Lett. 1977, 3529. 2. Pig . This is often effective for the enantioselective cleavage of a meso diester. General preparations of esters: O O PLE OCH3 OH O EDC•HCl or DCC, DMAP O OCH3 pH = 6.8 OCH3 R'OH 98%, 96% ee R OH R OR' O O Kobayashi, S.; Kamiyama, K.; Iimori, T.; Ohno, M. Tetrahedron Lett. 1984, 25, 2557. EDC•HCl = 1-[3-(dimethylamino)propyl]-3-ethyl hydrochloride O O H3C PLE N N C N Et O CH3O O OCH3 •HCl CH O CH3 3 OCH3 O O DCC = dicyclohexylcarbodiimide O O CH O 3 OH N C N O er = 21.5

EDC•HCl is more expensive, but the by-product is water soluble and simplifies the Mohr, P.; Rosslein, L.; Tamm, C. Tetrahedron Lett. 1989, 30, 2513. purification of products P. Hogan/Seth B. Herzon

65 20 t-Butyl esters 1,1-Dimethylallyl esters

Formation: Formation:

CH3 O O 1. CH3 CH CH3 3


O CuI, Cs2CO3 O CH3 CH3 1. Isobutylene, H2SO4, Et2O, 25 °C. McCloskey, A. L.; Fonken, G. S.; Kluiber, R. W.; Johnson, W. S. Org. Synth., Collect. Vol. IV. 1963, 261. R OH R O 2. H2, Lindlar's .

2. 2,4,6-trichlorobenzoyl chloride, Et3N, THF; t-BuOH, DMAP, benzene, 20 °C. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. • The 1,1-dimethylallyl ester is removed under the same conditions as an allyl ester, but is less 3. t-BuOH, EDC•HCl, DMAP, CH2Cl2. Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org. Chem. susceptible to nucleophilic attack at the acyl carbon. 1982, 47, 1962. Sedighi, M.; Lipton, M. A. Org. Lett. 2005, 7, 1473. 4. i-PrN=C(O-tBu)NH-i-Pr, toluene, 60 °C. Burk, R. M.; Berger, G. D.; Bugianesi, R. L.; Girotra, N. N.; Parsons, W. H.; Ponpipom, M. M. Tetrahedron Lett. 1993, 34, 975.

Benzyl esters Cleavage:

O O 1. CF3CO2H, CH2Cl2. Bryan, D. B.; Hall, R. F.; Holden, K. G.; Huffman, W. F.; Gleason, J. G. J. Am. Chem. Soc. 1977, 99, 2353. R OH R O 2. Bromocatechol borane. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

Benzyl esters are typically prepared by the methods outlined in the general methods section.

Allyl esters Cleavage: Formation:

1. H2, Pd–C. Hartung, W. H.; Simonoff, R. Org. React. 1953, 7, 263. 2. BCl3, CH2Cl2. Schmidt, U.; Kroner, M.; Griesser, H. Synthesis 1991, 294. O O

R OH R O Phenyl esters Formation:

1. Allyl bromide, Cs2CO3, DMF. Kunz, H.; Waldmann, H.; Unverzagt, C. Int. J. Pept. Res. 1985, 26, 493. O O 2. Allyl alcohol, TsOH, benzene, (–H2O). Wladmann, H.; Kunz, H. Liebigs Ann. Chem. 1983, 1712. R OH R O

Cleavage: Phenyl esters are typically prepared by the methods outlined in the general methods section. They have the advantage of being cleaved under mild, basic conditions.

1. The use of allyl esters in synthesis has been reviewed. Guibe, F.: Tetrahedron 1998, 1. H2O2, H2O, DMF, pH = 10.5. Kenner, G. W.; Seely, J. H. J. Am. Chem. Soc. 1972, 94, 54, 2967. 3259. 2. Pd(Ph3P)4, RSO2Na, CH2Cl2. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932. P. Hogan/ Seth B. Herzon

21 Ortho Esters: The synthesis of simple ortho esters has been reviewed: Dewolfe, R. H. Synthesis, 1974, 153.

OBO ester

O O 1. Esterification O O R CH3 R OH HO O CH3 2. BF3•OEt2, CH2Cl2 –15 °C.

Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571.

Alternatively, ortho esters can be prepared from a :

1. HCl, MeOH O Br CN Br O 2. OH O

HO OH 68%

Voss, G.; Gerlach, H. Helv. Chim. Acta. 1983, 66, 2294.

Special , !-Hydroxy and "-Hydroxy:

n n R O R O


R'' Formation:

1. or , Sc(NTf2)3, CH2Cl2, MgSO4. Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett 1996, 839. 2. Pivaldehyde, acid catalyst. Seebach, D.; Imwinkelried, R.; Stucky, G. Helv. Chim. Acta. 1986, 70, 448, and references cited therein.

P. Hogan

67 22 Myers Protective Groups – Protection of the Amino Group Chem 115

Protection of : Formation of :


If primary amines are the starting materials, dibenzylamines are the products. 9-Fluorenylmethyl Methyl 9-Fluorenylmethyl Carbamate 2,2,2-Trichloroethyl Carbamate t-Butyl Carbamate Carbamate 2,2,2-trichloroethyl Carbamate t-Butyl Carbamate O RHN (Fmoc) (Troc) (Boc) RNH Mix and remove water; 2 H NaBH , alcoholic solvent O O O O 4 RR'N RR'N RR'N RR'N O O O CF3 Si(CH3)3 Formation of :

2-(Trimethylsilyl) Allyl Carbamate Benzyl carbamate Base Trifluoroacetamide Br RR'NH RR'N (Teoc) (Alloc) (Cbz)

If primary amines are the starting materials, diallylamines are the products.

RR'N RR'N RR'N , OAc RR'NH RR'N Pd(PhPd(PPh3P)3)4

Benzylamine Tritylamine Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109. General preparation of carbamates:

Formation of tritylamines: O O Base RR'N RR'NH RO Cl OR


O Base O RR'NH RR'N RO O–Su Mutter, M.; Hersperger, R. Synthesis 1989, 198. OR Su = succinimide

Bases that are typically employed are tertiary amines or aqueous . P. Hogan

23 Cleavage of carbamates: 2,2,2-Trichloroethyl Carbamate:

Methyl Carbamate: O RR'N O O RR'NH RR'N RR'NH CCl3 OCH3

1. Zn, H2O, THF, pH = 4.2. Just. G.; Grozinger, K. Synthesis, 1976, 457. 1. TMSI, CH2Cl2. Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc. 1987, 109, 442. 2. Cd, AcOH. Hancock, G.; Galpin, I. J.; Morgan, B. A. Tetrahedron Lett. 1982, 23, 249. 2. MeLi, THF. Tius, M.; Keer, M. A. J. Am. Chem. Soc. 1992, 114 , 5959. 2-Trimethylsilylethyl Carbamate: 9-Fluorenylmethyl Carbamate:


+ – 1. Bu4NNF,F KF, KF•H•H2O,2O, CH CH3CN,3CN, 50 50 ºC. °C. Carpino, Carpino, L. A.;L. A.; Sau, Sau A. A.C. C. J. J.Chem. Chem. Soc., Soc., Chem. Chem. Commun. 1979, 514. 1. base. The half- for the deprotection of Fmoc-ValOH have been studied:studied Atherton, E.; Sheppard R. C. in The , Udenfriend, Udenfriend, S. S. and and Meienhefer Meienhefer Eds., Eds., 2. CF3COOH, 0 °C. Carpino, L. A.; Tsao, J. H,; Ringsdorf, H.; Fell, E.; Hettrich, G. J. Chem. Academic Press: New York, 1987, Vol. 9, p. 1. Soc., Chem. Commun. 1978, 358.

Amine base in DMF Half-Life 3. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), DMF. Roush, W. R.; Coffey, D.S.; Madar, D. J. J. Am. Chem. Soc. 1997, 49, 2325. 20% piperidine 6 s

5% piperidine 20 s t-Butyl Carbamatecarbamate:

50% 1 min O 50% 35 min RR'N CH3 O CH3 RR'NH 10% p-dimethylaminopyridine 85 min CH3 50% diisopropylethylamine 10.1 h

2. Bu +NF,F–, DMF.DMF. Ueki, Ueki, M.; M.; Amemiya, Amemiya, M. M. Tetrahedron Tetrahedron Lett. Lett. 1987 1987, 28, 28, 6617., 6617. 1. CF3COOH, PhSH. Thiophenol is used to scavenge t-butyl cations. TBS and TBDMS ethers 4 are reported to be stable under these conditions. Jacobi, P, A.; Murphree, F.; Rupprecht, F.; Zheng, W. J . Org. Chem. 1996, 61, 2413. + – 3. Bu4NF,F , nn-C-C88HH1717SH.SH. Thiols can can be be used used to to scavenge scavenge liberated liberated fulvene. fulvene. Ueki, M.; Nishigaki, N.; Aoki, H.; Tsurusaki, T.; Katoh, T. Chem. Lett. 1993, 721. 2. Bromocatecholborane. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

P. Hogan

24 Allyl Carbamate: :


1. Pd(PhPd(PPh3P)3)4, Bu3SnH, AcOH, 7070– –100% 100% yield. yield. Dangles, Dangles, O.; O.; Guibe, Guibe, F.; F.; Balavoin, Balavoin, G.; G.; Lavielle, Lavielle, S.; Marquet, A. J. Org. Chem. 1987, 52, 4984. 1. Pd–C, ROH, HCO2NH4. Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.

2. Pd(Ph3P)4, (CH3)2NTMS, 89 – 100% yield. Merzouk A.; Guibe, F. Tetrahedron Lett. 1992, 2. Na, NH3. Bernotas, R. C.; Cube, R. V. Synth. Comm. 1990, 20, 1209. 33, 477. Allylamine:

Benzyl Carbamate: RR'N RR'NH

O RR'N 1. Pd(Ph3P)4, RSO2Na, CH2Cl2. Most allyl groups are cleaved by this method, including O RR'NH allyl ethers and esters. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932.


1. H2/Pd–C./Pd–C. Bergmann,Bergmann, M.;M.; Zervas,Zervas, L.L. Chem.Chem. Ber.Ber .1932 1932, ,65 65, ,1192. 1192. RR'N RR'NH 2. H2/Pd–C,/Pd–C, NH3. TheseThese conditionsconditions cleavecleave thethe benzylbenzyl carbamatecarbamate inin thethe presencepresence ofof aa benzylbenzyl ether. Sajiki, Sajiki, H. H. Tetrahedron Tetrahedron Lett. Lett. 1995 1995, ,36 36, ,3465. 3465.

3. BBr3, CHCH22ClCl22.. Felix, Felix, A. A. M. M. J. J.Org. Org. Chem. Chem. 1974 1974, 39, 39, 1427., 1427.

4. Bromocatecholborane. This reagent is reported to cleave benzyl carbamates in the presence 1. 0.2% TFA, 1% H2O, CH2Cl2. Alsina, J.; Giralt, E.; Albericio, F. Tetrahedron Lett. 1996, of benzyl ethers and TBS ethers. Boeckman Boeckman Jr., Jr., R. R. K.; K.; Potenza, Potenza, J. J. C. C. Tetrahedron Tetrahedron Lett. Lett. 37, 4195. 1985, 26, 1411.



1. K2CO3, MeOH. Bergeron, R. J.; McManis, J. J. J. Org. Chem. 1988, 53, 3108.

P. Hogan

25 Myers Protective Groups – Protection of a Terminal Chem 115

• Buffered TBAF was used to deprotect the silylalkynessilyalkynes inin thethe exampleexample shownshown belowbelow toto preventprevent protecting groups: elimination of the sensitive vinyl bromide.

Cl N Cl N R SiR'3 H3C CH3 H3C CH3

O O O O O O trialkylsilylalkyne TBAF, o-nitrophenol HO OTBS HO OH Br THF, 87% Br

• Typical silyl groups include TMS, TES, TBS, TIPS, and TBDMS.TBDPS. Many silyl are TBS H commercially available, and are useful acetylene equivalents. TBS H

General preparation of silyl acetylenes: Myers,Myers, A. A.G.; G.; Goldberg, S. D. Angew. Chem., Int. Ed. Engl. 2000, 1539, 2732.

R'3SiX RM R SiR'3

M = Li, Mg X= Cl, OTf

• Silyl chorides are suitable for smaller silyl groups, but the preparation of more hindered silyl acetylenes may require the use of the more reactive silyl triflate.

• In general, a strong fluoride source such as TBAF is used to cleave silylalkynes. In the case of trimethylsilylalkynes, milder conditions can be used.


Cleavage of trimethysilylalkynes:

1. KF, MeOH, 50 °C. Myers, A. G.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1991, 113, 694.

2. AgNO3 ,2,6-lutidine. 2,6-lutidine. Carreira, Carreira, E. E. M.; M.; Du Du Bois, Bois, J. J. J. J. Am. Am. ChemChem. Soc. Soc. 1995 1995, ,117 117, ,8106. 8106.

3. K2CO3, MeOH. Cai, C.; Vasella, A. Helv. Chim. Acta. 1995, 78, 732.

P. Hogan