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Diastereoselective Borocyclopropanation of Allylic Ethers Using a Boromethylzinc Carbenoid Guillaume Benoit, and André B. Charette J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09090 • Publication Date (Web): 18 Jan 2017 Downloaded from http://pubs.acs.org on January 18, 2017
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Diastereoselective Borocyclopropanation of Allylic Ethers Using a Boromethylzinc Carbenoid. Guillaume Benoit and André B. Charette* Centre in Green Chemistry and Catalysis, Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, Québec, Canada H3C 3J7.
Supporting Information Placeholder ABSTRACT: A borocyclopropanation of (E)- and (Z)-allylic
ethers and styrene derivatives via the Simmons–Smith reaction using a novel boromethylzinc carbenoid is described. The carbenoid precursor is prepared via a 3-step sequence from inexpensive and commercially available starting materials. This methodology allows for the preparation of 1,2,3substituted borocyclopropanes in high yields and diastereoselectivities. Several post-functionalization reactions were also performed to illustrate the versatility of these building blocks.
Mono- and disubstituted cyclopropane rings have been incorporated in pharmaceutically relevant compounds and are now routinely included in SAR studies of new drug candidates in order to modulate their activity, metabolism or conformational rigidity.1,2 Moreover, some of these subunits are often embedded in peptide backbones. Indeed, βturn/hairpins or others were found to behave as isosteres of amino acid side-chains.3 Conversely, 1,2,3-trisubstituted cyclopropane units are present in many biologically active natural products.4 Direct access to these highly substituted cyclopropanes from alkenes is not always straightforward through conventional routes: 1) their syntheses require diazo or dihalide carbenoid precurors that are not easily prepared and highly reactive, and 2) their reactivity is very dependent on their degree of substitution.5 Novel powerful strategies to access highly substituted cyclopropane derivatives are highly desirable. An attractive and divergent strategy towards 1,2,3trisubstituted cyclopropanes consists of installing a reactive synthetic handle on a cyclopropyl moiety that allows for rapid diversification of a common intermediate towards multiple classes of cyclopropanes. Borocyclopropanes can serve this role; they represent key synthetic building blocks for the integration of the cyclopropyl motif onto complex frameworks through the Suzuki–Miyaura cross-coupling reaction. Several strategies have been developed to access
cyclopropylboronic acids. The most common approaches are: lithium/halogen exchange followed by trialkylborate trapping;6 cyclopropanation of vinylboronates;7,8 enantioselective Rh-catalyzed hydroboration of cyclopropenes,9 C–H borylation of cyclopropanes;10 and borometalation/cyclization of Z-allylic phosphonates.11 Takai has also shown that treatment of an alkene with dichloropinacolboronate and excess chromium(II) chloride results in the formation of borocyclopropane, albeit with low diastereoselectivities (eq 1).12 In this communication, we report an efficient synthesis of borocyclopropanes in a single step through the direct borocyclopropanation of olefins via the use of a novel boronate-substituted zinc carbenoid (eq 2).13 Takai's work
Cl 2CHBpin (2.0 equiv) CrCl 2 (8.0 equiv) TMEDA (8.0 equiv) LiI (4.0 equiv)
R
R
THF, 50 °C, 12 h
This work
i) I 2CHBpin (2.0 equiv) ii) EtZnO 2CCF3•MTBE (2.1 equiv) iii) Substrate (1.0 equiv)
R1 R2
OR 4
1,2-DCE (0.2 M), −40 °C to rt, 20 h
R3
(1)
Bpin
R = BnO-CH 2-: 75%, 1.1:1 dr (E:Z) R = n-C10H 21-: 75%, 1.7:1 dr (E:Z)
Bpin R2 R3
R1
(2) OR 4
Since dichloromethylpinnacol boronate could not be used as the zinc carbenoid precursor, due to the low C–Cl bond reactivity an efficient method for the preparation of the more reactive diiodo precursor was required. We were pleased to find that this compound could be readily prepared from the corresponding dichloromethylpinnacol boronate by a double Finkelstein reaction with NaI in acetone (eq 3).14 Using this simple procedure, 1 could be prepared on a multi-gram scale in 60% overall yield in 3 steps starting from dichloromethane and without any flash column chromatography.15 O B
Cl Cl
NaI (2.30 equiv) O
acetone, reflux, 48 h 94%
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O B
I I
(3) O
1 (>12-gram scale)
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We then directed our attention towards optimizing the conditions to generate the boro-substituted carbenoid. Since it was anticipated that this intermediate would be quite unstable because of the lability of C–B bonds in the presence of organozinc reagents,16 we elected to form the carbenoid in the presence of alkene 2a (Table 1). Although only traces of borocyclopropane were obtained using Et2Zn, our first breakthrough came when EtZnI was employed as the zinc source in a Zn:1 ratio of 1.0:1.0 in DCM. When stirred for 20 h from 0 °C to rt, this reaction provided the desired borocyclopropane 3a in 43% yield and excellent diastereoselectivities (Table 1, entry 1). After an extensive optimization of the nature of zinc reagent,17,18 reaction temperature, solvent, reagents' stoichiometry and additives (Table 1, entries 2– 11), the desired borocyclopropane 3a was obtained in 90% isolated yield after flash chromatography (Table 1, entry 12). Unlike in most of the previously reported cyclopropanation reactions, MTBE was found to be a superior complexing additive than diethyl ether (Table 1, entry 2 vs 3). Further modification of the ethylzinc source indicated that the trifluoroacetate was optimal (Table entries 4–11). Table 1. Optimization of the Borocyclopropanation Reaction i) 1 (X equiv) ii) "Zn" source (Y equiv) iii) Substrate (1.0 equiv)
OBn
Bpin
CH 2Cl 2 (0.2 M), T °C to rt
Ph
OBn
Ph
2a
3a
entry
"Zn"
Y (equiv)
1 (equiv)
T (°C)
yield (%)a
1
EtZnI
1.1
1.1
0
43
2
EtZnI•OEt2
1.1
1.1
0
24
3
EtZnI•MTBE
1.1
1.1
0
51
4
EtZnI•MTBE
1.6
1.5
0
67
5
EtZnOHFIP •MTBE
1.6
1.5
0
67
6
EtZnOPO3Bu2 •MTBE
1.6
1.5
0
0
7
EtZnOC6H2Cl3 •MTBE
1.6
1.5
0
17
8
EtZnO2CCF3 •MTBE
1.6
1.5
0
42
9
EtZnOCH2CF3 •MTBE
1.6
1.5
0
70
10
EtZnOCH2CF3 •MTBE
2.1
2
0
81
11
EtZnO2CCF3 •MTBE
2.1
2
–40
81
12b
EtZnO2CCF3 •MTBE
2.1
2
–40
90c
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*
For entry 1, carbenoid generated in situ in presence of 2a; for entries 2–12, carbenoid generated first followed by addition of 2a.a NMR yields using triphenylmethane as internal standard, for each entry, a 20:1 dr is measured. b Reaction performed in 1,2-dichloroethane (0.2 M). c Isolated yield.
In contrast to the previously reported cyclopropanation reactions using substituted zinc carbenoids, the major product 3a has the Bpin group cis to the benzyl ether side-chain.19 This structure was confirmed by nOe NMR and X-ray crystallography. To explore the generality of the optimized conditions, a series of protected allylic alcohols were submitted to our optimized reaction conditions (Scheme 1). Cyclopropanes arising from electron-rich aryl and haloaryl substituents on (E)-allylic benzyl ethers were obtained in good yields and excellent diastereoselectivities (3a–3h). However, the analogous trifluoromethyl substituted product (3i) was isolated in lower yield likely due to the decreased nucleophilicity of the starting olefin. Trisubstituted olefins reacted cleanly to provide 3j and 3p in good yields and excellent diastereocontrol. Unfortunately, secondary benzyl ethers (3k) were less reactive under the reaction conditions and gave poor selectivities (1.9:1 dr). We also applied the reaction to alkyl-substituted olefins. In comparison to the cinnamyl ether series, the reaction proceeded with similar yields and selectivities for either (E)- and (Z)olefins (3l–3r). With (E)-olefins, the major isomer was the 1R, 2R, 3R whereas with (Z)-olefins, the major isomer was the 1S, 2R, 3S (for example, see 3l vs 3m)(confirmed by nOe). We determined that a 1,2-disubstituted alkene is a requirement for high diastereocontrol. The reaction of allyl benzyl ether yielded the corresponding borocyclopropane 3s in a 75% yield and poor diastereoselectivity (1.5:1 dr), providing the cis isomer as the major product. Similarly, the borocyclopropane 3t was generated with 2.2:1 dr, favoring the cis isomer. The reaction proceeds efficiently with silyl ethers. Various TBS-protected allylic alcohols were converted into the corresponding cyclopropane 3q, 3r and 3u–3x in satisfying yields and diastereoselectivities. The chemoselectivity of the reaction was successfully evaluated as well by cyclopropanating substrates bearing sensitive functional groups (3y–3ac). The scope of the reaction was also extended to styrenes. Although the desired products could be obtained, the yields and the selectivities were not as high as the ones observed in the allylic ether series. The obtained transborocyclopropanes were found to be major diastereoisomers (Scheme 2). When trans-β-methylstyrene was submitted to the cyclopropanation conditions to generate 4e, a significant drop in yield and selectivity was observed. The observed diastereoselectivities are consistent with a transition state model in which minimization of steric inter-
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actions between the pinacolboron group and the R1 and R2 is also consistent with the lower diastereocontrol observed substituents plays a key role (Figure 1, TS-1 vs TS-2). Coorwith allylic ethers, 1,1-disubstituted allylic ethers, and stydination between the zinc center and the allylic ether oxygen rene derivative. is likely only occurring in the benzyl ether series. This model Scheme 1. Synthesis of Borocyclopropanes from Protected Allylic Alcohols R1 R2
OPG
Ph (3a) 2-MeC6H 4 (3b) 4-MeC6H 4 (3c) 4-MeOC6H 4 (3d) 3,5-MeOC6H 4 (3e) 4-FC6H 4 (3f) 4-ClC6H 4 (3g) 4-BrC6H 4 (3h) 4-CF 3C6H 4 (3i)
Bpin
Bpin Me
Ph
OBn
Ar
90%a, >20:1 dr 74%a, >20:1 dr 87%a, >20:1 dr 74%a, >20:1 dr 88%a, 12:1 dr 83%a, >20:1 dr 75%a, >20:1 dr 71%a, >20:1 dr 36%a, >20:1 dr Bpin
H
Ph OBn
Ph
OBn
3l 92%a >20:1 dr
3q 88%a >20:1 dr
OTBS
Ph
3u 70%a 12:1 dr
Bpin
OTBS
nPr
Me
OBn
OBn
3t 85%b 2.2:1 dr
3s 75%b 1.5:1 dr
Bpin
Bpin
3v 83%a >20:1 dr
3o 79%a >20:1 dr
Bpin
3r 43%a >20:1 dr
Ph
OBn
Me
3n 38%a >20:1 dr
OBn
Bpin
Bpin OBn
Me
3m 81%a >20:1 dr
OBn TBDPSO
Bpin
68%a, >20:1 dr 82%a, >20:1 dr 53%a,c, >20:1 dr 81%a, >20:1 dr 50%a, >20:1 dr
OBn
Bpin
TIPSO
3p 94%a >20:1 dr
Bpin
nPr
Bpin
Me
OPG
Bpin OBn
nPr
Bpin
R R: -OAc (3y) R: -NPhth (3z) R: -OH (3aa) R: -O2C-C6H 4-4-CN (3ab) R: -N3 (3ac)
OBn
R1
R3
Bpin
Me 3k 55%b 1.9:1 dr
3j 77%a >20:1 dr
OBn
Bpin R2
1,2-DCE (0.2 M), −40 °C to rt, 20 h
R3 Bpin
i) I 2CHBpin (2.0 equiv) ii) EtZnO 2CCF3•MTBE (2.1 equiv) iii) Substrate (1.0 equiv)
OTBS
OTIPS
Ph
3w 88%a >20:1 dr
3x 58%a >20:1 dr
a
Isolated yield of major diastereomer. b Combined isolated yield of both diastereomer. c Obtained from the corresponding -OBoc protected substrate (2aa).
Scheme 2. Cyclopropanation of Styrenes i) I 2CHBpin (2.0 equiv) ii) EtZnO 2CCF3•MTBE (2.1 equiv) iii) Substrate (1.0 equiv)
Ar
1,2-DCE (0.2 M), −40 °C to rt, 20 h
Bpin
To illustrate the versatility of the highly substituted borocyclopropanes, we have carried out subsequent postfunctionalizations to access 1,2,3-trisubstituted cyclopropanes. X
Ar
I Zn
O
Bpin
Bpin
Bpin
PG
R3
R2 pinB Bpin H R2 R1
R1 H Zn
O
R3
favored with R2 = H
Bpin R1 R2
cis
R3
OPG
X
PG
Ph
4-t-Bu-C 6H 4
4a 41%a (30%)b 5.8:1 dr
TS-1
4-F-C6H 4
4b 64%a (56%)b 7:1 dr
R2
4c 59%a (49%)b 5.6:1 dr
Bpin
X
Zn
O PG
Bpin
I
R3
R1 Bpin
H
H Bpin R2 R1
Zn O
R3 X
favored with R1 = H
Bpin R1 R2
R3
trans OPG
PG
2-MeO-C6H 4 4d 56%a (48%)b 10:1 dr a
TS-2
Ph 4e 10% a 1:1 dr
Figure 1. Proposed transition state model for the borocyclopropanation.
Yield measured by 1H NMR using triphenylmethane as internal standard. b Combined isolated yield of both isomers.
Boronate 3l was oxidized to the corresponding cyclopropanol 5 in the presence of H2O2 and NaOH in 70% yield. We could also achieve a Suzuki–Miyaura cross-coupling of 3a
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with 3-bromopyridine as the coupling partner in 99% yield using Pd(dba)2/PCy3 in a biphasic toluene/KOH aqueous mixture. A second Suzuki–Miyaura coupling was achieved on boronate 3u in 81% yield. The product of this reaction successively underwent TBAF-mediated deprotection of the TBS group to provide the free alcohol 8 in 96% yield (Scheme 3).
In summary, we have developed a highly efficient borocyclopropanation using a novel boromethylzinc carbenoid. This reaction generally proceeds with good yields and selectivities with a wide range of alkenes. The product are versatile building blocks to access polysubstituted cyclopropane derivatives in a stereocontrolled fashion. Further work is in progress to expand this reaction into an enantioselective version. Scheme 3. Post-functionalization of Borocyclopropane Derivatives OH R1
Bpin
(a) OBn
5: R1 = nPr 70%
3-Pyr
(b) OR2
R1
OBn
R1
3l: R1 = n-Pr; R2 = Bn 3a: R1 = Ph; R2 = Bn 3u: R1 = Ph; R2 = TBS
6: R1 = Ph 99%
(c) Ph
(d) OTBS
R1 7:
R1 = 81%
Ph
Ph OH R1 1 8: R = Ph 96%
a
H2O2 (30%, 2 equiv), NaOH (aq) (1 equiv), THF, 0 °C, 30 min.10a b Pd(dba)2 (5 mol %), PCy3 (10 mol %), 3bromopyridine (2 equiv), KOH (3 N) (6 equiv), toluene, 115 °C, 20 h. c Pd(dba)2 (7 mol %), PCy3 (15 mol %), iodobenzene (2 equiv), KOH (3 N) (6 equiv), toluene, 115 °C, 20 h. d TBAF (1.2 equiv), THF, 0 °C to rt, 110 min.
ASSOCIATED CONTENT Supporting Information. Experimental procedures, compound characterization data, and NMR spectra for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
[email protected]. Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT This work was supported through funding from the Natural Science and Engineering
Research Council of Canada
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(NSERC) Discovery Grant RGPIN-06438, the Canada Foundation
for Innovation Leaders Opportunity Funds 227346, the Canada Research Chair Program CRC-227346, the
FRQNT Team Grant PR-190452, the FRQNT Centre in Green Chemistry and Catalysis (CGCC) Strategic Cluster RS-171310, and Université de Montréal. The authors are grateful to S. Goudreau and É. Lévesque for helpful discussions and suggestions.
REFERENCES 1
Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. 2 Gagnon, A.; Duplessis, M.; Fader, L. Org. Prep. Proced. Int. 2010, 42, 1. 3 Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433. 4 (a) Connor, D. T.; Greenough, R. C.; Strandtmann, M. V. J. Org. Chem. 1977, 42, 3664; b) Donaldson, W. A. Tetrahedron 2001, 57, 8589; c) Elliott, M.; Janes, N. F. Chem. Soc. Rev. 1978, 7, 473; d) Epstein, W. W.; Gaudioso, L. A.; Brewster, G. B. J. Org. Chem. 1984, 49, 2748. e) Kashman, Y.; Saltoun, M.; Rudi, A.; Benayahu, Y. Tetrahedron Lett. 1994, 35, 8855; f) Pietruszka, J. Chem. Rev. 2003, 103, 1051. 5 a) Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977; b) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. 6 de Meijere, A.; Khlebnikov, A. F.; Sünnemann, H. W.; Frank, D.; Rauch, K.; Yufit, D. S. Eur. J. Org. Chem. 2010, 3295. 7 a) Hohn, E.; Paleček, J.; Pietruszka, J.; Frey, W. Eur. J. Org. Chem. 2009, 3765. b) Luithle, J. E. A.; Pietruszka, J. J Org Chem 1999, 64, 8287. c) Mark, I. E.; Kumamoto, T.; Giard, T. Adv. Synth. Catal. 2002, 344, 1063. d) Mark, I. E.; Giard, T.; Sumida, S.; Gies, A. E. Tetrahedron Lett. 2002, 43, 2317. e) Pietruszka, J.; Witt, A.; Frey, W. Eur. J. Org. Chem. 2003, 3219. 8 a) Bassan, E. M.; Baxter, C. A.; Beutner, G. L.; Emerson, K. M.; Fleitz, F. J.; Johnson, S.; Keen, S.; Kim, M. M.; Kuethe, J. T.; Leonard, W. R.; Mullens, P. R.; Muzzio, D. J.; Roberge, C.; Yasuda, N. Org. Process Res. Dev. 2012, 16, 87. b) Hohn, E.; Pietruszka, J.; Solduga, G. Synlett 2006, 1531. c) Hussain, M. M.; Li, H. M.; Hussain, N.; Urena, M.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 6516. d) Lin, H. K.; Pei, W. B.; Wang, H.; Houk, K. N.; Krauss, I. J. J. Am. Chem. Soc. 2013, 135, 82. e) Lin, H. K.; Tian, L. M.; Krauss, I. J. J. Am. Chem. Soc. 2015, 137, 13176. 9 a) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198. b) Rubin, M.; Gevorgyan, V. Synthesis 2004, 796. 10 a) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 3375. b) Miyamura, S.; Araki, M.; Suzuki, T.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed. 2015, 54, 846. c) He, J.; Jiang, H.; Takise, R.; Zhu, R. Y.; Chen, G.; Dai, H. X.; Dhar, T. G. M.; Shi, J.; Zhang, H.; Cheng, P. T. W.; Yu, J. Q. Angew. Chem., Int. Ed. 2016, 55, 785. 11 Zhong, C. M.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 11440. 12 Takai, K.; Toshikawa, S.; Inoue, A.; Kokumai, R.; Hirano, M. J. Organomet. Chem. 2007, 692, 520. 13 For an alternative approach to cyclopropylborinate derivatives see: Zimmer, L. E.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 15624. 14 For the preparation of dichloromethylboronate and related Finkelstein reaction of chloromethylboronate see: a) Wuts, P. G. M.; Thompson, P. A. J. Organomet. Chem. 1982, 234, 137. b) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706. 15 The dichloromethylboronic acid was synthesized according literature procedure14a-b whereas the corresponding pinacol boronate was synthesized by a modified procedure: Cl2CHB(OH)2 (1 equiv), pinacol (1.05 equiv), MgSO4, DCM, rt, 18h, 88% yield (for a complete procedure see Supporting Information). 16 a) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 61, 8229. b) Bolm, C., Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850. c) Li, H.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
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Soc. 2008, 130, 3521. d) Hussain, N.; Hussain, M. M.; Carroll, P. J.; Walsh, P. J. Chem. Sci 2013, 4, 3946. e) Tatina, M. B.; Kusunuru, A. K.; Mukherjee, D. Org. Lett. 2015, 17, 4624. 17 For a review of the importance of zinc carbenoids anionic ligand, see: Cornwall, R. G.; Wong, O. A.; Du, H. F.; Ramirez, T. A.; Shi, Y. A. Org. Biomol. Chem. 2012, 10, 5498. 18 For zinc phosphates, see: a) Lacasse, M. C.; Poulard, C.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 12440. For zinc trifluoroacetate, see: b) Lorenz, J. C.; Long, J.; Yang, Z. Q.; Xue, S.; Xie, Y.; Shi, Y. J. Org. Chem. 2004, 69, 327. c) Yang, Z. Q.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 862. For zinc trifluoroethoxide, see: d) Kim, H. Y.; Lurain, A.
E.; Garcia-Garcia, P.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138. 19 a) Beaulieu, L.-P. B.; Zimmer, L. E.; Charette, A. B. Chem. Eur. J. 2009, 15, 11829. b) Goudreau, S. R.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 15633. c) Beaulieu, L.-P. B.; Zimmer, L. E.; Gagnon, A.; Charette, A. B. Chem. Eur. J. 2012, 18, 14784. d) Beaulieu, L.-P. B.; Schneider, J. F.; Charette, A. B. J. Am. Chem. Soc. 2013, 135, 7819. e) Taillemaud, S.; Diercxsens, N.; Gagnon, A.; Charette, A. B. Angew. Chem. Int. Ed. 2015, 54, 14108.
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TOC GRAPHIC
O
O B
Zn I
R1 R2
OR 4 R3
O
CF3 O Bpin
Boromethylzinc Carbenoid 1,2-DCE, −40 °C to rt, 20 h
R2 R3
R1
OR 4
29 examples up to 20:1 dr 36−94% yield
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