Catalytic Stereoselective Borylative Transannular Reactions

Article abstract of DOI:10.1002/anie.201913438

Medium-sized carbocycles containing an α,β-unsaturated ketone moiety as Michael acceptor site and a ketone moiety as internal electrophilic site are ideal substrates to conduct Cu(I)-catalyzed conjugated borylation followed by electrophilic intramolecular

Full text of DOI:10.1002/anie.201913438

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Accepted Article
Title: Catalytic Stereoselective Borylative Transannular Reactions
Authors: Elena Fernandez, Jose Luis Vicario, Jana Sendra, Efraim
Reyes, and Ruben Manzano
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913438
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10.1002/anie.201913438
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Catalytic Stereoselective Borylative Transannular Reactions
Jana Sendra,[a,b] Ruben Manzano,[b] Efraim Reyes,[b] Jose L. Vicario*[b] and Elena Fernández*[a]
Dedication ((optional))
Abstract: Medium-sized carbocycles containing an -unsaturated
ketone moiety as Michael acceptor site and a ketone moiety as
internal electrophilic site are ideal substrates to conduct Cu(I)-
catalyzed conjugated borylation followed by electrophilic
intramolecular trapping that results into a pioneer transannular
borylative ring closing reaction. The relative configuration of three
adjacent stereocenters is controlled, giving access to a single
diastereoisomer for a wide range of substrates tested. Moreover,
On the other hand, borylative ring closing of functionalized
alkenes bearing internal electrophilic sites appears as a very
efficient strategy for the strategic construction of carbocycles.
There are many literature examples involving borylative
cyclization of enynes, endiynes, allenynes and enallenes under
Pd, Au, Rh or Ni catalysis that show the excellent performance of
this approach.[8] On the contrary, copper-catalyzed borylative ring
closing reactions that take place through C-B bond formation with
concomitant C-C coupling based on the 1,2-carboboration
concept has been more scarcely studied (Scheme 1, top). Most
of the reactions reported involve borylcupration of the alkene
followed by intramolecular nucleophilic substitution,[9] together
with some limited examples in which the internal electrophile
reacting with the alkylcuprate intermediate is a carbonyl-based
functionality[10] or an imine.[11] There are also some examples in
which chiral ligands are incorporated to achieve enantiocontrol.[12]
On the contrary, examples of borylative ring closing reactions that
involve an initial conjugated borylation process that generates a
copper enolate intermediate that is subsequently trapped by the
internal electrophile is restricted to just three limited examples in
the literature.[13]
when
a chiral ligand is incorporated, the reaction provides
enantioenriched polycyclic products up to 99% e.e.
Generating molecular complexity from simple starting materials is
intrinsically associated to the task of organic synthesis. Often,
these are a combination of several cyclic structures and, in this
sense, chemists typically face the generation of such cyclic
molecular scaffolds by using either cyclization or cycloaddition
processes. As an alternative, transannular reactions in which the
two reacting centers are tethered together as part of a macrocyclic
starting material show up as an appealing alternative for the fast
and reliable construction of complex polycyclic molecular
scaffolds.[1] In fact, several research groups have demonstrated
that transannular reactions can be an excellent strategic decision
when designing the synthesis of complex natural products.[2]
However, in almost all cases, the reported examples make use of
chiral starting materials, therefore relying on substrate control
during the diastereoselective generation of new stereocentres.
On the other hand, catalytic and enantioselective variants of
transannular reactions are limited to a handful of examples. In
particular, and after the seminal report by Jacobsen dealing with
an elegant example of a transannular Diels-Alder reaction under
chiral oxazaborolidine catalysis,[3] only four additional
transformations have been reported up to date. Jacobsen himself
described an enantioselective transannular ketone-ene reaction
using a salen-Cr(III) Lewis acid catalyst[4] and Hierseman has
reported the use of Cu(II)-bis-oxazoline compexes as catalysts in
a transannular Claisen rearrangement.[5] Alternatively, enamine
catalysis has been used by List in a transannular aldol reaction,[6]
and some of us have also very recently reported one example of
a catalytic and enantioselective transannular Morita-Baylis-
Hillman reaction under chiral phosphine catalysis.[7]
In view of these precedents, we envisaged the possibility of
developing transannular reactions initiated by a copper catalyzed
borylation/ring closing process on a macrocyclic substrate
containing an -unsaturated ketone as suitable moiety for the
initial conjugated borylation reaction and a ketone as internal
electrophilic site to promote the transannular process (see
Scheme 1, bottom). The addition of a chiral ligand at the Cu(I)
catalyst would also provide an opportunity to control the
stereochemical outcome of the concomitant C-B and C-C bond
forming steps, enabling an overall enantioselective transannular
reaction, which would significantly expand the toolbox of chemical
synthesis through different manipulations of the stereogenic alkyl
boronate.[14]
Previous work: Stereoselective intramolecular 1,2-carboboration
R
Cu(I) cat.
R
Chiral ligand
Bpin
B2pin2
+
*
*
Electrophilic
site
R'
R'
This work: Stereoselective transannular 1,2-carboboration
Cu(I) cat.
Chiral ligand
Bpin
*
B2pin2
+
*
[a]
[b]
Dr. E. Fernández, Ms. J. Sendra
Department Química Física i Inorgànica
University Rovira i Virgili
Transannular
reaction
*
Electrophilic
site
C/ Marcel·lí Domingo s/n
Scheme 1. Catalytic enantioselective borylative ring closing reactions.
E-mail: mariaelena.fernandez@urv.cat
Dr. J. L. Vicario, Dr. R. Manzano, Dr. E. Reyes,
Department of Organic Chemistry II
University of the Basque Country (UPV/EHU)
P.O. Box 644, 48080 Bilbao (Spain)
E-mail: joseluis.vicario@ehu.es
We first started our work by evaluating the viability of the
envisaged domino conjugated borylation/transannular aldol
reaction using (Z)-cyclodec-2-ene-1,6-dione (1) as a suitable
model compound that would lead to the formation of adduct 2
showing an octahydroazulene-type architecture, which is a
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.201913438
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general motif present in a variety of natural products and bioactive
compounds.[15] We decided to use the catalytic system based on
CuCl/base to promote the activation of B2pin2, via -bond
metathesis step.[16] As it can be seen in Table 1, the projected
transannular reaction took place smoothly with NaOtBu or KOtBu
The precise arrangement of the relative possition of the functional
groups in undecane macrocyclic architectures also allowed to
convert substrate (Z)-cycloundec-7-ene-1,6-dione (3) and (Z)-
cycloundec-2-ene-1,6-dione (5) into the corresponding adducts
with
the
bicyclo[5.4.0]undecane
structure
(±)-4
and
as
bases
(entries
1-2),
providing
the
borylated
bicyclo[6.3.0]undecane core (±)-6, respectively, in both cases as
bicyclo[5.3.0]decane adduct (±)-2 as a single diastereoisomer
generating three consecutive stereocenters. Interestingly, no
reactivity was observed when NaOMe was the base of choice
(entry 3). Since NaOtBu resulted the most efficient base, we next
explored the influence of several mono- and diphosphines in the
reaction outcome. It was found that PPh3, P(nBu)3, dppe and dppf
were convenient ligands to achieve high conversions and isolated
yields, keeping the formation of the bycyclic product as a single
diastereoisomer (entries 4-8). Under optimized reaction
conditions, other copper (I) sources were employed without any
significant improvement (entries 9-10), whereas no product
formation was detected using a Cu(II) salt or in the absence of
copper catalysts (entries 11-12). Interestingly, in all the examples,
the reaction was fully regioselective, in line with our initial
hypothesis that expected an initial -boration of the enone to
generate a copper enolate intermediate.
single diastereoisomers (Scheme 2).
Scheme 2. Cu-catalyzed diastereoselective borylative transannular reaction of
substrates 3 and 5.
The highly diastereoselective aldol reaction might be
explained by the preferred formation of a chelated (Z)-configured
cyclic copper enolate intermediate (Scheme 3). The relative
stereochemistry has been assigned by comparison of the 1H NMR
spectra of the three new products. The bicyclo[5.3.0]decane
adduct (±)-2 has a characteristic doublet at 3.37 ppm for H with
a coupling constant value (J=8.5 Hz) indicative of this proton
being cis-axial/equatorial to and the adjacent proton (confirmed
by the X-ray structure of a derivative compound, see SI). Similarly,
the 1H NMR spectrum for (±)-4 and (±)-6 shows a doublet for H
at 3.05 ppm and 3.17 ppm, respectively, with similar coupling
constant values (J=6.4 Hz and J=8.6 Hz) (Scheme 3). These
values are in contrast to the typical trans-diaxial coupling
constants for similar products.[17] When adducts (±)-2 and (±)-4
were oxidized, the corresponding diols (±)-7a and (±)-7b show
doublets for H at 3.33 ppm and 4.37 ppm respectively, and
coupling constants values about J=2.4 Hz and J=1.5 Hz,
suggesting a quasi-coplanar disposition of the two adjacent
protons probably due to the repulsion of the cis diol moieties.
Table 1. Cu-catalyzed diastereoselective borylative transannular reaction of
model substrate 1.[a]
O
O
CuCl / base / ligand
B2pin2 (1.1 equiv)
Bpin
H
MeOH / THF, 30ºC
OH
( )-2
O
1
Entry
Cu catalyst
base
ligand
Conv
(%)[b] IY
[%][c]
1
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
NaOtBu
KOtBu
---
92
2
---
63
3
NaOMe
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
---
0
4
PPh3
PCy3
P(nBu)3
dppe
dppf
dppf
dppf
dppf
dppf
99
5
82
[d]
6
99 [91]
99
7
8
99 [86]
45
9
10
11
12
[Cu(CH3CN)4]OTf
NaOtBu
NaOtBu
NaOtBu
91
CuO
-
0
0
[a] Reactions were performed at 0.1 mmol of substrate, with Cu catalyst (15
mol%), base (20 mol%), ligand (20 mol%), B2pin2 (1.1 equiv), THF (6 mL),
MeOH (2 equiv), 30ºC, 16h. [b] Conversion calculated by NMR using
naphthalene as internal standard, [c] IY: isolated yields of pure product after
column chromatography, [d] 15 mol% of ligand was used.
Scheme 3. Proposed stereochemical models and conversion of borylated
adducts into diols
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In order to establish the general behavior of the diastereoselective
conjugated borylation / transannular aldol reaction, we first
were obtained with higher isolated yields possibly due to the
higher estabilization of the products (entries 5-6). On the other
hand the presence of two fused arene moieties next to both the
enone and to the ketone in 20, provided tetracyclic product (±)-21
focused on macrocycles
with cyclodec-2-en-1,6-dione
architectures that contain fused aromatic systems with diverse
substitution patterns. All these substrates were efficiently
converted into the corresponding borylated tricyclic products
under optimized conditions as single diastereoisomers (Table 2).
with only one stereocenter (entry 7), presumably as
a
consequence of a dehydration process favoured by the highly
conjugated nature of this final product.
Table 2. Scope of the diastereoselective Cu/dppf diastereoselective
borylative transannular reaction.[a]
With a view to complete the substrate scope, we conducted the
Cu/dppf catalyzed borylative transannular reaction of cycloundec-
2-en-1,7-dione
macrocyclic
substrates
toward
the
Entry
Substrate
Product
Conversion (%)[b]
Isolated Yield [%][c]
diastereoselective formation of bicyclo[5,4,0]undecane scaffolds
(Scheme 4). These substrates also contain a fused aromatic
group adjacent to the enone moiety with different substitution
patterns. The control on the diastereoselectivity was complete for
all substrates explored when dppf was used as ligand, despite the
fact that, as it was observed before, isolated yields were
dependent on the nature of the substituents at the arene moiety.
In the case of substrate 23, when P(nBu)3 was used as ligand, the
expected product (±)-24 was formed in 55% together with a minor
amount of its diastereoisomer (±)-25 that could be fully
characterized by X-ray analysis (Scheme 4).
99 [86]
90 [31]
1
2
96 [47]
99 [46]
3
4
CuCl (15 mol%)
R
ligand (20 mol%)
R
R
NaOtBu (20 mol%)
B2pin
2 (1.1 equiv)
Bpin
O
Bpin
O
O
H
H
R'
THF / MeOH
30ºC, 16h
R'
R'
O
OH
OH
n
ligand:
ligand:
P( Bu)3
dppf
()-24
()-24
23 R=H, R'=H
[55%]
()-25 [22%]
[64%]
[22%]
[32%]
----
O
O
ligand:
ligand:
ligand:
26 R=Me, R'=Me
28 R=Br, R'=H
dppf
dppf
dppf
()-27
()-29
()-31
----
----
95 [60]
99 [71]
5
6
7
30 R=OMe, R'=H
[70%]
----
16
Scheme 4. Cu-catalyzed diastereoselective borylative transannular reaction on
cycloundecane substrates.
Finally, to demonstrate the feasibility of developing
enantioselective variants of this diastereoselective borylative
transannular reaction, macrocyle 1 was subjected to standard
reaction conditions using a type of Josiphos chiral ligand (Scheme
5).[18] Interestingly, in addition to the complete diastereoselectivity
observed, high levels of asymmetric induction could be achieved
(92% e.e. for (+)-2). The absolute stereostructure of the
enantiomers was established by single-crystal X-ray analysis of
an enantiopure sample of (+)-17 (Scheme 5).
99 [58]
[a] Reactions were performed at 0.2 mmol of substrate, with Cu catalyst (15
mol%), NaOtBu (20 mol%), dppf (20 mol%), B2pin2 (1.1 equiv), THF (6 mL),
MeOH (2 equiv), 30ºC, 16h. [b] Conversion calculated by NMR using
naphthalene as internal standard, [c] IY: isolated yields of pure product.
For those substrates with a fused arene at the enone moiety
the isolated yield of the bicyclic adduct was strongly dependent
on the nature of the substituents at the aryl core, although in all
cases the reaction proceeded cleanly towards full conversion
towards the corresponding borylated transannular product as
NMR analysis indicates (entries 1-4). When this fused aromatic
ring was located next to the ketone group, that plays the role of
the internal electrophilic site, the expected borylated adducts
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CuCl (15 mol%)
noteworthy considering the possibilities for the alkyl boronate unit
to undergo stereospecific transformations.
PCy2
Me
Josiphos(20 mol%)
NaOtBu (20 mol%)
Ph2P
Bpin
O
Fe
O
H
B2pin
2 (1.1 equiv)
m
MeOH / THF
30ºC, 16-24h
n= 1,2 m= 1,2
n
m
O
O
OH
n
Acknowledgements
O
Bpin
O
Bpin
Bpin
This research was supported by the Spanish Ministerio de Ciencia,
Innovación y Universidades (MCIU) through projects FEDER-
CTQ2016-80328-P and FEDER-CTQ2017-83633-P and by the
Basque Government (IT908-16). J. S. acknowledges the Spanish
MCIU for an FPI fellowship and R. M. acknowledges the Basque
Government for a postdoctoral contract. We thank AllyChem for
the gift of diboranes.
H
H
H
OH
OH
IY: [95%]
92% e.e. (16h)
Bpin
OH
( )-6,
 IY: [81%]
( )-2,

( )-4,

IY: [72%]
88% e.e. (16h)
88% e.e. (16h)
Bpin
O
O
Bpin
O
H
F
H
H
MeO
Keywords: transannular borylation • ring closing • stereogenic
alkyl boronate • copper catalysts • electrophilic intramolecular
trapping
OH
IY: [43%]
74% e.e. (16h)
Bpin
OH
IY: [89%]
74% e.e. (20h)
OH
IY: [98%]
>99% e.e. (24h)
( )-9,

( )-11,

( )-15,

O
Bpin
O
H
H
[1]
For some reviews se: (a) E. Marsault, A. Toro, P. Nowak, P.
Deslongchamps, Tetrahedron 2001, 57, 4243. (b) S. Handa, G.
Pattenden, Contemp. Org. Synth. 1997, 4, 196. (c) A. M. Montana, C.
Batalla, J. A. Barcia, Curr. Org. Chem. 2009, 13, 919. (d) A. Rizzo, S. R.
Harutyunyan, Org. Biomol. Chem. 2014, 12, 6570.
=
OH
OH
Br
IY: [74%]
88% e.e. (16h)
( )-17,
84% e.e. (20h)

IY: [65%]
( )-19,

[2]
For a focused review see E. Reyes, U. Uria, L. Carrillo, J. L. Vicario,
Tetrahedron 2014, 70, 9461.
MeO
Br
O
Bpin
[3]
[4]
[5]
[6]
E. P. Balskus, E. N. Jacobsen, Science 2007, 317, 1736.
O
O
Bpin
Bpin
H
H
H
N. S. Rajapaksa, E. N. Jacobsen, Org. Lett. 2013, 15, 4238.
T. Jaschinski, M. Hiersemann, Org. Lett. 2012, 14, 4114.
(a) C. L. Chandler, B. List, J. Am. Chem. Soc. 2008, 130, 6737. There is
also one example of an enantioselective transannular aldol reaction
using stoichiometric amounts of a chiral metal alkoxide as Bronsted base.
(b) O. Knopff, J. Kuhne, C. Fehr, Angew. Chem. Int. Ed. 2007, 46, 1307.
R. Mato, R. Manzano, E. Reyes, L. Carrillo, U. Uria, J. L. Vicario J. Am.
Chem. Soc. 2019, 141, 9495.
OH
IY: [56%]
88% e.e. (16h)
OH
IY: [44%]
64% e.e. (16h)
OH
IY: [67%]
( )-31,
( )-24,
( )-29,



62% e.e. (16h)
[7]
[8]
[9]
Scheme 5. Cu-catalyzed enantioselective transannular conjugated
borylation/aldol cyclization with decane and undecane macrocyclic substrates.
For an excellent review on this concept see: E. Buñuel, D. J. Cárdenas,
Chem. Eur. J. 2016, 2016, 5446.
Synthetic manipulations on compound (+)-4 as representative
model of the enantioenriched polycyclic products prepared was
also surveyed (Scheme 6). In particular, oxidative protocol was
explored which proceeded with complete stereochemical
retention from C-B to C-OH bond.
For a review see (a) K. Kubota, H. Iwamoto, H. Ito, Org. Biomol. Chem.
2017, 15, 285. For some examples: (b) H. Ito, T. Toyoda, M Sawamura,
J. Am. Chem. Soc., 2010, 132, 5990. (c) K. Kubota, E. Yamamoto, H. Ito,
J. Am. Chem. Soc., 2013, 135, 2635. (d) J. Royes, S. Ni, A. Farre, E. La
Cascia, J. J. Carbó, A. B. Cuenca, F. Maseras, E. Fernández, ACS Catal.,
2018, 8, 2833. (e) Y.-J. Zuo, X.-T. Chang, Z.-M. Hao, C.-M. Zhong, Org.
Biomol. Chem., 2017, 15, 6323.
O
Bpin
O
[10] (a) E. Yamamoto, R. Kojima, K. Kubota, H. Ito, Synlett, 2015, 26, 272.
(b) A. Whyte, K. I. Burton, J. Zhang, M. Lautens, Angew. Chem. Int. Ed.,
2018, 57, 13927. (c) A. R. Burns, S. González, H. W. Lam, Angew. Chem.
Int. Ed., 2012, 51, 10827. (d) A. Whyte, B. Mirabi, A. Torelli, L. Prieto, J.
Bajohr, M. Lautens, ACS Catal., 2019, 9, 9253. (e) A. Whyte, A. Torelli,
B. Mirabi, M. Lautens Org. Let., 2019, DOI: 10.1021/acs.orglett.9b03144.
[11] (a) H.-M. Wang, H. Zhou, Q.-S. Xu, T.-S. Liu, C.-L.; Zhuang, M.-H. Shen,
H.-D. Xu, Org. Lett., 2018, 20, 1777. (b) G. Zhang, A. Cang, Y. Wang, Y.
Li, G. Xu, Q. Zhang, T. Xiong, Q. Zhang, Org. Lett., 2018, 20, 1798
[12] (a) H. Ito, Y. Kosaka, K. Nonoyama, Y. Sasaki, M. Sawamura, Angew.
Chem. Int. Ed., 2008, 47, 7424. (b) C. Zhong, S. Kunii, Y. Kosaka, M.
Sawamura, H. Ito, J. Am. Chem. Soc., 2010, 132, 11440. (c) See also
refs. 10b-d and 11b.
OH
H
H
NaBO3·H2O
OH
OH
( )-4,
88% e.e.
( )-32, [99%]
82% e.e.
Scheme 6. Stereospecific C-B bond oxidation of (+)-4.
In conclusion, we have shown that copper-catalyzed
conjugate borylation can be used to trigger highly
diastereoselective transannular reactions that enable the
construction of complex bicyclic scaffolds such as the azulene
core in a simple and straightforward manner. In addition the
reaction can also be carried out in a highly enantioselective
fashion through the incorporation of a chiral ligand in the catalytic
system. The practical synthetic utility of this transformation is
[13] M. Tobisu, H. Fujihara, K. Koh, N. Chatani, J. Org. Chem., 2010, 75,
4841. Se also refs. 9e and 10c.
[14] (a) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2nd ed. (Eds.: D. G. Hall), Wiley-VCH, Weinheim,
2011. (b) Synthesis and Applications of Organoboron Compounds
Topics in Organometallic Chemistry, Vol. 49 (Eds.: E. Fernández, A.
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Whiting), Springer, Berlin, 2015. (c) E. C. Neeve , S. J. Geier , I. A. I.
Mkhalid , S. A. Westcott, T. B. Marder , Chem. Rev., 2016, 116 , 9091.
[15] (a) B. M. Fraga, Nat. Prod. Rep. 2004, 21, 669. (b) G. Rücker, Angew.
Chem. Int. Ed. Engl. 1973, 12, 793.
[16] J. Cid, H. Gulyás J. J. Carbó, E. Fernández, Chem. Soc. Rev, 2012, 41,
3558.
[17] K. Agapiou, D. F. Cauble, M. J. Krische, J. Am. Chem. Soc. 2004, 126,
4528.
[18] See Supporting Information for screening of chiral ligands.
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Entry for the Table of Contents (Please choose one layout)
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Jana Sendra, Ruben Manzano, Efraim
Reyes, Jose L. Vicario* and Elena
Fernández*
Page No. – Page No.
Catalytic Stereoselective Borylative
Transannular Reactions
Copper-catalyzed conjugate borylation can be used to trigger highly
diastereoselective and enantioselective transannular reactions that enable the
construction of complex bicyclic scaffolds.
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