Highly Diastereoselective Synthesis of Methylenecyclobutanes by Merging Boron-Homologation and Boron-Allylation Strategies

Article abstract of DOI:10.1002/anie.201507444

A highly diastereoselective synthesis of methylenecyclobutanes possessing a quaternary stereocenter is reported, in which boron homologation of an easily-generated cyclobutenylmetal species is performed, followed by an allylation reaction. Combining three

Full text of DOI:10.1002/anie.201507444

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507444
German Edition: DOI: 10.1002/ange.201507444
Synthetic Methods
Highly Diastereoselective Synthesis of Methylenecyclobutanes by
Merging Boron-Homologation and Boron-Allylation Strategies
Michael Eisold and Dorian Didier*
Dedicated to Professor Paul Knochel on the occasion of his 60th birthday
Abstract: A highly diastereoselective synthesis of methylene-
cyclobutanes possessing a quaternary stereocenter is reported,
in which boron homologation of an easily-generated cyclo-
butenylmetal species is performed, followed by an allylation
reaction. Combining three steps in a one-pot process further
optimized the method, which afforded the expected adducts in
excellent yields and stereoselectivity, starting from commer-
cially available 4-bromobutyne.
the construction of elaborated structures[9] by applying
a
reagent-controlled asymmetric homologation using
Hoppeꢀs carbamates.[10]
We report herein the results of our successful investiga-
tion of unprecedented boron allylation reactions based on
cyclobutenylmethylboronic esters for the sequential one-pot
diastereoselective synthesis of MCBs possessing a quaternary
stereocenter.
Cyclobutenylmethylboron derivatives (3a and 3b;
Scheme 2) were identified as key units of this study. Since
they would directly undergo an allylation reaction in the
presence of an electrophile, their synthesis was undertaken
first. Performing an iodine–lithium exchange on 1a[11a] or
1b[11b] at À508C, followed by introduction of the boronic ester
2 led to formation of the desired cyclobutenylmethylboronic
esters 3a and 3b (65% and 71% respectively).
P
ossessing a unique geometry, alkylidenecyclobutanes
(ACBs) are fascinating motifs that are encountered in natural
compounds[1] and found as key intermediates in their
syntheses.[2] Moreover, ACBs can undergo valuable ring-
expansion reactions towards the synthesis of substituted
cyclopentanones, cyclopentenes, or eight-membered-ring
derivatives.[3] Despite several reports reviewing stereoselec-
tive access to substituted cyclobutanes,[4] the chemistry of
alkylidenecyclobutanes remains a relatively unexplored and
challenging domain among strained systems.[5] Commonly
generated through gold(I)-catalyzed [2+2] cycloadditions
between an allene and an unsaturated system,[6] ACBs have
recently been accessed by other transition-metal-mediated
processes.[7] On the other hand, if one could access a cyclo-
butenylmetal species, boron homologation could lead to
in situ formation of the desired methylenecyclobutane
(MCB) through a simple allylation reaction (Scheme 1).
Following pioneering work by Matteson et al.,[8] Aggarwal
et al. showed the high synthetic potential of such a method for
Scheme 2. Synthesis of cyclobutenylmethylboronic esters 3a and 3b.
Next, we investigated the allylation reaction of benzalde-
hyde in the presence of 3a. The reaction was carried out at
room temperature in dichloromethane and completion was
reached in less than five minutes. Surprisingly, low-temper-
ature conditions were not required to achieve high levels of
diastereoselectivity, and the alkylidenecyclobutane 4a was
isolated in good yield and stereoselectivity (84%, d.r. > 97:3,
Table 1). Aromatic aldehydes possessing an electron-donat-
ing group (o-OMe, m-OMe, p-NMe2) or an electron-with-
drawing group (p-NO2) also led to the desired products (4c–
4 f) with comparable levels of stereoselectivity. Halogenated
aromatic aldehydes also underwent boron allylation to form
MCBs 4g and 4h in moderate to good yields (58–73%).
Interestingly, heteroaromatic aldehydes also reacted quickly
with 3a, leading to the synthesis of MCBs with greater
functionalization. Oxygen-, nitrogen-, and sulfur-containing
heterocycles were introduced in the same way, furnishing
MCBs 5a–5 f in good yields and excellent diastereoselectivity
(d.r. > 97:3). To further extend the reaction scope, we
employed aliphatic aldehydes: dihydrocinnamal, isovaleral-
dehyde, and 11-hexadecenal gave products 6a–6c to good
yields and excellent diastereoselectivity. However, even using
reported methods for the enhancement of allylation reactions,
ketones and imines did not lead to the expected products.[12]
Scheme 1. Unprecedented approach to MCBs containing quaternary
stereocenters.
[*] M. Eisold, Dr. D. Didier
Department of Chemistry and Pharmacy
Ludwig-Maximilians-University Munich
Butenandtstrasse 5–13, 81377 Munich (Germany)
E-mail: dorian.didier@cup.uni-muenchen.de
Supporting information (experimental procedures and spectroscopic
characterization (IR, HRMS, and 1H and 13C NMR data) of all new
compounds) and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/anie.
201507444.
15884
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Chemie
Table 1: Diastereoselective synthesis of MCBs from 3a.
We additionally investigated the possibility of merging the
different steps of the sequence into a one-pot process to
facilitate the production of MCBs from commercially avail-
able materials. Cyclobutene iodides 1a and 1b were evaluated
first. After carrying out lithium–iodine exchange, iodome-
thylboronic ester 2 was subsequently introduced to perform
the boron homologation. Dichloromethane was added to the
reaction mixture along with the electrophile (Table 2) to
Table 2: One-pot synthesis of MCBs starting from 1a and 1b.
Entry
Substrate
Product
Yield[a]
d.r.[b]
1
2
3
1a
1a
1b
4a
5b
7a
68%
55%
56%
>97:3
>97:3
>97:3
[a] Yield of isolated product. [b] Determined by 13C NMR.
allow the allylation reaction to proceed directly on the in situ
generated allylboron intermediate. In these cases, completion
of the reaction was only observed after one hour, thus
indicating a possible competitive interaction of the coordina-
tive solvent (diethyl ether) with the substrate. Similar results
were obtained in terms of diastereoselectivity (d.r. > 97:3),
but the yields of isolated product were lower compared to the
two-step procedure (Table 1). Addition of benzaldehyde led
to 4a and 7a (61% and 56%, respectively), and 3-pyridine-
carboxaldehyde furnished 5b in 55% yield.
Having successfully performed the two-step, one-pot
procedure, we took on the challenge of forming the metalated
cyclobutene in situ, starting the sequence directly from
commercially available 4-bromobutyne (Table 3).
Deprotonation of the alkyne with n-butyllithium is
followed by a carbometallation reaction (Me3Al/Cp2ZrCl2
or allylzinc bromide), which leads to the formation of gem-
bimetallic intermediate B.[14] Nucleophilic substitution of the
bromide takes place at 208C, giving the desired metalated
cyclobutene species of Al or Zn (C). The homologation is
performed by adding 2 to the reaction mixture to furnish the
intermediate 3. After diluting the solution with dichloro-
methane, the allylation reaction proceeds after the addition of
aldehydes to give the product with high diastereoselectivity
(d.r. > 97:3) and in good yields (78 to 85%), which
demonstrates the efficiency of this four-step, one-pot
sequence. Different allylzinc species were also used to
promote the formation of a wider range of compounds (7a,
7d and 7e) with the same stereoselectivity and in good yields
(52 to 72%).
Promising results obtained with 3a encouraged us to
explore the potential and versatility of 3b in allylation
reactions towards the synthesis of more diverse MCBs.
Gratifyingly, the reaction with benzaldehyde was complete
within five minutes and 7a was isolated in 77% yield with
a high diastereoisomeric ratio (d.r. > 97:3). 4-Biphenylcar-
boxaldehyde led to similar results (7b, 71% yield, d.r. > 97:3).
3-Pyridine-carboxaldehyde afforded the MCB 7c with
a lower diastereoisomeric ratio (d.r. = 83:17).
The relative configuration of MCBs was assigned by
analogy with 4 f, which could be crystallized as a single
diastereoisomer (d.r. > 99:1 by GC) and analyzed by X-ray
diffraction (see the Supporting Information).[13]
More elaborate chiral substrate were further studied.
Iodocyclobutene 8 was synthesized according to Negishiꢀs
procedure,[11] from which the chiral cyclobutenylmethylbor-
onic ester 9 (Table 4) was generated in situ through the
procedure described above (Table 2).
The addition of aldehydes to achieve the formation of
MCBs possessing three consecutive stereocenters, with one
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Table 3: One-pot synthesis of MCBs starting from 4-bromo-1-butyne.
To highlight the synthetic utility of the method, we
considered the transformation of 6a into a substituted 1-
oxaspiro[2.3]hexane. The epoxidation of 6a was performed in
the presence of m-CPBA to furnish 11, which possesses three
stereocenters, two of which are quaternary, in high yield and
diastereoisomeric ratio (Scheme 3).
Entry
R-[M][a]
Product
Yield[b]
d.r.[c]
1
2
3
4
Me3Al/[Zr]
Me3Al/[Zr]
Me3Al/[Zr]
Allyl-ZnBr
4a
5b
6a
7a
85%
78%
84%
52%
>97:3
>97:3
>97:3
>97:3
Scheme 3. Further transformation of MCB into chiral 1-oxaspiro-
[2.3]hexane.
A Zimmermann–Traxler transition state is proposed to
explain the stereochemical outcome of the allylation reaction
(Scheme 4).[17] The chain of the aldehyde preferentially
adopts the pseudo-equatorial position, thereby minimizing
the energy of the system. In the cases of achiral substrates 3a
5
6
72%
66%
>97:3
>97:3
[a] See the Supporting Information. [b] Yield of isolated product.
[c] Determined by 13C NMR.
Table 4: One-pot synthesis of MCBs starting from 8.
Scheme 4. Zimmerman–Traxler models explain the syn-diastereoselec-
tivity in MCBs.
and 3b, the proposed model furnishes a syn relative config-
uration, which correlates with the configuration observed by
X-ray diffraction. Concerning the chiral substrate 9, the
attack from one or the other diastereotopic faces has to be
considered. We assume that the methyl group shields one of
the two faces, thereby orienting the approach of the aldehyde
from the opposite face, which leads to formation of the “all-
syn” MCB based on a Zimmermann–Traxler transition state.
In conclusion, we have reported an unprecedented and
straightforward way of approaching methylenecyclobutanes
possessing up to three adjacent stereocenters through multi-
step one-pot sequences, starting from either easily synthe-
sized or commercially available starting materials. Perfect
diastereocontrol of the allylation process is achieved under
mild conditions, in short periods of time, and without the
addition of a catalyst.
being quaternary, was then pursued with the crude mixture
after changing the solvent system to dichloromethane. A
selection of aldehydes was used, leading to the formation of
10a–10e with high diastereoselectivity and 55–67% yield.
Since allylation reactions could be performed within short
periods of time, the specific cyclobutane geometry plays an
incontestable role. In fact, only a few boron allylation
processes have been described in which tetrasubstituted
olefins were used. Up to 24 h and/or the presence of a catalyst
were needed to achieve good yields.[15] The particularly good
reactivity of our cyclobutenylmethyl boron system could be
attributed to strain release when going from cyclobutene to an
ACB.[16]
Acknowledgments
We thank the Chemical Industry Fund (FCI Liebig-fellow-
ship) for financial support, Prof. Dr. Konstantin Karaghiosoff
and Prof. Dr. Paul Knochel for moral support.
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diastereoselectivity · methylenecyclobutanes · one-pot reactions
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15884–15887
Angew. Chem. 2015, 127, 16112–16115
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Received: August 10, 2015
Revised: September 21, 2015
Published online: November 13, 2015
Angew. Chem. Int. Ed. 2015, 54, 15884 –15887
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