Asymmetric Allylation Reactions Chem 115

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. 1N HCl, Et2O CO2i-Pr –78 A –50 °C 3. DIPT, MgSO4 2 98% E 1. B(OCH ) 3 3 O 15 min Et2O, –78 °C 70-75 % MgBr B CO2i-Pr O CO2i-Pr 2. 2N HCl, Et2O 3. (+)-DIPT, MgSO4 1. B(Oi-Pr)3 O n-BuLi, KOt-Bu –78 °C B CO2i-Pr O 77% CH3 THF H C K 2. 1N HCl, Et2O CH3 3 CH3 3 99% Z 3. DIPT, MgSO • The stability of allylboronate reagents permits their purification by distillation. Allyl –78 A –25 °C 4

diisopinocamphenyl reagents cannot be distilled. 45 min 70-75 % • Crotylboronates are configurationally stable at or slightly above room temperature. CO2i-Pr OH O O toluene • TartrateTartrate-modiﬁed modified (E)- and (Z)-Crotylboronates can be stored for several months at –20 °C in + B CO2i-Pr RH O R neat form or in solution with little noticeable deterioration. –78 °C, 4Å4Å-MS-MS

aldehyde yield (%) ee (%) • Competition experiments have shown that (E)-crotylboronates react faster with aldehydes than the corresponding (Z)-isomers. n-C9H19CHO 86 79

c-C6H11CHO 77 78 • Essentially identical results are obtained with a range of commercially available tartrate esters C6H5CHO 78 71 (CH3, Et, i-Pr). (R,R)-2 or (R,R)-3 • Enantioselectivities are typically moderate. O OH OH • 4Å-MS are necessary to achieve the highest levels of selectivity. toluene RH R + R Proposed Origin of Selectivity in TartarateTartrate Derived Derived Allylboronate Allylboronate Additions Additions –78 °C, 4Å-MS CH3 CH3

a O R reagent yield (%) anti:syn ee (%) O OR OR H n-C9H19 2 90 95:5 86 H O H H O H H OR n-C9H19 3 70 1:>99 77 OR B B O O O H O c-C6H11 2 94 >99:1 86 H R O O R H c-C6H11 3 90 2:98 83 H TBSOCH2CH2 2 71 98:2 85 FAVORED DISFAVORED TBSOCH2CH2 3 68 2:98 72 aee of major diastereomer.

OH OH

R R Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339-6348. • The favored transition state is believed to minimize unfavorable lone-pairlone pair-lone lone-pair pair Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem. 1987, 52, 316-318. interactions. Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186-8190. M. Movassaghi

5 Reaction of Tartrate-Derived Allyl- or Crotylboronates with Chiral Aldehydes (–)-Bafilomycin A1:

CO2i-Pr MATCHED: CO i-Pr 2 DMPO O CH3 O CH3 CHO H CBCO2i-Pr CO i-Pr OTBS 3 O OTBS + B 2 H3C + OHC O CO2i-Pr CH3 (S,S)-2 OH O 71%, 78% de CO i-Pr DMP = 3,4-dimethoxy- H3CB 2 OHC MISMATCHED: phenyl O + OPMB CO2i-Pr (R,R)-2 CH3 CH3 O CH3 1. (S,SS,S)-21, Toluene OTBDPS B CO2i-Pr OTBDPS OHC + O –78 °C (R,RR,R)-21, Toluene 2. TBSOTf OH MATCHED –78 °C, 8 h MISMATCHED 72%, 74% de 85%, 96% de MATCHED: 92%, 70% de CO2i-Pr

CH3 O CH3 CH3 OTBS H CBCO2i-Pr OTBS OHC + 3 O DMPO OTBS OH OH 80%, 94% de H3C OPMB MISMATCHED: CO2i-Pr CH3 CH3 CH3 CH3 CH3 O CH3 CH3 OTBDPS H CBCO2i-Pr OTBDPS OHC + 3 O OH 85%, 76% de MATCHED: CO2i-Pr CH CH CH 3 O 3 3 OH OTBS B CO2i-Pr OTBS TESOTBSO OH OHC + O CO2CH3 B(OH)2 I H3C + CH3 OH CH3 CH3 CH3 CH3 OCH3 71%, 90% de CH3 CH3 OCH3 MISMATCHED: CO2i-Pr 1. Pd(PPh3)4, TlOH CH3 O CH3 CH3 THF, 23 °C, 30 min OTBDPS + B CO2i-Pr OTBS 65% OHC O 2. KOH, 1,4-dioxane; OH CH3 2,4,6-trichlorobenzoyl chloride, 28% de i-Pr2NEt, THF; DMAP, toluene, reflux 52% • All reactions were performed in toluene at –78 °C in the presence of 4Å-MS. CH3O CH3 CH3 OTES O Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186-8190. OTBSO O H3C

Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem. 1987, 52, 316-318. H3C CH3 CH3 OCH3 CH3 M. Movassaghi

6 CH3O CH3 CH3 OTES OH O Catalytic, Enantioselective Addition of Allylsilanes to Aldehydes OH TBSO O OTBSO O H3C

H3C H + H3C

CH3 CH3 CH3 CH3 OCH3 CH3 (S)-(–)-BINOL 1 1. (S)-(–)-BINOL (20 mol%) O TiF4 (10 mol%) OH CH2Cl2, CH3CN, 0 °C + Si(CH3)3 RH R 1. TMSCl, Et3N, LHMDS 2. Bu4NF, THF CH2Cl2, –78 °C, 30 min 2. 1, BF3•OEt2, –78 °C, 30 min aldehyde time (h) yield (%) ee (%) 85% CHO 4 90 94 H3C CH3

CH3O CH3 CH3 CHO 20 93 84 OTES TIPSO O H3C CH3 TBSO OH OTBSO O H3C (CH3)3CCHO 4 91 94 H3C CHO CH3 CH3 CH3 CH3 OCH3 CH3 Ph 20 92 93

O TASF = [(CH3)2N]3S[(CH3)3SiF2] TASF, DMF, H2O a 23 °C, 4 h O CHO 20 81 74 93% CH3 PhCHO 4 85 80

c-C6H11CHO 4 72 60 CH3O CH3 CH3 H C CH 3 3 OH O PhCH2CH2CHO 4 69 61 H3C O OH O H3C aBased on 25% recovered aldehyde. HO HO CH CH OCH CH 3 3 3 3 • Allyltrimethylsilane initially reacts with the HF produced during catalyst preparation to give propene and (CH3)3SiF.

(–)-Bafilomycin A1 • It is important that the reaction be conducted in the presence of small amounts of CH3CN to solubilize the polymeric TiF4. Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W. R. Angew. Chem., Int. Ed. Engl. 1999, 38, 1652-1655. • _,_-Disubstituted aldehydes afford the highest enantioselectivities. Gauthier, D. R. Jr.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2363-2365. Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33, 3587-3590. M. Movassaghi

7 Catalytic, Enantioselective Addition of Allyltin Reagents to Aldehydes Enantioselective Allylation Using a Stoichiometric Chiral Controller Group

CFCF33 F3C (S)-(–)-BINOL (10 mol%) PhPh O R Ti(Oi-Pr)4 (10 mol%) OH R 2 2 F C 4Å-MS F33C CF3 + Sn(n-Bu)3 N N 3 R1 H R1 S B S O O O O CH2Cl2, –20 °C Br 1

R1 R2 time (h) yield (%) ee (%)

C6H5 H 70 88 95 R2 1. 1, PhCH3 HO H R2 23 °C Sn(n-Bu)3 C6H5 CH3 60 75 91 R1 2. R1CHO c-C6H11 H 70 66 94 –78 °C

c-C6H11 CH3 48 50 84

(E)-C6H5CH=CH H 70 42 89 aldehyde R2 yield (%) ee (%)

(E)-C6H5CH=CH CH3 12 68 87 PhCHO H 92 96

C6H5CH2CH2 H 70 93 96 PhCHO Cl 80 90 c-C H CHO H 84 92 C6H5CH2CH2 CH3 40 97 98 6 11

c-C6H11CHO Cl 76 88 i-C3H7 H 70 89 96

furyl H 70 73 96

furyl CH3 12 99 99

p-CH3OC6H4 CH3 48 61 93

p-CH3OC6H4CH2OCH2 H 70 81 96 • Reagent 1 is produced from the corresponding (R,R)-bis-sulfonamide by reaction with BBr3 in CH2Cl2. BnOCH2 H 60 84 95 • Transmetallation of allyltin reagents with the chiral B-bromoboron-Bromoboron reagent 1 in toluene • Addition occurs to the re face of the aldehyde with the catalyst prepared from (R)-(+)-BINOL. is complete in 3-20 h.

• This procedure allows for the efficient asymmetric methallylation of aldehydes, typically a • The (R,R)-bis-sulfonamide can be recovered from the reaction mixture. difficult transformation.

Keck, G. E.; Krishnamurthy, D. Org. Syn. 1998, 75, 12-18. Corey, E. J.; Kim, S. S. Tetrahedron Lett. 1990, 31, 3715-3718.

Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467-8468.

Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543-6544. M. Movassaghi

8 Enantioselective Allyltitanation of Aldehydes Diastereoselective Allyltitanation of Chiral Aldehydes

Ph Ph O Et3N, Et2O TiCpL OH OH O Ph (R,R) HO CH 23 °C Ph Ph Ph Ph 3 + Ti Cl Ti O H + HO CH O 3 Cl or Cl O 91–91-94%94% Cl O H C H C H C Ph Ph cyclohexane, 3 3 3 Ph CH3 reflux Ph O MATCHED 99.5 : 0.5 (R,R)-TADDOL CH3

O OH OH • The chiral diol is readily available in both enantiomeric forms from the corresponding TiCpL(R,R) Ph Ph Ph tartrate esters. H + • Complex formation is driven to completion by neutralization of HCl with Et3N, or by 91–91-94%94% removal of HCl by heating. H3C H3C H3C • The complex may be used in crude form, as prepared in solution, or the complex may MISMATCHED 95 : 5 be crystallized and isolated. • Exceptionally high reagent selectivity is observed in the mismatched allylation of (R)-2-phenyl- butyraldehyde (90% de) (cf., (–)-Ipc2BCH2CH=CH2: 34% de). Ph Ph Ph Ph Ti O RMR Ti O Cl O O O O OH OH M = Li, MgX Ph CH3 Ph CH3 CHO Ph O Ph O + CH3 CH3 O O O N N N H3C Boc H3C Boc H3C Boc • (E)-Crotyltitanium reagents are produced from (E)- or (Z)-crotyl anion precursors. CH3 CH3 CH3

reagent yield

OH TiCpL(R,R) 93 Ph 1.R1 M Ph 98.1 1.9 Ph Ph 2. R2CHO, –74 °C Ti O R Ti O R 1 2 TiCpL(S,S) 95 0.5 99.5 Cl 3. NH F, H O O O Et2O, 0 °C O O 4 2 R1 TiCp(Oi-Pr) CH CH 2 89 37.3 62.7 Ph O 3 Ph O 3 Ph CH Ph CH 3 3 MgCl 86 55.1 44.9

R1 R2 ee (%) de (%) yield (%) OH H Ph 95 93 CHO H3C TiCpL(R,R) H (CH3)2CH 97 88 O O H CH =CH 95 79 2 N N CH3 CH3 Ph 98 97 89 H3C Boc H3C Boc CH3 93% CH Ph Ph 97 98 54 3 a single diastereomer (CH3)3Si Ph 98 98 68 EtO Ph 95 75 77 CH3 CH3(CH2)8 98 98 86 Hafner, A.; Duthaler, R. O; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F. J. Am. Chem. (CH3)3Si CH3(CH2)8 98 98 69 Soc. 1992, 114, 2321-2336.

• (E)-Crotyltitanation of aldehydes affords anti products, presumably by a chair-like TS. Duthaler, R. O.; Hafner, A.; Riediker, M. Pure & Appl. Chem. 1990, 62, 631-642.

M. Movassaghi

9 Myers Asymmetric Allylation Reactions Chem 115

Krische Allylation and Crotylation Reactions: Proposed Catalytic Cycle:

Hassan, A.; Krische, M. J. Org. Proc. Res. Devel. 2011, 15, 1236. Han, S. B.; Kim, I. S.; Krische, M. J. Chem. Commun. 2009, 7278. NO2 O m-NO2BzOH OAc III [Ir(cod)Cl]2 General Allylation Reaction: P IrIr O P [Ir(cod)Cl]2 (2.5 mol %) OH OH AcOH OAc + (R)-BINAP (5 mol %) R R O m-NO2BzOH (10 mol %) O O 55-80% yield R = aryl, alkyl Cs2CO3 (20 mol %) O O O THF, 100 °C 90-93% ee III P III NO P III NO P Ir NO2 IrIr 2 Ir 2 P P O P O R OH 1 (X-Ray) H R 3 [Ir(cod)Cl ] (2.5 mol %) R 2 OH Hexa-Coordinate O AcO– OAc + (–)-TMBTP (5 mol %) 18 Electron Complex O OH H R R m-NO2BzOH (10 mol %) 55-80% yield H R R R = aryl, alkyl Cs2CO3 (20 mol %) OAc i-PrOH (200 mol %) 90-93% ee 2 4 THF, 100 °C O O O TMBTP = 2,2',5,5'-Tetramethyl-4,4'-bis(diphenylphoshino)-3,3'-bithiophene O O O III P I NO P III NO2 P Ir NO2 • Couplings of primary alcohols or aldehydes with allyl acetate utilizing Ir catalysts generate Ir 2 Ir Ir P Base P O P O allylation products without the use of stoichiometric allyl-metal(oid) reagents. H 7 6 H R 5 H R General Crotylation Reaction: H

[Ir(cod)Cl2] (2.5 mol %) OH OAc OH • The Ir catalyst 1 (generated in situ) undergoes addition to aldehyde 2 via a 6-membered chair-like (S)-SEGPHOS (5 mol %) III + R transition state to generate the Ir alkoxide 3. This does not undergo further dehydrogenation as the CH R 3 4-CN-3-NO2BzOH (10 mol %) olefin is thought to occupy a coordination site, blocking !-hydride elimination. CH3 R = aryl, alkyl Cs2CO3 (20 mol %) THF, 90 °C 65-73% yield • Ligand exchange with the reactant alcohol (or isopropanol) generates the homoallylic alcohol 4. 86-97% ee O 4:1 to 8:1 dr • The Ir alkoxide 5 undergoes !-hydride elimination to produce the IrIII hydride 6. Dissociation of the aldehyde 2 produces an IrIII hydride which undergoes deprotonation by the base to provide the IrI O PPh 2 anion 7. O PPh2 • Oxidative addition of allyl acetate to 7 regenerates "-allyl IrIII catalyst 1. O (S)-SEGPHOS • To use aldehydes as substrates in lieu of an alcohol, the use of a terminal reductant (isopropanol) is [Ir(cod)Cl ] (2.5 mol %) 2 OH necessary for the catalytic cycle to proceed. OAc O (S)-SEGPHOS (5 mol %) + R • Enantioselectivites are high for both alcohol and aldehyde reactants. CH3 H R 4-CN-3-NO2BzOH (10 mol %) CH3 Cs2CO3 (20 mol %) R = aryl, alkyl i-PrOH (200 mol %) 66-82% yield Kim, I. S.; Ngai, M, -Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6340-6341. THF, 90 °C 96-98% ee Kim, I. S.; Nagi, M. -Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14891-14899. 6:1 to 13:1 dr Anne-Marie Schmitt, Fan Liu

10 Myers Asymmetric Allylation Reactions Chem 115 Stereochemical Model in Asymmetric Crotolation Reactions: Bis Allylation and Crotylation of Glycols • Couplings of aldehydes display higher diastereoselectivities than with alcohols, as higher [Ir(cod)Cl]2 (5 mol %) concentrations of aldehyde promote rapid capture of the kinetically formed trans-crotyl iridium (S)-Cl,MeO-BIPHEP complex. OH OH (10 mol %) OH OH H R' OAc Cs CO (40 mol %) R' H 2 3 [Ir] O R [Ir] O R 4-Cl-3-NO -BzOH (20 mol %) 2 70%, >30:1 dr H H Dioxane (0.2 M) >99% ee 90 °C • Kinetically formed trans-crotyl • Equilibration to the cis-crotyl iridium iridium complex generates the anti complex causes erosion in • Equivalent bis aldehyde counterparts are unstable or unknown. diastereomer. diastereoselectivity. O Ph2 Kim, I. S.; Han, S. B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514–2520. O Ir P O P O Other allyl donors have been used with alcohols and aldehydes as reactants: Ph2 O O Allyl Donor Products Generated OH OH OH OH CN OH OAc NO2 OBz R = aryl, alkyl CH CH CH 62-77% Yield CH 3 3 3 R 3 CH3 THF:H2O (4:1, 1.6 M) OBz 96-99% ee OH K3PO4 (100 mol %) pseudo-C2 symmetric 70 °C 62%, >6:1 dr OH >99% ee O R = aryl, alkyl O R 58-74% Yield • Predominantly 1 of 16 possible stereoisomers was formed. O 93-99% ee • Chromatographic isolation of the pre-formed iridium catalyst allows crotylations to be run at lower OH temperatures. OH OBz R = aryl, alkyl Application to the Total Synthesis of Roxaticin R 57-80% Yield • Catalyst Generation: CF3 87-99% ee CF3 Cl Ph2 OH OCH3 Ir P O P OH [Ir(cod)Cl]2 (R)-Cl,MeO-BIPHEP OCH3 OBz R = aryl, alkyl O Ph2 Cl 58-78% Yield Cs2CO3 O R Cl SiMe3 90-99% ee Dioxane, 110 °C SiMe3 OAc Cl NO2 NO2 (R)-I Generated in situ O O OH R = aryl, alkyl EtO 58-79% Yield O EtO R 92-99% ee OH Ph2 OBoc O P [Ir(cod)Cl] (S)-SEGPHOS Ir 2 O O P O Ph2 Han, S. B.; Han, H. Krische, M. J. J. Am. Chem Soc. 2010, 132, 1760–1761. Cs2CO3 O CN O Zhang, Y. J.; Yang, J. H.; Kim, S. H.; Krische, M. J. J. Am. Chem Soc. 2010, 132, 4562–4563. THF, 80 °C OAc NO NC Gao, X.; Zhang, Y. J.; Krische, M. J. Angew. Chem. Int. Ed. 2011, 50, 4173–4175. 2 92% (S)-II Han, S. B.; Gao, X.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 9153–9156. (isolated via precipitation) NO2 Hassan, A.; Zbieg, J. R.; Krische, M. J. Angew. Chem. Int. Ed. 2011, 50, 3493–3496. Anne-Marie Schmitt, Fan Liu

11 Myers Asymmetric Allylation Reactions Chem 115 Application to the Synthesis of Roxaticin, continued. Allylation of Epimerizable Aldehydes from the Alcohol Oxidation Level: • Allylation of !-chiral aldehydes and "-chiral alcohols: the transiently generated aldehyde is prone to OH OH epimerization under the reaction conditions: OAc OH OH (R)-I OH OTBDPS Dioxane, 110 °C 1. PPTS , (MeO)2CMe2 70% Yield, >30:1 dr CH2Cl2 , 25 °C, 91% >99% ee CH3 OH OTBDPS [Ir(cod)Cl]2 (2.5 mol%) desired diastereomer 2. O3, CH2Cl2:MeOH OAc (S)-Cl-MeO-BIPHEP (5 mol%) dr < 2 : 1 –78 °C; NaBH4, 86% Cs2CO3 (20 mol%) OH OTBDPS CH3 3-NO2-BzOH (10 mol%) "Second Iteration" THF, 100 °C CH H C CH H C CH H C CH 1. (S)-I, Allyl Acetate, 71% H C CH 3 3 3 3 3 3 3 3 3 epimerized diastereomer 2. TBSCl, imidazole, 85% OH O O O O O O OH OH O O OH 3. O3; NaBH4, 85% • Optimized Reaction Conditions: "Third Iteration" "First Iteration" 1. (S)-I, Allyl Acetate, 78% OH OTBDPS OH OTBDPS 3 steps 2. PPTS, (MeO)2CMe2, 93% 3. O3; NaBH4, 78% OH OTBDPS CH3 CH3 Three interations, 9 total steps Catalyst (5 mol%) A B

H3C CH3 H3C CH3 H3C CH3 CH3 Cs2CO3 (1 equiv), OH OTBDPS OH OTBDPS O O O O O O 3,4-(NO ) -BzOH (10 mol%) OAc (S)-II (10 mol%) 2 2 CH3 + H2O (10 equiv) OAc CH3 CH3 CH K3PO4, H2O THF (0.4 M), 100 °C, 24 h CH 3 C D HO PMBO 3 THF, 70 ºC 85%, dr = 14 : 1 CH3 Catalyst Yield (A : B : C : D) Cl III 79% (97 : 2 : 1 : 0) Ph2 H C CH H C CH H C CH H3CO 3 3 3 3 3 3 ent-III 80% (4 : 94 : 0 : 2) P Ir H CO P O O O O O O O 3 Ph2 Cl CH3 O

7 steps CH • Increased loadings of base improve the yield of A while suppressing O2N HO PMBO 3 epimerization of the transient !-chiral aldehyde. III NO2 CH CH 3 3 • Water improves the yield of A, possibly by facilitating the exchange between OH OH OH OH OH product and reactant alkoxide and by increasing the amount of Cs2CO3 in solution. CH3 • The enhanced Lewis acidity at iridium may strengthen the agostic interaction between the iridium CH center and the carbinol C-H bond, facilitating alcohol dehydrogenation. It may also accelerate OH O 3 carbonyl addition with respect to aldehyde epimerization. CH HO O 3 • Inductive electron withdrawal by the 3,4-dinitro benzoate ligand may facilitate deprotonation of the Roxaticin CH Ir(III) hydride intermediate, allowing for faster catalyst turnover. 3 20 Steps Longest Linear Sequence 29 Total Steps Schmitt, D. C.; Dechert-Schmitt, A.-M. R.; Krische, M. J. Org. Lett. 2012, 14, 6302–6305.

Han, S. B.; Hassan, A.; Kim, I. S.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559–15561. Anne-Marie Schmitt, Fan Liu

12 Myers Asymmetric Allylation Reactions Chem 115

Leighton Silicon Allylation Chemistry: Enantioselective Addition to Acylhydrazones: Leighton, J. L. Aldrichimica Acta 2010, 43, 3–14. Ph O Ac Si Ac Ac Background: N Cl N H3C H N H N N H CH N H Recrystallization N H • In 2000, Leighton reported an allylation reaction where a Lewis acidic silicon atom is embedded in 3 CH Cl , 10 °C, 16h a strained ﬁve-membered ring: Ph H 2 2 Ph 80%, 98% ee Ph (5 g) 88% ee H3C O 1. PhCHO (6 equiv) H3C OH Si sealed tube, 130 °C Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596–9597. 2. HCl, 87% Ph CH3 Ph O Bz Si Bz Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587–8588. N Cl H N N H3C N H CH3 H3C N H • By incorporating another electronegative element bound to silicon, the reaction takes place at CH CHCl3, 23 °C room temperature. With a chiral ligand, the reaction becomes enantioselective: 3 78%, 94% ee

H3C 1. PhCHO H C O OH 3 PhCH , 23 °C Si 3 Ph 1. Ph H C O Cl O 3 2. HCl, 52% H3C Si Bz Bz Cl H C N H N •HCl N 3 SmI , THF N H CH3 H3C N H 2 H3C NH2 Ph 1. t-BuCHO CHCl , 40 °C Ph Ph O Ph CH3 3 86% PhCH3, –10 °C OH 2. HCl, Et O Si (5 g) 2 74%, 98% ee N Cl 3. Recrystallize H3C 2. HCl t-Bu CH3 80%, 96% ee Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686–5687. Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920–7921. Mechanism:

Preparation of Allylsilane Ph

• Two diastereomers are generated upon complexation with pseudoephedrine, which converge on H N N Ph O Ph a common complex prior to allyl transfer: Ph Ph O Ph 1. CH2Cl2, 23 ºC, 15min Si O Si + N O N H N Cl Ph N H Me 2. PhCH3, 23 ºC, 12h Cl– Ph Ph H CH OH O Me Ph H 3 Et3N, CH2Cl2 90% H CH + Si 3 Cl Si NH 3 0–15 °C, 12h N Cl H3C Me CH3 (150-g scale) CH3 • A 5-coordinate trigonal bipyramidal silicon species is proposed. 92%, dr = 2 : 1 • The strained silacyclopentane increases the Lewis acidity of silicon. • Aldehydes and acylhydrazones react, but not ketones, aldimines, or ketimines. Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596–9597. Angela Puchlopek-Dermenci, Fan Liu

13 Myers Asymmetric Allylation Reactions Chem 115

A C2-symmetric Chiral Controller for Aldehyde Allylation and Crotylation: Allylation and Crotylation of !-Diketones:

• The C2-symmetric N,N'-dialkylcyclohexanediamine silane shown below shows improved • The ﬁrst example of enantioselective nucleophilic addition to !-diketones was achieved selectivites in the allylation and crotylation of aldehydes: using the C2-symmetric N,N'-dialkylcyclohexanediamine silane reagent:

4-BrC6H4 4-BrC6H4 OH N O CH2Cl2, –10 °C N Br O O OCH3 Br O HO OCH3 Si + Si + CHCl3, 23 °C N Cl Ph H 90%, 98% ee Ph N Cl 89%, 92% ee 4-BrC H 4-BrC H 6 4 6 4 regioselectivity > 20 : 1

4-BrC6H4 4-BrC H N CH 6 4 3 O O CHCl3, 23 °C O HO CH3 Si + N O CH2Cl2, 0 °C OH N Cl Ph CH3 75%, 97% ee Ph Si CH3 + Cl BnO BnO CH N H 83%, 99% ee 4-BrC6H4 dr > 20 : 1 3 regioselectivity > 20 : 1 4-BrC6H4 CH3

Allylation and Crotylation of !-Diketones:

O O OH Si 4-BrC H O Si 6 4 R R O Ph 1 2 N O R CH2Cl2, 0 °C CH 1 Si CH3 + 3 R2 Ph H + N Cl 79%, 97% ee 4-BrC6H4 R2 O Fast O R1 Fast 4-BrC6H4 NH Si O O (2.09 g) NH Si R R Si O O 1 2 O O 90% recovered 4-BrC6H4 Fast R1 R2 R1 R2 Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946–948. Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375–4377.

• Using 2-hydroxybenzene as an activating group, imines can be allylated or crotylated R2 R1 with high selectivity: O HO R2 O R O Ar 1 Ar R1 R2 HO HO O Si N H O Si N H Cl– O Ph HO R1 O CH3 N N CH2Cl2, 23 °C Ar Ar Si + N HN H R H Cl H 2 H Me N H 74%, 99% ee Me dr = 96 : 4 CH3 • Four possible diastereomers undergo fast interconversion. • Regioselectivity is determined by Curtin-Hammett kinetics. Steric interactions are minimized and conjugation is maximized in the lower energy transition state.

Rabbat, P. M. A.; Valdez, S. C.; Leighton, J. L. Org. Lett. 2006, 8, 6119–6121. Chalifoux, W. A.; Reznik, S. K.; Leighton, J. L. Nature 2012, 487, 86–89. Angela Puchlopek-Dermenci, Fan Liu

14 Myers Asymmetric Allylation Reactions Chem 115

Hoveyda Boron Allylation Chemistry: Mechanism:

• The Hoveyda group demonstrated that Cu-complexed C1-symmetric ligands I and II, can effect enantioselective allylation of phosphinoylimines: Ph Ph Ph Ph Me R N O B(pin) N N P Ar1 Ar2 Mes N N N N Ph Ph Cu BF4 Mes iPr Mes BF4 H CO B(pin) I II 3

Ph Ph O I (5.0 mol%) O Mes R2 P CuCl (5 mol% ) P N N N N N Ph CH3 HN Ph Ar Ar Ph H3C Ph 1 2 NaOt-Bu (12 mol%) H C R1 O Cu Cu 3 H + H3C O R B MeOH, THF, –50 °C N H3C O OCH Br 92%, 97% ee Br 3 Ph P Ph

N N Ar1 Ar2 CH3OH I (2.5 mol%) Cu R N O O CuCl (2.5 mol% ) O P H C CH3 P 3 NaOt-Bu (6 mol%) P Ph Ph Ph H C N Ph H3C HN H 3 Ph O Ph R N O + H3C B MeOH, THF, –50 °C P H C H H C O H3C 3 3 61%, 92% ee Ph Ph

II (5 mol%) O CuCl (5 mol% ) O CH • Allylation is driven by the formation of an energetically favorable B–O bond. P H3C 3 NaOt-Bu (12 mol%) P N Ph Ph NH CH Ph O CH3 Ph 3 + H3C • Methanol releases the product alkoxide from the NHC–Cu complex. <5% conversion was observed B MeOH, THF, –50 °C Ph H H C O Ph 3 96%, 90% ee in the absence of methanol.

• The product phosphinoylamides can be convered to free amines under aqueous acidic conditions.

• High selectivity is observed with aromatic, heteroaromatic, conjugated, and some aliphatic phosphinoylimines. Crotylation reactions proceed with modest yield and enantioselectivity but low diastereoselectivity.

Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 3332–3335. Angela Puchlopek-Dermenci, Fan Liu

15 Myers Asymmetric Allylation Reactions Chem 115

• Simple amino alcohol catalysts III and IV were found to promote stereoselective boron allylation of Mechanism: phospinoyl imines and isatins: H C CH i-Pr 3 3 i-Pr i-Pr i-Pr H3C CH3 N(CH3)2 N(CH3)2 N(CH3)2 N N HO OH N N N H H H B O O O O O OH OH OH t-Bu H C CH3 t-Bu III t-Bu III t-Bu IV 3 O H3C H B O O H3C O III (3.0 mol%) CH O Bpin P Ph H3C 3 P Ph N NaOt-Bu (2.5 mol%) HN H3C Ph + O Ph H3C H B MeOH, PhCH3, 22 °C H C O t-Bu t-Bu 3 75%, 96% ee O N N P N Ph Ph O O CH R H R H C 3 CH3 O O 3 N B H3C B III (6.0 mol%) (H C) N N N H CH 3 2 (H3C)2N P Ph H3C 3 NaOt-Bu (8.5 mol%) P Ph N HN O H H P Ph + O Ph O O Ph H3C B MeOH, PhCH3, 22 °C Ph H H C 3 O 71%, 95% ee

t-Bu

O O P H C CH3 IV (3 mol%) P O N Ph 3 HN Ph Ph O NaOt-Bu (20 mol%) Ph CH3 H3C B + H3C N t-Bu H B (H C) N B S H C O MeOH, PhCH3, 22 °C S 3 2 O 3 D D pin N CH3 86%, 91% ee N H3C H D D O H3C MeOH H C dr = 39 : 1 H C 3 3 O R t-Bu CH H C 3 O 3 N B N H (H C) N P 3 2 HN Ph H P O Ph O O Ph O H C CH3 III (6.0 mol%) O 3 Ph Zn(Ot-Bu)2 (8.5 mol%) P Ph CH3 R P O HN H3C B N Ph + H3C Ph N Ph B (H3C)2N H C O MeOH, PhCH3, 22 °C Bpin OCH 3 Ph H 3 Ph H Cy CH 70%, 90% ee O 3 H3C Cy dr = 8 : 1 • <2% conversion was observed in the absence of methanol. • The internal hydrogen bond between the protonated amine and the amide carbonyl rigidiﬁes the O 1. III (0.25 mol%) complex and increases the Lewis acidity of the boron center to facilitate substrate binding. CH HO H3C 3 NaOt-Bu (0.4 mol%) • • Substrate release is accelerated by intramolecular protonation. O + O H3C O N B • MeOH, PhCH3, 22 °C N H3C O TBS 2. aq. HCl, MeOH, 22 ºC H Silverio, D. L.; Torker, S.; Pilyugina, T.; Vieira, E.; Snapper, M. L.; Haeffner, F.; Hoveyda, A. H. ( an "isatin") 90%, >99% ee Nature 2013, 494, 216–221. Angela Puchlopek-Dermenci, Fan Liu