Stereospecific Synthesis of α-Hydroxy-Cyclopropylboronates from Allylic Epoxides

Article abstract of DOI:10.1002/anie.201812836

Herein, we report a catalytic and stereospecific method for the preparation of enantioenriched α-hydroxy cyclopropylboronates with control in four contiguous stereocenters. The reaction involves the borylation of readily available allylic epoxides using an inexpensive Cu(I) salt and a commercially available phosphine ligand. High diastereocontrol is achieved and different diastereomers can be selectively prepared. Functionalization of the carbon–boron bond provides access to different enantiomerically enriched trisubstituted cyclopropanes from a common intermediate.

Full text of DOI:10.1002/anie.201812836

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Stereospecific Synthesis of α-Hydroxy-Cyclopropylboronates
from Allylic Epoxides
Authors: Mariola Tortosa, Laura Amenós, Laura Trulli, Luis Nóvoa, and
Alejandro Parra
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812836
Angew. Chem. 10.1002/ange.201812836
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10.1002/anie.201812836
Angewandte Chemie International Edition
COMMUNICATION
Stereospecific Synthesis of α-Hydroxy-Cyclopropylboronates
from Allylic Epoxides
Laura Amenós, Laura Trulli, Luis Nóvoa, Alejandro Parra and Mariola Tortosa*[a]
Abstract: Herein, we report a catalytic and stereospecific method for
the preparation of enantioenriched a-hydroxy cyclopropylboronates
with control in four contiguous stereocenters. The reaction involves
the borylation of readily available allylic epoxides using an
inexpensive Cu(I) salt and a commercially available phosphine
ligand. High diastereocontrol is achieved and different diastereomers
can be selectively prepared. Functionalization of the carbon-boron
bond provides access to different enantiomerically enriched
trisubstituted cyclopropanes from a common intermediate.
cyclopropenes[7] and borylative ring closure of allylic carbonates
and phosphates.[8],[9] However, one important subclass of
cyclopropylboronates that is still underdeveloped is that
containing a secondary a-hydroxy group, such as those shown
in Scheme 1. The introduction of a boryl moiety to this fragment
would provide a modular platform to incorporate a-hydroxy
cyclopropanes into organic molecules. The main approach used
for the preparation of a-hydroxy cyclopropylboronates is the
diastereoselective cyclopropanation of vinyl boronates or allylic
alcohols (eq. 1-2, Scheme 2). This strategy presents limitations
in the structural scope and the stereoselectivity. Starting from
hydroxy vinyl boronates (eq. 1, Scheme 2) only trans-
disubstituted products can be formed (R2 = H).[10] Alternatively,
the use of allylic alcohols and in situ generated boronate-
substituted zinc carbenoids (eq. 2, Scheme 2) provides low
diastereselectivity.[11]
Stereodefined cyclopropanes are increasingly important
scaffolds in modern drug discovery research.[1] The introduction
of the cyclopropyl fragment into a lead compound can enhance
the potency, increase metabolic stability, improve binding to the
target and reduce the off-target effects.[2] Cyclopropanes with
multiple stereocenters provide rigidity while also increasing
three-dimensionality. These two properties make them ideal
fragments to explore new areas of chemical space in medicinal
chemistry.[3] Among biologically active cyclopropane derivatives,
the a-hydroxy cyclopropyl fragment represents a prevalent core
structure present in several natural products and drugs (Scheme
1).
Previous approach:
(1)
(2)
R2
R2
Bpin
I2CHBpin
Et2Zn/CH2I2
(5-10 equiv)
R1
E
R1
R1
EtZnO2CCF3
Bpin
(R2= H)
OH
low diastereoselectivity
OH
OH
Limited scope:
trans-disubstituted products
This work:
Ar
Ar
R1
R2
LCu(I) cat.
B2pin2
✓ Diastereoselective and stereospecific
✓ Ligand-controlled cyclization
✓ Four contiguous stereocenters
✓ Secondary sp3 electrophile
O
H
R1
OH
OH
O
OH
O
O
R2
H
N
Bpin
H
S
O
A
C
N
H
OH
O
C5H11
O
OH
Ar
?
N
O
Halicholactone
Remikiren
R1
HN
Me
CuL
regioselectivity?
diastereoselectivity?
R2
OH
Me
Bpin
B
Me
H
OH
Me
Scheme 2. Synthesis of enantioenriched α-hydroxy cyclopropylboronates.
Me
H
OH
Based on our previous experience on copper-catalyzed
borylation reactions,[7b],[12] we designed a novel strategy to
prepare this class of compounds. We envisioned that allylic
epoxides A could provide trisubstituted a-hydroxy cyclopropanes
C through a regio- and diastereoselective borylation/cyclization
sequence. Enantiomerically enriched allylic epoxides can be
easily prepared by direct epoxidation of dienes or from a-epoxy
alcohols through an oxidation-olefination sequence.[13] We
planned to take advantage of the myriad of enantioselective
methods to epoxidize alkenes[14] to develop a catalytic and
stereospecific process in which the chirality of the epoxide would
be transferred to the cyclopropane. Ideally, switching the
geometry of the epoxide and/or the alkene would selectively
provide different diastereoisomers with control in four contiguous
stereocenters.
Calcipotriol
OH
Omphadiol
HO
Scheme 1. α-Hydroxy cyclopropanes in natural products and drugs.
Recently, we and others have been involved in the design of
new
synthetic
methods
to
prepare
stereodefined
cyclopropylboronates.[4] These versatile molecules are promising
synthetic intermediates for the preparation of functionalized
cyclopropanes. The carbon-boron bond is configurationally
stable and the boryl moiety offers
a
handle for further
enriched
prepared
functionalization.[5]
Enantiomerically
have been
cyclopropylboronates
through
cyclopropanation of vinyl boronates,[6] desymmetrization of
We began our investigation by examining the reactivity of
enantiomerically enriched vinyl epoxide 1a with B2pin2 (1.2
equiv.) in the presence of a catalytic amount of a Cu(I) salt and
a variety of phosphine ligands (Table 1). The use of CuCl (10
mol%), PCy3 (11 mol%) and NaOtBu (1 equiv) in THF, failed to
deliver detectable amounts of cyclopropylboronate 2a. We did
not observe formation of the 1,4-addition product either,[12a] with
only diene 3a being obtained (Table 1, entry 1). We reasoned
[a]
Laura Amenós, Dr. Laura Trulli, Luis Nóvoa, Dr. Alejandro Parra and
Dr. Mariola Tortosa
Organic Chemistry Department
Institute for Advance Research in Chemical Sciences (IAdChem)
Universidad Autónoma de Madrid, 28949 Madrid, Spain
E-mail: mariola.tortosa@uam.es
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201812836
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COMMUNICATION
are reported in the literature and they all involved the use of an
excess of highly reactive organometallic species.[17] 2) This is
that diene 3a could be formed from intermediate 4 (Table 1) via
elimination of the boryl moiety and subsequent ring opening
followed by isomerization of the resulting allyl copper
intermediate and b-oxygen elimination.[15] The use of a bidentate
phosphine with a small bite angle, dppBz (bn = 83º), still favored
the formation of 3a, but we could identify a small amount of
cyclopropane 2a (Table 1, entry 2). Increasing the bite angle of
the ligand had a dramatic effect on the formation of 2a. Using
DPEPhos (bn = 102º) cyclopropane 2a and diene 3a were
obtained in almost a 1:1 mixture (Table 1, entry 3). Switching to
xantphos (bn = 111º) the formation of diene 3a was significantly
diminished and cyclopropane 2a was formed in high yield (Table
1, entry 4). Therefore, the ligand played a key role in the control
of the cyclization over the diene formation. We then studied the
effect of the base in the transformation. Changing the counterion
from sodium to lithium resulted in lower yield of cyclopropane 2a
(Table 1, entry 5). On the contrary, KOt-Bu allowed us to
completely suppress the formation of diene 3a (Table 1, entry 6).
When we reduced the amount of base (Table 1, entry 7) the
yield for 2a dropped down significantly.
the first example of
cyclization involving
a
a
copper-catalyzed borylative endo-
secondary sp3-electrophile.[8],[18]
Compared to other endo-cyclizations, our method provides
diastereoselective control and affords trisubstituted
cyclopropanes with the boryl moiety and the aryl group in a cis
relationship.[19] 3) This is an unusual example of a copper-
catalyzed reaction of an allylic epoxide and a nucleophile that
does not proceed via 1,4-addition.[13],[20]
Scope on the aryl group
R2 1b, R2 = o-Me 1g, R2 = m-Me
1c, R2 = p-Me 1h, R2 = m-CF3
Me
Me
O
1d, R2 = p-OMe
1e, R2 = p-F
1i, R2 = m-CN
1j, R2 = p-CN
R1
=
R1
1f, R2 = p-Ph
Me
(2S,3S)-1
Me
OMe
F
Me
R1
Me
R1
R1
R1
Me
OH
Me
OH
Me
OH
OH
2e, 94%
Bpin
Bpin
Bpin
Bpin
2d, 54%
dr ≥ 98:2
2c, 82%
dr ≥ 98:2
2b, 43%
dr ≥ 98:2
Ph
dr ≥ 98:2
Table 1. Reaction Optimization[a]
CuCl (10 mol%)
L (10 mol%)
NaOtBu (1.0 equiv)
CN
Me
CF3
R1
Ph
Ph
R1
Me
O
R1
R1
Me
R1
Me
R1
R1
Me
Ph
+
Me
3a
Ha
Bpin
B2pin2 (1.2 equiv)
OH
Me
Me
OH
OH
Bpin
OH
OH
THF, 12 h
Bpin
Bpin
Bpin
(2S,3S)-1a
2a
0.57 ppm, dd
J = 10.4, 7.2 Hz
2g, 92%
2f, 42%
2i, 43%
2h, 88%
dr ≥ 98:2
R1
=
dr ≥ 98:2
dr ≥ 98:2
dr ≥ 98:2
CN
Ph
O
R1
R1
CuL
CuL
Ph
CuL
0.99 ppm, t
J = 7.2 Hz
R1
R1
Ha
Bpin
Me Bpin
4
Ph
3a
Me
OH
Me OH
Me OH
2j
t-BuO
2j, 76%
dr ≥ 98:2
Change in other
parameters
Yield
Yield
Scope on the epoxide and alkene geometry
Entry
Ligand
2a (%)[b]
3a (%)[b]
O
O
O
H
Ph
H
H
O
O
Ph
E
Ph
1
2
3
4
5
6
PCy3
–
–
56
60
30
6
R1
Me
n-Hex
Ar
n-Hex
(2R,3S)-1o
cis
R1
dppBz
–
4
26
OBn
Ph
Me
DPEPhos
xantphos
xantphos
xantphos
–
(2S,3S)-1k,l
(2R,3S)-1m
(2S,3R)-1n
(2R,3S)-1p
–
77
Using LiOtBu
Using KOtBu
Using KOtBu
(0.5 equiv)
33
85 (81)[c]
8
Ar
Ph
Ph
Ph
Ph
R1
Me
H
Me
R1
H
H
–
n-Hex
OH
n-Hex
OH
OH
OH
OH
OBn
Bpin
7
xantphos
29
7
Bpin
Bpin
Bpin
Bpin
2k, Ar = Ph
69%, dr ≥98:2
[a]
2p, 39%
dr ≥ 98:2
2n, 70%
dr = 85:15
2o, 87%
dr ≥ 98:2
2m, 67%
dr ≥ 98:2
Reaction conditions: 1 (0.2 mmol), B2pin2 (0.24 mmol), NaOtBu (0.2 mmol),
[b]
Yield calculated by 1H-NMR
2j, Ar = pCN-C6H4
51%, dr ≥98:2
CuCl (10 mol%), L (11 mol%), THF (0.2 M).
using 1,4-diacetylbenzene as internal standard.[c] Isolated yield.
Scheme 3. Scope of vinyl epoxides. Reaction conditions: Table 1, entry 6.
Cyclopropane 2a was obtained as a single diastereomer,
indicating that the insertion step to form 4 and the cyclization
took place with complete diastereocontrol. The relative
configuration for the four contiguous sterocenters was
determined from single-crystal X-ray crystallography of 2a.[16]
The exquisite control of the regio- and the diastereoselectivity in
the insertion step is noteworthy and it is in contrast with our
previous borylation of alkyl-substituted allylic epoxides, in which
the anti-1,4-addition product was formed.[12a] There are several
aspects of this transformation that are worth highlighting: 1) Only
a few examples of cyclopropane formation from allylic epoxides
Having optimized the reaction parameters for the
cyclopropane formation, we evaluated the substrate scope
(Scheme 3). We first modified the stereoelectronic effects of the
aryl group on the alkene. The reaction showed good tolerance to
ortho- (2b), para- (2c-2f) and meta- (2g-2i) substitution. In all
cases, cyclopropanes 2 were obtained as single diastereomers.
Surprisingly, epoxide 1j, with a cyano group in para-, cleanly
afforded cyclopropylboronate 2j, with the boronic ester and the
1
aromatic ring in a trans relationship. The H NMR of 2j showed
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10.1002/anie.201812836
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COMMUNICATION
significant differences (shift and multiplicity) for the proton
adjacent to the boryl moiety (Ha) compared to the rest of the
series (Scheme 3). Indeed, single-crystal X-ray crystallography
(compound 2k) via a similar transition state. Finally, reaction
between copper alkoxide
D
and B2pin2 would form
cyclopropylboronate E with regeneration of the copper-boryl
complex.[27]
analysis of 2j revealed the formation of
a
different
diastereomer.[21] This unexpected result could be explained by
formation of an extended copper-enolate, favored by the
electron-deficient aryl group.[22]
a) Oxidation-benzoylation
Ph
Ph
Me
Me
Me
Me
1) H2O2/NaOH
We next introduced changes in the geometry of the epoxide
and the double bond. The relative configuration of the products
can be controlled by careful selection of the structural features of
the starting material. Allylic epoxides 1k and 1l, with an E-alkene,
afforded cyclopropane 2k and 2j respectively, with a trans
arrangement between the phenyl and the Bpin groups.[23]
Additionally, epoxide 1m, with a cis geometry in the oxirane ring,
gave diastereomer 2m, with a different relative stereochemistry
between the oxygenated carbon and the three stereocenters on
the cyclopropyl ring. Finally, cis-disubstituted epoxides 1n-p
provided cyclopropyl boronates 2n, 2o and 2p in good and
moderate yields. The diastereoselectivity observed for epoxide
1n was slightly lower (dr = 85:15) but, cyclopylboronate 2n was
Me OH
5, 54%
Me OH
2) BzCl, Et3N, DMAP
OBz
Bpin
2a
(two steps)
b) Homologation-oxidation sequence
Ph
Ph
CH2ClBr (3 equiv.)
nBuLi (2.5 equiv.)
Me
Me
Et2O
Me
Me OR
Me
Me OR
Bpin
Bpin
2a, R = H
6, R = TMS
7, 82%
TMSCl
95%
NaBO3·4H2O
Ph
Me
Me
THF/H2O
Me OR
OH
8, 71%
easily obtained as
a
single diastereomer after column
c) Suzuki-Miyaura cross-coupling reaction
Ph
chromatography. Cyclopropylboronate 2o showed again that a
trans arrangement between the phenyl and the Bpin groups is
possible starting from an allylic epoxide with an E-alkene. The
results above prove that our method is stereospecific and shows
the potential to selectively access different stereoisomers.
Starting from optically active epoxides, enantioenriched a-
hydroxy cyclopropylboronates could be synthesized with
excellent chirality transfer.[24]
Ph
Pd(dba)2 (10 mol%)
SPhos (20 mol%)
Me
Me
Me
Me
Me OR
Me OR
Bpin
KOtBu (2 equiv.)
PhI (3 equiv.)
DME
Ph
9, 50%
6, R =-TMS
Scheme 4. C-B bond functionalization.
KOtBu
CuCl + L
R1
R2
LCuCl
LCuOtBu
To demonstrate the versatility of the products we performed
different transformations of the C-B bond (Scheme 4). Oxidation
of compound 2a followed by benzoylation afforded
Ar
B2pin2
Ar
O
R1
R2
OBpin
A
Bpin
LCu Bpin
functionalized
cyclopropanol
derivative
5.
Matteson
E
homologation of TMS-protected cyclopropylboronate 6 provided
cyclopropane 7 in excellent yield. Boronates such as 7 are
valuable synthetic intermediates that could be used as
homoallylation and homocrotylation reagents.[25] Oxidation of the
carbon-boron bond in 7 provided functionalized cyclopropane 8
in good yield. Finally, a Suzuki-Miyaura cross coupling reaction
between boronate 6 and iodobenzene allowed us to prepare
cyclopropane 9 with retention of the configuration in the newly
formed stereocenter.[8a,b]
B2pin2
Ar
H
R1
R2
Ar
CuL
R1
O
Bpin
2 OCuL
R
Bpin
B
D
Scheme 5. Proposed mechanism.
A
plausible mechanism for the copper-catalyzed
stereospecific cyclopropanation is shown in Scheme 5. The
catalytically active copper(I)-boryl complex is first formed from
copper tert-butoxide and a diboron compound. Next, insertion of
the alkene into the copper-boryl complex takes place. In this
stereo-determining step intermediate B is formed. The observed
stereochemical outcome could be explained by a syn approach
of the copper(I)-boryl complex to an allylic epoxide in an s-trans
conformation (as shown in A). This syn approach could be
directed by coordination of the oxygen of the epoxide to the
boron atom. From B, intramolecular SN2 type reaction would
afford cyclopropylboronate D. The cis relationship between the
boryl moiety and the aryl group may result from a W-shaped
transition state (blue bonds in B).[26] When starting from an E
allylic epoxide such as 1k this relationship would be trans
In summary, starting from readily available allylic epoxides,
we have developed a catalytic and stereospecific method for the
preparation of enantioenriched a-hydroxy cyclopropylboronates
with control of four contiguous stereocenters. Good yields and
excellent diastereoselectivities are observed using an
inexpensive Cu(I) salt and a commercially available phosphine
ligand. The use of xantphos as ligand is critical to control
undesired reaction pathways. Structural changes in the allylic
epoxide allows for the selective synthesis of different
diastereomers, without modifying the reaction conditions.
Functionalization of the carbon-boron bond in the products
provides
a variety of enantiomerically enriched a-hydroxy
trisubstituted cyclopropanes.
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10.1002/anie.201812836
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COMMUNICATION
2012, 134, 15165. c) C. Jarava-Barrera, A. Parra, A. López, F. Cruz-
Acosta, D. Collado-Sanz, D. J. Cárdenas, M. Tortosa, ACS. Catal. 2016,
6, 442. d) M. Guisán-Ceinos, A. Parra, V. Martín-Heras, M. Tortosa,
Angew. Chem. Int. Ed. 2016, 55, 6969. e) A. López, T. B. Clark, A.
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[13] a) M. Pineschi, F. Bertolini, V. Di Bussolo, P. Crotti, Curr. Org. Synth.
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[14] A. Berkessel, H. Engler, T. M. Leuther, in Science of
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Acknowledgements
We thank the European Research Council (ERC-337776) and
MINECO (CTQ2016-78779-R) for financial support. L.T. thanks
the Università degli Studi di Roma "La Sapienza" for
postdoctoral fellowship.
a
Keywords: cyclopropane • boron • copper • allylic epoxide •
cyclopropylboronate
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[16] CCDC 1873299 contains the supplementary crystallographic data for
2a. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html.
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moiety is directly attached to the ring formed. On the other hand,
borylative exo-cyclization is that in which the boryl moiety is not directly
[4]
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attached to the ring formed.
LG
LG
LG
Bpin
CuL
Bpin
exo
endo
Bpin
Bpin
CuL
LCuBpin
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catalyzed borylative radical cyclization, see: H. Iwamoto, S. Akiyama, K.
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[7]
[8]
[9]
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[21] CCDC 1873303 contains the supplementary crystallographic data for 2j.
These
data
can
be
obtained
free
of
charge
at
Recent diastereoselective methods that do not provide enantiomerically
enriched cyclopropylboronates: a) M. M. Hussain, H. Li, N. Hussain, M.
Ureña, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc. 2009, 131, 6516;
b) C. W. Liskey, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 3375; c) S.
Miyamura, M. Araki, T. Suzuki, J. Yamaguchi, K. Itami, Angew. Chem.
Int. Ed. 2015, 54, 846; Angew. Chem. 2015, 127, 860; d) J. He, H.
Jiang, R. Takise, R.-Y. Zhu, G. Chen, H.-X. Dai, T. G. Murali Dhar, J.
Shi, H. Zhang, P. T. W. Cheng, J.-Q. Yu, Angew. Chem. Int. Ed. 2016,
55, 785; Angew. Chem. 2016, 128, 795; e) G. Benoit, A. B. Charette, J.
Am. Chem. Soc. 2017, 139, 1364. f) M. Murai, C. Mizuta, R. Taniguchi,
K. Takai, Org. Lett. 2017, 19, 6104. g) M. Sayes, G. Benoit, A. B.
Charette, Angew. Chem. Int. Ed. 2018, 57, 13514.
www.ccdc.cam.ac.uk/conts/retrieving.html.
[22] The electron deficient aryl unit probably favors the formation of an
extended copper-enolate that could cyclize to give 2j, leaving Hb cis to
the boryl moiety to minimize steric effects. Although
a rapid
isomerizacion of the double bond of the allylic epoxide cannot be ruled
out, we did not detect any E-allylic epoxide when we monitored the
reaction by 1H NMR.
Hb
CuL
R1
R2
R1
R2
O
Bpin
O
Bpin
C
CuL
CN
N
For the formation of a related extended copper-enolate from a benzylic
intermediate, see: J. Lee, S. Radomkit, S. Torker, J. del Pozo, A. H.
Hoveyda, Nat. Chem. 2018, 10, 99.
[10] a) J. Pietruszka, A. Witt, Synlett 2003, 91; b) S. A. Murray, E. C. M. Luc,
S. J. Meek, Org. Lett. 2018, 20, 469. We have only considered methods
in which the starting hydroxyl vinyl boronates could be prepared in an
enantiomerically enriched form.
[23] The relative configuration of 2k was by stablished by comparison of the
the 1H NMR data with compound 2j.
[24] The enantiomeric ratio of the products is expected to be the same as
the allylic epoxides, since one of the stereocenters in the oxirane ring is
not modified through the transformation. Nevertheless, we proved that
the enantiomeric ratio of epoxide 1m was preserve in
cyclopropylboronate 2m. See Supporting Information for details.
[11] Reference 9e reports one example of cyclopropanation with
a
secondary allylic alcohol (R1 ¹ H). The cyclopropylboronates were
obtained as a 1.9:1 mixture of diastereomers.
[12] a) M. Tortosa, Angew. Chem. Int. Ed. 2011, 50, 3950. b) R. Alfaro, A.
Parra, J. Alemán, J. L. García Ruano, M. Tortosa, J. Am. Chem. Soc.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812836
Angewandte Chemie International Edition
COMMUNICATION
[25] a) W. Pei, I. J. Krauss, J. Am. Chem. Soc. 2011, 133, 18514. b) H. Lin,
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S. Norsikian, I. Marek, J.-F. Poisson, J. F. Normant, J. Org. Chem.
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[27] Compound E provides cyclopropylboronate 2 after hydrolysis of the O-
B bond during work-up.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812836
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Laura Amenós, Laura Trulli, Luis Nóvoa,
Alejandro Parra and Mariola Tortosa*
Page No. – Page No.
Copper-Catalyzed Stereoespecific
Synthesis of α-Hydroxy-
Cyclopropylboronates
Rigid sp3 scaffolds: A catalytic and stereospecific method for the preparation of
enantioenriched a-hydroxy cyclopropylboronates with control in four contiguous
stereocenters is described. The reaction involves the borylation of readily available
allylic epoxides using an inexpensive Cu(I) salt and a commercially available
phosphine ligand. High diastereocontrol is achieved and different diastereomers
can be selectively prepared.
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