Chem 115 Myers

Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

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 OH OH 2 mol % NH CH3 2 CH3 H + (C2H5)2Zn Background: 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. • 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. O OH 5 mol % TMEDA CH3 H3C CH3 H + (C2H5)2Zn toluene, 23°C, 14 h N(CH3)3 Bz Bz 93% OH racemic H3C

(–)-DAIB Soai, K.; Watanabe, M.; Koyano, M. Bull. Chem. Soc. Jpn. 1989, 25, 2124–2125.

O 2 mol % (–)-DAIB OH + R' Zn • X-Ray structures of dimethylzinc and its adduct with 1,3,5-trimethylhexahydro-1,3,5-triazine 2 R H toluene, 0 °C R R' 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 R R' % yield % ee carbonyl compounds. Ph Et 97 98 CH3 H3C Ph 91 N N Me 59 H C 3 N p-ClC6H4 Et 93 N N N CH3 86 2 H3C CH3 H3C H3C Zn CH3 p-CH OC H 145 ° Zn CH3 3 6 4 Et 96 93 H3C N CH 180 ° N 3 (E)-PhC(H)=CH Et 81 96 N Zn—C PhCH2CH2 Et 80 90 H3C 1.95 Å n-C H Et 81 61 Zn—C 6 13 1.98 Å

Hursthouse, M. B.; Motewaili, M.; O'Brien, P.; Walsh, J. R.; Jones, A. C. J. Mater. Chem. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-6072. 1991, 1, 139–140. Fan Liu, Michael Furrow

1 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

Mechanism: • 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: • The stoichiometry of aldehyde, diethylzinc, and DAIB ligand determines reactivity: alkylation occurs

only when the ratio of Et2Zn : DAIB is greater than 1:

O OH 8 mol % (–)-DAIB OH cat. (–)-DAIB CH O 3 15 % ee CH3 H + (C2H5)2Zn toluene, 0 °C, 6 h H + (C2H5)2Zn

92% yield, 95% ee

aldehyde : Et2Zn : DAIB % yield % ee 1 : 1 : 0 0 — H3C CH3 H CH CH3 3 R Zn O 1 : 1 : 1 1 0 N 50 : 50 : 1 97 98 Zn Et + N O H3C H3C CH H C H 3 3 H3C CH3 Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028–4036. (–)-DAIB (+)-DAIB • This observation is consistent with a mechanistic proposal involving two Zn atoms per aldehyde:

H C CH 3 3 H C CH H C CH 3 3 CH3 3 3 CH CH 3 N(CH3)3 3 CH3 N N OH Zn R Zn R Et2Zn H3C H3C O O H3C H H3C H3C CH3 H CH3 H R Zn O O H C CH 3 3 R Zn CH3 N N H3C CH3 H C CH N 3 H 3 H3C H3C Zn Et H3C CH3 CH3 N O Zn Et H3C CH O 3 H3C CH Zn + 3 Et Et heterochiral dimer, more stable, does not readily dissociate CH3 EtZnO H O H H CH3 N Et Ar Ar Zn R O H CH3 CH3 R Zn O H3C CH3 H3C CH3 H3C CH3 CH3 CH3 N Et slow Et H3C N Zn N Zn H C 3 H3C CH3 O O H3C CH3 H3C CH3 O H O H Zn Zn Et Et Et Ar Et Ar homochiral dimer, less stable, dissociates

Itsuno, S.; Fréchet, J. M. J. J. Org. Chem. 1987, 52, 4142–4143. Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028-4036. Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237–5240. Oguni, N.; Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc. 1988, 110, 7877. Evans, D. A. Science 1988, 240, 420–426. Fan Liu, Michael Furrow

2 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

Preparation of Organozinc Reagents: • In many cases, lithium or magnesium halide byproducts must be removed to avoid salt complexation with chiral additives in subsequent enantioselective processes. 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 • Metallic Zinc Insertion: additions to carbonyl compounds: • One of the early methods involves treatment of an alkyliodide or bromide with zinc dust or an 1. activated form of Zn, such as zinc-copper couple (Zn(Cu)). The method requires rather harsh MgBr (salt free) conditions and is limited to low molecular weight dialkylzinc species due to the need to distill the (1.0 M in Et2O) 2. dioxane ZnCl2 Zn products while avoiding competitive Wurtz coupling: (1.0 M in Et2O) 3. ﬁltration

O OH Schlenk O THF, –75 ºC O Zn-Cu [EtZnI] Equilibrium Et2Zn distillation H N N EtI + EtBr + + Et2Zn OLi neat, reﬂux 200 ºC OBn OBn [EtZnBr] BrZnI <30 mmHg CH3 >80% 93% ee 89 % N

• methanesulfonic acid can be used to activate zinc metal: O

von dem bussche-Hünnefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719–5730. NC F Brubaker, J. D.; Myers, A. G. Org. Lett. 2007, 9, 3523–3525. O 1. Zn EtO2C F • Zn(OCH3)2 can also be used. The byproduct, CH3OMgCl, precipitates from the reaction mixture and MsOH (5 mol%) Cl Cl EtO2C Br EtO2C ZnBr 10.0 kg salt-free ethereal solutions of diorganozinc can be obtained after ﬁltration or centrifugation: THF, 70 ºC Cl Cl 2. 6N HCl 11.5 kg 10.6 kg Et O 72% CH3 2 CH3 CH3 2 x MgCl + Zn(OCH3)2 Zn + 2 CH3OMgCl H3C 0 ! 23 ºC H3C CH3 Choi, B. S.; Chang, J. H.; Choi, H.-W.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.; Heo, T.; Nam, > 95% D. H.; Shin, H. Org. Process Res. Dev. 2005, 9, 311–313.

• Transmetallation with a Zinc Salt: Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771–2773. • N,N,N,N-tetraethylethylenediamine (TEEDA) can be used to scavenge salts and the resulting in situ • Substrates that are less readily prepared by direct reduction can be prepared by treatment of a formed zinc reagents function in catalytic asymmetric addition reactions to aldehydes: Zinc(II) halide with two equivalents of alkyllithium or alkylmagnesium halide: 3. O

H OH Pd(PPh3)4 Br 1. n-BuLi 2. ZnCl2 (5 mol%) N O

N O 1. n-BuLi N O ZnCl2 N O 60 ºC MTBE hexanes H3C CH3 O THF, –60 ºC Br H Li ZnCl 90% N SO2CH3 OH TEEDA unstable stable N N H3C (equiv) yield ee above –50 ºC H3C CH3 (5 mol%) SO CH 2 3 H3C CH3 0 – 2 TEEDA 0.8 99 92

Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino, R. J.; Pangborn, J. J. Org. Process Res. Dev. 2003, 7, 696–699. Kim, J. G.; Walsh, P. J. Angew. Chem. Int. Ed. 2006, 45, 4175–4178. Fan Liu, Michael Furrow

3 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

• Transmetallation with a Diorganozinc Reagent: • Halogen-Diorganozinc Exchange: • Functionalized diorganozinc reagents can be prepared via transmetallation of organolithium, • Iodine-zinc exchange reactions have been used to prepare dialkylzinc species containing esters, organoboron, organonickel, and organozirconium with dimethyl-, diethyl-, or diisopropylzinc: nitriles, chlorides, sulfonamides, and boronic acids. CuI or UV light were found to accelerate the

reaction. Removal of excess Et2Zn and EtI was necessary to drive the reaction: • organolithium:

Et2Zn, CuI (0.1 mol%) O OZn–Et Li+ O neat, 50 °C; 2 HO OPiv Me2PhSiLi, OPiv OPiv AcOCH2(CH2)3CH2I (AcOCH2(CH2)3CH2)2Zn ZnEt2; 0.1 mm Hg, 50 °C Ph Ph OBn MoOPH Si OBn Si OBn > 95% H H3C H H3C H OTBS 82% CH3 OTBS CH3 OTBS Rozema, M. J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P. Tetrahedron Lett. 1993, 34, 3115–3118. Substrate decomposition occurred in the absence of ZnEt . 2 Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem. 1992, 57, 1956–1958. Milgram, B. C.; Liau, B. B.; Shair, M. D. Org. Lett. 2011, 13, 6436–6439. n-Hex OAc • organoboron: Et2Zn O O O CuI (3 mol%) n-Hex O neat, 50 °C O t-Bu OEt CO Et CO2Et 1. Et2BH, Et2O, 0 °C 2 O O I OEt 0.1 mm Hg EtO )2Zn ) Zn TMSOTf, CH2Cl2 EtO C 2 50 °C EtO2C 2. Et2Zn, neat, 0 °C 2 –78 ºC, 67% 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 OAc i-Pr2Zn H3CO I H3CO Zn )2Zn Et2Zn (0.6 equiv), Ni(acac)2 (1 mol%) Li(acac)2 (10 mol%) i-Pr Li(acac)2 2 x Et O, NMP OPiv COD (2 mol%), neat, 50–60 °C OPiv 2 25 ºC, 12 h > 40% H O H O >90%

OAc Vettel, S.; Vaupel, A.; Knochel, P. J. Org. Chem. 1996, 61, 7473–7481. H3CO I CH3 • organozirconium: OAc OAc AcO O

H3CO Zn OCH3 H3CO Zn OTBDPS OTBDPS OTBDPS H O O CH3 Cp ZrHCl ZnMe i-Pr 2 2 Li+

CH2Cl2 toluene H O O H H O 0 ! 23 ºC –60 ! 0 ºC Li(acac)2 ZrCp2Cl > 86% Zn CH3 Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 1017–1021. Wipf, P.; Xu, W. Org. Synth. 1997, 74, 205–211. Fan Liu, Michael Furrow

4 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

Alkylzinc Addition to Aldehydes: • 3-exo-morpholinoisoborneol (MIB), 4, more stable and easier to prepare than DAIB, catalyzes • 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 reagents to give enantiomerically enriched secondary alcohols. Only a few representative ones are selectivity with !-branched, aliphatic aldehydes: shown here: O O Et2Zn OH ent-4 (5 mol%) H3C H3C HO N H3C CH3 O H Et Ph hexanes, toluene N CH3 CH3 Ph CH3 Ph 0 ºC, 94% N OH OH 99% ee HO N(n-Bu)2 CH3 H3C Nugent, W. A. Chem. Commun. 1999, 1369–1370. 1 2 3 4 • Using 5 as a chiral additive, either enantiomer of the product can be obtained by changing the N Ph Ph Ph Ph reaction conditions: Et2Zn O O O O OH H3C CH3 5 (10 mol%) Ti NHTf H C CH OH Et2Zn Ti(Oi-Pr) 3 O O O O 3 OH O 4 OH 5 (2 equiv) (1.2 equiv) Ph Ph Ph Ph NHTf N Et H Et toluene toluene 5 6 7 H3CO 0 " 23 ºC, 89% H3CO –75 " 23 ºC, 86% H3CO 98% ee 94% ee • Ligand 1 extends the scope of the initial DAIB reaction to include aliphatic aldehydes:

Et2Zn Schmidt, B.; Seebach, D. Angew. Chem. Int. Ed. 1991, 30, 99–101. O 1 (6 mol%) OH hexanes, 0 ºC n-Bu2Zn, Ti(Oi-Pr)4 Ph H Ph Et O OH 94%, 95% ee 6 (2 mol%) Ph H toluene, –30 ºC Ph n-Bu Hayasaka, T.; Yokoyama, S.; Soai, K. J. Org. Chem. 1991, 56, 4264–4268. 99%, 98% ee

• Chemoselective addition to aldehydes can be achieved in the presence of ketones: 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, O O 7095–7098. Et2Zn n-BuLi, 2 (8 mol%) Ph Ph • 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: H toluene, 0 ºC Et 82%, 96% ee O OH neat, 25 °C (Cl(CH ) )Zn(CH TMS) (Cl(CH2)4)2Zn + (TMSCH2)2Zn 2 4 2

Watanabe, M.; Soai, K. J. Chem. Soc., Perkin Trans. 1, 1994, 3125–3128. O 6 (8 mol%) OH Ti(Oi-Pr)4 H Et2Zn O OH Et O, –20 °C 3 (5 mol%) Cl 2 H3C H H3C Et hexanes, toluene 86%, > 94% ee H3C 0 ºC, 91% H3C 99% ee Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.; Reddy, C. K. Angew. Chem., Int. Ed. Nugent, W. A. Org. Lett. 2002, 4, 2133–2136. Engl. 1997, 36, 1496–1498. Fan Liu, Michael Furrow

5 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

Dialkylzinc Reagents in Synthesis: Alkenylzinc Addition to Aldehydes: • 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) OH 4 OCH OH OCH3 O 3 N(CH ) 6 (20 mol%) N 3 2 H3CO H H3CO CH3 O toluene H3C (20 mol%) OH –78 ! –20 °C 88% yield, >98% ee n-Bu H n-Bu Zn O hexanes, 0 ºC 90%, 96% ee O OH O H O Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645–5648.

CH3 • Mixed organozinc reagents, formed via transmetallation of organoboron or organozirconium with (–)-Gloeosporone dialkylzinc, can be used to form enantiomerically enriched allylic alcohols in the presence of a chiral amino alcohol catalyst: Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130–9136.

O HO 1. (Cy)2BH•S(CH3)2 H hexanes –20 ! 23 °C

2. Et2Zn O O (–)-DAIB (1 mol%) O O (Br(CH2)5)2Zn H3C H C O Ti(Oi-Pr)4 OH 60%, 82% de 3 6 (8 mol%) Br H toluene CH3 CH3 –60 ! –20 °C Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta. 1992, 75, 170–173. 69%, 92% ee Oppolzer, W.; Radinov, R. N.; De Brabander, J. Tetrahedron Lett. 1995, 36, 2607–2610.

OH (10 mol%) Bu2Cu(CN)Li2 1. Cp2ZrHCl CH3 OH THF, –60 ! 0 °C CH Cl , 23 ºC CH H C 2 2 SH N(CH ) 3 3 n-Bu H Zn 3 2 95% n-Bu CH3 n-Bu Ginnol 2. Me2Zn O toluene, –65 ºC Cl Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 61, H 83%, 97% ee 8229–8243. Cl toluene, –30 ºC

Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454–6455. Fan Liu, Michael Furrow

6 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

• Hydride migration from a boron ate complex provides access to enantiomerically enriched Z-allylic • Direct transmetallations from vinyl iodides provide alkenylzinc reagents not accessible through alcohols: hydroboration or hydrozirconation:

H3C CH3 1. (Cy)2BH H t-BuLi 2. Et2Zn MTBE I O CH3 Cy2B –78 ! 23 °C HO OTBDPS OTBDPS Li(acac)2 Cl (26 mol%) 7 (10 mol%) H CH3 –20 ! 23 °C Cl H3CO n-Bu NMP, 0 ºC CH Cl Li H 2 2 H3CO n-Bu H H O H3C O H C Cy B 3 OTBDPS Cy 94%, >99% ee Cl DeBerardinis, A. M.; Turlington, M.; Pu, L. Angew. Chem. Int. Ed. 2011, 50, 2368–2370.

Alkenylzinc Reagents in Synthesis: 4 (5 mol%) Et2Zn OH OTBDPS –78 ! 23 °C TEEDA H S H OTBDPS 1. t-BuLi O –78 °C BCy Et2O, –78°C TIPS CH3 69%, 93% ee S 2 H 2. ZnBr2, TBSO I Et2O, 0 ºC TMS CH3 3. H3C NMe2 OCH3 Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2007, 129, 16119– + TMS CH3 OH 16125. Ph OLi 91% yield, 95% ee TIPS CH3 (2.5 equiv) toluene, 0°C • Tri-substituted Z-allylic alcohol can also be prepared: TBSO

H CH OCH3 3 O HO H Cy H 1. (Cy)2BH 2. Et2Zn + toluene Cy B Cy B 2 –78 ! 0 °C n-Bu HO OCH Br n-Bu n-Bu Et 1. as above 3 Br Br TBSO I OH 0 ! 23 °C 2. TBAF, THF 0 ! 23 °C 97% yield, 90% ee

TMEDA H3C 4 (5 mol%) H H OH n-Bu toluene, 0 ºC Cy Cy O n-Bu Et2Zn n-Bu O H CH3 O Zn B Et Et Cy Cy H O H OHC 50%, 95% ee O (–)-Longithorone A CH3

Kerrigan, M. H.; Jeon, S.-J.; Chen, Y. K.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775. 2009, 131, 8434–8445. Fan Liu, Michael Furrow

7 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

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. Wu, X.-F.; Neumann, H. Adv. Synth. Catal. 2012, 354, 3141–3160. Trost, B. M.; Weiss, A. Adv. Synth. Catal. 2009, 351, 963–983. • Ligand 7 (see page 5) has been found to promote highly enantioselective additions of diphenylzinc Pu, L. Tetrahedron 2003, 59, 9873–9886. and functionalized diaryl zinc to aromatic and aliphatic aldehydes: • Mixed alkylalkynylzinc reagents can be prepared directly from terminal acetylenes and have been O shown to undergo catalyzed 1,2-additions to aldehydes with good enantioselectivities. Et2Zn OH H I Li(acac)2 (26 mol%) 7 (10 mol%) O NMP, 0 ºC THF, 0 ºC 23 ºC OCH3 OCH3 R H 2 OH Et2Zn 10 mol % (S)-cat. R1 R ZnEt DeBerardinis, A. M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L. J. Org. Chem. 2010, 75, 2836–2850. 1 R2 THF, reﬂux 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: H3C CH3 O O CH3 8 (10 mol%) t-Bu N (S)-cat. DiMPEG OH OH OH N Et2Zn (10 mol%) Ph B(OH)2 Ph ZnEt Ph Fe Ph Ph toluene toluene, –10 ºC Cl 8 60 ºC, >95% O

H p-ClC6H4 R1 R2 T (°C) % yield % ee DiMPEG = dimethoxy poly(ethyleneglycol) C6H5 C6H5 0 64 90

C6H5 c-Hx 0 88 91 Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850–14851. C6H5 t-Bu 0 61 95

Ph3Si c-Hx 23 55 91 OTBS OTBS N C6H13 t-Bu 23 67 87 Ph C H C H 23 41 78 O Ph Ph OH 6 13 6 5 B B Et2Zn (20 mol%) OH CN O O B toluene O TBSO 60 ºC CN • The low yields in these reactions was attributed in part to competitive addition of ethyl groups to the H 88%, >94% ee aldehydes. 47.6 kg 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

8 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

• In 2000, Carreira et al. published an in situ preparation of alkynylzinc reagents and their addition to • Enantioselective additions of 2-methyl-3-butyn-2-ol to aldehydes provide access to optically active aldehydes with excellent enantioselectivities and yields. terminal acetylenes after cleavage of acetone from the products.

• The reactions can be carried out without rigorous exclusion of oxygen or moisture using reagent- • Protection of the 2° propargylic alcohol prior to cleavage of acetone from the adducts leads to grade toluene (84–1000 ppm H2O). improved yields.

• All reagents are stoichiometric or superstoichiometric.

OH H OBz CH3 OH cat. 18-cr-6 O CH3 OBz O H3C NMe2 R K CO H R2 OH 2 3 R1 R H (–)-N-methyl ephedrine R R1 H CH3 toluene, 110 ºC (+)-N-methyl ephedrine R2 Ph OH H3C Zn(OTf)2, Et3N H Zn(OTf)2, Et3N (+)-N-methylephedrine toluene, 23 °C; toluene, 23 °C benzoyl chloride R % overall yield % ee

R1 R2 yield (%) ee (%) n-C3H7 68 99

n-C5H11 CH2CH2Ph 94 97 n-C5H11 71 98 n-C5H11 Ph 90 97 t-Bu 65 98 i-Pr Ph 96 92 c-C6H11 73 99 Ph Ph 82 93 TIPSO(CH2)2 71 97

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.; Lopez, F.;Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett. 2000, 2, 4233–4236. 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. • 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 OBz CH3 (–)-N-methyl ephedrine CH + H 3 CH3 Zn(OTf)2, Et3N H CH3 O toluene, 60 °C (+)-N-methyl OH OH O OTMS ephedrine (22 mol%) H C 72%, 99% ee, dr = 92 : 8 H C 3 3 H + H CH3 OTMS CH CH3 Zn(OTf)2 (20 mol%) 3 CH CH3 3 CH3 Et3N, toluene, 60 °C

77%, 98% ee Diez, S. R.; Adger, B.; Carreira, E. M. Tetrahedron. 2002, 58, 8341–8344.

Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687–9688. Fan Liu, Michael Furrow

9 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

• A mannose-derived auxiliary was employed to promote diastereoselective alkynylzinc additions to • Hydroxylamines are readily reduced to free amines: nitrones. The nitrone auxiliary was prepared from mannose, acetone and N-hydroxylamine.

Ph Ph Zn, AcOH, H O H C CH OH 2 3 3 N NHBn H R H3C 81% H3C O O 2 HO X * Bn N c Zn(OTf) (0.5 equiv) – 2 O + O R N O CH3 Me2NCH2CH2OH (0.5 equiv) 1 H H Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Vallee, Y. Org. Lett. 2002, 4, 1463–1466. R2 O CH3 Et3N, CH2Cl2, 23 °C; R1 H • The oxazepanedione shown below, prepared in 3 steps from ephedrine and dimethyl malonate,

undergoes condensation with aldehydes mediated by TiCl4. Conjugate addition of zinc alkynylides followed by hydrolysis and decarboxylation give !-alkynyl acids in good yields and selectivities: H3C CH3

OH O O H2NOH•HCl, NaOAc HN H C O H C + 3 O 3 O Ph N N MeOH, H O, 60 ºC R O H3C , TiCl H3C H 2 1 HOHN O CH H R 4 H H 3 R2 CH3 O Ph O pyridine, THF Ph O R Zn(OTf)2 (60 mol%) O –78 " 23 ºC O Et3N, CH2Cl2, 23 ºC

R1 R2 overall yield (%) dr

Ph CH3 Ph 88 95:5 Ph

i-Pr C(OH)Me H3C 2 98 96:4 R = i-Pr, 97%, O 1. KOH, PrOH, 97 ºC H C N >98% ee 3 O t-Bu Ph 91 97:3 R = c-C H , 83%, 6 11 2. DMSO, 100 ºC Ph R >98% ee HO R O Ph SiMe3 88 95:5 O

Fassler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 2002, 41, • Lowering the loading of Zn(OTf)2 to 20 mol% resulted in lower selectivites and isolated yields. 3054–3056. Knöpfel, T. F.; Boyall, D.; Carreira, E. M. Org. Lett. 2004, 6, 2281–2283.

• The use of ZnCl2 homogenizes the reaction mixture and obviates the need for N,N- dimethylethanolamine: • 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 OH O H Ph O O ZnCl , Et N HO Xc* 2 3 N + p-BrC H H3C NHTs H p-BrC H H 6 4 – toluene, 23 °C 6 4 (S)-BINOL (10 mol%) O + O R Ph N O CH3 1 Ligand (10 mol%) H H 92%, dr = 96 : 4 Ph OH R2 Zn(CH ) , THF, 0 °C O CH3 3 2 R1 H Ligand 85%, 99% ee

Li, X.; Lu, G.; Kwok, W. H.; Chan. A. S. C. J. Am. Chem. Soc. 2002, 124, 12636–12637. Topic, D.; Aschwanden, P.; Fässler, R.; Carreira, E. M. Org. Lett. 2005, 7, 5329–5330. Fan Liu, Michael Furrow

10 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

Alkynylzinc Reagents in Synthesis: H3C CH3 H3CO CH3 CH3 TBDPSO O O OTES H3CO2C (+)-N-Me-ephedrine H + H C CH OTBS 3 Zn(OTf)2, i-Pr2NEt Ph 3 H3C (–)-N-Me-ephedrine CH3 CH3 O toluene, 23 ºC H + H CO2CH3 CH Zn(OTf) , Et N 3 91%, dr > 95 : 5 O CH(OMe) 2 3 2 toluene, 23 ºC 90%, dr = 6 : 1

H CO CH CH O H3CO CH3 CH3 3 3 3 i-Pr O OH H3CO2C OTES O CH3 H3C Ph CH3 OTBS O OH O BOMO H3C H3C CH3 H3C O CO2CH3 CH3 O 10 steps HO TBDPSO O O HO 13 steps OH CH(OMe)2 CH CH OCH CH O 3 3 3 3 H3C CH3 (CH3O)2HC CH CH OH (–)-Baﬁlomycin A1 3 3

TBAF, DMF, THF –78 ! 5 ºC, 99% Kleinbeck, F.; Carreira, E. M. Angew. Chem. Int. Ed. 2009, 48, 578–581. single diastereomer

O (+)-N-Me-ephedrine O H C5H11 + Zn(OTf)2, i-Pr2NEt O CH 3 CH3 toluene, 23 ºC O O 91%, dr > 95 : 5 O O H H H AcO BOMO O O Me C5H11 Me 7 steps 1. Red-Al, Et O OH CH I 2 CH 3 C H 3 H3CO2C 3Å MS, 0 ! 23 ºC 5 11 (CH3O)2HC 2. I , –20 ºC, 99% (–)-Salvinorin A 2 OH CH3 CH3 OH CH3 CH3

C5H11

CH3

7 steps

O O CH3 Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am. Chem. Soc. 2007, 129, 8968– 8969. OH HO H3C OH

CH3 (–)-Tulearin C

Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, B. Fürstner, A. Angew. Chem. Int. Ed. 2011, 123, 11575–11579. Fan Liu, Michael Furrow

11 Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Compounds Chem 115

Asymmetric Addition to Ketones: • Salen ligand 10 and Schiff base ligand 11 were found to promote efﬁcient addition of zinc acetylides • Ketones are less reactive than aldehydes and often give 1,2-addition products in lower yields to ketones: because of competitve enolization or reduction of the carbonyl group.

• Using Ti(Oi-Pr)4 as a Lewis acid, ligand 9 catalyzes the formation of tertiary alcohols with high selectivity: N N

OH HO Ph H C O O Ph 3 CH3 Ph Ph O S NH HN S O N Ph OH

9 H3C OH HO CH3

O OH 10 11 9 (2 mol%) CH Et Zn, Ti(Oi-Pr) CH3 3 2 4 Et 10 (8 mol%) O HO CH hexanes + (CH3)2Zn 3 CH3 toluene, 23 ºC CH3 t-Bu CH3 t-Bu CH Cl 78%, 99% ee 2 2 toluene, 23 ºC 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.

O 10 (8 mol%) 1. Cp ZrHCl 3. O HO n-Pr 2 + (CH3)2Zn CH Cl , 23 ºC Ph CH H C OH 2 2 Zn 3 3 Ph n-Pr Ph Ph H3C CH Cl 2. Zn(CH ) Ph 2 2 Ph 3 2 9 (10 mol%) toluene, 23 ºC toluene, –78 ºC Zn(CH ) , Ti(Oi-Pr) 3 2 4 61%, 87% ee toluene, 23 ºC 90%, 95% ee

Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538–6539. Saito, B.; Katsuki, T. Synlett. 2004, 1557–1560.

1. Cp2ZrHCl CH2Cl2, 23 ºC Zn H3C 11 (1 mol%) 2. Zn(CH3)2 F O Et Zn F HO CH toluene, –78 ºC 2 3 CH + Ph 3 hexanes, –18 ºC Ph O H3C OH 83%, 94% ee H C H3C 3 CH 3 9 (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