Stereoselective Access to Alkylidenecyclobutanes through γ-Selective Cross-Coupling Strategies

Article abstract of DOI:10.1021/acs.orglett.7b01803

Alkylidenecyclobutanes (ACBs) containing all-carbon quaternary stereocenters were simply and efficiently synthesized by combining boron-homologation and γ-selective cross-coupling strategies. This unique sequence led to excellent regio- and diastereoselec

Full text of DOI:10.1021/acs.orglett.7b01803

Letter
pubs.acs.org/OrgLett
Stereoselective Access to Alkylidenecyclobutanes through
γ‑Selective Cross-Coupling Strategies
Michael Eisold and Dorian Didier*
Department of Chemistry and Pharmacy, Ludwig-Maximilians-University, Butenandtstraße 5-13, 81377 Munich, Germany
S
* Supporting Information
ABSTRACT: Alkylidenecyclobutanes (ACBs) containing all-
carbon quaternary stereocenters were simply and efficiently
synthesized by combining boron-homologation and γ-selective
cross-coupling strategies. This unique sequence led to
excellent regio- and diastereoselectivities in the generation of
targeted four-membered rings with up to 99% enantiomeric
excess using chiral substrates. In addition to the original
synthesis of ACBs, the first asymmetric catalytic formation of quaternary stereocenters based on γ-selective cross-coupling
reactions is finally shown.
hile the Suzuki−Miyaura cross-coupling is already a
Scheme 1. Approach to ACBs Containing a Quaternary
Stereocenter through γ-Selective Cross-Coupling
W
well-established method in pharmaceutical sciences,1 the
use of allylic boronic esters therein still remains scarcely
described. Pioneering studies by Szabo
́
and Miyaura2
demonstrated that the reaction of allylboronic ester at the γ-
position can be triggered by employing an appropriate
palladium precatalyst. Since then, however, this interesting
transformation was only examined by a few groups.
Recently, the groups of Morken, Buchwald, and Organ
independently illustrated highly regioselective γ-cross-coupling
reactions,3 while Aggarwal and Crudden described very good
stereoselectivities of these transformations when employing
substituted allyl- and propargylboronic esters.4
We envisioned that combining such a powerful tool with an
in situ generation of cyclobutenylmethylboronic esters (CMBs)
would result in a straightforward formation of alkylidenecyclo-
butanes (ACBs). These small architectures have a rather limited
accessibility but are encountered in many natural products and
biologically active substances.5 Moreover, the relatively strained
nature of ACBs allows for a variety of further transformations.6
Recently, merging boron homologation of cyclobutenyl metal
species and allylboration strategies in a one-pot sequence, we
have described a very efficient approach toward stereodefined
ACBs.7
Similar conversions were observed when replacing THF by
MTBE or ethyl acetate (Table 1, entries 8 and 9), nonetheless
requiring 14 h to reach completion. Attempts to replace
potassium hydroxide as the base only resulted in decreasing
either conversion or regioselectivity levels (Table 1, entries 4
and 5).
With optimal conditions in hand, a set of various aryl halides
were engaged in the presence of 1a,b (Scheme 2). With an
exception for aldehydes (that would lead to a fast allylboration)
and alcohols, a wide range of functional groups were tolerated.
Not only aryl iodides or bromides but also aryl chlorides
were successfully engaged, although with lower yield (2f: 57%
compared to 91% for the corresponding aryl bromide). The
In this communication, we present a unique combination of
boron homologation with a highly γ-selective Suzuki−Miyaura
cross-coupling for the diastereo- and enantioselective con-
struction of ACBs containing a quaternary stereocenter
(Scheme 1) starting from achiral CMBs (1a,b) and chiral α-
or δ-substituted CMBs (1c−g).
Negishi π-cyclization8 of readily available 4-bromobutynes
followed by a Matteson homologation led to CMBs 1.
Morken’s conditions were initially employed for optimizing
our reaction conditions when 4-iodotoluene was used as the
cross-coupling partner.3d After a short screening, reactions
performed in THF with KOH introduced from a stock solution
proved to give the best results (Table 1, entry 3) in only 1 h.
Received: June 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01803
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Organic Letters
Letter
Table 1. Survey of Base and Solvent in γ-Cross-Coupling
Reactions
Scheme 3. γ-Selective Cross-Coupling of Chiral Substrates
1c and 1d
a
a
entry
solvent
THF
base
KOH
conv (%)
γ/α
1
2
3
4
5
6
7
8
9
72
80
>99:1
>99:1
>99:1
86:14
>99:1
>99:1
72:28
>99:1
>99:1
THF/H2O (1:1)
THF
KOH
KOH(aq)
TBAF
CsF
b
c
>99
THF
74
THF
65
b
dioxane
acetonitrile
MTBE
KOH(aq)
KOH
91
94
KOH
>99
>99
ethyl acetate
KOH
a
b
c
Determined by GC. 8.0 M solution. After 1 h.
Scheme 2. Electrophilic Scope of γ-Selective Cross-Coupling
well as heteroaromatic-substituted methylenecyclobutanes 2j−
o were obtained with high yields up to 95% and with a full
control over the diastereochemical outcome of the trans-
formation (dr >99:1).
As postulated by Buchwald et al. (Scheme 4), we propose to
explain the high diastereoselectivity by a ZT transition state in
which the transmetalation step would follow a chair model.10
Scheme 4. (a) Proposed ZT Model and (b) Observed NOEs
Supporting the Proposed Configuration
In this case, the palladium complex preferably approaches
from the less hindered diastereotopic face of the double
bondopposite side of the R chainleading selectively to the
described isomer. The 2D-NMR assignments of 2k supported
the above-mentioned hypothesis, placing the aromatic moiety
anti to the preinstalled R chain (Scheme 4).
To further expand the scope toward more elaborated
structures and to open the possibility of synthesizing
enantioenriched ACBs, we chose to study the reactivity of α-
chiral boronic esters in γ-selective cross-coupling reactions.
First experiments using previously described catalytic systems
led to expected compounds but without control over E/Z ratios
(50:50). Screening of diverse conditions showed the best
results when PCy3 or dppb (1,4-bis(diphenylphosphino)-
butane) was employed as ligands in the presence of Pd(OAc)2
or Pd(PPh3)2Cl2, respectively (Table 2, entries 1 and 12).
However, when full conversion was to be observed, other
conditions only led to worse E/Z ratios. In most cases bidentate
ligands gave better E/Z ratios, a trend that could be attributed
to a favorable shielding of the pseudoaxial position toward the
formation of the E-product. Presenting similar stereoselectiv-
lower reaction rate of aryl chloride was exploited in the
chemoselective synthesis of 2i, accounting for only negligible
side reactions. Electron-donating (2a,b and 2h) as well as
electron-withdrawing groups (2f,g) led to good yields up to
91%, while heterocyclic products were isolated in up to 83%
yield (2d and 2e). Interestingly, free amines led to a complete
conversion of the starting material, giving the expected cross-
coupled compound in 76% yield. In all cases the γ-selective
cross-coupling products were exclusively detected, probably
enhanced by a strain release when shifting the π-system outside
of the ring structure.9
Having established an efficient route toward alkylidenecy-
clobutanes, we took a step further by employing chiral
cyclobutenylmethylboronic esters (1c,d) (Scheme 3) possess-
ing a lateral chain R. Performing reactions in dioxane showed
slightly better diastereoselectivities in this case, and aromatic- as
B
DOI: 10.1021/acs.orglett.7b01803
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Organic Letters
Letter
substituents and subsequently cross-coupled with different
halides, achieving overall good to excellent yields (up to 97%).
None of the reactions showed α-cross-coupling, and E-3a−h
were obtained in more than 97% of stereochemical purity. In
the case of 4, a 2-cyanoethyl substituent was introduced
through the double-homologation sequence, pointing out the
functional group tolerance of the transformation. Worthy of
note, the starting cyclobutenylmethylboronic ester bearing the
2-cyanoethyl chain was engaged in the γ-cross-coupling after
simple filtration of residual salts, avoiding fastidious purification
steps and furnishing 4 in 45% yield. 2D NMR experiments on
3f supported the favored formation of E-isomers.
Table 2. Survey of Conditions for Synthesis of
Alkylidenecyclobutanes
a
b
entry
Pd species
ligand
PCy3
E/Z
1
2
Pd(OAc)2
Pd(OAc)2
95:5
87:13
66:34
49:51
89:11
88:12
92:8
XPhos
DavePhos
RuPhos
Tetraphos-Li
dppBz
dppb
3
Pd(OAc)2
4
Pd(OAc)2
Taking advantage of a substituent present at the α-position
that can easily be introduced in a stereoselective waywe took
on the challenge of relaying the chiral information from the
boronic ester moiety to the quaternary stereocenter.
5
Pd(OAc)2
6
Pd(OAc)2
7
Pd(OAc)2
8
Pd(OAc)2
dppp
92:8
A preinstalled enantiomerically pure ligand on the boron
atom led to enantiomerically enriched cyclobutene derivatives
((R)-1e and (R)-1f) via successively diastereoselective and
diastereospecific boron-homologation sequences. 5-Bromoin-
dole and 4-bromoaniline were chosen for the γ-selective cross-
coupling, and corresponding ACBs were obtained in very good
yields up to 94% and with a perfect control of the
stereochemistry (99% E and 99% ee) (Scheme 6). High
stereoselectivities observed in this reaction can be attributed to
a sterically favored pseudo-equatorial positioning of the α-
substituent R in the ZT transition state.
9
Pd(OAc)2
PPh3
50:50
91:9
10
11
12
13
14
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
[Allyl-PdCl]2
PCy3
dppp
92:8
dppb
94:6
91:9
PCy3
PCy3
93:7
a
10 mol % of monodentate, 5 mol % of bidentate ligands.
Determined by GC.
b
ities, the Pd(OAc)2/PCy3 (Table 2, entry 1) system was
preferentially employed for economic reasons.
Pd(OAc)2 was thus chosen as precatalyst, and the trans-
formation was exemplified with a range of coupling partners
(Scheme 5). Boronic esters 1e,f were readily prepared by a
double boron homologation in order to introduce α-
Scheme 6. Diastereoselective Access to Enantioenriched
ACBs 3d and 3g
Scheme 5. Synthesis of Alkylidenecyclobutanes from 1e and
1g
The next step toward enantioenriched ACBs was designed
through asymmetric catalysis, employing chiral palladium
ligands in the presence of achiral substrates 1b.
To the best of our knowledge, intermolecular enantiose-
lective formation of a quaternary stereocenter through γ-
selective cross-coupling remains unexplored. While TADDOL-
11
PNMe2 failed our expectations, the first positive results were
observed when employing (R)-BINAP as the chiral ligand (er =
64:36) (Table 3, entry 2). Changing the ligand to the JosiPhos
series (entries 3−8) could improve the enantiomeric ratio to
81:19 with L1 at 60 °C. Performing the reaction at room
temperature gave the best enantioselectivities (er = 85:15).
Adjustments on the ligand structure (L2−5) did not lead to
any amelioration on the stereoselectivity of the reaction.
Finally, methylenecyclobutanes (−)-2c and (−)-2g werefor
the first timegenerated from corresponding allylboron
species through stereoselective γ-cross-coupling in up to 77%
yield and moderate enantiomeric ratios (up to 85:15 er).
C
DOI: 10.1021/acs.orglett.7b01803
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Organic Letters
Letter
Alonso Benito (ERASMUS+, I.E.S. Ramon y Cajal, Valladolid)
for their assistance.
Table 3. Survey of Conditions for Enantioselective Synthesis
of MCBs
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01803.
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Contains all experimental procedures and character-
1
ization (IR, HRMS, and H and 13C NMR data) for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dorian.didier@cup.uni-muenchen.de.
ORCID
Michael Eisold: 0000-0002-2314-3990
Dorian Didier: 0000-0002-6358-1485
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.E. and D.D. are grateful to the Chemical Industry Fund (FCI
Liebig-fellowship) for financial support. Prof. Dr. P. Knochel
(LMU, Munich) is kindly acknowledged for his generous
support. We thank A. Muller-Deku (LMU, Munich) and I. R.
̈
D
DOI: 10.1021/acs.orglett.7b01803
Org. Lett. XXXX, XXX, XXX−XXX