Myer Organozinc Reagents: Asymmetric Additions to Carbonyl Chem

sRecent Reviews: Compounds

 In 1984, Oguni and Omi found that a small amount of (S)-leucinol catalyzed the 115
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– H3C
O OH OH
1932.
2 mol % CH3 NH2 CH3
H + (C2H5)2Zn
Background:
toluene, 20 °C, 43 h
96% yield, 49%
 The reactivity of dialkylzinc reagents towards ketones and aldehydes is low; the rate of addition
ee
of Et2Zn to benzaldehyde is negligible at room temperature.
Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823–
 The addition of a catalytic amount of TMEDA will promote the addition of diethylzinc at 2824.
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 % CH3
H + (C2H5)2Zn H 3C CH3
TMEDA
toluene, 23°C, 14 N(CH3)3
Bz Bz
h 93% OH
racemic
H3C

(–)-DAIB
Soai, K.; Watanabe, M.; Koyano, M. Bull. Chem. Soc. Jpn. 1989, 25, 2124–
2125.
O 2 mol % (–)- OH
+ R'2Zn DAIB
 X-Ray structures of dimethylzinc and its adduct with 1,3,5-trimethylhexahydro-1,3,5- toluene, 0 R R'
R H
triazine show that upon bis-complexation, dimethylzinc shifts from a linear geometry to a °C
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
R R' % yield % ee
addition to carbonyl compounds.
Ph Et 97 98
CH3 H3C
Ph Me 59 91
N N
N H 3C p-ClC6H4 Et 86 93
CH3 H3 C N N CH 3
2 H3C N
H3C Zn CH3 145 ° Zn p-CH3OC6H4 Et 96 93
CH3
180 ° H3 C N
(E)-PhC(H)=CH Et 96
N CH3 81
N
Zn—C PhCH2CH2 Et 80 90
H3C
1.95 Å n-C6H13 Et 81 61
Zn—C
1.98 Å

Hursthouse, M. B.; Motewaili, M.; O'Brien, P.; Walsh, J. R.; Jones, A. C. J. Mater. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-
Chem. 6072.
1991, 1, 139–140. Fan Liu, Michael
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Myer Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
sMechanism: Compounds
 A non-linear dependence of product ee on catalyst ee was observed. Heterochiral115
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 Et 2Zn : DAIB is greater than 1:

O OH 8 mol % (–)-DAIB OH
cat. (–)- CH3 O
15 % ee CH3
H + (C2H5)2Zn DAIB
toluene, 0 °C, 6 H + (C2H5 2) Zn
h
92% yield, 95%
% ee ee
aldehyde : Et2Zn : DAIB % yield
1:1:0 0 — H3 C CH3 H
CH3 O CH3
1:1:1 1 0 R Zn
N
50 : 50 : 1 97 98 Zn Et + N
O H3C
H 3C H CH3 H3C H C
3 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:

H3C CH3
H3C CH3 CH3 H3C CH3
CH3
N(CH3)3 CH3 CH3
N N
OH Zn R Zn R H3C
H3C Et2Zn O O
H3 C H H H3C H H3C CH3
CH3
R Zn ON O
H3C CH3 R Zn
CH3 N
H3C CH3 H3C H3C H3C CH3
CH3 N H3C H
Zn Et CH3
N O
Zn Et H3C CH3
O Zn +
H3C CH3 Et heterochiral dimer,
Et more stable, does not
readily dissociate
EtZnO O H H CH3 CH 3
H N
Et Ar Zn R
Ar
O H
CH3
CH3 R Zn
O
H3C CH3 H3C CH3 H3C
CH3 CH3 CH3 N
N slow N H3C
Et Et H3C H C
Zn Zn CH3
O O 3
H3C CH H3C CH3O H
3 H
O Zn
Zn Et Et
Et Et homochiral dimer,
Ar less stable,
Ar
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. Oguni, N.;
Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237– Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc. 1988, 110, 7877.
5240. Evans, D. A. Science 1988, 240, 420–426. Fan Liu, Michael
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Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
Preparation of Organozinc Reagents: 115
 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
 Metallic Zinc Insertion:
asymmetric additions to carbonyl compounds:
 One of the early methods involves treatment of an alkyliodide or bromide with zinc dust or an
1. MgBr
activated form of Zn, such as zinc-copper couple (Zn(Cu)). The method requires rather harsh (salt
conditions and is limited to low molecular weight dialkylzinc species due to the need to distill (1.0 M in Et2O) 2. free)
ZnCl2 Zn
the products while avoiding competitive Wurtz coupling: dioxane
(1.0 M in Et2O) 3.
filtration
O OH
Schlenk O O
[EtZnI] Equilibrium Et2Zn distillatio H N THF, –75 ºC N
Zn-Cu
EtI + + + n Et2Zn OLi
EtBr neat, reflux 200 ºC
[EtZnBr] BrZnI OBn CH3 >80% OBn
<30 mmHg
93% ee
89 % N

 methanesulfonic acid can be used to activate zinc O

metal:
von dem bussche-Hünnefeld, J. L.; Seebach, D. Tetrahedron 1992, 48, 5719–
NC F 5730. Brubaker, J. D.; Myers, A. G. Org. Lett. 2007, 9, 3523–3525.
O
1. Zn F  Zn(OCH3)2 can also be used. The byproduct, CH3OMgCl, precipitates from the reaction mixture
MsOH (5 mol Cl Cl EtO2C
EtO2C %) EtO2C ZnBr 10.0 kg and salt-free ethereal solutions of diorganozinc can be obtained after filtration or centrifugation:
Br THF, 70 Cl Cl
ºC 2. 6N HCl
11.5 10.6 kg Et2O
kg 72% CH3 CH3 CH3
2x MgCl + Zn(OCH3)2 Zn + 2
H 3C 0 → 23 ºC H 3C CH3 CH3OMgCl
Choi, B. S.; Chang, J. H.; Choi, H.-W.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.; Heo, T.; > 95%
Nam,
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
formed zinc reagents function in catalytic asymmetric addition reactions to aldehydes:
a Zinc(II) halide with two equivalents of alkyllithium or alkylmagnesium halide:
3. O

H OH
Pd(PPh 3)4
N O Br 1. n-BuLi 2. ZnCl2
(5 mol%)
ZnCl2 N O 60 ºC MTBE
N O 1. n-BuLi N O H3C CH3
hexanes O
H THF, –60 Li ZnCl Br N
90%
ºC SO2CH3 OH TEEDA
unstable stable N N
H3C (equiv) yield ee
above –50 ºC H3C CH3 (5 mol%)
SO2CH3 H3C CH3 0 –
TEEDA 2
Reeder, M. R.; Gleaves, H. E.; Hoover, S. A.; Imbordino, R. J.; Pangborn, J. J. Org. Process 0.8 99
Res.
Dev. 2003, 7, 696–699. Kim, J. G.; Walsh, P. J. Angew. Chem. Int. Ed. 2006, 45, 4175– Fan Liu,92Michael
4178. Furrow
3
Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
 Transmetallation with a Diorganozinc Reagent:  Halogen-Diorganozinc Exchange: 115
 Functionalized diorganozinc reagents can be prepared via transmetallation of  Iodine-zinc exchange reactions have been used to prepare dialkylzinc species containing
organolithium, organoboron, organonickel, and organozirconium with dimethyl-, diethyl-, or esters, nitriles, chlorides, sulfonamides, and boronic acids. CuI or UV light were found to
diisopropylzinc: 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
OPiv Me2PhSiLi, HO AcOCH2(CH2)3CH2I (AcOCH2(CH2)3CH2)2Zn
OPiv OPiv
ZnEt2; 0.1 mm Hg, 50
Ph Ph °C
Si OBn Si OBn
H OBn MoOPH H3C H H > 95%
OTBS 82% CH3 OTBS H3C OTBS
CH 3
Rozema, M. J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P. Tetrahedron
Lett.
Substrate decomposition occurred in the absence of 1993, 34, 3115–3118.
ZnEt2.
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.
 organoboron n-Hex OAc
Et2Zn CuI O O O
: (3 mol%) n-Hex
O neat, 50 O t-Bu OEt
CO2Et 1. Et2BH, Et2O, 0 °C CO2Et °C O
I OEt 0.1 mm EtO )2Zn
) 2Zn TMSOTf, CH2Cl2 O
EtO2C 2. Et2Zn, neat, 0 EtO2C Hg 50 t-Bu
°C –78 ºC, 67%
°C
> 86%
Powell, N. A.; Rychnovsky, S. D. J. Org. Chem. 1999, 64, 2026–
Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 2037.
61, 8229–8243.  Aryl and alkenyl iodides can undergo halogen-zinc exchange with i-P2rZn. Li(acac)2 activates
the intermediate mixed diorganozinc as an ate complex and promotes the second exchange:
 organonickel
: OAc
OAc I i-Pr2Zn Zn
)2Zn H3CO H3CO
Et2Zn (0.6 equiv), Ni(acac)2 (1 mol%) i-Pr
Li(acac) 2 (10 mol%)
Li(acac)2
2x
OPiv COD (2 mol%), neat, 50–60 OPiv Et2O, NMP 25
°C
H O ºC, 12 h H O
> 40% >90%
OAc
Vettel, S.; Vaupel, A.; Knochel, P. J. Org. Chem. 1996, 61, 7473– I
H3CO
7481. CH3
 organozirconium
: OAc OAc AcO O
H3CO Zn OCH3 H3CO Zn
OTBDPS OTBDPS OTBDPS H O 3
Cp2ZrHCl ZnMe2 O CH
i-Pr
CH2Cl2 toluene Li+
0 → 23 ºC –60 → 0 ºC H O O H Li(acac)2 H O
ZrCp2Cl > 86%
CH3
Zn Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 1017–
Wipf, P.; Xu, W. Org. Synth. 1997, 74, 205– 1021.
211. Fan Liu, Michael
Furrow
4
Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
Alkylzinc Addition to Aldehydes:  3-exo-morpholinoisoborneol (MIB), 4, more stable and easier to prepare than DAIB,115
catalyzes
 A variety of chiral catalysts and ligands have been developed that promote the addition of enantioselective additions to aldehydes with similar selectivity and efficiency. It also shows
dialkylzinc reagents to give enantiomerically enriched secondary alcohols. Only a few improved selectivity with α-branched, aliphatic aldehydes:
shown
representative ones are O O Et2Zn OH
here:
H3C ent-4 (5 mol%) H3C
HO N H 3C CH3 O H Et
Ph hexanes,
Ph CH3 N CH3 CH3
Ph toluene 0 ºC,
N OH
OH 94%
HO N(n-Bu)2 CH3 H3 C
99% ee
Nugent, W. A. Chem. Commun. 1999, 1369–
1 2 3 4
1370.
 Using 5 as a chiral additive, either enantiomer of the product can be obtained by changing the
N reaction conditions:
Ph Ph Ph Ph Et2Zn
O OO O OH
H3C CH3 5 (10 mol%)
Ti NHTf OH
H3C O O CH3 OH Et2Zn O Ti(Oi-Pr) 5 (2 equiv) 4 OH
OO
N (1.2 equiv)
Ph Ph Ph NHTf Et H Et
toluene toluene
5
Ph 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–
O 1 (6 mol%) OH 101.

Ph H hexanes, 0 Ph Et n-Bu2Zn, Ti(Oi-Pr)4

O OH
ºC 6 (2 mol%)
94%, 95% ee Ph H toluene, –30 Ph n-Bu
ºC
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 Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989, 30, 1657–1660.
ketones: Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989,
O 30, 7095–7098.
Et2Zn
O
Ph n-BuLi, 2 (8 mol%) 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%
O ee OH neat, 25
(Cl(CH2)4)2Zn (TMSCH2)2Zn °C (Cl(CH2)4)Zn(CH2TMS)
+
Watanabe, M.; Soai, K. J. Chem. Soc., Perkin Trans. 1, 1994, 3125–
O
3128. 6 (8 mol%)
OH Ti(Oi-Pr)4 H
Et2Zn
O OH Et2O, –20 °C
3 (5 mol%) Cl
H3C H H 3C Et
hexanes, 86%, > 94%
H3C toluene 0 ºC, H3C ee
91%
99% ee Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.; Reddy, C. K. Angew. Chem., Int.
Nugent, W. A. Org. Lett. 2002, 4, 2133– Ed. Engl. 1997, 36, 1496–1498.
Fan Liu, Michael
2136. Furrow
5
Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
Dialkylzinc Reagents in Synthesis: Alkenylzinc Addition to Aldehydes: 115
 The first example of catalytic asymmetric vinylzinc additions to aldehydes was reported using
a
chiral diaminoalcohol ligand:
H3 C CH3
(n-C5H11)2Zn
OH
OCH3 O Ti(Oi-Pr)4 OCH3 OH
N N(CH3)2
6 (20 mol%)
H3CO H H3CO CH3 O
toluene H3C (20 mol%) OH
88% yield, >98% n-Bu
–78 → –20 °C H n-Bu
ee Zn
O
hexanes, 0
ºC
O OH O 90%, 96% ee
O
H 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
Gloeosporone
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%)
(Br(CH2)5)2Zn O O
H3C H3C
O Ti(Oi-Pr)4 OH 60%, 82%
6 (8 mol%) Br de
H
CH3 toluene CH3
–60 → –20 °C Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta. 1992, 75, 170–173.
69%, 92% Oppolzer, W.; Radinov, R. N.; De Brabander, J. Tetrahedron Lett. 1995, 36, 2607–
ee 2610.

OH
(10 mol
Bu2Cu(CN)Li2
1.Cp2ZrHCl %)
CH3 OH
THF, –60 → 0 °C
CH3H3C CH2Cl2, 23 ºC Zn SH N(CH )3 2
95% n-Bu H 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, H 83%, 97%
61, 8229–8243. ee
Cl
toluene, –30 ºC

Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454–

6455. Fan Liu, Michael
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Myer Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
s Hydride migration from a boron ate complex provides access to enantiomerically enriched Z- 115
 Direct transmetallations from vinyl iodides provide alkenylzinc reagents not accessible
allylic alcohols: through hydroboration or hydrozirconation:

H3C CH3
1. (Cy) 2BH H
2. t-BuLi Et2Zn O CH3
MTBE Cy2B I HO
OTBDPS OTBDPS –78 → 23 °C Li(acac)2
Cl Cl (26 mol%) 7 (10 mol%) H CH3
–20 → 23 °C
H3CO n-Bu NMP, 0 ºC CH2Cl2
Li H H3CO n-Bu
H H O
H3C O
H3C Cy B
OTBDPS 94%, >99%
Cy
Cl ee
DeBerardinis, A. M.; Turlington, M.; Pu, L. Angew. Chem. Int. Ed. 2011, 50, 2368–
2370.
4 (5 mol%) Et2Zn Alkenylzinc Reagents in Synthesis:
OH OTBDPS –78 → 23 °C H
TEEDA
S H
O OTBDPS 1. t-BuLi
–78 °C Et2O, –78°C
S BCy2 TIPS CH3
69%, 93% H 2. ZnBr2,
ee I TBSO
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, + TMS CH3 OH
16119– 16125.
Ph 91% yield, 95%
TIPS CH3 OLi ee
 Tri-substituted Z-allylic alcohol can also be TBSO (2.5 equiv)
prepared: toluene, 0°C
H
OCH3 CH3
O HO
H Cy H
1. (Cy)2BH 2 +
2. Et Zn
Cy B
toluene Cy2B –78 → 0 °C n-Bu 1. as above HO OCH3
Br n-Bu n-Bu Et
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 Cy Cy O
n-Bu Et2Zn n-Bu
ºC OH CH3
O Zn B
Et Et Cy
Cy O
H
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.
2009, 131, 8434–8445. Fan Liu, Michael
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775.
Furrow
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Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
Arylzinc Addition to Aldehydes: Alkynylzinc Additions to Aldehydes 115
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 Wu, X.-F.; Neumann, H. Adv. Synth. Catal. 2012, 354, 3141–
variants. 3160. Trost, B. M.; Weiss, A. Adv. Synth. Catal. 2009, 351, 963–
 Ligand 7 (see page 5) has been found to promote highly enantioselective additions of 983.
diphenylzinc and functionalized diaryl zinc to aromatic and aliphatic aldehydes: Pu, L. Tetrahedron 2003, 59, 9873–9886.
 Mixed alkylalkynylzinc reagents can be prepared directly from terminal acetylenes and have
O been shown to undergo catalyzed 1,2-additions to aldehydes with good enantioselectivities.
Et2Zn OH
I H
Li(acac)2
(26 mol%) 7 (10 mol%)
O
NMP, 0 THF, 0 23 ºC
OCH3 ºC ºC OCH3 R2 H OH
Et2Zn 10 mol % (S)-cat.
R1 R1 ZnEt R2
DeBerardinis, A. M.; Turlington, M.; Ko, J.; Sole, L.; Pu, L. J. Org. Chem. 2010, 75, 2836– THF
THF,
2850. R1
reflux
 Widely available aryl boronic acids and boroxines can be directly transformed into arylzinc
reagents and undergo enantioselective arylation of aldehydes with excellent selectivity:
H3C CH
3
O O
8 (10 mol%) t-Bu
N CH3
DiMPEG (S)-cat.
OH OH
Et2Zn (10 mol%) OH N
Ph B(OH)2 Ph ZnEt Ph
toluene Fe Ph Ph
toluene, –10 ºC
60 ºC, O Cl 8
>95%
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 t-Bu 23 67 87
C6H13
Ph
O Ph Ph OH C6H5 23 41 78
B C6H13
Et2Zn (20 mol%) OH
O CN
B
O toluene O TBSO
60 ºC CN  The low yields in these reactions was attributed in part to competitive addition of ethyl groups to
H the aldehydes.
88%, >94%
47.6 kg ee
17.6 kg
OTBS –5 → –10 ºC
Ishizaki, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5,
1901.
Magnus,
B. N. A.; Anzeveno,
W.; Staszak, M. A. Org. P. B.; Coffey,
Process Res. D. S.;2007,
Dev. Hay, D.
11,A.; Laurila, M. E.; Schkeryantz, J. M.; Shaw,
560– Fan Liu, Michael
567. Furrow
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Myer Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
s In 2000, Carreira et al. published an in situ preparation of alkynylzinc reagents and their addition  Enantioselective additions of 2-methyl-3-butyn-2-ol to aldehydes provide access to115
optically
to aldehydes with excellent enantioselectivities and yields. active terminal acetylenes after cleavage of acetone from the products.

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

 All reagents are stoichiometric or

superstoichiometric.
OH
H CH3 OBz
OH CH3 cat. 18-cr-
O R 6 K2CO OBz
O H3C NMe2
H R2 OH
R1 R H (–)-N-methyl ephedrine 3 R
R1 H toluene, 110
(+)-N-methyl ephedrine R2 Ph OH Zn(OTf)2, Et N H
ºC
Zn(OTf)2, Et3N (+)-N-
3
methylephedrine
toluene, 23 °C toluene, 23 °C; R % overall yield % ee
R1 R2 yield (%) ee (%) benzoyl
chloride 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 73 99
c-C6H11
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–
Boyall, D.; Lopez, F.;Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett. 2000, 2, 4233–
381. Boyall, D.; Frantz, D.; Carreira, E. M. Org. Lett. 2002, 4, 2605–2606. 4236.
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 OBz OBz
CH3 (–)-N-methyl ephedrine
reaction. + CH3
H
CH3 Zn(OTf)2, Et3N
H CH3
O
(+)-N-methyl OH toluene, 60 °C OH
O ephedrine (22 mol
OTMS H3C 72%, 99% ee, dr = 92 : 8
H3 C + H CH3 %)
H OTMS
CH3 Zn(OTf)2 (20 mol%) CH3 CH3
CH3
CH3
Et3N, toluene, 60 °C

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

Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687– Fan Liu, Michael
9688. Furrow
9
Myer Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
s A mannose-derived auxiliary was employed to promote diastereoselective alkynylzinc additions  Hydroxylamines are readily reduced to free
115
to nitrones. The nitrone auxiliary was prepared from mannose, acetone and N-hydroxylamine. amines:
Ph Ph
Zn, AcOH, H2O
H3C CH OH
N NHBn
3 H3C 81%
H R2 Bn H 3C
O HO Xc*
O N
–O +
Zn(OTf)2 (0.5 equiv)
O CH3 R1
NH O Me2NCH2CH2OH (0.5 equiv) Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Vallee, Y. Org. Lett. 2002, 4, 1463–
CH3 Et3N, CH 2Cl2 , 23 °C; R2 1466.
O
H  The oxazepanedione shown below, prepared in 3 steps from ephedrine and dimethyl malonate,
R1 undergoes condensation with aldehydes mediated by TiCl 4. Conjugate addition of zinc
H alkynylides followed by hydrolysis and decarboxylation give β-alkynyl acids in good yields and
H3C CH3 selectivities:
OH O O
H2NOH•HCl, NaOAc HN O
+ H3C O H 3C O Ph
MeOH, H2O, 60 ºC R1 O H3 C N H3 C N H
HOHN CH3 H R , TiCl4
R2 HOH CH3
O Ph Ph R Zn(OTf) (60
2 mol%)
O pyridine, THF O
O O Et3N, CH2Cl2, 23 ºC
–78 → 23 ºC
R1 R2 overall yield dr
(%)
CH3 Ph 88 95:5 Ph Ph

i-Pr C(OH)Me2 98 96:4 H 3C O

R = i-Pr, 97%,
1. KOH, PrOH, 97 ºC H3C N
>98% ee
t-Bu Ph 91 97:3 O
R = c-C6H11, 83%,
1. DMSO, 100 ºC Ph O R
Ph 88 95:5 >98% ee HO R O
SiMe3

Fassler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 2002,  Lowering the loading of Zn(OTf)2 to 20 mol% resulted in lower selectivites and isolated
41, 3054–3056. yields.

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 ZnCl2, Et3N HO Xc*
+ H N p-BrC6H4
p-BrC6H4 H (S)-BINOL (10 mol%) H 3C NHTs
toluene, 23 °C R1 Ph
–O +N O CH3 Ligand (10 mol%)
O Ph
H 92%, dr = 96 : 4 R2
CH3 Zn(CH3)2, THF, 0 °C OH
R1 H O
H 85%, 99% Ligand
ee
Li, X.; Lu, G.; Kwok, W. H.; Chan. A. S. C. J. Am. Chem. Soc. 2002, 124, 12636–
Topic, D.; Aschwanden, P.; Fässler, R.; Carreira, E. M. Org. Lett. 2005, 7, 5329– 12637. Fan Liu, Michael
5330. Furrow
10
Myer Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
sAlkynylzinc Reagents in Synthesis: Compounds
H3C CH 3
115
H 3CO CH3 CH
3
TBDPS O OTES
H3CO2C (+)-N-Me-ephedrine
O H +
H 3C O H3C Zn(OTf)2, i-Pr2NEt
Ph CH3 OTBS
(–)-N-Me-ephedrine CH3 CH 3O
H + CO2CH3 toluene, 23 ºC
CH3 91%, dr > 95 : 5
H Zn(OTf)2, Et3N
O CH(OMe)2 toluene, 23 ºC
90%, dr = 6 : 1

H3CO CH3 CH3

O H3CO CH3 CH3 O
i-Pr OH H3CO2C OTE
O CH3 Ph H 3C S
CH3 OTBS O OH O H 3C
BOMO H3C CH 3 H3C
O CO2CH3
CH3 O 10 HO 13 TBDPS
HO O
steps OH CH(OMe)2 CH3 CH3 OCH3 CH3 steps O
O H3C CH3
(CH3O)2HC O
(–)-Bafilomycin A1 CH3 CH3 OH

TBAF, DMF,
THF
–78 → 5 ºC, 99%
Kleinbeck, F.; Carreira, E. M. Angew. Chem. Int. Ed. 2009, 48, 578–
single 581.
diastereomer
O (+)-N-Me-ephedrine
O C5H11 H
+
Zn(OTf)2, i-Pr NEt
O CH3 CH3 2 23 ºC
toluene,
O O 91%, dr > 95 : 5
O O H H
H AcO
BOMO O
O Me C5H11
Me
7 steps I 1. Red-Al, Et2O
OH CH3
CH3 H3CO2C
(CH3O)2HC 3Å MS, 0 → 23 ºC C5H11

(–)-Salvinorin 2. I2, –20 ºC, 99%

OH CH 3 CH3 OH CH 3 CH3
A

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, 50,
11373–
11377. Fan Liu, Michael
Furrow
11
Myers Organozinc Reagents: Asymmetric Additions to Carbonyl Chem
Compounds
Asymmetric Addition to Ketones:  Salen ligand 10 and Schiff base ligand 11 were found to promote efficient addition 115
of zinc
 Ketones are less reactive than aldehydes and often give 1,2-addition products in lower acetylides to ketones:
yields 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
Ph
H3 C O O Ph
CH3 OH HO
O S NH HN S O N Ph
Ph Ph OH
9
H3C OH HO CH3

O OH 10 11
9 (2 mol%)
CH3
CH3 Et2Zn, Ti(Oi-Pr)4 Et 10 (8 mol%)
O
hexanes + (CH3)2Zn HO CH3
CH3 toluene, 23 CH3 t-Bu t-Bu
CH3
ºC CH2Cl2
78%, 99% toluene, 23 ºC
Garcia, C.; Larochelle, L K.; Walsh, P. J. J.eeAm. Chem. Soc. 2002, 124, 10970– 53%, 93% ee
10971. Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291–
2293.
O 10 (8 mol%)
3. O HO n-Pr
1. Cp2ZrHCl + (CH3)2Zn
Zn Ph CH3 H3C OH Ph
CH2Cl2, 23 ºC H3C Ph n-Pr Ph
2. Zn(CH 3) 2 CH2Cl2 Ph
9 (10 mol%) Ph
toluene, –78 toluene, 23 ºC
Zn(CH3)2, Ti(Oi-Pr)4
ºC 90%, 95% 61%, 87% ee
toluene, 23 ºC ee

Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538– Saito, B.; Katsuki, T. Synlett. 2004, 1557–
6539. 1560.
1.Cp2ZrHCl
Zn
CH2Cl2, 23 ºC H3C
11 (1 mol%)
2. Zn(CH3)2 F F HO CH3
Et2Zn
O
toluene, –78 ºC + Ph
CH3
hexanes, –18 ºC
Ph
O H3C OH 83%, 94% ee
H3 C H3C
CH3 9 (5 mol%)
Zn(CH3)2, Ti (Oi-Pr)4
92%, 92%  This method is only effective for aromatic
toluene, 23 ºC
ee ketones.
Chen, C.; Hong, L.; Xu, Z.-Q.; Liu, L.; Wang, R. Org. Lett. 2006, 8, 2277–
Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355– 2280.
8361. Fan Liu, Michael
Furrow
12