Enantio- and Diastereoselective Synthesis of Functionalized Carbocycles by Cu-Catalyzed Borylative Cyclization of Alkynes with Ketones

Article abstract of DOI:10.1021/acs.orglett.9b01769

A single-pot Cu-catalyzed enantio- and diastereoselective tandem hydroboration/borylative cyclization of alkynes with ketones for the synthesis of carbocycles is reported. The reaction proceeds via desymmetrization and generates four contiguous stereocent

Full text of DOI:10.1021/acs.orglett.9b01769

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantio- and Diastereoselective Synthesis of Functionalized
Carbocycles by Cu-Catalyzed Borylative Cyclization of Alkynes with
Ketones
Joseph M. Zanghi, Shuang Liu, and Simon J. Meek*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: A single-pot Cu-catalyzed enantio- and diaster-
eoselective tandem hydroboration/borylative cyclization of
alkynes with ketones for the synthesis of carbocycles is
reported. The reaction proceeds via desymmetrization and
generates four contiguous stereocenters, including an all-
carbon quaternary center. The method provides rapid access
to [6,5]- and [5,5]-bicycles and cyclopentane products.
Catalyst-controlled diastereoselectivity by selection of bi-
sphosphine ligand is noted. Utility of the products is
demonstrated by site- and chemoselective transformations that afford valuable alkenyl and allyl organoborons.
Scheme 1. Enantio- and Diastereoselective Cu-Catalyzed
Multicomponent Carboborylative Cyclizations
ulticomponent tandem reactions, wherein subsequent
Mreactions occur as a result of functionality generated in
a previous step, allow for the formation of several bonds in a
single operation, without the need of additional reagents.1
Such reactions minimize the economic, environmental, and
labor costs associated with multistep syntheses.1 Of particular
interest are tandem catalytic reactions that stereoselectively
form all-carbon quaternary stereocenters, structural motifs that
remain a significant synthetic challenge in organic chemistry.2
One strategy to generate quaternary stereocenters is through
enantioselective desymmetrization processes.3 Accordingly,
incorporating an enantioselective desymmetrization step into
a tandem reaction would rapidly generate stereochemical
complexity in a highly efficient manner.4 In addition to the
growing importance of constructing all-carbon quaternary
centers, alkyl organoborons have become important inter-
mediates in the synthesis of pharmaceuticals and agrochemicals
due to the range of stereospecific functional group trans-
formations they undergo.5−7
Recently, we reported a Cu-catalyzed enantio- and
diastereoselective tandem borylation/1,2-addition of alkenyl
boronic esters to ketones (Scheme 1B).8 To construct more
complex structures in a simpler protocol, we sought to develop
a process to efficiently construct carbocycles bearing four
contiguous stereocenters.
In order to achieve these objectives, we decided to examine
two changes (Scheme 1C): (1) Catalytic desymmetrization of
1,3-diketones substrates that access stereodefined, highly
substituted hydrindanes, diquinanes, and cyclopentanes
bearing two boronic esters. Ideally, the two C−B bonds
could be sequentially functionalized, offering access to a range
of stereodefined products. (2) Change from alkenyl borons to
alkynes due to their ease of accessibility. Notably, alkynes pose
an inherent site-selectivity challenge as hydroboration can
result in α- and β-borylation isomers.9
A number of studies related to Cu-catalyzed bis-borylation
of alkynes have been reported; however, trapping of the
resulting copper−C(sp3) with an electrophile other than
proton has not been reported to the best of our knowledge.10
Enantioselective Cu-catalyzed bis-hydroboration of terminal
alkynes and SiMe3-protected alkynes have been reported.11
Related enantioselective Cu−B(pin)-initiated carboboration
reactions of olefins have also been disclosed.12,13 In this regard,
Cu-catalyzed conjugate borylation of Michael acceptors and
Received: May 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01769
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
subsequent aldol addition of the Cu enolate with a diketone
has been shown intramolecularly (Scheme 1A).4b
Table 1. Reaction Scope
We initiated our studies by investigating the catalytic
desymmetrization of cyclohexanedione 1a to afford bis-boryl
hydrindane 3a (Table 1). Treatment of alkyne 1a with 5 mol %
of CuCl, 6 mol % of (R)-BINAP (L1), 6 mol % of KO-t-Bu,
2.2 equiv of B2(pin)2, and t-BuOH (2.0 equiv) in THF at 22
°C for 18 h afforded 3a in 65% yield, 5:1 dr, and 99:1 er.
Examination of a number of other chiral phosphine ligands
(L2−L6) generated either significantly lower conversion or
diastereoselectivity (Scheme 2). In contrast, it was found that
employing furyl-MeO-Biphep (L7) greatly improved the dr
while maintaining good yield and excellent enantioselectivity
providing 3a in 64% yield, 12:1 dr, and 99:1 er. Furthermore, it
was found that increasing the catalyst loading to 10 mol %, and
switching from t-BuOH to MeOH, led to an improved 78%
yield of 3a while maintaining high stereoselectivity (9:1 dr, and
>99:1 er).
With conditions in hand for the alkyne desymmetrization,
we next examined the substrate scope of the tandem reaction
(Table 1). In general, the yields are moderate to good, and
enantio- and diastereoselectivity are generally excellent.
Product 3a was isolated in 70% yield, 13:1 dr, and >99:1 er.
Additional substitution on the 6-membered ring was tolerated
(3b) (the X-ray structure of 3b was obtained (see Scheme 5A)
(vide infra)). Prenyl-containing substrate 1c was found to
cyclize to 3c with lower diastereoselectivity (5:1 dr) but in
excellent enantioselectivity (98:2 er, and >99:1 er). Incorpo-
ration of benzyl (1d) and thiophene (1e) substituents led to
3d and 3e in 60% (>20:1 dr) and 65% (3:2 dr), respectively.
Notably, upon isolation, the minor diastereomer of 3e
decomposes affording a single diastereomer (>20:1 dr, and
94:6 er). Terminal alkenes are also tolerated, and bis-boron 3f
is isolated in 46% yield, 17:1 dr, and in 88:12 er; the lower er is
possibly due to coordination of the unhindered alkene to the
catalyst.
For [5,5]-fused carbocycles (entries 7−9), however, L1 was
found to be a slightly better ligand compared to L7. Methyl-
substituted diquinane 5a is formed in 69% yield, 2:1 dr, and
90:10 er.14 Increasing the size of the group on the quaternary
center to an allyl (1h) or n-propyl group (1i) provided
products 5b and 5c in 57% yield (>20:1 dr, 89:11 er) and 64%
yield (>20:1 dr, 94:6 er), respectively. Diquinane 5c could be
recrystallized once to 97.5:2.5 er. For cyclopentane products
6a−c, yields again were moderate, but reactions proceeded
with generally excellent enantio- and diastereoselectivities
(Table 1). For example, product 6a, formed in 56% NMR
yield, was isolated as the tris-boronate (>20:1 dr, > 99:1 er).15
Simply switching from Me to Et provided tertiary alcohol bis-
boronate 6b in 42% yield as a single stereoisomer (>20:1 dr, >
99:1 er). Prenyl-substituted diketone 1l was found to undergo
smooth cyclization to afford 6c in 17:1 dr (>99:1 er) when
compared to the [6,5]-prenyl 3c formed in 5:1. The alkyne
cyclization strategy was also tested for the generation of 6-
membered rings to form decalins (entry 13, Table 1).
Unfortunately, large amounts of double hydroboration are
observed (<2% conversion to 7); starting from the vinyl
boronic ester failed to improve the reaction (see the SI for
details).
Next, in order to determine the efficiency of the alkyne
hydroboration and carboboration steps, we undertook a brief
comparison of the catalytic reaction starting from the
preformed alkenyl boronic esters versus alkyne (Scheme 3).
a
Same conditions and analytical methods as in Scheme 2; see the SI
b
for details. Yields of purified hydroxyl bis-boronate products.
B
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Organic Letters
Letter
a
Scheme 2. Reaction Optimization
Scheme 4. Proposed Dual Catalytic Cycles
ester 12. In the carboboration cycle, migratory insertion of 9
across vinyl boronic ester 12 sets the absolute stereochemistry,
which is followed by diastereoselective cyclization (13 → 14).
Protonation of Cu-bound product 14 releases the product and
regenerates catalyst 8.
As noted previously, the X-ray structure of tertiary alcohol
3b was obtained (Scheme 5A). The structure shows a cis [6,5]
ring juncture, with the B(pin) anti to the hydroxyl group.16
Importantly, borylation of the E-alkenyl boron with (R)-furyl-
biphep-derived catalyst results in R stereochemistry (e.g., in
13). The syn relationship between the two B(pin) moieties in
3b can be explained by a stereoretentive mode of addition by
the (L)Cu-alkyl to the ketone. A result rationalized by use of
the small furylphosphine ligand in combination with a methyl
group on the substrate, which results in a sterically accessible
(L)Cu−alkyl (e.g., 13).
a
Reactions performed under N2 atmosphere. Yield and diastereomeric
ratios (dr) determined by analysis of 400, 500, or 600 MHz 1H NMR
spectra of crude reactions with hexamethyldisiloxane as internal
standard. Enantiomeric ratios (er) determined by HPLC or SFC
b
analysis; see the SI for details. nd = not determined. CuCl (10 mol
%), L7 (11 mol %), KOtBu (10 mol %), MeOH (2.0 equiv).
Scheme 3. Comparison to Alkenyl Boronic Esters in Ketone
Desymmetrization
a
Later in our study, surprisingly, we found that when alkyne
1a is cyclized with BDPP (L8), syn,anti,syn- diastereomer 15 is
formed instead in 97% yield and 11:1 dr (Scheme 5B). With
other [6,5] products, we found that L8 afforded the same
diastereomers (e.g., 3f) as L7 and L1 in >20:1 dr. These
unexpected results encouraged us to further investigate the
stereochemistry. The X-ray structure of 3f was obtained
(Scheme 5A). Remarkably, the stereochemistry of three of the
stereocenters was different compared to 3b. As the stereo-
chemistry of the boronic ester γ to the hydroxyl is set in the
initial hydroboration, we assigned this stereocenter as R for all
substrates based on the absolute configuration of 3b. The anti
boronic esters of 3f indicate a stereoinvertive cyclization,
observed in previous work by our group and others.8,17 To
account for this, we propose that the cyclization occurs
invertively for R substituents larger than Me (e.g., 3f) due to
increased steric repulsion between the R group and the PAr2
phosphine ligand, which prevents coordination of Cu to the
ketone (Scheme 5C). The change in stereochemistry at the
ring junction is due to cyclization on the other diastereotopic
ketone due to unfavorable B(pin)↔R steric interaction. The
stereochemistry of the [5,5] products was confirmed as
syn,anti,anti on the basis of the X-ray structure of 5b (Scheme
5A). Since reactions with L1, L7, and L8 result in increasing dr
for methyl and with high dr for larger substituents, all [5,5]
products predominantly arise from a stereoinvertive cyclization
pathway.18 Cyclopentane products 6a−c have been assigned
by analogy: 6a as stereoretentive syn,anti,syn and 6b,c as
stereoinvertive syn,anti,anti. This is also supported by the
decrease in dr for 6a going from L7 to L1.19
a
Same conditions and analytical methods as in Scheme 2; see the SI
for details.
The reactions of the three vinyl boronic esters 2a, 2g, and 2j
were examined, and the results are illustrated in Scheme 3.
With 1.1 equiv of B2(pin)2 and 1.0 equiv of t-BuOH,
cyclization to cyclopentane products 3a, 5a, and 6a resulted
in only a marginal improvement in yield compared to starting
from the corresponding alkynes, indicating efficient alkyne
hydroboration.
A proposed mechanism for the Cu-catalyzed tandem alkyne
cyclization method is shown in Scheme 4, which depicts dual
catalytic cycles that proceed contemporaneously.9,10 Accord-
ingly, a Cu-catalyzed alkyne boryl−protonation cycle occurs
followed by a carboboration cycle. In the hydroboration cycle,
transmetalation of (L)Cu−OR 8 with B2(pin)2 generates
(L)Cu−B(pin) complex 9. Regioselective syn migratory
insertion of 9 across alkyne 10 is followed by protonation of
alkenyl copper 11 by MeOH to liberate trans-β-vinyl boronic
C
DOI: 10.1021/acs.orglett.9b01769
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Letter
a
Scheme 5. Stereochemical Analysis and Ligand-Controlled
Diastereoselectivity
Scheme 6. Utility of Bis-boronate Products
a
a
See the SI for details.
boron−hydroxyl elimination (Scheme 6C). For example, allyl
borons 21 and 22 are generated in 57% and 68% isolated yield
from 5b and 5c, respectively. We believe the divergence in
reactivity arises from the σC−B aligning better with the
carbocation p-orbital in the more planar [5,5]-bicycle versus
the σC−H. To the best of our knowledge, this reactivity is the
first time an anti boron−hydroxyl elimination has been
reported for a tertiary alcohol and is the first example of
Martin’s sulfurane used in transformation of an organoboron.21
Further transformation of allyl boronic ester 22 to alcohol 23
was accomplished by a stereospecific allylation with form-
aldehyde, generating vicinal all-carbon quaternary stereo-
centers in 73% yield and 18:1 dr (Scheme 6D).
In conclusion, we present a catalytic tandem enantio- and
distereoselective method for the preparation of borylated
carbocycles. We demonstrate the formation of four contiguous
stereocenters, including an all-carbon quaternary center, in
good yield and selectivity (up to >98:2 dr, and >99:1 er).
Stereoinvertive and stereoretentive cyclization pathways were
found to be operative and dependent on ligand and substrate.
Site- and chemoselective eliminations with Martin’s sulfurane
highlight valuable alkenyl and allyl organoborons accessible
through the method. Development of additional catalytic
a
b
See the SI for details. Data given in Scheme 5B refer to NMR
yields.
The synthetic utility of organodiboron carbocycles accessible
through the tandem Cu-catalyzed bis-borylation/cyclization
protocol is highlighted through several site- and chemo-
selective transformations depicted in Scheme 6. (1) Oxidation
of 3c with H2O2/NaOH affords triol 18 in 73% yield (Scheme
6A). (2) Exposure of the tertiary alcohol products to Martin’s
sulfurane20 results in site- and chemoselective eliminations that
are dependent on the hydrocarbon bicycle. For example,
treatment of [6,5]-product 3a with Martin’s sulfurane effects a
site-selective dehydration to afford alkenyl boron 19 in 59%
yield (Scheme 6B). Subjecting benzyl derivative 3d to the
same reaction conditions also provides dehydrated alkenyl
boron product 20 in 78% yield, despite the change in relative
stereochemistry. This is in direct contrast to [5,5]-bicycles,
which when treated with Martin’s sulfurane result in an anti
D
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Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary
Stereocenters: Assembly of Key Building Blocks for the Synthesis of
Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740−751.
carboboration methods continues to be investigated in these
laboratories.
́
(h) Alam, R.; Vollgraff, T.; Eriksson, L.; Szabo, K. J. Synthesis of
ASSOCIATED CONTENT
■
Adjacent Quaternary Stereocenters by Catalytic Asymmetric Allylbo-
ration. J. Am. Chem. Soc. 2015, 137, 11262−11265.
S
* Supporting Information
(3) For a recent review of the area, see: Zeng, X.-P.; Cao, Z. Y.;
Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic Enantioselective
Desymmetrization Reactions to All-Carbon Quaternary Stereocenters.
Chem. Rev. 2016, 116, 7330−7396.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01769.
Experimental procedures and spectral and analytical data
for all products (PDF)
(4) For representative examples of tandem conjugate addition/aldol
desymmetrization of 1,3-diketones, see: (a) Bocknack, B. M.; Wang,
L.-C.; Krische, M. J. Desymmetrization of Enone-Diones via
Rhodium-Catalyzed Diastereo- and Enantioselective Tandem Con-
jugate Addition-Aldol Cyclization. Proc. Natl. Acad. Sci. U. S. A. 2004,
101, 5421−5424. (b) Burns, A. R.; Gonzalez, J. S.; Lam, H. W.
Enantioselective Copper(I)-Catalyzed Borylative Aldol Cyclizations
of Enone Diones. Angew. Chem., Int. Ed. 2012, 51, 10827−10831.
(5) Hall, D. G. In Boronic Acids: Preparation and Applications in
Organic Synthesis and Medicine; Wiley-VCH: Weinheim, 2011.
(6) For reviews of Suzuki−Miyaura cross-couplings, see: (a) Chem-
ler, S. R.; Trauner, D.; Danishefsky, S. J. The B-Alkyl Suzuki-Miyaura
Cross-Coupling Reaction: Development, Mechanistic Study, and
Applications in Natural Product Synthesis. Angew. Chem., Int. Ed.
2001, 40, 4544−4568. (b) Lennox, A. J. J.; Lloyd-Jones, G. C.
Selection of Boron Reagents for Suzuki-Miyaura Coupling. Chem. Soc.
Rev. 2014, 43, 412−443.
(7) For stereospecific transformations, see: (a) Scott, H. K.;
Aggarwal, V. K. Highly Enantioselective Synthesis of Tertiary Boronic
Esters and their Stereospecific Conversion to other Functional
Groups and Quaternary Stereocenters. Chem. - Eur. J. 2011, 17,
13124−13132. (b) Leonori, D.; Aggarwal, V. K. Stereospecific
Couplings of Secondary and Tertiary Boronic Esters. Angew. Chem.,
Int. Ed. 2015, 54, 1082−1096. (c) Sandford, C.; Aggarwal, V. K.
Stereospecific Functionalizations of Secondary and Tertiary Boronic
Esters. Chem. Commun. 2017, 53, 5481−5494.
(8) Green, J. C.; Joannou, M. V.; Murray, S. A.; Zanghi, J. M.; Meek,
S. J. Enantio- and Diastereoselective Synthesis of Hydroxy Bis-
(boronates) via Cu-Catalyzed Tandem Borylation/1,2-Addition. ACS
Catal. 2017, 7, 4441−4445.
(9) Jang, H.; Zhugralin, A. R.; Lee, Y.; Hoveyda, A. H. Highly
Selective Methods for Synthesis of Internal (α-) Vinylboronates
through Efficient NHC-Cu-Catalyzed Hydroboronation of Terminal
Alkynes. Utility in Chemical Synthesis and Mechanistic Basis for
Selectivity. J. Am. Chem. Soc. 2011, 133, 7859−7871.
(10) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Copper-Catalyzed
Borylative Transformations of Non-Polar Carbon−Carbon Unsatu-
rated Compounds Employing Borylcopper as an Active Catalyst
Species. Tetrahedron 2015, 71, 2183−2197.
(11) (a) Lee, Y.; Jang, H.; Hoveyda, A. H. Vicinal Diboronates in
High Enantiomeric Purity through Tandem Site-Selective NHC-Cu-
Catalyzed Boron-Copper Additions to Terminal Alkynes. J. Am.
Chem. Soc. 2009, 131, 18234−18235. (b) Jung, H.-Y.; Yun, J. Copper-
Catalyzed Double Borylation of Silylacetylenes: Highly Regio- and
Stereoselective Synthesis of Syn-Vicinal Diboronates. Org. Lett. 2012,
14, 2606−2609.
Accession Codes
CCDC 1916345−1916346 and 1922369 contain the supple-
mentary 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 data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sjmeek@unc.edu.
ORCID
Simon J. Meek: 0000-0001-7537-9420
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the United States National
Institutes of Health, Institute of General Medical Sciences
(R01GM116987) and the University of North Carolina at
Chapel Hill. We thank Quentin Bruch, Tia Cervarich, and Dr.
Chun-Hsing Chen of UNC for X-ray structure elucidation of
3b, 3f, and 5b. AllyChem is acknowledged for donations of
B2(pin)2.
REFERENCES
■
(1) For selected reviews, see: (a) Tietze, L. F. Domino Reactions in
Organic Synthesis. Chem. Rev. 1996, 96, 115−136. (b) Pellissier, H.
Stereocontrolled Domino Reactions. Chem. Rev. 2013, 113, 442−524.
(c) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Catalytic C−C Bond-
Forming Multi-Component Cascade or Domino Reactions: Pushing
the Boundaries of Complexity in Asymmetric Organocatalysis. Chem.
Rev. 2014, 114, 2390−2431. (d) Eppe, G.; Didier, D.; Marek, I.
Stereocontrolled Formation of Several Carbon−Carbon Bonds in
Acyclic Systems. Chem. Rev. 2015, 115, 9175−9206.
(2) For selected reviews, see: (a) Corey, E. J.; Guzman-Perez, A. The
Catalytic Enantioselective Construction of Molecules with Quaternary
Carbon Stereocenters. Angew. Chem., Int. Ed. 1998, 37, 388−401.
(b) Peterson, E. A.; Overman, L. E. Contiguous Stereogenic
Quaternary Carbons: A Daunting Challenge in Natural Products
Synthesis. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11943−11948.
(c) Christoffers, J.; Baro, A. Stereoselective Construction of
Quaternary Stereocenters. Adv. Synth. Catal. 2005, 347, 1473−1482.
(d) Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik,
H.; Das, J. P. All-Carbon Quaternary Stereogenic Centers in Acyclic
Systems through the Creation of Several C−C Bonds per Chemical
Step. J. Am. Chem. Soc. 2014, 136, 2682−2694. (e) Quasdorf, K. W.;
Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary
Carbon Stereocenters. Nature 2014, 516, 181−191. (f) Long, R.;
Huang, J.; Gong, J.; Yang, Z. Direct Construction of Vicinal All-
Carbon Quaternary Stereocenters in Natural Product Synthesis. Nat.
Prod. Rep. 2015, 32, 1584−1601. (g) Liu, Y.; Han, S.-J.; Liu, W.-B.;
(12) For a recent example of nonenantioselective carboboration of
vinyl-B(pin), see: (a) Yoshida, H.; Kageyuki, I.; Takaki, K. Copper-
Catalyzed Three-Component Carboboration of Alkynes and Alkenes.
Org. Lett. 2013, 15, 952−955. (b) Kageyuki, I.; Osaka, I.; Takaki, K.;
Yoshida, H. Copper-Catalyzed B(Dan)-Installing Carboboration of
Alkenes. Org. Lett. 2017, 19, 830−833.
(13) For recent examples of catalytic carboboration of olefins, see:
(a) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M.
Synthesis of Optically Active Boron-Silicon Bifunctional Cyclo-
propane Derivatives through Enantioselective Copper(I)-Catalyzed
Reaction of Allylic Carbonates with a Diboron Derivative. Angew.
Chem., Int. Ed. 2008, 47, 7424−7427. (b) Zhong, C.; Kunii, S.;
Kosaka, Y.; Sawamura, M.; Ito, H. Enantioselective Synthesis of Trans
E
DOI: 10.1021/acs.orglett.9b01769
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Organic Letters
Letter
-Aryl- and -Heteroaryl-Substituted Cyclopropylboronates by Copper-
(I)-Catalyzed Reactions of Allylic Phosphates with a Diboron
Derivative. J. Am. Chem. Soc. 2010, 132, 11440−11442. (c) Kubota,
K.; Yamamoto, E.; Ito, H. Copper(I)-Catalyzed Borylative Exo
-Cyclization of Alkenyl Halides Containing Unactivated Double
Bond. J. Am. Chem. Soc. 2013, 135, 2635−2640. (d) Su, W.; Gong, T.-
J.; Lu, X.; Xu, M.-Y.; Yu, C.-G.; Xu, Z.-Y.; Yu, H.-Z.; Xiao, B.; Fu, Y.
Ligand-Controlled Regiodivergent Copper-Catalyzed Alkylboration of
Alkenes. Angew. Chem., Int. Ed. 2015, 54, 12957−12961. (e) Cheng,
(21) For boron−Wittig elimination of a tertiary acyclic alcohol and a
borane using KH, see: Kawashima, T.; Yamashita, N.; Okazaki, R. J.
Am. Chem. Soc. 1995, 117, 6142−6143.
Y.; Muck-Lichtenfeld, C.; Studer, A. Transition Metal-Free 1,2-
̈
Carboboration of Unactivated Alkenes. J. Am. Chem. Soc. 2018, 140,
6221−6225. (f) Wang, H.-M.; Zhou, H.; Xu, Q.-S.; Liu, T.-S.;
Zhuang, C.-L.; Shen, M.-H.; Xu, H.-D. Copper-Catalyzed Borylative
Cyclization of Substituted N -(2-Vinylaryl)Benzaldimines. Org. Lett.
2018, 20, 1777−1780. (g) Chen, B.; Cao, P.; Liao, Y.; Wang, M.;
Liao, J. Enantioselective Copper-Catalyzed Methylboration of
Alkenes. Org. Lett. 2018, 20, 1346−1349. (h) Logan, K. M.;
Sardini, S. R.; White, S. D.; Brown, M. K. Nickel-Catalyzed
Stereoselective Arylboration of Unactivated Alkenes. J. Am. Chem.
Soc. 2018, 140, 159−162.
(14) Lam and co-workers also observed poor diastereoselectivity
(60:40) for a [5,5]-bicycle using methyl at the quaternary stereo-
center; see ref 4b.
(15) Compound 6a is somewhat unstable to silica gel, resulting in a
difference between NMR and isolated yield.
(16) A syn relationship would likely lead to a boron-Wittig syn-
elimination from the Cu-bound product. For example, see:
(a) Matteson, D. S.; Moody, R. J. Deprotonation of 1,1-Diboronic
Esters and Reactions of the Carbanions with Alkyl Halides and
Carbonyl Compounds. Organometallics 1982, 1, 20−28. (b) Matteson,
D. S.; Moody, R. J.; Jesthi, P. K. The Reaction of Aldehydes and
Ketones with
a Boron-Substituted Carbanion, Bis-
(ethylenedioxyboryl)methide. A Simple Aldehyde Homologation. J.
Am. Chem. Soc. 1975, 97, 5608−5609. (c) Matteson, D. S.; Jesthi, P.
K. J. Lithium bis(ethylenedioxyboryl)methide and its Reactions with
Carbonyl Compounds and with the Chlorotriphenyl Derivatives of
Germanium, Tin, and Lead. J. Organomet. Chem. 1976, 110, 25−37.
(d) Matteson, D. S.; Moody, R. J. Carbanions from Deprotonation of
gem-Diboronic Esters. J. Am. Chem. Soc. 1977, 99, 3196−3197.
(e) Coombs, J. R.; Zhang, L.; Morken, J. P. Synthesis of Vinyl
Boronates from Aldehydes by a Practical Boron-Wittig Reaction. Org.
Lett. 2015, 17, 1708−1711.
(17) For other stereoinvertive Cu-catalyzed 1,2-additions, see:
(a) Yang, Y.; Perry, I. B.; Buchwald, S. L. Copper-Catalyzed
Enantioselective Addition of Styrene-Derived Nucleophiles to Iminies
Enabled by Ligand-Controlled Chemoselective Hydrocupration. J.
Am. Chem. Soc. 2016, 138, 9787−9790. (b) Itoh, T.; Kanzaki, Y.;
Shimizu, Y.; Kanai, M. Copper(I)-Catalyzed Enantio- and Diaster-
eodivergent Borylative Coupling of Styrenes and Imines. Angew.
Chem., Int. Ed. 2018, 57, 8265−8269.
(18) L8 was tested for products 3c,d,f, 5a, 6a, and 6b, and it affords
the same diastereomers as L1 and L7 in all cases (except 6a,b, <5%
conversion observed).
(19) Attempts to grow X-ray quality crystals of cyclopentane
products 6a−c proved unsuccessful.
(20) (a) Martin, J. C.; Arhart, R. J. Sulfuranes. III. A Reagent for the
Dehydration of Alcohols. J. Am. Chem. Soc. 1971, 93, 4327−4329.
(b) Martin, J. C.; Arhart, R. J. Sulfuranes. VI. Reactions Involving the
Alkoxy Ligands of Dialkoxydiarylsulfuranes. Formation of Olefins and
Ethers. J. Am. Chem. Soc. 1972, 94, 5003−5010. (c) Martin, J. C.;
Arhart, R. J. Single-Step Syntheses of Epoxides and Other Cyclic
Ethers by Reaction of a Diaryldialkoxysulfurane with Diols. J. Am.
Chem. Soc. 1974, 96, 4604−4611. (d) Engel, P. S.; Keys, D. E.;
Kitamura, A. Spring-Loaded” Biradicals. The Radical and Electron-
Transfer Photochemistry of Bridgehead Cyclopropyl-Substituted 2,3-
Diazabicyclo[2.2.2]oct-2-enes (DBO’s). J. Am. Chem. Soc. 1985, 107,
4964−4975.
F
DOI: 10.1021/acs.orglett.9b01769
Org. Lett. XXXX, XXX, XXX−XXX