Single-Pot Asymmetric Approach toward Enantioenriched Quaternary Stereocenter-Containing Alkylidenecyclobutanes

Article abstract of DOI:10.1021/acs.orglett.6b01432

Enantioenriched alkylidenecyclobutanes possessing a quaternary stereogenic center, usually difficult to access, have been synthesized by combining a double boron-homologation and an allylboration through a highly efficient and diastereoselective one-pot p

Full text of DOI:10.1021/acs.orglett.6b01432

Letter
pubs.acs.org/OrgLett
Single-Pot Asymmetric Approach toward Enantioenriched
Quaternary Stereocenter-Containing Alkylidenecyclobutanes
Michael Eisold,‡ Gabriel M. Kiefl,‡ and Dorian Didier*
Department of Chemistry and Pharmacy, Ludwig-Maximilians-University, Butenandtstrasse 5-13, 81377 Munich, Germany
S
* Supporting Information
ABSTRACT: Enantioenriched alkylidenecyclobutanes pos-
sessing a quaternary stereogenic center, usually difficult to
access, have been synthesized by combining a double boron-
homologation and an allylboration through a highly efficient
and diastereoselective one-pot process. Starting from com-
mercially available substrates, this protocol represents a simple
way of accessing chiral unsaturated four-membered ring
systems with excellent stereoisomeric ratios.
asymmetric formation of α-chiral boronic esters.9 While
mall, unsaturated ring systems have received great interest
Sin organic chemistry due to their fascinating and enantiomerically pure diols as ligands for allylboron species
blossoming panel of reactivity.1−6 Among them, alkylidenecy-
usually lead to an incomplete transfer of chirality for
allylboration reactions,10 boron-homologations have proven to
clobutanes (ACBs) are important synthons and core patterns
that can be found in various natural architectures.2 Only a few
furnish α-chiral boronic esters with a perfect control of the new
stereocenter.11 We envisioned combining asymmetric homo-
logations with allylborations to synthesize chiral alkylidenecy-
clobutanes.
reports relate their accessibility via cycloadditions,3 rearrange-
ments,4 or other transition-metal-assisted processes.5 However,
their synthesis is often limited by the lack of efficient and
selective methodologies. Possessing a relatively higher ring
strain than alkylidenes of larger cycloalkanes, ACBs have been
studied for their exceptional reactivity toward the synthesis of
substituted cyclopentenes, cyclopentanones, or eight-mem-
bered-ring derivatives.6
We recently reported a highly diastereoselective sequence to
allow for accessing methylenecyclopropanes7 and -butanes8 in
their racemic forms (Scheme 1), starting from simple substrates
or commercially available materials. We wish to report herein
efficient one-pot diastereo- and enantioselective sequences for
the construction of unsaturated four-membered ring systems
containing a quaternary stereocenter (Scheme 1, eq 1).
We based our study on the interesting work of Matteson
about boron-homologation and establishments he made on the
The stereochemical information would then be relayed by
the newly generated stereocenter (Schemes 1, eq 2), α to the
boronic ester moiety, to the allylic position when preforming
the final allylation reaction, controlled by the transition state.
First, we optimized the conditions for the synthesis of
racemic alkylidenecyclobutanes, starting from α,α-dichlorome-
thylboronic esters (Scheme 2). One equivalent of nucleophile
(MeMgCl) was added to perform the first boron-homologa-
tion, in the presence of zinc chloride, followed by the addition
of a preformed cyclobutenyl metal species, to allow for the
formation of 3, through a second, in situ, boron homologation.
After the solvent was switched to dichloromethane, benzalde-
hyde was added to allow the allylboration to proceed.
Scheme 2. Optimization of the One-Pot Sequence
Scheme 1. Access to ACBs via One-Pot Sequences
Received: May 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01432
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Organic Letters
Letter
a
When pinacol was used as a ligand, a mixture of ACBs syn-E-
4a and syn-Z-4a (33:67, respectively) was obtained. This ratio
was further improved to 89:11 (with syn-E-4a as the major
isomer) by employing neopentyl glycol as a ligand. As a matter
of fact, it has been previously shown that the E/Z ratio can
easily be changed by modifying the composition of the
allylboronate.12 Lowering the temperature to 0 °C gave the
best results in terms of E/Z ratio (>97:3).
Scheme 4. Scope of the Method
Such a difference in the stereoselectivity can be explained by
steric effects of methyl groups in the case of pinacol ligands,
hindering the pseudoequatorial position and forcing the R2
chain to adopt the pseudoaxial position. Less hindered diols
(1b) (Scheme 3) do not shield the pseudoequatorial position,
Scheme 3. Diastereoselective Approach to ACBs
balancing the equilibrium toward eq-I, leading to the exclusive
formation of (E)-4 derivatives. This same transition state also
allows us to explain the diastereoselectivity observed in the
allylation reaction for the relative syn configuration of the two
new stereocenters following the model proposed by Hoff-
mann,13 giving syn-(E)-4 as the major product.
On the strength of this successful experiment, different
racemic α-chiral cyclobutenylmethylboronic esters made of
neopentyl glycol were generated in situ to explore the synthetic
scope of such a methodology for the formation of
alkylidenecyclobutanes containing a quaternary stereocenter.
The scope of the double-homologation/allylation sequence is
depicted in Scheme 4.
Employing various organometallic nucleophiles (R2-[M1])
for the first homologation could furnish α-chloro boronic esters
2, to which was subsequently added the ex situ generated
cyclobutenylmetal species, leading to the formation of 3.
The first boron-homologation was performed by introduc-
tion of MeMgCl (4a,u,w), EtMgCl (4b−f), i-PrMgCl (4g−k
and 4p−q), n-BuLi (4l−o,r,v), PhCH2CH2MgBr (4s) or c-
PrMgBr (4t), affording the respective α-chloroboronic ester. In
parallel, cyclobutenylmetal species were generated ex situ by
addition of allylzinc bromide (4a−o), (2-methylallyl)zinc
bromide (4p−u), or Me3Al/Cp2ZrCl2 (4v) to the commercially
available 4-bromobutyne after deprotonation and were
subsequently added to 2, leading to a large panel of chiral
cyclobutenylmethylboronic esters 3. Allylation reactions were
then performed, furnishing alkylidene cyclobutanes 4a−v in
exceptionally high levels of diastereoselectivity (dr up to 99:1,
E/Z ratio up to 99:1) (Table 1) and in good to high yields (up
to 90%).
a
dr (syn/anti) and E/Z ratios were determined by GC and 13C NMR.
to similar results in terms of diastereoselectivity and 83% yield.
However, the reaction reached its completion only after 18 h at
room temperature, when 30 min was usually necessary for
allylation in dichloromethane at 0 °C. We attributed this
difference of reactivity to a possible competition of the solvent
with the aldehyde in the coordination to the boron atom.
In the case of 4u (90%), the solvent was not switched to
dichloromethane and allylation was performed in THF, leading
B
DOI: 10.1021/acs.orglett.6b01432
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Organic Letters
Letter
As previously proposed, a Zimmermann−Traxler model
could explain the diastereoselective formation of ACBs 4,
obtained as their pure enantiomeric forms (ee up to 99%).14
The results are described in Table 1. Through this highly
diastereoselective one-pot process, organoboron derivatives,
cyclobutenylmetal species, and aldehydes of different natures
could furnish ACBs with excellent diastereo- and enantiomeric
ratios (up to >99:1) and good to excellent yields. Ultimately,
both enantiomers (R,R)-5 and (S,S)-5 were used to obtain
isomers of 4l, 4p, 4q, and 4r of opposite absolute
configurations.
Table 1. Access to ACBs in Their Enantiopure Form
Importantly, we finally show that starting from either (R,R)-
5, possessing the dichloromethyl moiety, or from (R,R)-8,
having the n-butyl chain preinstalled, followed by addition of
dichloromethyllithium led to obtaining (S,R)-4r (after sub-
sequent introduction of the appropriate aldehyde) in
comparably high levels of enantio- and diastereoselectivities
(ee = 99%, de = 99%). This observation supports the
involvement of the intermediate boron−ate complex II
(Scheme 6) in the diastereoselective 1,2-metalate rearrange-
ment.
a
b
c
Isolated yields. Determined by GC. Determined by HPLC utilizing
a chiral stationary phase.
To push the method further, we envisioned that a chiral
ligand for the formation of the organoboronic ester would
ultimately lead to the formation of enantiomerically enriched
ACBs. Pioneered by Matteson, the introduction of 1,2-
dicyclohexylethanediols (Cy = cyclohexyl) has proven to
efficiently promote a transfer of chirality to the α-position
when performing a boron-homologation of an organoboron
derivative 5 by addition of a nucleophile R2-[M] (Scheme 5).11
(R,R)-5 was then submitted to homologation, furnishing the
boronate species II.
Scheme 6. Comparison between (R,R)-5 and (R,R)-8 as
Substrates for the Sequence Leading to (S,R)-4r
Scheme 5. Substrate-Controlled Synthesis of Enantiopure
ACBs
In conclusion, we have assembled an efficient route for the
preparation of ACBs through highly diastereoselective one-pot
sequences involving boron-homologation and allylboration
strategies. Moreover, a powerful tool involving chiral auxiliaries
for rapidly accessing enantiomerically pure ACBs was
developed using commercially available starting material.
ASSOCIATED CONTENT
* Supporting Information
■
S
According to the literature, the presence of ZnCl2 is
necessary for the stereoselectivity to be maximal. In the
proposed model, coordination of ZnCl2 by an oxygen atom of
the diol helps the positioning of the dichloromethyl side chain,
with one of the diastereotopic chlorides being antiperiplanar to
R1 and the other one away from the salt II. Moreover, a H-
bonding between a chloride atom (ZnCl2) and the residual H
of the dicholoromethyl chain reinforces the diastereoselectivity
of the 1,2-metalate rearrangement. A diastereoselective intra-
molecular substitution takes place, leading to the formation of
6. A cyclobutenylmetal species was subsequently added, giving
stereospecifically the α-chiral allylboronic ester 7, through the
intermediate III, in which the substitution occurs antiperipla-
nary. Finally, allylborations were performed after the solvent
was switched to dichloromethane and the appropriate electro-
phile was added.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01432.
Experimental procedures and spectroscopic character-
1
ization (IR, HRMS, and H and 13C NMR data) of all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dorian.didier@cup.uni-muenchen.de.
Author Contributions
‡M.E. and G.M.K. contributed equally.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b01432
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Organic Letters
Letter
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ACKNOWLEDGMENTS
■
M.E. and D.D. are grateful to the Chemical Industry Fund (FCI
Liebig-fellowship) for financial support through Liebig-
Stipendium. Prof. Dr. Paul Knochel (Ludwig-Maximillians
University, Munich) is kindly acknowledged for his generous
support.
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