Aminohydroxylation of Olefins: Development and Applications

Aminohydroxylation of lefins: Development and Applications by Manish awat Michigan State University Jan 17 th, 2001

utline 1. Aminohydroxylation of olefins a. t-butyl amine as source b. Chloramine-T as source c. -Argentocarbamates as source 2. Asymmetric aminohydroxylation (AA) of olefins a. Chloramine-T/M as source b. -Sodiocarbamates as source c. -Chloro--sodio trimethylsilylethoxycarbamates as source d. -Bromo--lithio carbamides as source 3. egioselectivity in AA reaction 4. AA on some useful substrates 5. Synthetic applications 6. Conclusion

Dihydroxylation of lefins Pyridine s + s 1 2 3 M s 4 H 2 H H 5

Dihydroxylation of olefins M + 1 2 M 1 2 H 1 H 2 analogue of transition metal oxo compound ' M M Aminohydroxylation of olefins M ' + 1 2 M ' 1 2 'H 1 H 2

1975 t-butylamine as Source for Aminohydroxylation s H 2 s 1 2 2 s CH 2 Cl 2 1 + 1 3 (1 eq.) CH 2 Cl 2 4 s 2 LAH, Et 2 1 s 2 7 LAH, Et 2 1 H H 6 2 + 1 H H 5 2 Sharpless, K. B.; Patrick, D. W.; Truesdale, L. K.; Biller, S. A. J. Am. Chem. Soc. 1975, 97, 2305-2307.

H t-butylamine as itrogen Source for Aminohydroxylation lefin Amino alcohol Solvent % yield % yield Amino alcohol Diol 1- Decene ( ) 62 6 7 Pyridine 78 1 HtBu CH 2 Cl 2 Me tbuh H Me CH 2 Cl 2 Pyridine 0 38 78 45 E-5- Decene HtBu ( ) 3 ( ) 3 CH 2 Cl 2 Pyridine > 20 50 (threo) > 95 < 3 H Z-5- Decene HtBu ( ) 3 ( ) 3 H CH 2 Cl 2 Pyridine 0 53 25 42 C - bond is formed at the least substituted carbon Diol formation is more prominent in the sterically hindered system Pyridine increases aminoalcohol:diol ratio and rate of the reaction trans-lefins give better results than cis olefins Sharpless, K. B.; Patrick, D. W.; Truesdale, L. K.; Biller, S. A. J. Am. Chem. Soc. 1975, 97, 2305-2307.

Solvent Effect on Aminohydroxylation eaction 1. s, solvent H H H + H A 2. LAH B C Solvent CH 2 Cl 2 % yield (B) % yield (C) 37 trace t-buh THF Pyridine 52 64 92 < 1 < 1 < 1 The rate of reaction and yield increase with the increase in coordination ability of the solvent. Sharpless, K. B.; Patrick, D. W.; Truesdale, L. K.; Biller, S. A. J. Am. Chem. Soc. 1975, 97, 2305-2307.

Proposed Mechanism of Aminohydroxylation of lefins +L s s s -L [2+2] cycloaddition L L 1 2 3 H H LAH s L 5 4

Two major limitations: Stoichiometric amount of smium reagent tert-butyl group is difficult to remove from the product Catalytic dihydroxylation reaction s s acl s H 2 H Catalytic aminohydroxylation reaction s ' s ' a ' Cl s ' ' H H 2 H 'H

1976 Trihydrate of Chloramine-T as Source s 1 TsCla 3H 2 Ts s 2 TsCla 3H 2 + 1% s 4 t-buh, 60 o C H TsH = CH 3 (CH 2 ) 3 In some cases Cl - inhibit the rate of reaction: Ag 3 addition ase transfer catalysis (1:1 benzene/h 2 + Et 3 BzCl) cis lefins give good yields along with trans olefins. Sharpless, K. B.; Chong, A.., shima, K. J. rg. Chem. 1976, 41, 177-179.

Proposed Mechanism of Catalytic Aminohydroxylation s 1 - a + Ts Cl s - Ts Cl H 2 Ts s Ts 6 H TsH acl s Ts 2 s 3 Ts acl Cl Ts s Ts 5 s a Ts Cl Ts 4

1978 -Chloro--Argento Carbamates as Source t-bucl, ah Bn Bn H 2 MeH 1 2 a + - Cl Ag Ag + 3 - Bn CH 3 C Cl 3 H Ag + 0.01 mmol s 4 + - Bn 4.5 mmol H 2 H Cl 3 4 CH 3 C Bn 5 59 % yield Benzyloxycarbonyl group is relatively easily removable protecting group cis lefins give good yields along with trans olefins Herranz, E.; Biller, S. A.; Sharpless, K. B. J. rg. Chem. 1978, 100, 3596-3598.

Effect of Excess Metallic Salt and Et 4 Ac in Aminohydroxylation of lefins ( ) 3 ( ) 3 BnC()Cla s 4, CH 3 C H ( ) 3 ( ) 3 HCbz 1 2 eagent atio xn time (h) eactivity BnC()Cla + Ag 3 1.5 : 1.5 80 BnC()Cla + Ag 3 1.5 : 3.0 60 BnC()Cla + Ag 3 + Et 4 Ac 1.5 : 1.5 : 1 18 ICEASE BnC()Cla + Hg( 3 ) 2 1.5 : 0.75 24 BnC()Cla + Hg( 3 ) 2 1.5 : 1.5 12 BnC()Cla + Hg( 3 ) 2 + Et 4 Ac 1.5 : 0.75 : 1 8 Herranz, E.; Sharpless, K. B. J. rg. Chem. 1979, 45, 2710-2713.

Chiral Ligands for Asymmetric Aminohydroxylation (AA) 1980 Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 4263-4265. (l)-2-(2-menthyl pyridine) Et Ac H Me Dihydroquinidine acetate Et H Ac Me Dihydroquinine acetate 1996 Li, G.; Chang, H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 451-453. H Et Et H Me Me Et H Et H Me (DHQD) 2 PHAL (DHQ) 2 PHAL

Chloramine-T as Source for AA C 2 CH 3 3eq. S _ a + Cl HS 2 p-tol C 2 CH 3 H C 2 CH 3 =, CH 3, C 2 CH 3 (DHQ) 2 PHAL (5%) K 2 s 2 (H) 4 (4%) CH 3 C/H 2 (1:1) rt, 3 h H 74-81% ee 52-65% yield HS 2 p-tol Li, G.; Chang, H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 451-453.

Chloramine-M as Source for AA H 3 C S H 2 t-bucl, ah MeH H 3 C 1 2 S a + Cl HS 2 CH 3 C 2 CH 3 3 eq. 2 C 2 CH 3 (DHQ) 2 PHAL (5%) K 2 s 2 (H) 4 (4%) nprh/h 2 (1:1) rt, 3 h H A 95% ee, 65% yield H C 2 CH 3 HS 2 CH 3 B A/B 9:1 All the hydroxysulfonamides obtained from Chloramine-M are crystalline solids Methanesulfonamide is soluble in water Li, G.; Chang, H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2810-2812.

Chloramine-T/M as Source for AA Z=p-tol-S 2 - Substrate Product %ee Yield HZ C 2 Me C 2 Me 81 64% a H Z=Me-S 2 - %ee Yield 95 65% b Me 2 C C 2 Me Me 2 C HZ C 2 Me H 77 65% 95 76% HZ H 62 52% 75 71% a) egioselectivity 5:1, b) egioselectivity 9:1. Li, G.; Chang, H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 451-453 and 2810-2812.

-Halo Carbamate as Source for AA H 2 t-bucl, ah nprh 1 2 a + Cl HCbz 2 H (DHQ) 2 PHAL (5 mol%) 3 K 2 s 2 (H) 4 (4 mol%) 4 nprh/h 2 (1:1) 60% yield Cbz = BnC() 90% ee Benzyloxycarbonyl is a relatively easily removable protecting group. Styrene type olefins give good results along with other olefins.. Li, G.; Chang, H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2810-2812.

Halocarbamate as Source for AA a + Cl H C 2 CH C 2 CH 3 3 (DHQ) 2 PHAL (5 mol% ) K 2 s 2 (H) 4 (4 mol%) nprh/h 2 (1:1) = Bn, Et H Major Isomer H H C 2 CH 3 %ee Yield Et 99 78% Bn 94 65% Li, G.; Chang, H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2810-2812.

-Halo-t-butylcarbamate as Source for AA Bn t-bu _ a + Cl K 2 s 2 (H) 4 (4 mol%) Bn (DHQ) 2 PHAL (5 mol%) n-prh/h 2 (1:1) 20 o C, 1h. Ht-Boc H + Bn Low Yield H Ht-Boc + Bn H Substantial amount H t-bu _a + Bn K 2 s 2 (H) 4 (4 mol%) (DHQ) 2 PHAL (6 mol%) Bn n-prh/h 2 (2:1) 0 o C, 1h. Cl Ht-Boc H For t-boc protected vicinal aminoalcohol formation: nprh/h 2 (2:1) ratio is lower than usual (1:1) Lower temperature (0 o C) Ligand concentration is higher A + Bn 68% yield 87:13 (A/B) 99%ee (A) H B Ht-Boc K. L. eddy, Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207-1217.

HMe3Si -Chloro--Sodio-2-Trimethyl Silyl Carbamate (Teoc) as Source Me 3 Si Cabonyldiimidazole aq. H 3, benzene H 2 t-bucl, ah, nprh Me 3 Si _ a + Cl Me 3 Si -a + Cl HTeoc H + H HTeoc K 2 s 2 (H) 4 nprh/ H 2 (1:1) (DHQ) 2 PHAL A 76% yield 97% ee 86:14 A/B B Trimethyl silyl carbamate is easily removable protecting group good regioselectivity, enantioselectivity styrene type olefins gives good yields eddy, K. L.; Dress, K..; Sharpless, K. B. Tetrahedron Lett.,1998, 39, 3667-3670.

Primary Amides as Source for AA of lefin ' H 2 DBI CH 2 Cl 2 ' HBr ipr + ' = Pr, ClCH 2, CH 2, X, HBr K 2 s 2 (H) 4 (4.4 mol%) (DHQ) 2 PHAL (4.0 mol%) ' H LiH (1.3 eq.) ipr t-buh/h 2 (2:3) H 0 o C-10 o C 38-94% yield 77-95% ee 2.0:1-23:1 regioselectivity Demko, P. Z.; Bartsch, M.; Sharpless, K. B. rg. Lett. 2000, 2, 2221-2223.

Steric, Electronic and Aromatic Substituent Effect on the egioselectivity 2 AcaBr 1 (DHQD) 2 PHAL (5%) K 2 s 2 (H) 4 (4%) t-buh/h 2 (2:3) HAc 2 + 2 1 1 A H H B HAc Entry 1 2 3 4 5 6 1 = H Et H Me H Me 2 = Si t-bu() 2 Et Me A/B >20:1 2:1 15.2:1 1.4:1 1.2:1 1:3.2 Han, H.; Cho, C.; Janda, K. D. Chem. Eur. J. 1999, 5, 1565-1569.

Steric and Aromatic Substituent Effect on the egioselectivity 1 2 AcaBr (DHQD) 2 PHAL (5%) K 2 s 2 (H) 4 (4%) t-buh/h 2 (2:3) 1 HAc A H 2 + 1 H 2 HAc B Entry 1 2 3 4 1 = TBDPS t-butyl TBDPS TBDPS 2 = p-methoxybenzoyl 2-naphthoyl (2-naphthyl)methyl B/A 11.9:1 14.2:1 20:1 3:1 Han, H.; Cho, C.; Janda, K. D. Chem. Eur. J. 1999, 5, 1565-1569.

1 Steric, Electronic and Aromatic Substituent Effect on the egioselectivity HAc H AcaBr 2 1 1 2 (DHQD) 2 PHAL (5%) 2 + K 2 s 2 (H) 4 (4%) H HAc t-buh/h 2 (2:3) A B Entry 1 2 3 4 5 6 1 = benzyl p-methoxybenzoyl (2-naphthyl)- methyl t-butyl TBDPS TBDPS 2 = ethyl p-methoxybenzyl (2-naphthyl)- methyl A/B 20:1.0 2.4:1.0 4.3:1.0 1.0:1.5 1.0:6.0 1.0:17.0 Han, H.; Cho, C.; Janda, K. D. Chem. Eur. J. 1999, 5, 1565-1569.

eversal of egioselection in the AA of Cinnamates by AQ and PHAL Ligands HCbz H C 2 CH 3 CbzCla (3 eq.) C 2 CH 3 C 2 CH 3 (DHQ) 2 PHAL (5%) K 2 s 2 (H) 4 (4%) n-prh/h 2 (1:1) rt, 3 h H A 7:1 A/B HCbz B 94% ee 65% yield HCbz C 2 CH 3 CbzCla (3 eq.) C 2 CH 3 H C 2 CH 3 = H, F, Cl, Br, Me Me. (DHQ) 2 AQ (4%) K 2 s 2 (H) 4 (4%) n-prh/h 2 (1:1) rt, 3 h H A 1:3-4 A/B HCbz B 89-95% ee 51-67% yield Tao, B.; Schlingloff, G; Sharpless, K. B. Tetrahedron lett. 1998, 39, 2507-2510

Et H Me Et H Me (DHQ) 2 AQ Et H Me Et H Me (DHQ) 2 PHAL

eversal of egioselection in the AA of Cinnamates of Aryl Ester Substrate Ar CBzCla (3 eq.) (DHQ) 2 AQ (5%) K 2 s 2 (H) 4 (4%) n-prh/h 2 (1:1) rt CbzH H A Ar HCbz Ar H B Entry 1 2 3 4 5 6 7 8 9 Ar: = H Me Me Br Cl F C 2 I A/B Yield % ee % 1:1 1:4 1:5 1:7 1:5 1:3 1:1.4 51 53 55 60 58 59 50 - - 10 16 30 87 89 96 3 - - Morgan, A. J.; Masse, C. E.; Panek, J. S. rg. Lett. 1999, 1, 1949-1952.

AA of Silyl Enol Ether TMS s 4, Chloramine-T t-buh/h 2, 1:1 HTs =CH 3, t-butyl (DHQD) 2 CLB (DHQD) 2 PY 72-92% ee 35-40% yield ukhan, P.; Sudalai, A. Tetrahedron: Asymmetry 1998, 9, 1001-1005. AA of Unsaturated osphonates =, P Et Et 3 eq. 'Cl a 5% (DHQ) 2 PHAL 4% K 2 s 2 (H) 4 1:1 CH 3 C/H 2 'H H P Et Et 32-53% yield 93-98% ee a) MsCl, TEA CH 2 Cl 2, -10 o C b) K 2 C 3, DMF Thomas, A. A.; Sharpless, K. B. J. rg. Chem. 1999, 64, 8379-8385. P C 2 Et Et Et

AA of Vinyl Furan H HCbz Furanyl glycine aminoacid CbzCla 1 mol% s 4 1.2 mol% (DHQ) 2 PHAL aq. t-buh steps H HCbz steps H HCbz 42% yield 86% ee steps H H H H H Aza sugars H H HCbz Serine Aminoacid 'Doherty, G. A.; Bushey, M. L.; Haukaas, M. H. J. rg. Chem. 1999, 64, 2984-2985.

Use of AA in the Synthesis of di--tbdms B[a]P DE-1 da c Diastereoisomers TBDMS TBDMS TBDMS H H TBDMS H H H H H H TBDMS cis opening TBDMS cis opening H 2 H H H H B[a]P DE-1 diastereoisomers Pilcher, A. S., Yagi, H.; Jerina, D. M. J. Am. Chem.Soc. 1998, 120, 3520-3521.

Conventional Method H H BA, base ah, TMSCl 1 2 H H TMS TMS 3 1. TMS 3 2. TBAF H H 2 H 2, 10% Pd/C H 3 3 H H H 6 da-f H + H H 4 H 5 90% yield trans opened cis opened H H da H 8 TBS TBS = da di--tbdms B[a]P DE-1 da c Pilcher, A. S; Yagi, H.; Jerina, D. M. J. Am. Chem. Soc. 1998, 120, 3520-3521.

AA Approach towards di--tbdms B[a]P DE-1 da c Diastereoisomers TBDMS H 2 TBDMS 1 t-bucl, nprh ah, 25 o C TBDMS Cl - a+ TBDMS 2 H 10% (DHQD) 2 PHAL H 8% K 2 s 2 (H) 4 3 H 2 -propanol, 3h, rt. 2 TBDMS TBDMS H H TBDMS + TBDMS H H H H A 85% yield 1:1 A/B H H B Pilcher, A. S., Yagi, H.; Jerina, D. M. J. Am. Chem.Soc. 1998, 120, 3520-3521.

Use of AA in Synthesis of (+)-Lactacystin H 2 C 1 Me 7 6 H 5 H 9 S 3 HAc Me 2 C H xazoline (+)-Lactacystin Isolated from a streptomyces bacterial strain in 1991 Potent activities against arthritis, ischemia and asthma. Panek, J. S.; Masse, C. E. Angew. Chem. Int. Ed. 1999, 38, 1093-1095.

Panek's Approach towards xazoline Me 2 C xazoline Br K 2 s 2 (H) 4 (4 mol%) (DHQ) 2 -AQ (5 mol%) H HCbz CbzCla, nprh/h 2 H Br rt, 4h, 60% 87% ee, 7:1 regioselectivity 1. Ti(iPr) 4 / MeH, rt. 2. H 2, 10% Pd/C, MeH 100%, 2 steps C(Me) 3 p-tsh/dme reflux, 4h 85% H 2 Me Panek, J. S.; Masse, C. E. Angew. Chem. Int. Ed. 1999, 38, 1093-1095.

Use of AA in the Synthesis of Azepine Core of (-) Balanol H H C 2 H H H H H Isolated from the fungus Verticillium balanoides in 1993. Potent inhibitor of human protein kinase C (PKC) Panek, J. S.; Masse, C. E. rg. Lett. 2000, 2, 2571-2573.

etrosynthetic Analysis of (-) Balanol H H Cl H H (-)-Balanol (1) Ar=p-bromophenyl H C 2H Ar H AA H 2 H H 2 H 2 Hexahydroazepine fragment Cyclization eduction H H 2 H (2S,3)-Hydroxylysine Panek, J. S.; Masse, C. E. rg. Lett. 2000, 2, 2571-2573.

Synthesis of Azepine Fragment of (-) Balanol Cl H DMS/(CCl) 2 Et 3, -78 o C Cl H (Et) 2 P ah/ TH,F 0 o C 90% Br 5 Cl H H 2 6 a 3, DMF rt, 2 days Br K 2 s 2 (H) 4 (4 mol%) (DHQD) 2 -AQ (5 mol%) Cbz-aCl, nprh/h 2 rt, 53% yield 82% ee > 20:1 regioselectivity Cl 4 Br Br H 3 H 2 7 Panek, J. S.; Masse, C. E. rg. Lett. 2000, 2, 2571-2573.

Synthesis of Azepine Fragment of (-)-Balanol 3 H H 2 Br 1. H 2,10% Pd/C, MeH 2. i. LiH, THF/H 2 (1:1) ii. 1 HCl 98%, 2 steps H 2 H H H 2 i. HMDS/ xylene reflux ii. 2-propanol H BH 3 THF H H H 2 THF, reflux, 18h 50%, 2 steps Azepine fragment H H 2 Panek, J. S.; Masse, C. E. rg. Lett. 2000, 2, 2571-2573.

Use of AA in Synthesis of Cyclohexyl norstatin, a key Component of Tripeptide KI 1314 H H H H C 2 ipr H 2 H C 2 H KI - 1314 Cyclohexyl norstatin Isolated in 1988 Potent renin inhibitor and hence potential agent of antihypertensive therapy Upadjua, T. T.; Sudalai, A. Tetrahedron:Asymmetry 1997, 21, 3685-3689.

Synthesis of Cyclohexyl norstatin H CH BH 3 DMS, THF (Et) 2 P()CH 2 C 2 Et C 2 Et ah, 30% H 2 2 H 2 C 2 H H Cyclohexyl norstatin ah, Benzene 6 HCl s 4 (DHQ) 2 PHAL Chloramine-T t-buh/h 2 (1:1) 10h, rt HTs H C 2 Et Upadjua, T. T.; Sudalai, A. Tetrahedron:Asymmetry 1997, 21, 3685-3689.

Use of AA in the Synthesis of Taxol Side Chain H H H H H Taxol side chain Paclitaxel Bruncko, M.; Schingloff, G.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 1483-1486.

Use of AA in the Synthesis of Taxol Side Chain ipr AcHBr (1.1 eq.) LiH (1.07 eq.) K 2 s 2 (H) 4 (DHQ) 2 PHAL HAc H ipr 10% HCl 100 o C, 4h H 2 H H 68% yield 99% ee Et H Me Et H Me H BzCl, 2 ah H 2 (DHQ) 2 PHAL H H 65% Taxol side chain Bruncko, M.; Schingloff, G.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 1483-1486.

Conclusions Using AA, alkenes can be converted to enantiomerically enriched -protected amino alcohols. a, b-unsaturated esters, styrenes, vinylarenes and cyclohexenes are good substrates for AA. sources with smaller substituent give higher yields and better enantioselectivity. Steric, electronic, and aromatic substituent effects can be used to influence the regiochemistry in AA. (DHQ) 2 PHAL and (DHQ) 2 AQ ligands give opposite regioselectivity.