A Modular Approach to the Synthesis of gem-Disubstituted Cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.8b00899

A diastereoselective, Pd-catalyzed Suzuki-Miyaura coupling reaction of geminal bis(boryl)cyclopropanes has been developed. The reaction offers a highly modular approach to the synthesis of tertiary cyclopropylboronic esters. The resulting boronic esters may be further functionalized to afford a range of gem-disubstituted cyclopropanes, which represent an important structural motif in the pharmaceutical industry. Sequential Suzuki-Miyaura cross-coupling reactions of gem-bis(boryl)cyclopropanes are also reported. The coupling protocols are compatible with a broad range of functionalized aryl and heteroaryl bromides.

Full text of DOI:10.1021/acs.orglett.8b00899

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Modular Approach to the Synthesis of gem-Disubstituted
Cyclopropanes
Michael R. Harris,* Hanna M. Wisniewska, Wenhua Jiao, Xiaochun Wang, and James N. Bradow
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A diastereoselective, Pd-catalyzed Suzuki−
Miyaura coupling reaction of geminal bis(boryl)cyclopropanes
has been developed. The reaction offers a highly modular
approach to the synthesis of tertiary cyclopropylboronic esters.
The resulting boronic esters may be further functionalized to
afford a range of gem-disubstituted cyclopropanes, which
represent an important structural motif in the pharmaceutical
industry. Sequential Suzuki−Miyaura cross-coupling reactions
of gem-bis(boryl)cyclopropanes are also reported. The
coupling protocols are compatible with a broad range of
functionalized aryl and heteroaryl bromides.
he cyclopropane moiety has been broadly utilized in
structure-based drug design for over 50 years.1 The
cyclopropanes. Excellent chemoselectivity for engagement of a
single boryl group is observed in a wide range of organic
transformations involving gem-bis(boryl)alkanes,9 allowing
sequential modification of the boryl groups.10 For example,
Shibata and co-workers developed an iterative Suzuki−Miyaura
coupling (SMC) reaction of gem-bis(boryl)alkanes (Scheme
1a).11 More recently, Morken and co-workers disclosed a
diastereoselective protocol for the synthesis of a gem-
disubstituted cyclopropane by deborylative alkylation (Scheme
1b).12
T
incorporation of the cyclopropyl scaffold into drug molecules
can improve metabolic stability,2 attenuate pKa3 and lip-
ophilicity,4 and provide entropically favorable binding through
conformational constraint.5 Of particular interest to our group
is the geminal disubstituted cyclopropane motif, which is
present in a significant number of therapeutically relevant small
molecules (Figure 1).6,7 A sustained interest in the exploitation
Inspired by the work of Shibata and Morken, we reasoned
that sequential SMC reactions of gem-bis(boryl)cyclopropanes
would provide a robust protocol for the modular synthesis of
gem-disubstituted cyclopropanes (Scheme 1c). While the SMC
reaction of primary gem-bis(boryl)alkanes has been well
documented,13 the analogous reaction of a secondary gem-
bis(boryl)alkane has no precedent. The added steric bulk from
substitution of the reactive carbon of a boron species results in
sluggish transmetalation and facile protodeborylation.14,15 To
achieve our goal of limiting the undesired reactivity associated
with a bulkier alkylboron species, we chose the simple,
unsubstituted gem-bis(boryl)cyclopropane 1a as our model
substrate in the SMC reaction.
Figure 1. Selection of bioactive molecules containing the gem-
An efficient synthesis of our model substrate 1a was
accomplished in a single step from commercially available
cyclopropyl bromide (Scheme 2).16,17 Generation of the
cyclopropyl lithioate described by Whitby18 and quenching
with bis(pinacolato)diboron afforded the desired material. No
decomposition of the gem-bis(boryl)cyclopropane 1a was
observed upon storage at room temperature for up to 10
months.
disubstituted cyclopropane motif.
of gem-disubstituted cyclopropanes in drug discovery has
spurred the development of elegant synthetic methods for
their preparation.8 However, the reported methods have limited
potential for high-throughput chemistry: the need for
prefunctionalized olefins and or diazo compounds poses a
particular challenge to the rapid modification of the geminal
substituents of the cyclopropane ring.
The reactivity of gem-bis(boryl)alkanes offers an attractive
approach to the modular construction of gem-disubstituted
Received: March 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2). The best results were obtained when the reaction was
performed at 100 °C; incomplete conversion of 1a was
observed at lower temperatures (entries 3 and 4). A dioxane−
water solvent mixture provided optimal results in the SMC
reaction, while anhydrous conditions and other solvents
decreased the yield of desired product 3aa (entries 5 and 6).
When cesium fluoride or a stronger base was employed, near-
quantitative conversion to protodeborylation side products was
observed (entries 7−9). The desired product was obtained in
good yields when bromobenzene was used as the limiting
reagent or equimolar to 1a (entries 10 and 11). The reaction is
scalable; 3aa was isolated in 64% yield on gram scale (entry
11).19
Scheme 1. Reactivity of Geminal Bis(boryl)alkanes and
Proposed Synthetic Route to gem-Diarylcyclopropanes
Having optimized the reaction conditions of the SMC
reaction, we turned our attention to the scope of this method
with respect to both the aryl bromide and gem-bis(boryl)cyclo-
propane coupling partners (Scheme 3). A broad range of aryl
bromides bearing a variety of functional groups were well
Scheme 3. Scope of the Suzuki−Miyaura Coupling Reaction
Scheme 2. Preparation of 1,1-
Bis[(pinacolato)boryl]cyclopropane (1a)
Our investigation of the Suzuki−Miyaura cross-coupling
reaction of the model substrate 1a began with an evaluation of
the reaction conditions (Table 1). We determined that
cataCXium A Pd G3 in the presence of cesium carbonate
catalyzes the cross-coupling of 1a with bromobenzene in
excellent yield. The precatalyst PdCl2(dppf) may be used
without significant impact on product distribution, but the use
of other catalysts resulted in lower yields of 3aa (entries 1 and
Table 1. Reaction Optimization
a
entry
deviation from “standard conditions”
yield (%)
1
PdCl2(dppf) (5 mol %)
77
47
14
52
<2
47
<2
7
2
XPhos Pd G 2 (5 mol %)
3
reaction performed at 50 °C
reaction performed at 75 °C
dioxane (anhydrous)
4
5
6
toluene/H2O (10:1)
7
CsF (3 equiv)
8
KOH (8 M in H2O, 3 equiv), 25 °C
KOH (8 M in H2O, 3 equiv), 100 °C
1 equiv of PhBr and 2 equiv of 1a
1 equiv of PhBr and 1 equiv of 1a
reaction performed on 7.48 mmol scale
9
<2
74
77
10
11
12
b
a
Yield determined by 1H NMR based on comparison with PhSiMe3 as
64
b
c
internal standard. Isolated yield. Reaction performed with
PdCl2(dppf) instead of cataCXium A Pd G3. Reaction was stopped
after 4 h. Reaction performed at 110 °C.
a
d
Yield determined by 1H NMR based on comparison with PhSiMe3 as
b
e
internal standard. Isolated yield.
B
DOI: 10.1021/acs.orglett.8b00899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tolerated under the reaction conditions.20 Electron-rich arenes
with substituents in the ortho-, meta-, and para-positions were
well tolerated, affording the desired products in good yields
(3ac, 3ad, and 3ak, respectively). The transformation was
compatible with a variety of reactive functional groups,
including NO2 (3ae), Cl (3af), CO2Me (3ag), NH2 (3ah),
C(O)Me (3ai), and CN (3aj). When aryl bromides containing
strongly electron-withdrawing substituents at the para position
were coupled, complete protodeborylation of the desired
tertiary boronic ester was observed (e.g., 3ag). Fortunately,
the yield of 3ag was recovered when the reaction was stopped
after 4 h. We were also pleased to find that heterocyclic
bromides [i.e., pyrimidone (3al), substituted pyridines (3am
and 3an), and pyrimidine (3ao)] underwent smooth cross-
coupling to furnish the desired boronic esters in excellent
yields.
Scheme 4. Suzuki−Miyaura Coupling Reaction of Tertiary
Trifluoroborate 4
The coupling of substituted gem-bis(boryl)cyclopropanes
resulted in a highly diastereoselective transformation (3ba).21
A
single diastereomer was observed for cis-disubstituted cyclo-
propanes (3cd and 3cP). The SMC procedure was applied to
the biologically relevant azabicyclo[3.1.0]hexane ring system to
afford single diastereomers of the corresponding Bpin reagents
(3dh and 3dd). We observed a directing group effect for the
ester-substituted cyclopropane 3ed, where transmetalation
occurred exclusively at the Bpin group that was cis to the
ester.22
a
Yield determined by 1H NMR based on comparison with PhSiMe3 as
b
c
internal standard. Isolated yield. Prepared from the HBr salt of 4-
bromopyridazine. Prepared from the corresponding vinyl triflate.
With a robust protocol for the synthesis of tertiary boronic
esters in hand, we planned a straightforward route to the
construction of gem-diarylcyclopropanes by sequential SMC
reactions. The transition-metal-mediated cross-coupling reac-
tion of a tertiary cyclopropyl boron species23 is challenging and
has precedents only in activated systems or in radical-mediated
alkyl transfer reactions.24 Guided by our previous work in the
cross-coupling of tertiary trifluoroborates of 3-azabicyclo-
[3.1.0]hexanes,24b we chose to convert 3aa to the tertiary
trifluoroborate 4 to enable the subsequent cross-coupling
reaction (Scheme 4).25,26 A reaction of 4 with bromobenzene
proceeded in excellent yield to afford the desired gem-
diphenylcyclopropane 5a. The reaction was tolerant of ester
(5b) and ortho-substituted Boc protected aniline (5c) func-
tional groups. A broad range of heterocyclic bromides were
coupled in good yields, including substituted pyridines (5d and
5e), pyridone (5f), pyrazolo[1,5-a]pyrimidine (5g), pyridazine
(5h), and pyrimidine (5i). Vinyl triflates could also be
employed as coupling partners, providing access to pyran
(5j) and piperidine (5k) scaffolds.
d
Scheme 5. Synthesis of gem-Disubstituted Cyclopropanes by
Derivatization of Tertiary Boron Species 4 and 3ab
To demonstrate further the synthetic utility of the tertiary
boronic esters generated by our SMC protocol, we carried out
derivatizations to afford a wide array of gem-disubstituted
cyclopropanes containing a diverse set of functional groups
(Scheme 5).27 Amination of 4 proceeded in excellent yield
under conditions reported by Aggarwal (6).28 Upon exposure
to a mild oxidant, 3ab was readily converted to the
corresponding alcohol 7.29 Illustrative examples of homologa-
tion reactions are also shown in Scheme 3, which provided
access to propenyl (8),30 vinyl (9),31 and ketone (10)32
functional groups.
In summary, we developed a highly efficient and modular
protocol for the synthesis of gem-diarylcyclopropanes. The
reaction proceeded in moderate to excellent yields and high
diastereoselectivity for a broad range of aryl bromides and
substituted gem-bis(boryl)cyclopropanes. The synthetic utility
of the tertiary boronic ester products was demonstrated by
further derivatization to other functional groups. A slight
modification of the SMC protocol allowed the coupling of
tertiary trifluoroborate 4, providing access to a wide array of
gem-diarylcyclopropanes containing diverse functional groups
and heterocycles. We believe the presented transformations will
be of particular interest in the context of accelerating drug
discovery programs due to the modularity afforded by the gem-
bis(boryl)cyclopropanes and mild reaction conditions of the
SMC procedures. Research on further applications for gem-
bis(boryl)cyclopropanes is ongoing in our laboratory.
C
DOI: 10.1021/acs.orglett.8b00899
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Coleman, P. J.; Vacca, J. P.; Summa, V.; Liverton, N. J. ACS Med.
Chem. Lett. 2012, 3, 332.
ASSOCIATED CONTENT
* Supporting Information
■
S
(6) (a) Nestico, P. F.; Morganroth, J.; Horowitz, L. N. Drugs 1988,
35, 286. (b) Shuto, S.; Takada, H.; Mochizuki, D.; Tsujita, R.; Hase, Y.;
Ono, S.; Shibuya, N.; Matsuda, A. J. Med. Chem. 1995, 38, 2964.
(c) Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang, L.; Zhang,
W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.;
Chen, Y. Bioorg. Med. Chem. Lett. 2009, 19, 6877. (d) Breitenstein, W.;
Huerzeler, M.; Kelly, T.; Mancuso, R.; Schneider, G.; Weitz-Schmidt,
G. WO Patent 2015/189265, Dec 15, 2015. (e) McHardy, S. F.; Heck,
S. D.; Guediche, S.; Kalman, M.; Allen, M. P.; Tu, M.; Bryce, D. K.;
Schmidt, A. W.; Vanase-Frawley, M.; Callegari, E.; Doran, S.;
Grahame, N. J.; McLean, S.; Liras, S. MedChemComm 2011, 2, 1001.
(7) For other relevant examples, see: (a) Taniko, K.; Miyazawa, T.;
Kaneko, T.; Kurumazuka, D.; Harada, S.; Izuchi, T.; Okabe, M.;
Iwamura, R.; Tsuzaki, Y.; Setoguchi, H.; Imura, Y.; Akaza, H.; Shimizu,
M.; Kimura, T. WO Patent 2015/076310, Sep 28, 2016. (b) Cee, V. J.;
Lin, J.; Yu, X. Y.; Zhang, Z. US Patent 2012/0129828, Sep 28, 2011.
(8) For reviews and selected examples of synthetic methods for the
preparation of cyclopropanes, see: (a) Lebel, H.; Marcoux, J.-F.;
Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977. (b) Pellissier,
H. Tetrahedron 2008, 64, 7041. (c) Bartoli, G.; Bencivenni, G.;
Dalpozzo, R. Synthesis 2014, 46, 979. (d) Ebner, C.; Carreira, E. M.
Chem. Rev. 2017, 117, 11651. (e) Marcoux, D.; Charette, A. B. Angew.
Chem., Int. Ed. 2008, 47, 10155. (f) Xu, X.; Zhu, S. F.; Cui, X.; Wojtas,
L.; Zhang, X. P. Angew. Chem., Int. Ed. 2013, 52, 11857.
(g) Chanthamath, S.; Takaki, S.; Shibatomi, K.; Iwasa, S. Angew.
Chem., Int. Ed. 2013, 52, 5818. (h) Wang, Z. J.; Renata, H.; Peck, N.
E.; Farwell, C. C.; Coelho, P. S.; Arnold, F. H. Angew. Chem., Int. Ed.
2014, 53, 6810. (i) Greszler, S. N.; Halvorsen, G. T.; Voight, E. A. Org.
Lett. 2017, 19, 2490. (j) McCabe Dunn, J. M.; Kuethe, J. T.; Orr, R. K.;
Tudge, M.; Campeau, L.-C. Org. Lett. 2014, 16, 6314.
(9) Geminal bis(boryl)alkanes react chemoselectively with a wide
variety of electrophiles. For selected examples, see: (a) Jo, W.; Kim, J.;
Choi, S.; Cho, S. H. Angew. Chem., Int. Ed. 2016, 55, 9690. (b) Liu, X.;
Deaton, T. M.; Haeffner, F.; Morken, J. P. Angew. Chem., Int. Ed. 2017,
56, 11485. (c) Coombs, J. R.; Zhang, L.; Morken, J. P. Org. Lett. 2015,
17, 1708. (d) Potter, B.; Szymaniak, A. A.; Edelstein, E. K.; Morken, J.
P. J. Am. Chem. Soc. 2014, 136, 17918. (e) Kim, J.; Park, S.; Park, J.;
Cho, S. H. Angew. Chem., Int. Ed. 2016, 55, 1498. (f) Ebrahim-Alkhalil,
A.; Zhang, Z.-Q.; Gong, T.-J.; Su, W.; Lu, X.-Y.; Xiao, B.; Fu, Y. Chem.
Commun. 2016, 52, 4891. (g) Kim, J.; Ko, K.; Cho, S. H. Angew. Chem.,
Int. Ed. 2017, 56, 11584. (h) Joannou, M. V.; Moyer, B. S.; Goldfogel,
M. J.; Meek, S. J. Angew. Chem., Int. Ed. 2015, 54, 14141.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00899.
Full experimental details and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Michael.harris@pfizer.com.
ORCID
Michael R. Harris: 0000-0001-8653-0843
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Matthew Teague, Chao Li, Allyn Londregan, Vincent
Mascitti (Pfizer Inc.), and Professor Richard Whitby (Uni-
versity of Southampton) for their advice and support in our
research.
REFERENCES
■
(1) (a) Talele, T. T. J. Med. Chem. 2016, 59, 8712. (b) Gagnon, A.;
Duplessis, M.; Fader, L. Org. Prep. Proced. Int. 2010, 42, 1.
(2) (a) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.;
Duong, L. T.; Falgueyret, J. P.; Kimmel, D. B.; Lamontagne, S.; Leger,
S.; LeRiche, T.; Li, C. S.; Masse, F.; McKay, D. J.; Nicoll-Griffith, D.
A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.;
Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.;
Truong, V. L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni,
R.; Black, W. C. Bioorg. Med. Chem. Lett. 2008, 18, 923. (b) Futatsugi,
K.; Kung, D. W.; Orr, S. T.; Cabral, S.; Hepworth, D.; Aspnes, G.;
Bader, S.; Bian, J.; Boehm, M.; Carpino, P. A.; Coffey, S. B.; Dowling,
M. S.; Herr, M.; Jiao, W.; Lavergne, S. Y.; Li, Q.; Clark, R. W.; Erion,
D. M.; Kou, K.; Lee, K.; Pabst, B. A.; Perez, S. M.; Purkal, J.;
Jorgensen, C. C.; Goosen, T. C.; Gosset, J. R.; Niosi, M.; Pettersen, J.
C.; Pfefferkorn, J. A.; Ahn, K.; Goodwin, B. J. Med. Chem. 2015, 58,
7173.
(3) Lerchner, A.; Machauer, R.; Betschart, C.; Veenstra, S.; Rueeger,
H.; McCarthy, C.; Tintelnot-Blomley, M.; Jaton, A. L.; Rabe, S.;
Desrayaud, S.; Enz, A.; Staufenbiel, M.; Paganetti, P.; Rondeau, J. M.;
Neumann, U. Bioorg. Med. Chem. Lett. 2010, 20, 603.
(10) For examples of one-pot sequential reactions of gem-bis(boryl)
alkanes, see: (a) Stephens, T. C.; Pattison, G. Org. Lett. 2017, 19, 3498.
(b) Li, H.; Zhang, Z.; Shangguan, X.; Huang, S.; Chen, J.; Zhang, Y.;
Wang, J. Angew. Chem., Int. Ed. 2014, 53, 11921. (c) Potter, B.;
Edelstein, E. K.; Morken, J. P. Org. Lett. 2016, 18, 3286. (d) Endo, K.;
Ohkubo, T.; Ishioka, T.; Shibata, T. J. Org. Chem. 2012, 77, 4826.
(11) (a) Endo, K.; Ohkubo, T.; Hirokami, M.; Shibata, T. J. Am.
Chem. Soc. 2010, 132, 11033. (b) Endo, K.; Ohkubo, T.; Shibata, T.
Org. Lett. 2011, 13, 3368.
(4) (a) Yu, K. L.; Sin, N.; Civiello, R. L.; Wang, X. A.; Combrink, K.
D.; Gulgeze, H. B.; Venables, B. L.; Wright, J. J.; Dalterio, R. A.;
Zadjura, L.; Marino, A.; Dando, S.; D’Arienzo, C.; Kadow, K. F.;
Cianci, C. W.; Li, Z.; Clarke, J.; Genovesi, E. V.; Medina, I.; Lamb, L.;
Colonno, R. J.; Yang, Z.; Krystal, M.; Meanwell, N. A. Bioorg. Med.
Chem. Lett. 2007, 17, 895. (b) Abe, H.; Kikuchi, S.; Hayakawa, K.; Iida,
T.; Nagahashi, N.; Maeda, K.; Sakamoto, J.; Matsumoto, N.; Miura, T.;
Matsumura, K.; Seki, N.; Inaba, T.; Kawasaki, H.; Yamaguchi, T.;
Kakefuda, R.; Nanayama, T.; Kurachi, H.; Hori, Y.; Yoshida, T.;
Kakegawa, J.; Watanabe, Y.; Gilmartin, A. G.; Richter, M. C.; Moss, K.
G.; Laquerre, S. G. ACS Med. Chem. Lett. 2011, 2, 320. (c) Wityak, J.;
Das, J.; Moquin, R. V.; Shen, Z.; Lin, J.; Chen, P.; Doweyko, A. M.;
Pitt, S.; Pang, S.; Shen, D. R.; Fang, Q.; de Fex, H. F.; Schieven, G. L.;
Kanner, S. B.; Barrish, J. C. Bioorg. Med. Chem. Lett. 2003, 13, 4007.
(5) (a) Davidson, J. P.; Lubman, O.; Rose, T.; Waksman, G.; Martin,
S. J. Am. Chem. Soc. 2002, 124, 205. (b) Harper, S.; McCauley, J. A.;
Rudd, M. T.; Ferrara, M.; DiFilippo, M.; Crescenzi, B.; Koch, U.;
Petrocchi, A.; Holloway, M. K.; Butcher, J. W.; Romano, J. J.; Bush, K.
J.; Gilbert, K. F.; McIntyre, C. J.; Nguyen, K. T.; Nizi, E.; Carroll, S. S.;
Ludmerer, S. W.; Burlein, C.; DiMuzio, J. M.; Graham, D. J.; McHale,
C. M.; Stahlhut, M. W.; Olsen, D. B.; Monteagudo, E.; Cianetti, S.;
Giuliano, C.; Pucci, V.; Trainor, N.; Fandozzi, C. M.; Rowley, M.;
(12) Hong, K.; Liu, X.; Morken, J. P. J. Am. Chem. Soc. 2014, 136,
10581.
(13) (a) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3,
894. (b) Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc. 2014, 136,
6534. (c) Sun, H. Y.; Kubota, K.; Hall, D. G. Chem. - Eur. J. 2015, 21,
19186. (d) Xu, S.; Shangguan, X.; Li, H.; Zhang, Y.; Wang, J. J. Org.
Chem. 2015, 80, 7779. (e) Cho, S. H.; Hartwig, J. F. Chem. Sci. 2014,
5, 694.
(14) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Sato, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (b) Dreher, S. D.;
Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc.
2008, 130, 9257. (c) Imao, D.; Glasspoole, B. W.; Laberge, V. S.;
Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024. (d) Cox, P. A.;
Leach, A. G.; Campbell, A. D.; Lloyd-Jones, G. C. J. Am. Chem. Soc.
2016, 138, 9145.
D
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(15) For a review of the transmetallation step of the Suzuki−Miyaura
reaction, see: Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed.
2013, 52, 7362.
(16) For conventional methods for the synthesis of gem-bis(boryl)
alkanes, see: (a) Matteson, D. S.; Moody, R. J. Organometallics 1982, 1,
20. (b) Kurahashi, T.; Hata, T.; Masai, H.; Kitagawa, H.; Shimizu, M.;
Hiyama, T. Tetrahedron 2002, 58, 6381. (c) Shimizu, M.; Schelper, M.;
Nagao, I.; Shimono, K.; Kurahashi, T.; Hiyama, T. Chem. Lett. 2006,
35, 1222. (d) Nallagonda, R.; Padala, K.; Masarwa, A. Org. Biomol.
Chem. 2018, 16, 1050.
(17) For a recent example, see: Teo, W. J.; Ge, S. Angew. Chem., Int.
Ed. 2018, 57, 1654.
(18) Thomas, E.; Kasatkin, A. N.; Whitby, R. J. Tetrahedron Lett.
2006, 47, 9181.
(19) Gram scale preparations of 3ab and 3an were also performed.
See the Supporting Information for additional details.
(20) Protodeborylation of the tertiary boronic esters is the major
byproduct and contaminant of the coupling reaction and was observed
to also occur during the workup and purification of the substituted
gem-bis(boryl)cyclopropanes. For best results, aqueous workups were
avoided and silica was pretreated with a solution of 0.5% triethylamine
in heptane. See the Supporting Information for additional details.
(21) All stereochemical assignments are based on NOE correlations.
(22) Carbonyls can act as directing groups in stereoretentive Suzuki−
Miyaura cross-coupling reactions; see: (a) Hoang, G. L.; Takacs, J. M.
Chem. Sci. 2017, 8, 4511. (b) Blaisdell, T. P.; Morken, J. P. J. Am.
Chem. Soc. 2015, 137, 8712. (c) Hoang, G. L.; Yang, Z.-D.; Smith, S.
́
M.; Pal, R.; Miska, J. L.; Perez, D. E.; Pelter, L. S. W.; Zeng, X. C.;
Takacs, J. M. Org. Lett. 2015, 17, 940.
(23) Cross-coupling of secondary cyclopropyl species is well
documented; see: (a) Wang, X.-Z.; Deng, M.-Z. J. Chem. Soc., Perkin
Trans. 1 1996, 1, 2663. (b) Hildebrand, J. P.; Marsden, S. P. Synlett
1996, 1996, 893. (c) Charette, A. B.; de Freitas-Gil, R. P. Tetrahedron
Lett. 1997, 38, 2809. (d) Luithle, J. E. A.; Pietruszka, J. J. Org. Chem.
1999, 64, 8287.
(24) (a) de Meijere, A.; Khlebnikov, A. F.; Sunnemann, H. W.;
̈
Frank, D.; Rauch, K.; Yufit, D. S. Eur. J. Org. Chem. 2010, 2010, 3295.
(b) Harris, M. R.; Li, Q.; Lian, Y.; Xiao, J.; Londregan, A. T. Org. Lett.
2017, 19, 2450. (c) Primer, D. N.; Molander, G. A. J. Am. Chem. Soc.
2017, 139, 9847.
(25) For selected examples of SMC reactions of secondary
cyclopropyl trifluoroborates, see: (a) Molander, G. A.; Gormisky, P.
E. J. Org. Chem. 2008, 73, 7481. (b) Molander, G. A.; Beaumard, F.;
Niethamer, T. K. J. Org. Chem. 2011, 76, 8126.
(26) For reviews of SMC reactions of alkyl and cyclopropyl boron
species, see: (a) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev.
2007, 107, 3117. (b) Doucet, H. Eur. J. Org. Chem. 2008, 2008, 2013.
(27) For a comprehensive review of transformations of alkyl boronic
esters, see: Sandford, C.; Aggarwal, V. K. Chem. Commun. 2017, 53,
5481.
(28) (a) Bagutski, V.; Elford, T. G.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2011, 50, 1080. (b) Matteson, D. S.; Kim, G. Y. Org. Lett.
2002, 4, 2153.
(29) Farthing, C. N.; Marsden, S. P. Tetrahedron Lett. 2000, 41, 4235.
(30) Fletcher, C. J.; Blair, D. J.; Wheelhouse, K. M. P.; Aggarwal, V.
K. Tetrahedron 2012, 68, 7598.
(31) Pulis, A. P.; Blair, D. J.; Torres, E.; Aggarwal, V. K. J. Am. Chem.
Soc. 2013, 135, 16054.
(32) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-
Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011,
50, 3760.
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DOI: 10.1021/acs.orglett.8b00899
Org. Lett. XXXX, XXX, XXX−XXX