One-Pot, Three-Step Synthesis of Cyclopropylboronic Acid Pinacol Esters from Synthetically Tractable Propargylic Silyl Ethers

Article abstract of DOI:10.1021/acs.orglett.7b01778

Simple propargylic silyl ethers can be converted to complex cyclopropylboronic acid pinacol esters in an efficient one-pot procedure. Terminal acetylenes undergo a Schwartz's reagent catalyzed hydroboration; subsequent addition of further Schwartz's reage

Full text of DOI:10.1021/acs.orglett.7b01778

Letter
pubs.acs.org/OrgLett
One-Pot, Three-Step Synthesis of Cyclopropylboronic Acid Pinacol
Esters from Synthetically Tractable Propargylic Silyl Ethers
Jonathan A. Spencer,‡,† Craig Jamieson,† and Eric P. A. Talbot*,‡
†University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
‡GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: Simple propargylic silyl ethers can be converted to
complex cyclopropylboronic acid pinacol esters in an efficient one-
pot procedure. Terminal acetylenes undergo a Schwartz’s reagent
catalyzed hydroboration; subsequent addition of further Schwartz’s
reagent and Lewis acid-mediated activation of neighboring silyl ether
allows cyclization to access a range of cyclopropylboronic acid pinacol
esters. The scope includes aromatic, aliphatic, quaternary, and spiro
substituted cyclopropyl rings, which can be transformed via Suzuki coupling into a range of lead-like substituted cyclopropyl aryl
products.
Scheme 2. Selection of Methods for Preparing
Cyclopropylpinacol Boronic Ester Derivatives
yclopropyl rings are ubiquitous motifs in natural
a
1a−e
Cproducts and bioactive molecules
(Scheme 1), with
their three-dimensional character offering novel vectors for
substitution.
Scheme 1. Structures of Selected Marketed Drugs
a
TBME = 2-methoxy-2-methylpropane.
Scheme 3. Proposed Hydrozirconation Approach
A number of methods for synthesis have been developed
including Simmons-Smith cyclopropanation,2a,b Pd-catalyzed
diazomethane addition,3 and Corey-Chaykovsky cyclopropa-
nation.4a−c Because of the high synthetic utility of pinacol
boronic esters,5 our focus was the synthesis of cyclopropyl
rings containing this functional unit to facilitate straightfor-
ward incorporation into bioactive scaffolds. Reported
approaches to these key building blocks include cyclo-
propanation of vinyl pinacol boronic esters,6 hydroboration
of cyclopropene rings,7 or C−H activation borylation of a
preformed cyclopropyl ring.8
Methods whereby the cyclopropyl ring and boron species
are introduced in the same sequence are also possible. These
include cyclopropanation using a modified Simmons-Smith
reagent9 and asymmetric copper(I)-catalyzed borylation/
cyclization10 (Scheme 2). However, all of these methods are
limited by scope, modularity, or starting material tractability.
Of initial interest was the cyclopropanation method
developed by Szymoniak (Scheme 3).11 Here, a hydro-
zirconation followed by Lewis acid-mediated cyclization yields
Received: June 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01778
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a range of substituted cyclopropyl rings. The use of Schwartz’s
reagent is an established method for alkene and alkyne
activation via a hydrozirconation to form an organozirconium
species.12 The resulting complex can then be transformed
using various reaction manifolds such as addition to an
electrophile13a−c or transmetalation.14a−c
Schwartz’s reagent to the vinyl pinacol boronic ester
intermediate. Variation in diastereomeric ratio was observed
dependent on the size of the silyl protecting group (Table 2).
Table 2. Influence of Size of Silyl Group on Diastereomeric
Ratio
This led us to the hypothesis that the method developed by
Szymoniak could be applied to vinyl pinacol boronic esters
since the synthesis of gem−borazirconocene complexes has
been reported.15a,b We further reasoned that these vinyl
pinacol boronic esters could be generated in situ from the
corresponding alkyne (Scheme 3).16a,b
On the basis of all of the above, initial studies focused on
the model substrates 3a−d and synthesis of the simplest
cyclopropyl pinacol boronic ester 4.
substrate (R =)
cis/trans
Initial studies using methyl propargyl ether 3a led to
encouraging results with modest conversion to product 2
observed by NMR with additional vinyl pinacol boronic ester
intermediate 5a remaining. After a limited solvent screen (see
Supporting Information), dichloromethane was found to be
optimal and hence was selected for further studies.
Exploration of the stoichiometry of Schwartz’s reagent in an
attempt to promote hydrozirconation onto the hindered vinyl
pinacol boronic ester intermediates 5a−d led to three
equivalents being selected, as it resulted in high conversion
to cyclopropyl product 4, with only a low amount of
intermediate 5a−d remaining. Next, a range of potential
leaving groups was examined with the silyl ether systems
proving to be optimal (Table 1).17 We hypothesize that the
availability of low-lying empty orbitals at the silicon center
resulted in a better leaving group and a more facile
cyclization.
1
2
3
4
5
6
6a (Si(OEt)3)
6b (SiEt3)
6c (SitBuPh2)
6d (SitBuMe2)
6e (SiiPr3)
0.4:1
0.6:1
1.1:1
1.2:1
1.5:1
3.8:1
6f (Si(SiMe3)3)
The largest tristrimethylsilyl group yielded predominantly cis-
diastereoisomer (3.8:1), and the smallest triethoxysilyl yielded
predominantly trans-diastereoisomer (0.4:1). However, selec-
tivity could not be improved further, and reduced yields were
observed (see Supporting Information). This led to the tert-
butyldimethylsilyl group being selected for further study.
With optimized conditions for the conversion in hand, we
next investigated the scope of the one-pot borylation/
cyclization reaction. A variety of silyl ethers were selected
containing a range of electron rich and electron poor benzylic
ethers, aliphatic ethers, and quaternary ethers.
Table 1. Optimization of Conditions for One-Pot
Borylation Cyclization Method
A number of benzylic substituted propargylic ethers could
be converted with both electron-donating and electron-
withdrawing substituents (7, 9a−d). It was observed that
the electronic properties of the aryl substituents influence the
diastereomeric ratio (9a, 4.3:1 to 9c, 0.9:1). The reaction was
found to be dependent on sterics with a reduction in yield
observed from phenyl 9e (66%) to ortho-tolyl 9e (29%) to
2,6-dimethylphenyl 9f (0%). From consideration of the
reaction profile, it can be inferred that steric bulk appears
to inhibit initial zirconium catalyzed hydroboration step. The
reaction was also found to proceed for aliphatic substituents
ethyl phenyl 9g (77%) and ethyl furanyl 9h (58%). With
more challenging quaternary substituted centers, product
formation was observed in slightly reduced yield, 2-methyl-
2-phenyl 9i (34%). No formation of product was observed for
pyridine containing product 9j, despite observation of a
vinylic boronic ester intermediate in the reaction mixture,18a
possibly due to coordination of nitrogen lone pair to reactive
species.18b The small fused spirocyclic derivative 9k was also
unsuccessful, with high ring strain in the system hypothesized
to prevent cyclization (Scheme 4).18a
a
substrate
(R =)
equiv
equiv
yield
a
Cp2ZrHCl
BF3OEt2
(%) 4
yield (%) 5a−d
1
2
3
4
5
3a (Me)
3a (Me)
3b (H)
3c (Bn)
1
3
3
3
3
2
2
2
2
2
43
50
21
4
b
b
-
-
61
66
0
1
3d
(TBDMS)
6
3d
3
0.5
77
0
(TBDMS)
a
b
With reference to bis(trimethylsilyl)benzene internal standard. No
conversion to intermediate vinyl Bpin 5b was observed. Deuterated
solvents were used to allow facile analysis of reaction milieu by NMR.
c
Having established the generality of the process, we next
sought to demonstrate the one-pot generation of a diverse
range of products relevant to medicinal and agrochemical
efforts. These syntheses were telescoped utilizing a Suzuki-
Miyaura cross-coupling protocol following on from the initial
cyclopropanation (Scheme 5).19 Simple propargylic ether
starting materials could easily be converted in one-pot to bis-
substituted cyclopropyl rings with electron-donating, 11a, or
Pleasingly, upon application of conditions to more complex
4-bromophenyl system, similar levels of conversion were
observed, however, as a mixture of diastereoisomers, which
could not easily be separated by chromatography. Further
studies were then carried out to explore the effect of silyl
ether group on diastereomeric ratio. It was reasoned that
variation of size of this group would affect the approach of
B
DOI: 10.1021/acs.orglett.7b01778
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Organic Letters
Letter
Scheme 4. Exploration of Scope of One-Pot Borylation/
Cyclization Reaction
Scheme 5. (a) Diversification of Cyclopropylboronic Ester
Products in Suzuki-Miyaura Cross-Coupling; (b) Synthesis
of Cyclopropyl-Containing Fungicide, Sedaxane
election-withdrawing, 11b, substituents. Lead-like spiro-cyclo-
propyl fragments could also be prepared, yielding products
11c and 11d in around 25% yield over four reaction steps
(71% average yield per step). Spiro derivatives 11c and 11d
are of interest in bioactive compounds as they exhibit a
significant degree of 3D character20 and conformationally
constrained growth vectors for drug discovery.21 The method
was also used to synthesize the bis-cyclopropyl derivative 11e,
an intermediate in the synthesis of bioactive compound
Sedaxane 12.
Sedaxane is a succinate dehydrogenase inhibitor and is
effective in producing higher and more consistent yields of
major crops such as cereals and soybean.22a,b Deprotection
and amide coupling of Boc-aniline 11ea yields Sedaxane 12.
This route allows a modular construction of the bicyclopropyl
template making late stage diversification of the system
possible.
a
Diastereomers could be separated by reverse phase chromatography.
This enables synthesis of chiral cyclopropylboronic esters
starting from readily accessible chiral propargylic alcohols.
These can easily be prepared through asymmetric addition of
alkyne systems to aldehyde or ketone23a−c derivatives or via
chiral reduction of propargylic ketones.24 Our results suggest
that the process is invertive at the alcohol center for substrate
13a. We therefore propose a distinct mechanism in contrast
to the stereoretentive mechanism proposed by Szymoniak
(Scheme 6).11
In conclusion, our method allows the conversion of
synthetically tractable propargylic alcohols to a range of aryl,
aliphatic, quaternary, and spiro substituted cyclopropyl pinacol
boronic esters using commercial reagents. This transformation
allows access to a range of complex building blocks for
synthesis and allows modular construction of cyclopropyl-
containing fragments. These can then be reacted to yield
In the final part of our study, we sought to explore the
mechanism of the exemplified reaction. Application of chiral
substrates enabled us to probe the mechanism of the Lewis
acid-mediated cyclization. This work indicates that racemiza-
tion does not occur during the reaction as both target
compounds 14a and 14b are isolated in high enantiopurity.
C
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Pendri, Y.; Sausker, J.; Soumeillant, M. Org. Process Res. Dev. 2008,
12, 178−182.
(3) Paulissen, R.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1972,
13, 1465−6.
Scheme 6. Application of Methodology to Chiral Substrates
and Proposed Mechanism for Key Step
(4) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84,
867−868. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965,
87, 1353−1364. (c) Appel, R.; Hartmann, N.; Mayr, H. J. Am. Chem.
Soc. 2010, 132, 17894−17900.
(5) Zhu, C.; Falck, J. R. Adv. Synth. Catal. 2014, 356, 2395−2410.
(6) Pietruszka, J.; Witt, A. Perkin 1 2000, 4293−4300.
(7) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003,
125, 7198−7199.
(8) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135,
3375−3378.
(9) Benoit, G.; Charette, A. B. J. Am. Chem. Soc. 2017, 139, 1364−
1367.
(10) Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am.
Chem. Soc. 2010, 132, 11440−11442.
(11) Gandon, V.; Szymoniak, J. Chem. Commun. 2002, 1308−1309.
(12) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115.
(13) (a) Ragan, J. A.; Nakatsuka, M.; Smith, D. B.; Uehling, D. E.;
Schreiber, S. L. J. Org. Chem. 1989, 54, 4267−4268. (b) Zhang, D.;
Ready, J. M. J. Am. Chem. Soc. 2007, 129, 12088−12089. (c) Strom,
A. E.; Hartwig, J. F. J. Org. Chem. 2013, 78, 8909−8914.
(14) (a) Wipf, P.; Kendall, C. Chem. - Eur. J. 2002, 8, 1778−1784.
(b) Venanzi, L. M.; Lehmann, R.; Keil, R.; Lipshutz, B. H.
Tetrahedron Lett. 1992, 33, 5857−5860. (c) Maksymowicz, R. M.;
Roth, P. M. C.; Fletcher, S. P. Nat. Chem. 2012, 4, 649−665.
(15) (a) Zheng, B.; Srebnik, M. Tetrahedron Lett. 1994, 35, 1145−
8. (b) Zheng, B.; Deloux, L.; Pereira, S.; Skrzypczak-Jankun, E.;
Cheesman, B. V.; Sabat, M.; Srebnik, M. Appl. Organomet. Chem.
1996, 10, 267−278.
drug-like scaffolds. Further work is ongoing to explore
optimization of the diastereomeric ratio.
ASSOCIATED CONTENT
* Supporting Information
■
S
(16) (a) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127−
3128. (b) Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y.
Tetrahedron Lett. 2005, 46, 8777−8780.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01778.
(17) OH, OTs, OTHP, and OBz were found to be unstable for
zirconium-mediated hydroboration.
Experimental procedures; characterization of all com-
pounds (PDF)
(18) (a) Conversion to a vinyl boronic ester intermediate was
1
observed by H NMR on an aliquot taken after completion of step i.
(b) Reaction was also unsuccessful upon addition of 2 equiv BF3·
AUTHOR INFORMATION
■
OEt2.
Corresponding Author
*E-mail: eric.p.talbot@gsk.com.
ORCID
(19) Miyamura, S.; Araki, M.; Suzuki, T.; Yamaguchi, J.; Itami, K.
Angew. Chem., Int. Ed. 2015, 54, 846−851.
(20) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752−6756.
Craig Jamieson: 0000-0002-6567-8272
Eric P. A. Talbot: 0000-0002-8867-3407
Notes
(21) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem. Lett.
2014, 24, 3673−3682.
(22) (a) Ehrenfreund, J.; Tobler, H.; Walter, H. O-Cyclopropyl-
carboxanilides and Their Use as Fungicides. Patent WO2003074491A1,
2003. (b) Zeun, R.; Scalliet, G.; Oostendorp, M. Pest Manage. Sci.
2013, 69, 527−534.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(23) (a) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4,
2605−2606. (b) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, S. J.
Am. Chem. Soc. 2005, 127, 13760−13761. (c) Kotani, S.; Kukita, K.;
Tanaka, K.; Ichibakase, T.; Nakajima, M. J. Org. Chem. 2014, 79,
4817−4825.
(24) Brinkmeyer, R. S.; Kapoor, V. M. J. Am. Chem. Soc. 1977, 99,
8339−8341.
■
Financial support for this work was provided by GSK via the
GSK/University of Strathclyde Centre for Doctoral Training
in Synthetic and Medicinal Chemistry.
REFERENCES
■
(1) (a) Salaun, J. Top. Curr. Chem. 2000, 207, 1−67. (b) Blass, B.
ACS Med. Chem. Lett. 2012, 3, 697−698. (c) Zhang, X.; Zhang, N.;
Chen, G.; Turpoff, A.; Ren, H.; Takasugi, J.; Morrill, C.; Zhu, J.; Li,
C.; Lennox, W.; Paget, S.; Liu, Y.; Almstead, N.; George Njoroge, F.;
Gu, Z.; Komatsu, T.; Clausen, V.; Espiritu, C.; Graci, J.; Colacino, J.;
Lahser, F.; Risher, N.; Weetall, M.; Nomeir, A.; Karp, G. M. Bioorg.
Med. Chem. Lett. 2013, 23, 3947−3953. (d) Chen, D. Y. K.; Pouwer,
R. H.; Richard, J.-A. Chem. Soc. Rev. 2012, 41, 4631−4642. (e) Talele,
T. T. J. Med. Chem. 2016, 59, 8712−8756.
(2) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80,
5323−5324. (b) Anthes, R.; Benoit, S.; Chen, C.-K.; Corbett, E. A.;
Corbett, R. M.; DelMonte, A. J.; Gingras, S.; Livingston, R. C.;
D
DOI: 10.1021/acs.orglett.7b01778
Org. Lett. XXXX, XXX, XXX−XXX