Myers Asymmetric Allylation Reactions Chem 115 Brown Allylation and Crotylation Reactions Enantioselective Allylboration O Et2O OH Reviews: –78 A 23 °C; RH+ (–)-Ipc2B R NaOH, H O Srebnik, M.; Ramachandran, P. V. Aldrichimica Acta 1987, 20, 9. 2 2 R yield (%) ee (%)a ee (%)b Roush, W. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 1-53. CH3 74 93 99 n-C3H7 71 86 - Synthesis of B-Allyldiisopinocampheylborane n-C4H9 72 87 96 t-C4H9 88 83 99 C6H5 81 96 96 CH3 CH3 H3C CH3 3 CH BHBH 3 H3B•S(CH3)2 aAllylboration carried out without filtration of = 2 Mg salts. bAllylboration carried out at –100 °C THF, 0 °C 72 h,h,72% 72% under Mg-salt free conditions. (1R)-(+)-_-Pinene (–)-Ipc2BH 91.3% ee 98.9% ee • The reaction is quite general; the stereochemistry of the addition is the same in all cases examined. CH3OH, 1 h 0 °C, 100% • Lower reaction temperatures (0 A –78 A –100 °C) lead to increased enantioselectivity. CH3 CH3 B BOCH B MgBr BOCH33 • Only Mg-salt free reagent can be used at –100 °C because the reactive borane is 2 2 sequestered by ate complex formation with CH3OMgBr at this temperature. –78 A 25 °C 25 °C, 1 h 98.9% ee 98.9% ee • Allylboration of aldehydes is essentially instantaneous at –78 or –100 °C in the absence of Mg salts. • Prolonged incubation at 0 °C affords enantiomerically enriched Ipc BH. This is due to 2 H C equilibration of tetraisopinocampheyldiborane with _-pinene and triisopinocampheyl- 3 diborane; the symmetrical dimer crystallizes preferentially. H3C • Allylation of aldehydes proceeds through a • Both enantiomers of _-pinene are commercially available and inexpensive .(Aldrich: H chair-like TS where R occupies an equatorial (1R)-(+)-_-pinene, 91% ee, $100/500mL; (1S)-(–)-_-pinene, 87% ee, $42/100mL). H H CH3 position and the aldehyde facial selectivity CH H H 3 derives from minimization of steric interactions • B-Allyldiisopinocampheylborane can be prepared and used in situ after filtration of B CH between the axial Ipc ligand and the allyl group. H 3 the magnesium salts produced during its formation. O H3C R H Brown, H. C.; Desai, M. C.; Jadhav, P. K. J. Org. Chem. 1982, 47, 5065-5069. H Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49, 945-947. Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-2093. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923. Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432-439. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401-404. M. Movassaghi 1 Asymmetric Isoprenylation of Aldehydes Diastereoselective Allylboration of Chiral, _-Substituted Aldehydes • The diastereofacial selectivity of the B-allyldiisopinocampheylborane reagent typically overrides CH3 THF (+)-Ipc2B CH3 any facial preference of the aldehyde for nucleophilic attack. (+)-Ipc2BH + • –25 °C, 6 h CH3 CH3 • Hydroboration of allenes is an efficient method for preparing B-prenyldiisopinocamphenylboranes.-allyldiisopinocamphenylboranes O OH OH allylboration H3C H C H C 3 H 3 + 3 Et O, –78 °C RCHO, Et O 2 2 OH H C (+)-Ipc B CH –78 °C, 12 h; 3 H3C H3C 2 3 81% R CH3 NaOH, H2O2 H3C CH3 MATCHED: (–)-Ipc2BCH2CH=CH2 96 : 4 (92% de) MISMATCHED: (+)-Ipc BCH CH=CH : R yield (%) ee (%) 2 2 2 5 95 (90% de) CH3 73 91 n-C4H9 79 92 O OH OH CH2=CH 70 95 allylboration H3C H C H C H 3 + 3 (CH3)2C=CH 85 96 OBz Et2O, –78 °C OBz OBz 80% Brown, H. C.; Jadhav, P. K. Tetrahedron Lett. 1984, 25, 1215-1218. Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432-439. MISMATCHED: (–)-Ipc2BCH2CH=CH2 94 : 6 (88% de) MATCHED: (+)-Ipc2BCH2CH=CH2 4 : 96 (92% de) Methallylation of Aldehydes RCHO, Et2O CH3 CH OH CH3 Et2O 3 –78 °C, 12 h; • Although the stereochemical outcome of the allylboration of aldehydes using B-allyldiisopino- (+)-Ipc BOCH + Li (+)-Ipc B 2 3 2 R campheylborane is typically reagent controlled, this selectivity may be challenged with certain –78 °C, 1 h NaOH, H2O2 substrates: R yield (%) ee (%) O OH OH allylboration 56 90 + CH3 H3C H H3C H3C Ph Et2O, –78 °C Ph Ph n-C3H7 54 90 72% n-C4H9 56 91 t-C4H9 55 90 MISMATCHED: (–)-Ipc2BCH2CH=CH2 67 : 33 (34% de) CH2=CH 57 92 MATCHED: (+)-Ipc2BCH2CH=CH2 2 : 98 (96% de) • The yields for methallylation of aldehydes are generally lower than in simple allylation reactions. Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1987, 52, 319-320. Brown, H. C.; Jadhav, P. K.; Perumal, P. T. Tetrahedron Lett. 1984, 25, 5111-5114. Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570-1576. Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432-439. M. MovassaghMovassaghii 2 Chair TS's Produce syn Adducts from (Z)-Crotylboranes and anti Adducts from (E)- (Z)-Crotylboranes Crotylboranes. CH3 OCH3 – n-BuLi, KOt-Bu (–)-Ipc2BOCH3 B H3C 2 K + CH3 THF CH3 –78 °C K CH3 H3C –45 °C BF3•OEt2 –78 °C H3C OH OH RCHO CH3 H H OH –78 °C; B H CH R + R CH H 3 2 H 3 R CH CH NaOH, H O CH3 B 3 3 2 2 CH CH3 A B H 3 O H3C R CH3 H Ipc aldehyde yield (%) A:B ee (%) "(Z)-crotylborane" "syn adduct" – CH3CHO 75 95:5 90 + CH3CHO 72 4:96 92 H3C – C2H5CHO 70 95:5 90 H C 3 + C2H5CHO 78 4:96 92 H H OH H CH – CH2=CHCHO 63 95:5 90 CH 3 H 3 H R B CH CH3 – C H CHO 72 94:6 88 H C 3 6 5 3 O H3C R H H • The crotylboranes are used immediately after decomplexation of methoxide from the ate complex by BF3•OEt2 at –78 °C to avoid crotyl isomerization. "(E)-crotylborane" "anti adduct" "Superbases" for Organic Synthesis • The "superbase" prepared by mixing n-butyllithium and potassium t-butoxide (1:1) can metalate • These adducts can be viewed as protected aldol products; "deprotection" is brought about by hydrocarbons of low acidity, in particular olefins. dihydroxylation/periodate cleavage or by ozonolysis. • Allylic methyl groups are much more readily metalated than allylic methylene or methine centers. • cis-2-alkenes generally react faster than their trans-isomers. K 3 • The large atomic radius of potassium favors ! -bonding R2 Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293-294. in allyl, crotyl and prenyl derivatives: Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923. R1 Roush, W. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 1-53. R , R = H, CH Schlosser, M. Pure & Appl. Chem. 1988, 60, 1627-1634. 1 2 3 Schlosser, M.; Stahle, M. Angew. Chem., Int. Ed. Engl. 1980, 19, 487-489. M. Movassaghi 3 (E)-Crotylboranes Diastereo- and Enantioselective vic-Diol Synthesis CH3 OCH3 CH OCH3 + – 3 – Li n-BuLi, KOt-Bu (–)-Ipc2BOCH3 B CH3 B CH CH3 s-BuLi (–)-Ipc2BOCH3 3 2 OCH H3C + 3 2 K Li OCH OCH3 THF K –78 °C THF, –78 °C 3 –78 °C –45 °C BF •OEt 3 2 BF3•OEt2 –78 °C –78 °C CH CH O OH OH 3 RCHO CH3 3 B OH OH B NH2 RCHO, –78 °C; B CH3 –78 °C; + R + R 2 2 OCH R + R 2 HOCH CH NH 3 OCH3 OCH3 2 2 2 CH CH NaOH, H2O2 3 3 (crystalline) E F C D • Treatment of the crude product mixture with ethanolamine allows for easy removal of the Ipc aldehyde yield (%) C:D ee (%) reagent by-product as a crystalline adduct; this is an alternative to oxidative work-up. – CH3CHO 78 95:5 90 + CH3CHO 76 4:96 92 Ipc aldehyde yield (%) E:F ee (%) – C2H5CHO 70 95:5 90 – CH3CHO 57 95:5 90 + C2H5CHO 69 4:96 92 + CH3CHO 59 4:96 92 – CH2=CHCHO 65 95:5 90 – C2H5CHO 65 96:4 92 – C6H5CHO 79 94:6 88 + C2H5CHO 68 5:95 90 – CH2=CHCHO 63 94:6 88 – C6H5CHO 72 95:5 90 • The crotylboranes are used immediately after decomplexation of methoxide from the ate complex by BF3•OEt2 at –78 °C to avoid crotyl isomerization. • Other vinyl ethers may be used, such as methoxymethyl vinyl ether (affording the MOM-protected vic-diol). Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293-294. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923. Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535-1538. M. Movassaghi 4 Roush Allylation and Crotylation Reactions Preparation of (E)- and (Z)-Crotylboronate Reagents Roush, W. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon CO2i-Pr Press: New York, 1991, Vol. 2, pp. 1-53. 1. B(Oi-Pr) K 3 Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348-6359. n-BuLi, KOt-Bu –78 °C O CO i-PPrr CH3 H3CB 2 Roush, W. R.; Halterman, R. L. J. Am. Chem. Soc. 1986, 108, 294-296. H3C H3C O THF 2.