Strain Release of Donor-Acceptor Cyclopropyl Boronate Complexes

Article abstract of DOI:10.1021/acs.orglett.9b01152

The reactivity of boronate complexes which resemble donor-acceptor cyclopropanes is described. The enantioenriched cyclopropyl boronate complexes were shown to undergo concerted 1,2-metalate rearrangement/ring opening upon activation with a Lewis acid. Th

Full text of DOI:10.1021/acs.orglett.9b01152

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Strain Release of Donor−Acceptor Cyclopropyl Boronate Complexes
Charlotte H. U. Gregson, Venkataraman Ganesh, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: The reactivity of boronate complexes which
resemble donor−acceptor cyclopropanes is described. The
enantioenriched cyclopropyl boronate complexes were shown
to undergo concerted 1,2-metalate rearrangement/ring open-
ing upon activation with a Lewis acid. This method provides
atom-efficient access to optically active γ-carbonyl boronic
esters in moderate to excellent yields with complete
enantiospecificity. Furthermore, a three-component variant
of the reaction was established through in situ alkylation, and the synthetic utility of the products as chiral building blocks was
demonstrated.
For example, the cleavage of both oxygen- and nitrogen-
containing small rings has been employed in 1,2-metalate
rearrangements of boronate complexes (Scheme 1B).10 In
these strategies, both strain release and stabilization of the
resulting anion contribute to the driving force for the 1,2-
metalate rearrangement. However, while heteroatoms have
been extensively employed in 1,2-metalate rearrangements,
examples of the use of a carbon leaving group are much rarer.
We recently reported the palladium-mediated 1,2-metalate
rearrangement of bicyclobutyl boronate complexes, which
involves a carbon leaving group (Scheme 1Ci).11 Critical to the
success of this chemistry is the very high ring strain of the
bicyclobutyl motif. Notably, the equivalent cyclopropyl
boronate complex does not undergo a 1,2-metalate rearrange-
ment under the same reaction conditions (Scheme 1Cii).11 We
wondered whether such metalate rearrangements could be
promoted by enhancing the stability of the carbon leaving
group by introducing a better acceptor (Scheme 1D). This
would create an unusual donor−acceptor (D-A) cyclo-
propane,12 in which the donor is a boronate complex. In
such a scenario, subsequent stereospecific 1,2-metalate
rearrangement of boronate 1, with cleavage of a cyclopropyl
C−C bond,13 would provide access to enantioenriched γ-
carbonyl boronic esters (Scheme 1D), a class of substrates with
rich functionality but few reports.14
he enantiospecific rearrangement of boronate complexes
Tis an invaluable tool in modern synthetic chemistry, as it
enables the formation of new C−C and C−X bonds with high
levels of stereocontrol.1,2 Furthermore, the boronic ester is
often retained in the product, allowing additional trans-
formations to be conducted, including iterative homologa-
tions.2,3
The classic Matteson homologation involves a 1,2-metalate
rearrangement with a halide leaving group in the α position,4,5
but carbamates or benzoate esters can also be employed
(Scheme 1A).2,6,7 Related reactions have been developed with
a heteroatom-incorporated small ring as the leaving group.8,9
Scheme 1. Examples of Leaving Group Employed in the 1,2-
a
Metalate Rearrangements of Boronate Complexes
Our investigation began with the asymmetric hydroboration
of cyclopropene 2 to prepare diactivated cyclopropyl boronic
ester 3 with 97:3 enantiomeric ratio (er) (Scheme 2A).15,16
Upon addition of n-butyllithium, full conversion to the
boronate complex was observed by 11B NMR spectroscopy.
Despite employing a malonate to stabilize the resulting anion,
the boronate complex converted very slowly at room
temperature to the ring-opened boronic ester. On heating to
60 °C, full conversion of the boronate complex was observed
a
Received: April 1, 2019
Cb = N,N-diisopropylcarbamoyl, TIB = 2,4,6-triisopropylbenzoyl.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01152
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Cyclopropyl Boronic Ester and
Scope of Organolithium Reagents for Enantiospecific 1,2-
Metalate Rearrangement/Ring-Opening
Scheme 3. Scope of Electrophiles for the Three-Component
Reaction
a
b
Determined by NMR using Pirkle’s alcohol shift reagent. Oxidation
with H2O2/NaOH was performed after crude NMR, before column
chromatography. Reaction conditions: 0.14 mmol scale, 0.14 M.
NMR yields given in parentheses.
in low yields. However, this side-reaction was minimized by
performing a solvent switch to toluene before the addition of
the Lewis acid, which afforded 4b in 38% yield with 98% es.
Phenyl and other aromatic migrating groups bearing −OMe
and −CF3 all worked well with good yields (88−62%) and
100% es (4c−4e). On a 1 mmol scale, the reaction employing
phenyllithium gave desired product 4c in similar yield. A
related reaction employing the diethyl ester analogue of 3 was
also explored but was found to give a reduced yield.17
Heteroaromatic migrating groups were also suitable
substrates in this methodology, giving the desired products
with complete enantiospecificity. With furyllithium, corre-
sponding furyl-coupled product 4f was obtained in 73% yield
and 98% es. Employing a lithiated Boc-protected indole gave
product 4g in only moderate yield (30%) due to reversible
boronate complex formation. 3-Pyridyllithium was also
successful; however, the boronic ester product underwent
rapid protodeboronation during aqueous workup. Therefore,
the crude mixture was subjected to oxidation with H2O2/
NaOH at 0 °C to give corresponding alcohol 5h in 63% and
98% es. Vinyl and allenyl boronate complexes underwent
successful 1,2-migration/ring-opening to give the correspond-
ing allyl and allenyl products 4i,j in 45% and 76% yield,
respectively, and with perfect es. A steroid-derived organo-
lithium was also a suitable substrate for the transformation.
Complete conversion to the boronate complex was possible
and, under the influence of magnesium bromide etherate, gave
boronic ester 4k in 65% yield and 100% ds.
We were interested to see if the product enolate could be
trapped with electrophiles in situ in a three-component
coupling process, as this would provide enhanced efficiency.
Furthermore, this could potentially enable substoichiometric
quantities of the Lewis acid to be employed.13b−k Indeed, our
initial attempts showed that the reaction was feasible with
20 mol % MgBr2·OEt2 and 2 equiv of MeI, which gave
methylated product 6a in 77% yield and 100% es (Scheme 3).
a
b
Determined by NMR using Pirkle’s alcohol shift reagent. Solvent
c
switch to toluene before addition of MgBr2·Et2O. Isolated yield for
1.09 mmol scale. Oxidation with H2O2/NaOH performed before
workup. Oxidation with H2O2/NaOH performed after crude NMR,
before column chromatography. NMR yields given in parentheses.
d
e
f
Reaction conditions: 0.14 mmol scale, 0.14 M, 1.1−1.2 equiv of RLi.
by 11B NMR, but the desired ring-opened boronic ester was
obtained in only 45% yield. We therefore screened a number of
Lewis acids and solvents and found that the addition of
magnesium bromide etherate was the most effective method to
induce a 1,2-metalate rearrangement/ring-opening sequence
(Scheme 2B). This gave boronic ester 4a in quantitative yield
and 100% enantiospecificity (es) (97:3 er), indicating a
concerted 1,2-metalate rearrangement/ring-opening.
The scope of migrating groups for the 1,2-metalate
rearrangement was then explored (Scheme 2C). With tert-
butyllithium, competing O-migration was observed, resulting
B
DOI: 10.1021/acs.orglett.9b01152
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Scheme 4. Enantiospecific Transformations of a γ-Carbonyl
Boronic Ester
Scheme 5. Reactivity of Different β-Carbonyl Boronate
Complexes with MgBr2·Et2O Studied by 11B NMR
a
Spectroscopy
a
b
Reaction conditions: 0.11 mmol scale. Reaction conditions:
a
Reaction conditions: (i) nBuLi (1.1 equiv), THF (0.14 M), −78 °C,
0.80 mmol scale. (i) 1. Vinyl lithium (3.2 equiv), THF, −78 °C to
rt, 3 min, 2. I2 (1.2 equiv), MeOH, −78 °C, 20 min, 3. NaOMe
(3 equiv), MeOH, rt, 1 h. (ii) 1. Furan-2-yllithium (2.4 equiv), THF,
−78 °C, 1 h, 2. MeOH/THF, NBS (1.2 equiv) in MeCN, −78 °C,
1 h. (iii) 1. (3-Fluoropyridin-4-yl)lithium (2.5 equiv), THF, −78 °C,
2 h, 2. Troc-Cl (2.5 equiv), −78 °C, 2 h to rt, 16 h, 3. NaOH/H2O2,
THF, rt, 16 h. (iv) NaOH/H2O2, THF, 0 °C to rt, 2 h. (v) 1. Formic
1 h, (ii) MgBr2·Et2O (1.5 equiv), −78 °C to rt, 16 h.
followed by a solvent switch to methanol and addition of NBS
gave desired product 9 in 61% yield.19 Furthermore, sp2−sp3
coupling to 3-fluoropyridine was also achieved with 2.5 equiv
of (3-fluoropyridin-4-yl)lithium. The 1,2-migration was
triggered upon addition of Troc-Cl, and oxidation with
NaOH/H2O2 gave coupled product 10 in 50% yield.20
Exploring these modifications for boronic ester 4c has
consequently broadened the scope of these existing enantio-
specific transformations to tolerate an acidic functional group.
The enantiospecific oxidation of boronic ester 4c yielded
alcohol 5c (Scheme 4C). This compound was then subjected
to hydrolysis and lactonization with formic acid and
subsequent decarboxylation to give γ-phenyl-γ-butyrolactone
(11, Scheme 4C).21 The optical rotation of 11 corresponded
to that reported for the S enantiomer, which confirmed that
the absolute stereochemistry of boronic ester 4c is S.13c,22 This
shows that the 1,2-metalate rearrangement/ring-opening
sequence of cyclopropyl boronate complexes proceeds through
inversion of stereochemistry at the boron-attached carbon.
With the knowledge that the cleavage of a strained,
diactivated carbon−carbon bond could indeed trigger a 1,2-
metalate rearrangement mechanism, we considered whether
the reaction could occur if the cyclopropane was substituted
with only one electron-withdrawing group. A 11B NMR study
was undertaken to evaluate this reactivity (Scheme 5).
c
acid, rt, 6 h, 2. Toluene, 110 °C, 16 h. Enantiomers not separable by
chiral HPLC.
Allyl iodide and Eschenmoser’s salt were also successfully
employed as electrophiles, giving 6b and 6c in 88% and 72%
yield, respectively, and complete enantiospecificity.
Chiral boronic esters are highly useful reagents for organic
synthesis due to the multitude of enantiospecific trans-
formations that have been developed.1,18 We therefore wanted
to demonstrate the synthetic utility of the chiral boronic esters
reported herein. However, many procedures using chiral
boronic esters begin with the addition of an organolithium
reagent to access a boronate complex.1 This is problematic for
the boronic esters shown in Scheme 2, as they possess an acidic
malonate functional group. It was therefore necessary to
modify existing procedures and account for the acidic group by
using additional equivalents of organolithium reagent to form
dianionic boronate complexes such as 7 (Scheme 4A). If
necessary, the enolate component of the dianionic boronate
complex could then be protonated with a proton source to
provide the desired boronate complex for further reactivity.
With boronic ester 4c (Scheme 4B), Zweifel olefination was
possible with 3.2 equiv of vinyllithium and methanol added as
a proton source. Upon addition of I2/methanol, Zweifel
olefination product 8 was obtained in 96% yield.9b Similarly,
sp2−sp3 coupling to furan with 2.4 equiv of furan-2-yllithium
Under the optimized reaction conditions and employing
boronic ester 3 (31 ppm), the conversion of boronate 12
(6 ppm) to boronic ester 13 (33 ppm) was followed by 11B
NMR spectroscopy (Scheme 5A). Monoactivated cyclopropyl
boronic ester 14 (32 ppm) was then subjected to the same
C
DOI: 10.1021/acs.orglett.9b01152
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reaction conditions (Scheme 5B).23 While conversion to
boronate 15 (8 ppm) proceeded as before, the addition of
magnesium bromide etherate led to the formation of borinic
ester 16, identified by a characteristic 11B NMR chemical shift
at 50 ppm. In this case, the cyclopropane was not activated
through coordination of the carbonyl oxygen to the Lewis acid.
Instead, the Lewis acid interacted with the pinacol group and
cleavage of an oxygen−boron bond occurred.24 We reasoned
that the malonate moiety in 12 could act as a bidentate ligand,
promoting complexation of the Lewis acid and thereby 1,2-
metalate rearrangement. We therefore investigated an alter-
native malonate without the cyclopropyl moiety to see if a
related 1,2-metalate rearrangement could occur (Scheme 5C).
However, boronic ester 17 (32 ppm), with an open chain
structure and two ester groups,25 also gave a borinic ester (19,
50 ppm) as the reaction product (Scheme 5C). These results
demonstrate that both strain release and the presence of two
ester groups are necessary to drive the 1,2-metalate rearrange-
ment. Without either structural feature, borinic ester formation
dominates completely.26
In conclusion, we have developed an enantiospecific
coupling reaction between an organolithium reagent and an
enantioenriched cyclopropyl boronic ester. The reaction
proceeds via a boronate complex with an activated cyclo-
propane in the α position. It was shown that both strain in the
cyclopropane and the presence of two ester groups in the β
position are essential for 1,2-metalate rearrangement to occur.
This method provides efficient access to synthetically useful,
enantioenriched γ-carbonyl boronic esters in moderate to
excellent yield with complete enantiospecificity.
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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.9b01152.
General procedures, characterization data, and copies of
NMR spectra for all novel compounds (PDF)
́
Chem., Int. Ed. 2018, 57, 4053−4057. (i) Richmond, E.; Vukovic, V.
AUTHOR INFORMATION
Corresponding Author
D.; Moran, J. Org. Lett. 2018, 20, 574−577. (j) Díaz, W.; Reyes, A.;
Uria, U.; Carrillo, L.; Tejero, T.; Merino, P.; Vicario, J. L. Chem. - Eur.
J. 2018, 24, 8764−8768. (k) Singh, K.; Bera, T.; Jaiswal, V.; Biswas,
S.; Mondal, B.; Das, D.; Saha, J. J. Org. Chem. 2019, 84, 710−725.
(14) For reported syntheses of highly enantioenriched γ-carbonyl
boronic esters see: (a) Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8,
2413−2415. (b) Larouche-Gauthier, R.; Elford, T. G.; Aggarwal, V. K.
J. Am. Chem. Soc. 2011, 133, 16794−16797. (c) Lovinger, G. L.;
Aparece, M. D.; Morken, J. P. J. Am. Chem. Soc. 2017, 139, 3153−
3160.
■
*E-mail: v.aggarwal@bristol.ac.uk (V. K. Aggarwal).
ORCID
Venkataraman Ganesh: 0000-0001-7893-109X
Varinder K. Aggarwal: 0000-0003-0344-6430
Notes
The authors declare no competing financial interest.
(15) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003,
125, 7198−7199.
ACKNOWLEDGMENTS
We thank H2020 ERC (670668) for financial support. We
thank Dr A. Noble for useful discussions.
■
(16) For other examples of asymmetric borylation of cyclopropenes
see: (a) Parra, A.; Amenos, L.; Guisan-Ceinos, M.; Lopez, A.; García
Ruano, J. L.; Tortosa, M. J. Am. Chem. Soc. 2014, 136, 15833−15836.
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1
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E
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