17 zinc final

Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Recent Reviews: • In 1984, Oguni and Omi found that a small amount of (S)-leucinol catalyzed the enantioselective addition (49% ee) of diethylzinc to benzaldehyde Pu, L.; Yu, H.-B Chem Rev 2001, 101, 757–824 Lemire, A.; Cote, A.; Janes, M K.; Charette, A B Aldrichimica Acta 2009, 42, 71–83 Lumbroso, A.; Cooke, M L.; Breit, B Angew Chem Int Ed 2013, 52, 1890–1932 H3C O H (C2H5)2Zn + mol % Background: OH OH CH3 NH2 CH3 toluene, 20 °C, 43 h 96% yield, 49% ee • The reactivity of dialkylzinc reagents towards ketones and aldehydes is low; the rate of addition of Et2Zn to benzaldehyde is negligible at room temperature Oguni, N.; Omi, T Tetrahedron Lett 1984, 25, 2823–2824 • The addition of a catalytic amount of TMEDA will promote the addition of diethylzinc at room temperature to 4-benzoylbenzaldehyde in 93% yield O • In 1986, Noyori et al published the first highly selective procedure for the asymmetric addition of diethyl- and dimethylzinc to aldehydes employing (–)-3-exo-(dimethylamino)isoborneol (DAIB) as a chiral catalyst OH H + mol % TMEDA (C2H5)2Zn CH3 H3C CH3 toluene, 23°C, 14 h Bz 93% N(CH3)3 OH Bz racemic H3C (–)-DAIB Soai, K.; Watanabe, M.; Koyano, M Bull Chem Soc Jpn 1989, 25, 2124–2125 CH3 N H3C Zn CH3 180 ° Zn—C H3C N N CH3 H3C N H3C N CH N H3C 145 ° Zn CH3 N H3C N CH3 N H3C 1.95 Å Zn—C + R OH mol % (–)-DAIB O • X-Ray structures of dimethylzinc and its adduct with 1,3,5-trimethylhexahydro-1,3,5-triazine show that upon bis-complexation, dimethylzinc shifts from a linear geometry to a tetrahedral geometry and that the carbon-zinc bond length increases from 1.95 Å to 1.98 Å This is proposed to increase the nucleophilicity of the methyl groups, accelerating addition to carbonyl compounds R'2Zn toluene, °C H R R' R R' % yield % ee Ph Et 97 98 Ph Me 59 91 p-ClC6H4 Et 86 93 p-CH3OC6H4 Et 96 93 (E)-PhC(H)=CH Et 81 96 PhCH2CH2 Et 80 90 n-C6H13 Et 81 61 1.98 Å Hursthouse, M B.; Motewaili, M.; O'Brien, P.; Walsh, J R.; Jones, A C J Mater Chem 1991, 1, 139–140 Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R J Am Chem Soc 1986, 108, 6071-6072 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Mechanism: • The stoichiometry of aldehyde, diethylzinc, and DAIB ligand determines reactivity: alkylation occurs only when the ratio of Et2Zn : DAIB is greater than 1: • A non-linear dependence of product ee on catalyst ee was observed Heterochiral dimerization to form an unreactive species was invoked to account for in situ amplification of product ee: OH O cat (–)-DAIB + H (C2H5)2Zn mol % (–)-DAIB O CH3 H toluene, °C, h OH 15 % ee CH3 (C2H5)2Zn + 92% yield, 95% ee aldehyde : Et2Zn : DAIB % yield % ee 1:1:0 1:1:1 50 : 50 : 1 97 — 98 H3C CH3 N H3C Kitamura, M.; Okada, S.; Suga, S.; Noyori, R J Am Chem Soc 1989, 111, 4028–4036 O H H CH3 Zn Et CH3 (–)-DAIB O R Zn + H3C CH3 N H3C H C CH3 (+)-DAIB • This observation is consistent with a mechanistic proposal involving two Zn atoms per aldehyde: H3C CH3 H3C N(CH3)3 OH N Et2Zn H3C H3C H3C H3C CH3 O H3C CH3 H3C Zn Et O Zn Et H O Et Ar H3C H3C CH3 Zn Et Et H H3C CH3 CH3 N O H3C Et Zn H3C Zn O Et CH3 slow Et CH3 CH3 H N H3C Ar Itsuno, S.; Fréchet, J M J J Org Chem 1987, 52, 4142–4143 Corey, E J.; Hannon, F J Tetrahedron Lett 1987, 28, 5237–5240 Evans, D A Science 1988, 240, 420–426 O Zn H O CH3 O H3C H H3C H C H CH3 O Zn Et Ar Et CH3 Zn R H3C H3C O R Zn CH3 CH3 N H3C H CH3 + heterochiral dimer, more stable, does not readily dissociate H CH3 N O H3C Et CH3 N Zn R Ar CH3 CH3 N CH3 N CH3 O H R Zn CH3 N EtZnO CH3 CH CH3 Zn R H CH3 R Zn O CH3 N H3C H3C H C CH3 CH3 homochiral dimer, less stable, dissociates Kitamura, M.; Okada, S.; Suga, S.; Noyori, R J Am Chem Soc 1989, 111, 4028-4036 Oguni, N.; Matsuda, Y.; Kaneko, T J Am Chem Soc 1988, 110, 7877 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds • In many cases, lithium or magnesium halide byproducts must be removed to avoid salt complexation with chiral additives in subsequent enantioselective processes Preparation of Organozinc Reagents: Lemire, A.; Cote, A.; Janes, M K.; Charette, A B Aldrichimica Acta 2009, 42, 71–83 Knochel, P.; Perea, J J A.; Jones, P Tetrahedron 1998, 54, 8275–8319 • 1,4-Dioxane forms insoluble complexes with magnesium halides and allows the synthesis of diorganozinc reagents that were not commercially available to subsequently be used in asymmetric additions to carbonyl compounds: • Metallic Zinc Insertion: • One of the early methods involves treatment of an alkyliodide or bromide with zinc dust or an activated form of Zn, such as zinc-copper couple (Zn(Cu)) The method requires rather harsh conditions and is limited to low molecular weight dialkylzinc species due to the need to distill the products while avoiding competitive Wurtz coupling: ZnCl2 (1.0 M in Et2O) MgBr (1.0 M in Et2O) (salt free) dioxane Zn filtration O + EtI [EtZnI] Zn-Cu EtBr neat, reflux Schlenk Equilibrium Et2Zn + + [EtZnBr] BrZnI H distillation OH O N OBn CH3 • methanesulfonic acid can be used to activate zinc metal: O Br Cl EtO2C ZnBr THF, 70 ºC von dem bussche-Hünnefeld, J L.; Seebach, D Tetrahedron 1992, 48, 5719–5730 Brubaker, J D.; Myers, A G Org Lett 2007, 9, 3523–3525 F NC EtO2C O Cl F EtO2C 10.0 kg Cl 6N HCl 72% 11.5 kg • Zn(OCH3)2 can also be used The byproduct, CH3OMgCl, precipitates from the reaction mixture and salt-free ethereal solutions of diorganozinc can be obtained after filtration or centrifugation: Cl 10.6 kg Et2O CH3 2x MgCl H3C + CH3 Zn(OCH3)2 → 23 ºC > 95% Choi, B S.; Chang, J H.; Choi, H.-W.; Kim, Y K.; Lee, K K.; Lee, K W.; Lee, J H.; Heo, T.; Nam, D H.; Shin, H Org Process Res Dev 2005, 9, 311–313 CH3 Zn H3C • Substrates that are less readily prepared by direct reduction can be prepared by treatment of a Zinc(II) halide with two equivalents of alkyllithium or alkylmagnesium halide: H n-BuLi THF, –60 ºC O N Li unstable above –50 ºC CH3OMgCl • N,N,N,N-tetraethylethylenediamine (TEEDA) can be used to scavenge salts and the resulting in situ formed zinc reagents function in catalytic asymmetric addition reactions to aldehydes: O H O + CH3 Cote, A.; Charette, A B J Am Chem Soc 2008, 130, 2771–2773 • Transmetallation with a Zinc Salt: N OBn >80% 93% ee N 89 % Zn MsOH (5 mol%) N OLi Et2Zn 200 ºC 95% OBn OTBS Rozema, M J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P Tetrahedron Lett 1993, 34, 3115–3118 Rozema, M J.; Sidduri, A.; Knochel, P J Org Chem 1992, 57, 1956–1958 Substrate decomposition occurred in the absence of ZnEt2 Milgram, B C.; Liau, B B.; Shair, M D Org Lett 2011, 13, 6436–6439 n-Hex • organoboron: Et2Zn CuI (3 mol%) neat, 50 °C O CO2Et Et2BH, Et2O, °C CO2Et Et2Zn, neat, °C EtO2C )2Zn EtO2C I OEt 0.1 mm Hg 50 °C OAc O O O O n-Hex t-Bu EtO )2Zn OEt O TMSOTf, CH2Cl2 –78 ºC, 67% O t-Bu > 86% Powell, N A.; Rychnovsky, S D J Org Chem 1999, 64, 2026–2037 Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P J Org Chem 1996, 61, 8229–8243 • Aryl and alkenyl iodides can undergo halogen-zinc exchange with i-Pr2Zn Li(acac)2 activates the intermediate mixed diorganozinc as an ate complex and promotes the second exchange: • organonickel: OAc )2Zn Et2Zn (0.6 equiv), Ni(acac)2 (1 mol%) OPiv COD (2 mol%), neat, 50–60 °C OPiv > 40% i-Pr2Zn Li(acac)2 (10 mol%) I H3CO 2x H Et2O, NMP 25 ºC, 12 h O OAc OTBDPS CH2Cl2 → 23 ºC ZnMe2 OTBDPS toluene –60 → ºC ZrCp2Cl Wipf, P.; Xu, W Org Synth 1997, 74, 205–211 > 86% i-Pr Li(acac)2 O OAc I H3CO • organozirconium: Cp2ZrHCl Zn H >90% Vettel, S.; Vaupel, A.; Knochel, P J Org Chem 1996, 61, 7473–7481 OTBDPS OAc H3CO OCH3 H O O Zn H3CO i-Pr H Zn AcO OAc Zn H3CO CH3 O O H Li(acac)2 H O CH3 Li+ O CH3 Kneisel, F F.; Dochnahl, M.; Knochel, P Angew Chem Int Ed 2004, 43, 1017–1021 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds • 3-exo-morpholinoisoborneol (MIB), 4, more stable and easier to prepare than DAIB, catalyzes Alkylzinc Addition to Aldehydes: • A variety of chiral catalysts and ligands have been developed that promote the addition of dialkylzinc enantioselective additions to aldehydes with similar selectivity and efficiency It also shows improved selectivity with α-branched, aliphatic aldehydes: reagents to give enantiomerically enriched secondary alcohols Only a few representative ones are shown here: O Et2Zn O OH ent-4 (5 mol%) H3C H3C H Et H3C CH3 N HO O hexanes, toluene Ph CH3 CH3 N Ph CH3 Ph ºC, 94% N OH 99% ee OH H3C N(n-Bu)2 CH3 HO Nugent, W A Chem Commun 1999, 1369–1370 H3C H3C Ph Ph Ph Ph O O O O Ti O O O O Ph Ph Ph Ph N CH3 CH3 OH OH NHTf N NHTf • Ligand extends the scope of the initial DAIB reaction to include aliphatic aldehydes: Et2Zn (6 mol%) O hexanes, ºC 94%, 95% ee H Ph • Using as a chiral additive, either enantiomer of the product can be obtained by changing the reaction conditions: Et2Zn (10 mol%) Et2Zn Ti(Oi-Pr)4 OH O (2 equiv) (1.2 equiv) Et H toluene toluene H3CO → 23 ºC, 89% H3CO –75 → 23 ºC, 86% H3CO 98% ee 94% ee Schmidt, B.; Seebach, D Angew Chem Int Ed 1991, 30, 99–101 Et Ph • Chemoselective addition to aldehydes can be achieved in the presence of ketones: Ph H O O Ph toluene, ºC 82%, 96% ee n-Bu2Zn, Ti(Oi-Pr)4 (2 mol%) O Hayasaka, T.; Yokoyama, S.; Soai, K J Org Chem 1991, 56, 4264–4268 Et2Zn n-BuLi, (8 mol%) Et H toluene, –30 ºC 99%, 98% ee OH Ph n-Bu Yoshioka, M.; Kawakita, T.; Ohno, M Tetrahedron Lett 1989, 30, 1657–1660 Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M Tetrahedron Lett 1989, 30, 7095–7098 • Unsymmetrical dialkyl zinc containing a trimethylsilylmethyl group as a non-transferable group can be prepared to avoid losing one equivalent of valuable alkyl zinc precursor: OH (Cl(CH2)4)2Zn + (TMSCH2)2Zn neat, 25 °C (Cl(CH2)4)Zn(CH2TMS) Watanabe, M.; Soai, K J Chem Soc., Perkin Trans 1, 1994, 3125–3128 H3C H3C OH Et2Zn (5 mol%) O H hexanes, toluene ºC, 91% 99% ee Nugent, W A Org Lett 2002, 4, 2133–2136 Et OH Ph O OH OH H3C H3C Cl (8 mol%) Ti(Oi-Pr)4 Et2O, –20 °C O H Et 86%, > 94% ee Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T A.; Reddy, C K Angew Chem., Int Ed Engl 1997, 36, 1496–1498 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Alkenylzinc Addition to Aldehydes: Dialkylzinc Reagents in Synthesis: • The first example of catalytic asymmetric vinylzinc additions to aldehydes was reported using a chiral diaminoalcohol ligand: H3C CH3 (n-C5H11)2Zn Ti(Oi-Pr)4 (20 mol%) O OCH3 H H3CO CH3 O 88% yield, >98% ee n-Bu H3C O OH O (20 mol%) OH n-Bu H Zn O H N(CH3)2 N H3CO toluene –78 → –20 °C OH OH OCH3 hexanes, ºC 90%, 96% ee O Oppolzer, W.; Radinov, R N Tetrahedron Lett 1988, 29, 5645–5648 CH3 • Mixed organozinc reagents, formed via transmetallation of organoboron or organozirconium with dialkylzinc, can be used to form enantiomerically enriched allylic alcohols in the presence of a chiral amino alcohol catalyst: (–)-Gloeosporone Fürstner, A.; Langemann, K J Am Chem Soc 1997, 119, 9130–9136 O H O O H CH3 (Br(CH2)5)2Zn Ti(Oi-Pr)4 (8 mol%) O H3C OH Et2Zn (–)-DAIB (1 mol%) O H3C 60%, 82% de CH3 69%, 92% ee Oppolzer, W.; Radinov, R N Helv Chim Acta 1992, 75, 170–173 Oppolzer, W.; Radinov, R N.; De Brabander, J Tetrahedron Lett 1995, 36, 2607–2610 OH (10 mol%) Bu2Cu(CN)Li2 95% O Br toluene –60 → –20 °C THF, –60 → °C HO (Cy)2BH•S(CH3)2 hexanes –20 → 23 °C CH3 H3C Ginnol n-Bu H Cp2ZrHCl CH2Cl2, 23 ºC n-Bu Me2Zn toluene, –65 ºC Zn CH3 Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P J Org Chem 1996, 61, 8229–8243 SH CH3 N(CH3)2 OH n-Bu O Cl H 83%, 97% ee Cl toluene, –30 ºC Wipf, P.; Ribe, S J Org Chem 1998, 63, 6454–6455 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds • Hydride migration from a boron ate complex provides access to enantiomerically enriched Z-allylic alcohols: OTBDPS Cl (Cy)2BH MTBE H Cy2B • Direct transmetallations from vinyl iodides provide alkenylzinc reagents not accessible through hydroboration or hydrozirconation: H3C t-BuLi –78 → 23 °C OTBDPS Et2Zn Li(acac)2 (26 mol%) I Cl –20 → 23 °C Li n-Bu NMP, ºC H3CO H H H3C H3C Cy B Cy O (10 mol%) CH3 H HO CH3 CH2Cl2 n-Bu H3CO O H CH3 O OTBDPS 94%, >99% ee Cl DeBerardinis, A M.; Turlington, M.; Pu, L Angew Chem Int Ed 2011, 50, 2368–2370 OH (5 mol%) –78 → 23 °C OTBDPS S O S 69%, 93% ee Alkenylzinc Reagents in Synthesis: Et2Zn TEEDA H H –78 °C t-BuLi Et2O, –78°C ZnBr2, Et2O, ºC OTBDPS BCy2 H I TMS CH3 Salvi, L.; Jeon, S.-J.; Fisher, E L.; Carroll, P J.; Walsh, P J J Am Chem Soc 2007, 129, 16119– 16125 H3C CH3 TBSO H OCH3 CH3 OH TMS TIPS • Tri-substituted Z-allylic alcohol can also be prepared: TBSO NMe2 + Ph OLi 91% yield, 95% ee (2.5 equiv) toluene, 0°C CH3 OCH3 O H (Cy)2BH toluene Br Cy2B n-Bu n-Bu TMEDA (5 mol%) toluene, ºC O Cy Cy Cy B Et Br → 23 °C OH n-Bu Et2Zn –78 → °C H Cy n-Bu Et Zn Et2Zn I TBAF, THF → 23 °C HO OCH3 OH 97% yield, 90% ee H3C O Cy Et as above TBSO H n-Bu HO + Br H CH3 TIPS n-Bu B OH Cy H 50%, 95% ee O H OHC O (–)-Longithorone A Kerrigan, M H.; Jeon, S.-J.; Chen, Y K.; Salvi, L.; Carroll, P J.; Walsh, P J J Am Chem Soc 2009, 131, 8434–8445 CH3 CH3 Layton, M E.; Morales, C A.; Shair, M D J Am Chem Soc 2002, 124, 773–775 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Arylzinc Addition to Aldehydes: Alkynylzinc Additions to Aldehydes Schmidt, F.; Stemmler, R T.; Rudolph, J.; Bolm, C Chem Soc Rev 2006, 35, 454–470 Recent Reviews: • Unlike dialkylzinc additions, diphenylzinc additions to aldehydes take place smoothly even without a catalyst This background reaction has made it more difficult to develop enantioselective variants • Ligand (see page 5) has been found to promote highly enantioselective additions of diphenylzinc and functionalized diaryl zinc to aromatic and aliphatic aldehydes: O I OCH3 Et2Zn Li(acac)2 (26 mol%) (10 mol%) NMP, ºC THF, ºC Wu, X.-F.; Neumann, H Adv Synth Catal 2012, 354, 3141–3160 Trost, B M.; Weiss, A Adv Synth Catal 2009, 351, 963–983 Pu, L Tetrahedron 2003, 59, 9873–9886 • Mixed alkylalkynylzinc reagents can be prepared directly from terminal acetylenes and have been shown to undergo catalyzed 1,2-additions to aldehydes with good enantioselectivities OH H O 23 ºC OCH3 R1 DeBerardinis, A M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L J Org Chem 2010, 75, 2836–2850 R2 H 10 mol % (S)-cat Et2Zn THF, reflux R1 ZnEt OH R2 THF R1 • Widely available aryl boronic acids and boroxines can be directly transformed into arylzinc reagents and undergo enantioselective arylation of aldehydes with excellent selectivity: Et2Zn Ph B(OH)2 Ph ZnEt toluene 60 ºC, >95% O O (10 mol%) DiMPEG (10 mol%) N OH t-Bu OH Ph Cl O p-ClC6H4 Bolm, C.; Rudolph, J J Am Chem Soc 2002, 124, 14850–14851 OTBS N O B B O Et2Zn toluene 60 ºC 47.6 kg OH N toluene, –10 ºC H B O CH3 (S)-cat Fe Ph Ph DiMPEG = dimethoxy poly(ethyleneglycol) OTBS H3C CH Ph Ph Ph (20 mol%) OH R2 T (°C) % yield % ee C6H5 C6 H 64 90 C6H5 c-Hx 88 91 C6H5 t-Bu 61 95 Ph3Si c-Hx 23 55 91 C6H13 t-Bu 23 67 87 C6H13 C6H5 23 41 78 CN TBSO O H OH R1 CN 88%, >94% ee • The low yields in these reactions was attributed in part to competitive addition of ethyl groups to the aldehydes 17.6 kg OTBS –5 → –10 ºC Ishizaki, M.; Hoshino, O Tetrahedron: Asymmetry 1994, 5, 1901 Magnus, N A.; Anzeveno, P B.; Coffey, D S.; Hay, D A.; Laurila, M E.; Schkeryantz, J M.; Shaw, B W.; Staszak, M A Org Process Res Dev 2007, 11, 560–567 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds • In 2000, Carreira et al published an in situ preparation of alkynylzinc reagents and their addition to aldehydes with excellent enantioselectivities and yields • Enantioselective additions of 2-methyl-3-butyn-2-ol to aldehydes provide access to optically active terminal acetylenes after cleavage of acetone from the products • The reactions can be carried out without rigorous exclusion of oxygen or moisture using reagentgrade toluene (84–1000 ppm H2O) • Protection of the 2° propargylic alcohol prior to cleavage of acetone from the adducts leads to improved yields • All reagents are stoichiometric or superstoichiometric OH CH3 CH3 H OH O R1 H H R2 H3C R1 R R2 (+)-N-methyl ephedrine O NMe2 Ph Zn(OTf)2, Et3N H R2 R (–)-N-methyl ephedrine OH (+)-N-methylephedrine OBz toluene, 110 ºC R H toluene, 23 °C; benzoyl chloride yield (%) cat 18-cr-6 K2CO3 OH H3C CH3 Zn(OTf)2, Et3N toluene, 23 °C R1 OBz R % overall yield % ee n-C3H7 68 99 n-C5H11 71 98 98 ee (%) n-C5H11 CH2CH2Ph 94 97 n-C5H11 Ph 90 97 t-Bu 65 c-C6H11 73 99 TIPSO(CH2)2 71 97 i-Pr Ph 96 92 Ph Ph 82 93 Frantz, D E.; Fassler, R.; Carreira, E M J Am Chem Soc 2000, 122, 1806–1807 Frantz, D E.; Fassler, R.; Tomooka, C S.; Carreira, E M Acc Chem Res 2000, 33, 373–381 Boyall, D.; Frantz, D.; Carreira, E M Org Lett 2002, 4, 2605–2606 For an investigation on the reaction mechanism, see: Fässler, R.; Tomooka, C S.; Frantz, D E.; Carreira, E M Proc Natl Acad Sci 2004, 101, 5843–5845 Boyall, D.; Lopez, F.;Sasaki, H.; Frantz, D.; Carreira, E M Org Lett 2000, 2, 4233–4236 • The resulting terminal acetylene can be used to prepare enantiomerically enriched 1,4-diols: • It was shown that by raising the reaction temperature to 60 °C, the in situ zinc acetylide formation and addition reaction can be made catalytic in both zinc and chiral ligand • The system is less effective for aromatic aldehydes because of a competitive Cannizzaro reaction OBz CH3 + H O H3C H CH3 + H OTMS CH3 CH3 (+)-N-methyl ephedrine (22 mol%) OH Et3N, toluene, 60 °C 77%, 98% ee Anand, N K.; Carreira, E M J Am Chem Soc 2001, 123, 9687–9688 CH3 O OBz CH3 Zn(OTf)2, Et3N toluene, 60 °C CH3 OH 72%, 99% ee, dr = 92 : H3C Zn(OTf)2 (20 mol%) H (–)-N-methyl ephedrine CH3 OTMS CH3 CH3 Diez, S R.; Adger, B.; Carreira, E M Tetrahedron 2002, 58, 8341–8344 Fan Liu, Michael Furrow Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds • A mannose-derived auxiliary was employed to promote diastereoselective alkynylzinc additions to nitrones The nitrone auxiliary was prepared from mannose, acetone and N-hydroxylamine • Hydroxylamines are readily reduced to free amines: Ph O –O + N R1 H H H O O R2 HO O CH3 Zn(OTf)2 (0.5 equiv) Me2NCH2CH2OH (0.5 equiv) O CH3 Et3N, CH2Cl2, 23 °C; H N N Bn H3C Xc* R1 Ph Zn, AcOH, H2O OH H3C CH3 NHBn H3C 81% Pinet, S.; Pandya, S U.; Chavant, P Y.; Ayling, A.; Vallee, Y Org Lett 2002, 4, 1463–1466 R2 • The oxazepanedione shown below, prepared in steps from ephedrine and dimethyl malonate, undergoes condensation with aldehydes mediated by TiCl4 Conjugate addition of zinc alkynylides followed by hydrolysis and decarboxylation give β-alkynyl acids in good yields and selectivities: H3C CH3 H2NOH•HCl, NaOAc HN O OH H3C N H3C + R1 MeOH, H2O, 60 ºC O HOHN R2 H O O CH3 CH3 H O R1 R2 CH3 Ph 88 95:5 i-Pr C(OH)Me2 98 96:4 overall yield (%) Ph O O R , TiCl4 H3C H3C N pyridine, THF –78 → 23 ºC Ph O O H O Ph O H R O Zn(OTf)2 (60 mol%) Et3N, CH2Cl2, 23 ºC dr t-Bu Ph 91 97:3 Ph SiMe3 88 95:5 Ph Ph R = i-Pr, 97%, >98% ee R = c-C6H11, 83%, >98% ee Fassler, R.; Frantz, D E.; Oetiker, J.; Carreira, E M Angew Chem., Int Ed Engl 2002, 41, 3054–3056 • The use of ZnCl2 homogenizes the reaction mixture and obviates the need for N,Ndimethylethanolamine: KOH, PrOH, 97 ºC H3C H3C N Ph O O O HO DMSO, 100 ºC R R O • Lowering the loading of Zn(OTf)2 to 20 mol% resulted in lower selectivites and isolated yields Knöpfel, T F.; Boyall, D.; Carreira, E M Org Lett 2004, 6, 2281–2283 • A highly effective two-catalyst system was reported for the addition of zinc acetylide to aromatic aldehydes The stereochemistry of BINOL determines the stereochemistry of the products, while the second ligand improves catalytic activity and enantioselectivity: H3C CH3 O O + –O + N R1 H H O O CH3 O CH3 H H ZnCl2, Et3N toluene, 23 °C 92%, dr = 96 : HO N O Xc* p-BrC6H4 R1 Topic, D.; Aschwanden, P.; Fässler, R.; Carreira, E M Org Lett 2005, 7, 5329–5330 R2 H H OH Ph (S)-BINOL (10 mol%) Ligand (10 mol%) Zn(CH3)2, THF, °C 85%, 99% ee H3C p-BrC6H4 NHTs Ph Ph OH Ligand Li, X.; Lu, G.; Kwok, W H.; Chan A S C J Am Chem Soc 2002, 124, 12636–12637 Fan Liu, Michael Furrow 10 Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Alkynylzinc Reagents in Synthesis: H3C CH3 TBDPSO Ph H + O O CH3 O CH3 OTBS CO2CH3 10 steps OH O H3C HO (CH3O)2HC H3CO O O HO H3CO CH3 CH3 OH OH O H3C CH3 CH3 OCH3 BOMO 13 steps TBDPSO CH3 (CH3O)2HC CH3 O O AcO O OH O O H3C CH3 CH3 CH3 OH Kleinbeck, F.; Carreira, E M Angew Chem Int Ed 2009, 48, 578–581 O Me OTE S H3C H3C CH3 C5H11 + (+)-N-Me-ephedrine H O H CH3 CH3 H3CO2C (–)-Bafilomycin A1 O O Zn(OTf)2, i-Pr2NEt toluene, 23 ºC 91%, dr > 95 : CH3 CH(OMe)2 TBAF, DMF, THF –78 → ºC, 99% single diastereomer (+)-N-Me-ephedrine H3C CH3 CH3 O i-Pr Ph BOMO OTES Zn(OTf)2, Et3N toluene, 23 ºC 90%, dr = : CH(OMe)2 CH3 CH3 CH3 H3CO2C + H (–)-N-Me-ephedrine O O H3CO O H3C CH3 OTBS CO2CH3 H O H H H3CO2C Zn(OTf)2, i-Pr2NEt toluene, 23 ºC 91%, dr > 95 : CH3 O Me steps CH3 O CH3 (–)-Salvinorin A C5H11 Red-Al, Et2O 3Å MS, → 23 ºC I OH CH3 CH3 C5H11 I2, –20 ºC, 99% OH CH3 CH3 C5H11 CH3 steps Scheerer, J R.; Lawrence, J F.; Wang, G C.; Evans, D A J Am Chem Soc 2007, 129, 8968– 8969 O H3C O CH3 OH HO OH CH3 (–)-Tulearin C Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, B Fürstner, A Angew Chem Int Ed 2011, 50, 11373– 11377 Fan Liu, Michael Furrow 11 Myers Chem 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Asymmetric Addition to Ketones: • Ketones are less reactive than aldehydes and often give 1,2-addition products in lower yields because of competitve enolization or reduction of the carbonyl group • Salen ligand 10 and Schiff base ligand 11 were found to promote efficient addition of zinc acetylides to ketones: • Using Ti(Oi-Pr)4 as a Lewis acid, ligand catalyzes the formation of tertiary alcohols with high selectivity: O O O S NH HN S O H3C N N Ph OH HO Ph Ph CH3 N Ph Ph OH H3C OH O HO CH3 CH3 Et 11 CH3 10 (8 mol%) (CH3)2Zn O hexanes toluene, 23 ºC CH3 10 OH (2 mol%) Et2Zn, Ti(Oi-Pr)4 + CH3 t-Bu CH3 CH2Cl2 toluene, 23 ºC 78%, 99% ee Zn(CH3)2 toluene, –78 ºC O H3C (10 mol%) Zn(CH3)2, Ti(Oi-Pr)4 toluene, 23 ºC H3C + H3C OH CH3 CH2Cl2 toluene, 23 ºC 90%, 95% ee 61%, 87% ee HO n-Pr Ph Ph Saito, B.; Katsuki, T Synlett 2004, 1557–1560 Zn Zn(CH3)2 toluene, –78 ºC F 11 (1 mol%) Et2Zn O CH3 H3C OH O H3C Ph n-Pr Ph Ph Li, H.; Walsh, P J J Am Chem Soc 2004, 126, 6538–6539 Cp2ZrHCl CH2Cl2, 23 ºC 10 (8 mol%) (CH3)2Zn O Ph Zn t-Bu 53%, 93% ee Garcia, C.; Larochelle, L K.; Walsh, P J J Am Chem Soc 2002, 124, 10970–10971 Yus, M.; Ramon, D J.; Prieto, O Tetrahedron: Asymmetry 2002, 13, 2291–2293 Cp2ZrHCl CH2Cl2, 23 ºC HO CH3 CH3 + Ph F HO CH3 hexanes, –18 ºC 83%, 94% ee Ph H3C (5 mol%) Zn(CH3)2, Ti (Oi-Pr)4 toluene, 23 ºC 92%, 92% ee • This method is only effective for aromatic ketones Chen, C.; Hong, L.; Xu, Z.-Q.; Liu, L.; Wang, R Org Lett 2006, 8, 2277–2280 Li, H.; Walsh, P J J Am Chem Soc 2005, 127, 8355–8361 Fan Liu, Michael Furrow 12 ... Chem Int Ed 2006, 45, 4175 – 4178 TEEDA (equiv) yield ee – 0.8 99 92 Fan Liu, Michael Furrow Myers • Transmetallation with a Diorganozinc Reagent: • Functionalized diorganozinc reagents can be prepared... 115 Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Alkenylzinc Addition to Aldehydes: Dialkylzinc Reagents in Synthesis: • The first example of catalytic asymmetric vinylzinc additions... H3C CH3 H HO Ph Si H3C CH3 OBn OTBS H • Halogen-Diorganozinc Exchange: • Iodine -zinc exchange reactions have been used to prepare dialkylzinc species containing esters, nitriles, chlorides, sulfonamides,