Protecting Groups in Organic Synthesis-1 Ready

Transcription

1 Protecting Groups in rganic Synthesis-1 eady Protecting Groups for Alcohols Protecting groups are a sad fact of synthetic chemistry They are usually needed, but rarely desired Many syntheses have stalled because of trouble putting on or removing protecting groups 4 basic questions to address when choosing a P.G.: 1. Can I put it on where and only where I want? 2. Can I take it and only it off? 3. Will it survive all future reaction conditions? 4. Will it affect the reactivity of my substrate? Your guide to these questions should be: Protective Groups in rganic Synthesis by Theodora Greene and Peter Wuts An even better strategy is to plan your syntheses to avoid protecting groups We will discuss general features of protecting groups, for specific examples and exotic methods for attachment or removal, see Greene Si TMS 4 major classes: silyl ethers, ethers, esters, acetals Si TES Si TBS or TBDMS Silyl Ethers TBS: Corey, JACS, 1972, 6190 (23rd most cited JACS paper) : 3 Si, Imidazole DMF via 3 Si Si TIPS Si 3 Si TBDPS 3 SiTf 2,6-lutidine, C 2 2 Si 3 These transformations are very water sensitive.

2 Protecting Groups in rganic Synthesis-2 eady Less Common methods for Silyl introduction: Brook earrangement SiMe 2 tbu Li Li SiMe 2 tbu _ X bond Si 3 BDE (kcal/mol) Si 3 _ X TBS Li C Si Si F Si /2 equiv. I 2 question: using approx. pka values and the BDE above, estimate Keq for different 's in the equation 1. 74% TBS SiMe t 2 Bu t Bu DBU DMS TBS t Bu TL, 1998, 5243 ther potential methods: TBS Corey, JACS, 2002, ydrosilylation of ketones: always some stupid silyl group Tamao oxidation of alkyl silanes: Silyl group rarely survives

3 Protecting Groups in rganic Synthesis- 3 eady silyl migrations -smaller is faster -1,2 and 1,3 most common -good if planned; usually not planned emoval Usually F - or Usually, bigger is more stable TBS DBU 83% TBS ote: 2 primary alcohols would make selective protection difficult how does this happen? TBDPS Bn >95%ee Br a C TBDPS Molander, JC 1994, 7148 Bn C % ee Welzel, Tet, 1987, 3803 Si 3 Silyl group - or k rel k rel - TMS 5,000, ,000 TES 100,000 50,000-5,000 TBDMS TIPS 10 5 TBDPS 1 1 ecall BDE: -Si (~100 kcal/mol) vs F-Si (~140 kcal/mol) Common F - sources: Migrations likely via associative displacement: - Si 3 Si - pentavalent intermediate 3 Si - TBAF (nbu 4 F) F-Pyridine 3F-Et 9 F TASF [tris(dimethylamino)sulfonium difluorotrimethylsilicate] Me 2 S Me 2 Me2 F F Si 3 C C 3 C 3

4 Protecting Groups in rganic Synthesis-3 eady relative rates of Fluoride-induced cleavage: Selective cleavage (review: Synthesis, 1996, 1065) TES Silyl group TBDMS Piv 2% F, C 3 C TBDMS Masamune, TL, 1985, 5239 Commercial TBAF is wet (to varying degrees). Dry TBAF is very basic; may need buffer: TBS TIPS texdms TBDPS TPS 1/2 life 20 min 15 min 15 min 50 min 2.5h = TBS = TBAF Ac, 7d, 37% Piv Conditions often need to be determined empirically Ac Ac TBS TBS Ac Ac TBS C 2tBu 90% Ac Ac C 2tBu 1 Ac C 3 Ac F-Pyridine C 3 C Ac C 3 Ac Ac TBS C 3 Ac 2 CC 2 90% F 3 C 2 F-Et 3 TBAF Ac C 2tBu 1 Ac C 3 Ac C 3 Carreira, Du Bois JACS, 1995, 8106

5 Protecting Groups in rganic Synthesis-5 eady Ethers usually very robust, with orthogonal modes of removal usually: common ethers: ' LG ' Methyl ether: easy on, hard off. Usually only good for phenols n: MeI, Me 2 S 4, Me 3 BF 4 ff: BBr 3, TMSI, Benzyl ether (Bn) n: usually Bn base; somtimes with cat. I - (do you know what I - does?) ff: 2, Pd/C - competitive (usually slower) than olefin reduction Lewis Acid: S 1 mechanism allyl ether on: usually allyl Br/ base. Usually easy Bu 2 Sn Bu Sn This is a general method for monprotection of a 1,2 diol (not limited to allyl). In this case, note selective formation with equitorial 's. Bu "stanylene acetal" Br 95% gawa, TL, 1988, 4097 ff: Isomerization with base or transition metal, then hydrolysis: a/ 3 2e -, _ B- or M 3 Cr 3 : via benzoate Cr - 3

6 Protecting Groups in rganic Synthesis-6 eady p-methoxybenzyl (PMB or MPM) n: PMB-, base CF 3 or Lewis Acid ff: xidation [] [] = DDQ, CA, 3 C BF 4, Br 2, BS intermediate can be intercepted: PMB Me DDQ 2 F 3 C Me 2 o-nitrobenzyl ff: hν example: 2 pka Ar = hν Triphenyl Methyl (trityl) n: 3 C, via S 1 Wen-ong Li, JACS, 2004, nm hν 1,5 abstraction 2 - C 2 - C 2 - C 2 - C 2 non-fluorescent fluorescent offman, ACIEE, 1993, 101 ff: Acid

7 Protecting Groups in rganic Synthesis-7 eady acetals of mono-ols: many eg's of the form advantages: acetals ' ' very active electrophile likely forms ' Tetrahydropyranyl (TP) Easy on, easy off, cheap. But get diastereomers with chiral molecues: Methoxy Methyl (MM) n: 'MM-' thought to be very toxic even more toxic ff: Acid can complicate M spectra (and sometimes chromatography) Benzyloxy methyl (BM) n: ff: all the methods for removing Bn groups: TES TES Li/ 3 Masamune, TL, 1985, 5239 TES

8 acetal protection of diols Protecting Groups in rganic Synthesis-8 eady Cyclic acetal are wonderful protecting groups for 1,2 and 1,3 diols. Some of the most common: Me cat. Ts 75% Corey...Falck...JACS, 1978, 4620 reactions often under thermodynamic control: 'acetonide' most stable Usually, 1,2 >1,3>1,4 least stable Ts 1:10 5 : 1 Ts >100:1 n: Me Me Cat. Me cat. or why not acetone? int: Consider pka's of protonated ketones vs ethers oxonium intermediates can be intercepted C 2 Bn C 2 Bn Me 3 Al C 2 Bn t Bu C 2 Bn TL 1988, 1823

9 benzylidene acetals Protecting Groups in rganic Synthesis-9 eady Me n: C/ or Lewis acid Al 2 ff: 3 or 2 Pd/C Can be converted to benzyl: P Me 2 C C 2 Me do you know how? Me i Bu 2 Al Bn Al 2 P >20:1 P P 1.404A Me 1.417A P from X-ray Bn P Schreiber, TL, 1988, Usually see protection of less hindered For protection of more hindered by a similar reaction, see Yamamoto, TL, 1988,

10 Protecting Groups in rganic Synthesis-10 eady diols can be protected as diacetals: CSA, C(Me) 3 Me Me Me Me Ley, Perkin 1, 1997, 2023 in situ generated active ester carbodiimides: " ' via " " '' ' " " Esters as protecting groups rxn is 'self-drying' removal of urea can be trouble most common egs: In general, ease of introduction and removal is function of sterics and electronics usually: egs ' LG ' DIC - liquid at rt, easy to use on small scale DCC - mp=34 o C reported sensitizer increased solubility EDCI - can extract urea with acid ' ' ' ' 'Yamaguchi conditions' more often for macrolactonizations BP-: P ' Et 3 ' Include C22 synthesis, 1980, 547

11 Protecting Groups in rganic Synthesis- 11 eady eavage: base hydrolysis rates depend on sterics and electronics desymmetrization stability to base F 3 C Me Piv Bz Ac TFA more stable less stable Ac Ac Ac lipase 96%ee for references, see Greene, 3rd ed.p156 Lipases: ester (usually Ac) on or off under mild conditions; often enantioselectively kinetic resolution (rac)- Ac 2 Lipase Ac 44%, 100%ee 54%, 88%ee TL, 1992, 1911

12 Protecting Groups in rganic Synthesis-12 eady Carbonates similar deal as with esters, but more stable to base. Also, some alternative cleavage methods possible. group Fmoc Troc Teoc SiMe 3 LA cleavage B B= Et 3, T 1/2 =20min Zn(0) or SiMe 3 SiMe 3 Zn LA=lewis acid pka ~ 10 F - Dimethyl Thiocarbamate on: a; S Me 2 or S ; Me 2 S Me 2 S stable to: Cr(VI); EtMgBr; DIBAL; LiAl 4; B 3 ; Me nbuli; Wittig; TBAF; DDQ; Ti 2 4 FF: S Me 2 or a/ 2 2 ai 4 S Me 2 2 Alloc cat Pd(0) u Pd II u C 2 Falck, rg. Lett., 2003,4755 u

13 Protecting Groups in rganic Synthesis-13 eady Protection for carboxylate Mostly, same deal as ester and carbonate ortho esters: not electophilic, no acidic protons step 1 K, Et Et common Eg's protected substrate Me CF 3 deprotection K 2 C 3 /Me (TFA,, Ts) step 2 eg Br various ways BF 3 Et 2 Corey, TL 1983, BF 3 Et 2 2. P 3 3. K(TMS) 3 3 P Pd(0), u C C 2 Me as before, enzymes can work Me Me PLE 96%ee 2 Pd/C or Li/ 3 Me PLE = pig liver esterase When enzymes work, they're nearly perfect. ard to get ent-ple cat 2 S 4 1. LiAl4 2. o- 2 C 6 4 SeC Bu 3 P 3. mcpba 0.3M a C 2 Me C 2 Corey, JACS, 1985, 4339

14 Protecting Groups in rganic Synthesis-14 eady Protection for amines Mostly carbamates; same deal as ester and carbonate n: 2 Group 2 Me -Su Bt F F emoval F a; PrSLi F F Group Boc SiMe 3 Teoc alloc Cbz emoval acid (TFA most common) F - (TBAF most common) Pd(0), u Meldrum's acid; common u 2, Pd/C; a/ 3 2 Fmoc amine base (piperidine most common) 2 CF 3 TFA a 2 C 3 Troc Zn(0)

15 Protecting Groups in rganic Synthesis- 15 eady Benzyl groups for amine protection n: Sulfonates Tosyl: Easy on (Ts); can be difficult to remove osyl (s) nice alternative: simple alkylation can be difficult 2 Bn Bn Bn 2 Bn 3-2 step method Bz LiAl 4 2 reductive amination C 8 17 C 2 Me S s s Br 3 5 DEAD, P 3 C 8 17 s s C 2 Me Br 5 2 Ac, acb 3 Schiff's bases: Many examples, benzhydryl one of most common C 8 17 s s S S S DBU Cs 2 C 3 0.1M 86% s -3 S 2-3 SAr ucleophilic aromatic substitution C 8 17 s s C 8 17 Br 5 s eview: Fukuyama Chem Comm. 2004, 353

16 Protecting Groups in rganic Synthesis-16 eady Protection of carbonyl group mostly of the form: X Y X and Y =, S,, C Most common: eavage: usually hydrolysis or transketalization. elative rate usually follows cation (oxonium) stability PPTS, acetone 2, 100% Me Me dimethyl acetal MeS SMe dimethyl thioacetal 1,3 dioxane S S 1,3 dithiane 1,3 dioxolane S S 1,3 dithiolane Dithioacetals 1M 71% acetals: Formation: (C 2 ) n ketone Ts or relative rates: for the ketone, relative rates same as normal addition to carbonyls: aldehyde>acylic ketone~cyclohexanone>cyclpentanone>enone>>aromatic ketone > > Me Me Me C Me S S BF 3 -Et 2 most common conditions other lewis acids work, too C 2 Et Me Weinreb, JC, 1978, 4172 C 3 I Me Me, 2 Me Me S S 90% S S C C 2 Et Many variations on this theme; in practice, consult Greene ther ffs: Sulfur-loving metals (g II ), [] (IBX, BS, I 2 )