Asymmetric Synthesis of Boryl-Functionalized Cyclobutanols

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Asymmetric Synthesis of Boryl-Functionalized Cyclobutanols Andrew Whyte, Bijan Mirabi, Alexa Torelli, Liher Prieto, Jonathan Bajohr, and Mark Lautens ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03216 • Publication Date (Web): 06 Sep 2019 Downloaded from pubs.acs.org on September 6, 2019

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ACS Catalysis

Asymmetric Synthesis of Boryl-Functionalized Cyclobutanols Andrew Whyte,† Bijan Mirabi,† Alexa Torelli,† Liher Prieto,†‡ Jonathan Bajohr,† and Mark Lautens†* †Davenport

Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada ‡Department of Organic Chemistry II, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain ABSTRACT: A diastereo- and enantioselective synthesis of boron-containing cyclobutanols is reported. We exploit an enantioselective borylcupration to generate a chiral benzylic copper intermediate that is intercepted with a proximally tethered ketone. The scaffolds contain an all-carbon quaternary center with a modular boronate moiety which allows access to a variety of synthetically valuable functional groups. This work represents an asymmetric approach to monocyclic cyclobutanols and highlights the utility of copper-catalysis in the generation of small-sized rings.

cyclobutanols, borylation, copper-catalysis, cyclization, cyclobutanes Small rings have fascinated organic chemists for decades due to their strain and rigid framework.1 Historically, cyclopropanes have been the most thoroughly investigated due to the variety of methods for their preparation,2 while their four-membered ring counterparts have received considerably less attention.3 In the past decade, interest in cyclobutanes has increased owing to their application in ring-opening reactions4 and potential in medicinal chemistry.5 As a result, numerous asymmetric strategies to synthesize cyclobutanes have been developed including [2+2] cycloadditions6 and ring expansion reactions.7 However, these methods are not often used to form the monocyclic scaffold nor are they applicable to heteroatom substitution.8 Cyclobutanols are prime examples of valuable heteroatomsubstituted four-membered rings. They are prevalent in a variety of natural products9 and have been adopted in ring-opening strategies to reveal γ-metalloketones.10 Despite their value, the enantioselective synthesis of cyclobutanols remains a largely unexplored topic.11 We envisaged a simple asymmetric approach towards highly functionalized cyclobutanols by employing copper-catalysis.

Scheme 1. Copper-catalyzed methods towards boroncontaining four-membered rings a) Ito (2015) O

Cu(I), L

R2

O [Cu]

R2

B2pin2

R2 O[Cu]

R2 OH

Bpin

Bpin

Bpin

(±)

b) Tortosa (2016) R

R

Cu(I), L*

R

B2pin2, MeOH

[Cu]

R

MeOH

Bpin

c) This work O R1 R3 R3

Cu(I), L*

R2

B2pin2, iPrOH

R1

[Cu]

R3

O

R3 R3 Bpin

R2

R1

R

R

H

Bpin

R3

R2 O[Cu] Bpin

R3 iPrOH

R1

R3

R2 OH Bpin

Scheme 1. Copper-catalyzed methods toward borylated cyclobutanes a) diastereoselective borylative cyclization of alkenyl ketones b) enantioselective desymmetrization of cyclobutenes c) enantioselective borylative cyclization of alkenyl ketones

Table 1. Optimization of reaction parameters Cu(MeCN)4PF6 (4 mol%) (S,S)-BDPP (6 mol%)

O R

Ph

R = 4Me-C6H4 1s

B2pin2 (1.5 equiv), NaOtBu (1.5 equiv) iPrOH (2 equiv) MTBE (0.05 M), 16 h, r.t.

PPh2 PPh2

R

Ph OH Bpin

(S,S)-BDPP

2s

entry

variations of standard condition

yielda

erb

1

none

78% (73%)

97:3

2

dppp instead of (S,S)-BDPP

28% (29%)

n.a.

3

dppe instead of (S,S)-BDPP

13%

n.a.

4

DPEphos instead of (S,S)-BDPP

25%

n.a.

5

dppBz instead of (S,S)-BDPP

24%

n.a.

6

(S,S)-DIOP instead of (S,S)-BDPP

81%

70:30

7

(S)-BINAP instead of (S,S)-BDPP

11%

n.d.

8

SL-J001-1 instead of (S,S)-BDPP

34%

n.d.

9

LiOtBu instead of NaOtBu

15%

93.5:6.5

10

KOtBu instead of NaOtBu

70%

95:5

11

THF instead of MTBE

80%

96:4

12

No iPrOH added

19%

98:2

13

MeOH instead of iPrOH

28%

96.5:3.5

14

tBuOH instead of iPrOH

36%

n.d.

aYield

determined by NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. Yield of isolated product shown in parentheses. bDetermined by chiral HPLC using IA or OD-H column in 4% IPA/hexanes

ACS Paragon Plus Environment

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Scheme 2. Copper-catalyzed methods towards boron-containing four-membered rings Cu(MeCN)4PF6 (4 mol%) (S,S)-BDPP (6 mol%)

O R1

R2

R1


1a-1ab

PPh2 PPh2

R2 OH Bpin

(S,S)-BDPP

2a-2ab

Scope of ketone substituants

Me OH Bpin

iPr OH Bpin

2a, 83% yield 94:6 er

OH Bpin 2c, 59% yield 95.5:4.5 er

2b, 99% yield 95:5 er

Me

OH Bpin

2g 89% yield 95.5:4.5 er

OH Bpin

Me

2j, 87% yield 96.5:3.5 er

OH Bpin

2h, 89% yield 96.5:3.5 er

OH Bpin

OMe

2k, 87% yield 96.5:3.5 er

2e, 90% yield 96:4 er

F

OH Bpin

2f, 93% yield 95.5:4.5 er

OH Bpin

2d, 88% yield 95.5:4.5 er

OMe

OH Bpin

OH Bpin

OH Bpin

2i, 39% yield 99:1 er

OH Bpin

F

2l, 84% yield 97.5:2.5 er

Me

OH Bpin

CF3

2m, 53% yield 99:1 er

OH Bpin

CN

2o, 27% yield 97:3 er

N

OH Bpin

2p, 82% yield 97:3 er

COOEt

2n, 63% yield 97.5:2.5 er

S OH Bpin

CF3

OH Bpin

2q, 90% yield 96:4 er

2r, 83% yield 95:5 er

Scope of alkenyl substituants

F Me

OH Bpin

Me

2s, 73% yield 97:3 er

MeO

2x, 90% yield 94:6 er

F

2t, 61% yield 97.5:2.5 er

F OH Bpin

OH Bpin

OH Bpin

OH Bpin

F MeO

2u, 63% yield 99:1 er

F3C

2y, 85% yield 95:5 er

OH Bpin 2z, 80% yield 95:5 er

OH Bpin 2v, 68% yield 98.5:1.5 er

Cl

OH Bpin 2aa, 85% yield 95:5 er

Me

OH Bpin 2w, 87% yield 96.5:3.5 er

S

OH Bpin 2ab, 82% yield 93.5:6.5 er

Scheme 2. Reactions performed on 0.2 mmol scale for 16 h. All reported yields are after isolation. All products observed in > 20:1 dr determined by 1H NMR spectroscopic analysis of the crude, er determined by chiral HPLC.

Copper-catalysis has evolved into a prominent method to access enantioenriched boron-containing products.12 The significance of this method lies within the versatile nature of the carbon-boron bond, which facilitates simple access to new functionalities.13 These reactions often proceed through an enantioselective 1,2-borylcupration of an olefin, followed by termination with an electrophile.12a Although the introduction of tethered electrophiles presents an efficient cyclization pathway, few asymmetric methods towards small-sized rings have capitalized on this strategy.14 The Ito and Tortosa labs have reported enantioselective routes towards boron-containing cyclopropanes via cyclization15 or desymmetrization.16 However, the analogous chiral cyclobutanes have only been accessed using desymmetrization approaches, which are hampered by intrinsic substrate constraints.17 We set out to employ a γ-δ unsaturated ketone as a simple precursor to perform a borylative cyclization. Ketones and imines have been widely utilized in asymmetric borylative cyclizations,18 however

their applicability towards chiral small-sized ring synthesis remains unexplored. We commenced our studies by employing (S,S)-BDPP as a chiral ligand which we recently identified for the asymmetric borylcupration of 1,1-disubstituted styrenes.19 We found optimal conditions using MTBE as a solvent and isopropanol as an additive which provided the product in 73% yield and 97:3 er (Table 1, Entry 1). Only a single diastereomer was observed in which the alcohol was anti to the boronate moiety. We found that the reaction was highly specific to (S,S)-BDPP as other achiral ligands (Table 1, Entries 2-5) or chiral ligands (Table 1, Entries 68) were ineffecitve for this reaction. Other tert-butoxide bases provided lower yields (Table 1, Entries 9-10), however other ethereal solvents could be employed (Table 1, Entry 11). We found that isopropanol was critical to the reaction’s success, as its removal or the use of other alcohols gave significantly lower yields (Table 1, Entries 12-14).


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ACS Catalysis

Following our optimization, we surveyed the influence of ketone substituents (Scheme 2). A methyl ketone provided the cyclobutanol (2a) at a slightly lower yield and enantioselectivity, however, we found the isopropyl ketone delivered the product (2b) in 99% yield, and 95:5 er. We explored saturated cyclic substituents and found cyclohexyl (2c) and cyclopropyl (2d) were well tolerated and provided the product in 95.5:4.5 er. We observed that a phenyl ketone furnished the product (2e) in 90% yield and 96:4 er. Next, we perturbed the electronic nature of the aryl ring and found that electron-donating groups (2f, 2g) gave slightly lower enantioselectivities than their electron-withdrawing counterparts (2h, 2i). In the case of the trifluoromethyl group (2i), we observed 99:1 er, however, we obtained the product in only 39% yield. We found a similar trend in the meta position where electron rich aryl rings (2j, 2k) provided products in slightly lower er than electron poor systems (2l, 2m). To probe functional group compatibility, we examined an ester (2n) and nitrile (2o ) and obtained the products in high enantioselectivity, albeit at diminished yields. We turned our attention to ortho-substituents and found that a methyl group (2p) was well tolerated at 97:3 er. Heterocycles such as thiophene (2q) and indole (2r) were also tolerated in the reaction.

the alkyl tether (Scheme 4). We first examined if a dimethyl substitution pattern could be tolerated and obtained the product (2ac) in 88% yield and 96.5:3.5 er. Building on this strategy, we synthesized the cyclic precursors and obtained the spirocyclic product (2ad) in 60% yield and 96:4 er. We attempted to further elaborate this concept towards the 5-membered spirocyclic product (2ae) containing a valuable aryl chloride and obtained the product in 38% yield and 97:3 er.

Scheme 3. Scope of hexasubstituted products

Scheme 4. All reported yields are after isolation. All products observed in >20:1 dr determined by 1H NMR spectroscopic analysis of the crude, er determined by chiral HPLC. See SI for details

Ph R3 R3

R2

1ac-1ae

R3

Cu(MeCN)4PF6 (4 mol%) (S,S)-BDPP (6 mol%)

O


Ph

R3

R2 OH Bpin

PPh2 PPh2

(S,S)-BDPP

2ac-2ae

Scope of alkyl tether Me Me OH Bpin 2ac, 88% yield 96.5:3.5 er

OH Bpin 2ad, 60% yield 96:4 er

OH BpinCl 2ae, 38% yield 97:3 er

Scheme 3. Reactions performed on 0.2 mmol scale for 16 h. All reported yields are after isolation. All products observed in > 20:1 dr determined by 1H NMR spectroscopic analysis of the crude, er determined by chiral HPLC.

Next, we examined the effect of different aryl substituents on the styrene moiety (Scheme 3). We observed higher er’s and lower yields when the aryl ring was para-substituted in electrondonating (2s, 2t) and electron-withdrawing (2u) cases. Substrates with chloride and methoxy substituents failed when in the paraposition (see SI for details). Interestingly, we found that the disubstituted aryl ring delivered the product (2v) in 68% yield and 98.5:1.5 er. When substituted at the meta-position, we found a variety of substitution patterns were tolerated without significant changes in yield and er. Both methyl (2w) and methoxy (2x) were tolerated, however we observed a slightly decreased er for product 2x. Electron-withdrawing substituents such as fluoro (2y) and trifluoromethyl (2z) participated in the reaction and furnished products in 95:5 er. A synthetically valuable chloride handle (2aa) could be incorporated at 85% yield and 95:5 er. Finally, we examined heteroaryl substituents using a 2-substituted thiophene and obtained the product (2ab) in 82% yield and 93.5:6.5 er. The analogous five-membered ring substrate was unsuccessful in the reaction (see SI for details). We considered the opportunity to generate 1,1,2,2,4,4hexasubstituted cyclobutane cores by introducing substituents on

Scheme 4. Scale-up procedure and protection of product Cu(MeCN)4PF6 (2 mol%) (S,S)-BDPP (3 mol%)

O Ph

Ph

1e 1.18 g, 5 mmol

Ph

Ph OH OBz

3a 46% yield, 96:4 er

B2pin2 (1.5 equiv) NaOtBu (1.5 equiv) iPrOH (2 equiv) MTBE (0.1 M) 16 h, r.t.

1) NaBO3 THF, H2O 2) BzCl, TEA DMAP, DCM

Ph

Ph

Ph OH Bpin

2e, 1.60 g 88% yield, 96:4 er

Ph OH Bpin

2e

2e

TBSOTf Lutidine DCM, r.t., 2 h

Ph

Ph OTBS Bpin

3b 91% yield, 96:4 er

We aimed to demonstrate the scalability of this protocol by performing the reaction using 5 mmol of the starting material (Scheme 5). We reduced the amount of catalyst, ligand, and solvent used in the reaction and obtained the product in 88% yield with no decline in the enantioselectivity compared to the smallscale trial. Single-crystal x-ray diffraction (Scheme 5) confirmed the absolute and relative stereochemistry. All other products were assigned by analogy. We briefly examined the versatility of the products by performing oxidation followed by protection of the neopentyl alcohol with benzoyl chloride to obtain product 3a in 65% yield. Furthermore, protection of the cyclobutanol using TBSOTf furnished the silylated product, 3b, in 91% yield. Next, we turned our attention to capitalize on the modular nature of the carbon-boron bond. We employed product 3b as a model system to diversify the carbon-boron linkage to form new carbon-carbon and carbon-heteroatom bonds. Oxidation using perborate furnished product 3c in 76% yield which compliments product 3a, as both differentially protected diols were accessible. Matteson homologation was successful to produce compound 3d in 67% yield. The boronate was readily converted to a new carbon-aryl bond using furan to obtain product 3e in 57% yield. Finally, the boronate could be converted to a synthetically valuable vinyl-moiety in 67% yield. Throughout the derivatizations, we observed no change in er.

Scheme 5. Derivatization of the alkylboronate group


ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Ph OTBS OH

Ph

NaBO3

nBuLi, CH2Br2

THF/H2O

THF, -78 oC

Ph

Ph OTBS Bpin

MgBr , I2

THF

O

3d 67% yield, 96:4 er

3b

nBuLi 2-Mefuran NBS

Ph

Ph OTBS

Ph

Bpin

3c 76% yield, 96:4 er Ph OTBS

Page 4 of 8

Ph OTBS

Ph

THF/MeOH

3f 67% yield, 96:4 er

3e 57% yield, 96:4 er

Scheme 5. Reactions performed on 0.2 mmol scale for 16 h. All reported yields are after isolation. All products observed in >20:1 dr determined by 1H NMR spectroscopic analysis of the crude, er determined by chiral HPLC.

Scheme

6.

Proposed

catalytic

cycle

and

a) Proposed catalytic cycle

enantio-

and

R OH Bpin

II

I Open

B2pin2

A

Cu

P

RO Bpin

Me P

H

B

LnCu

Ph

H

Bpin

H

O

Me

D

Blocked

H

LnCu OR

R2 OCuLn Bpin

models

b) Proposed quadrant diagram

2

ROH

diastereoselectivity

Blocked

R2

C

R O

III

2

Open

IV Bpin

O

CuL*

O

CuLn Bpin

(S)

Ph

c) Proposed diasteroselective model Ph L*Cu O

L*Cu(Bpin) syn migratory insertion

(S)

Bpin

O

Bpin

O Ph

Stereoinvertive 1,2-addition

(S) (R)

OH Bpin

CuL* Ph L*Cu Bpin

Ph O

Stereoinvertive 1,2-addition

(R) (R)

OH Bpin

Scheme 6. a) Proposed catalytic cycle for the reaction b) Proposed quadrant diagram for enantioinduction c) Proposed model for diastereoselectivity

Based on our results and previous literature,20 a plausible mechanism is shown in Scheme 7a. Initial σ-bond metathesis of A with B2pin2 yields intermediate B. The copper-boryl species then undergoes an enantioselective migratory insertion with the styrene to give the chiral benzylic copper species, C. The alkylcopper species then cyclizes with the tethered ketone to obtain intermediate D. Finally, intermediate D undergoes protodemetallation with an alcohol to furnish the product and recycle the catalyst. In order to further understand the mechanism, we generated a quadrant diagram to predict the enantiomer of the migratory insertion step (Scheme 7b). Our model predicted the Sbenzylic stereocenter inferring a stereoinvertive cyclization process which have been previously reported by Meek,18e,f Buchwald,21 and Shimizu and Kanai.22 We hypothesize the diastereomeric preference is based on reducing steric interaction between the two phenyl groups during the cyclization step.

In conclusion, we have developed a mild method to access boryl-functionalized cyclobutanols in a highly stereocontrolled fashion. The simple substrates unlocked access to complex and congested frameworks containing a wide array of substituents. The products were all observed in excellent diastereoselectivities, and generally excellent enantioselectivities and served as a valuable precursor to a plethora of new molecules. This report represents one of the first methods to access chiral cyclobutanols, which are invaluable in organic synthesis and medicinal chemistry.

ASSOCIATED CONTENT The Supporting Information material is available free of charge on the ACS Publications Website. Experimental procedures, characterization data, 1H/13C NMR


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ACS Catalysis

spectra, X-ray structures of 2e, and HPLC spectra for new compounds (PDF) Crystallographic data for 2e (CIF) CCDC 1944262 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION Corresponding Author * Email: [email protected]

ORCID Andrew Whyte: 0000-0001-7261-4309 Bijan Mirabi: 0000-0002-4852-3439 Mark Lautens: 0000-0002-0179-2914

ACKNOWLEDGMENT We thank the University of Toronto, the Natural Science and Engineering Research Council (NSERC), Alphora/Eurofins, and Kennarshore Inc. for financial support. A.W. thanks the Walter C. Sumner Memorial Fellowship, Province of Ontario (OGS). A.T. and B.M. thank the Province of Ontario (OGS) for funding. L.P. acknowledges the Basque Government (Grupos IT908-16) and UPV/EHU for financial support. We thank Alan Lough (University of Toronto) for X-ray crystallography of 2e. We thank Dr. Darcy Burns and Dr. Jack Sheng (University of Toronto) for their assistance in NMR experiments. We thank A. Yen (University of Toronto) for proofreading.

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Toste, F. D. Phosphoramidite Gold(I)-Catalyzed Diastereo- and Enantioselective Synthesis of 3,4-Substituted Pyrrolidines. J. Am. Chem. Soc. 2011, 133, 5500–5507. (i) Ishihara, K.; Fushimi, M. Catalytic Enantioselective [2 + 4] and [2 + 2] Cycloaddition Reactions with Propiolamides. J. Am. Chem. Soc. 2008, 130, 7532–7533. (j) Müller, C.; Bauer, A.; Maturi, M. M.; Cuquerella, M. C.; Miranda, M. A.; Bach, T. Enantioselective Intramolecular [2 + 2]-Photocycloaddition Reactions of 4-Substituted Quinolones Catalyzed by a Chiral Sensitizer with a Hydrogen-Bonding Motif. J. Am. Chem. Soc. 2011, 133, 16689–16697. (9) Examples of cyclobutanol natural products see: Wang, C. F.; Liu, J. Q.; Yan, Y. X.; Chen, J. C.; Lu, Y.; Guo, Y. H.; Qiu, M. H. Three New Triterpenoids Containing Four-Membered Ring from the Fruiting Body of Ganoderma Sinense. Org. Lett. 2010, 12, 1656–1659. (b) Zhou, J.; Zhang, J.; Cheng, A.; Xiong, Y.; Liu, L.; Lou, H. Highly Rigid LabdaneType Diterpenoids from a Chinese Liverwort and Light-Driven Structure Diversification. Org. Lett. 2015, 17, 3560–3563. (c) Pan, L.; Zhou, P.; Zhang, X.; Peng, S.; Ding, L.; Qiu, S. X. Skeleton-Rearranged Pentacyclic Diterpenoids Possessing a Cyclobutane Ring from Euphorbia w Allichii. Org. Lett. 2006, 8, 2775–2778. (d) Marrero, J.; Rodríguez, A. D.; Baran, P.; Raptis, R. G. Isolation and Structure of Providencin: A Highly Oxygenated Diterpene Possessing a Unique Bicyclo[12.2.0]Hexadecane Ring System from the Sea Plume Pseudopterogorgia Kallos. Org. Lett. 2003, 5, 2551–2554. (e) Doroh, B.; Sulikowski, G. A. Progress toward the Total Synthesis of Bielschowskysin: A Stereoselective [2 + 2] Photocycloaddition. Org. Lett. 2006, 8, 903–906. (f) Rodríguez Brasco, M. F.; Seldes, A. M.; Palermo, J. A. Paesslerins A and B: Novel Tricyclic Sesquiterpenoids from the Soft Coral Alcyonium p Aessleri. Org. Lett. 2001, 3, 1415– 1417. (g) Zheng, Y.; Shen, Y. Clavicorolides A and B, Sesquiterpenoids from the Fermentation Products of Edible Fungus Clavicorona Pyxidata. Org. Lett. 2009, 11, 109–112. 10) (a) Nishimura, T.; Uemura, S. Palladium-Catalyzed Arylation of Tert -Cyclobutanols with Aryl Bromide via C−C Bond Cleavage: New Approach for the γ-Arylated Ketones. J. Am. Chem. Soc. 1999, 121, 11010–11011. (b) Nishimura, T.; Ohe, K.; Uemura, S. Oxidative Transformation of Tert -Cyclobutanols by Palladium Catalysis under Oxygen Atmosphere. J. Org. Chem. 2001, 66, 1455–1465. (c) Wang, D.; Ren, R.; Zhu, C. Manganese-Promoted Ring-Opening Hydrazination of Cyclobutanols: Synthesis of Alkyl Hydrazines. J. Org. Chem. 2016, 81, 8043–8049. (11) (a) Johnson, T.; Choo, K.-L.; Lautens, M. Rhodium-Catalyzed Arylative Cyclization for the Enantioselective Synthesis of (Trifluoromethyl)Cyclobutanols. Chem. Eur. J. 2014, 20, 14194–14197. (b) Ishihara, K.; Nakano, K. Enantioselective [2 + 2] Cycloaddition of Unactivated Alkenes with α-Acyloxyacroleins Catalyzed by Chiral Organoammonium Salts. J. Am. Chem. Soc. 2007, 129, 8930–8931. (12) For reviews on copper-catalyzed borylation see: (a) Hemming, D.; Fritzemeier, R.; Westcott, S. A.; Santos, W. L.; Steel, P. G. CopperBoryl Mediated Organic Synthesis. Chem. Soc. Rev. 2018, 47, 7477– 7494. (b) Pulis, A. P.; Yeung, K.; Procter, D. J. Enantioselective Copper Catalysed, Direct Functionalisation of Allenes via Allyl Copper Intermediates. Chem. Sci. 2017, 8, 5240–5247. (c) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Copper-Catalyzed Borylative Transformations of Non-Polar Carbon–Carbon Unsaturated Compounds Employing Borylcopper as an Active Catalyst Species. Tetrahedron 2015, 71, 2183– 2197. (13) (a) Hall, D. G. Boronic Acids; Hall, D. G., Ed.; Wiley: Weinheim, Germany, 2011. (b) Neeve, E. C.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.; Marder, T. B. Diboron(4) Compounds: From Structural Curiosity to Synthetic Workhorse. Chem. Rev. 2016, 116, 9091–9161. (14) (a) Yamamoto, E.; Kojima, R.; Kubota, K.; Ito, H. Copper(I)Catalyzed Diastereoselective Borylative Exo-Cyclization of Alkenyl Aryl Ketones. Synlett 2015, 27, 272–276. (b) Amenós, L.; Trulli, L.; Nóvoa, L.; Parra, A.; Tortosa, M. Stereospecific Synthesis of αHydroxy-Cyclopropylboronates from Allylic Epoxides. Angew. Chem. Int. Ed. 2019, 58, 3188–3192. (c) Ozawa, Y.; Iwamoto, H.; Ito, H. Copper-Catalysed Regio- and Diastereoselective Intramolecular Alkylboration of Terminal Allenes via Allylcopper Isomerization. Chem. Commun. 2018, 54, 4991–4994. (c) Ito, H.; Toyoda, T.; Sawamura, M. Stereospecific Synthesis of Cyclobutylboronates through Copper(I)Catalyzed Reaction of Homoallylic Sulfonates and a Diboron Derivative. J. Am. Chem. Soc. 2010, 132, 5990–5992. (d) Kubota, K.; Yamamoto, E.; Ito, H. Copper(I)-Catalyzed Borylative Exo -Cyclization of Alkenyl

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R3

O R

Cu (I), L*

1

R3 R3

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R

2

B2pin2, base, ROH

R1

R3

R2 OH Bpin

 access to highly substituted cyclobutanols  highly diastereo- and enantioselective  mild reaction conditions


29 examples up to 99% yield up to 99:1 er

Asymmetric Synthesis of Boryl-Functionalized Cyclobutanols

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