Use of Strain-Release for the Diastereoselective Construction of Quaternary Carbon Centers

Article abstract of DOI:10.1021/jacs.1c03492

Herein, we describe the formation of quaternary carbon centers with excellent diastereoselectivity via a strain-release protocol. An organometallic species is generated by Cp*Rh(III)-catalyzed C-H activation, which is then coupled with strained bicyclobut

Full text of DOI:10.1021/jacs.1c03492

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Use of Strain-Release for the Diastereoselective Construction of
Quaternary Carbon Centers
Tobias Pinkert, Mowpriya Das, Malte L. Schrader, and Frank Glorius*
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ABSTRACT: Herein, we describe the formation of quaternary carbon centers with excellent diastereoselectivity via a strain-release
protocol. An organometallic species is generated by Cp*Rh(III)-catalyzed C−H activation, which is then coupled with strained
bicyclobutanes (BCBs) and a prochiral carbon electrophile in a three-component reaction. This work illustrates a rare example of
BCBs in transition metal catalysis and demonstrates their broad potential to access novel reaction pathways. The method developed
exhibits ample functional group tolerance, and the products can be further transformed into valuable α-quaternary β-lactones.
Preliminary mechanistic investigations suggest a twofold C−C bond cleavage sequence involving σ-bond insertion and an ensuing β-
carbon elimination event.
uring the past decades strain-release driven trans-
formations have gathered significant attention in
catalyzed cycloisomerization-cyclopropanation sequence that
resulted in the formation of pyrrolidines and azepines (Figure
1c).15 The development of novel metal catalyzed method-
ologies and exploration of further reaction pathways of BCBs is
therefore highly desirable.5g,15c In order to expand the library
of known reactivity, we envisioned the reaction of an
organometallic species with a BCB and identified C−H
activation as a suitable strategy, since it enables the mild
generation of these intermediates from ubiquitous C−H bonds
that are known to engage a multitude of different coupling
partners (Figure 1d).16 In this context, especially multi-
component reactions have recently17 revealed their potential in
generating complex molecular structures in a single step, which
represents an attractive feature for organic synthesis.18
We began our studies to develop such a transition metal
catalyzed, three-component protocol by reacting oxime ether
1a together with benzyl BCB ester 2a and ethyl glyoxylate 3 as
an additional electrophile in the presence of
[Cp*Rh(CH3CN)3](SbF6)2 as the catalyst and CsOAc as a
base in TFE. We were intrigued when we observed the anti-
product 4aa in 60% yield with excellent E-selectivity and
diastereoselectivity that was formed upon twofold C−C bond
cleavage of the BCB moiety and subsequent addition to
aldehyde 3 (Table 1, entry 1). This class of compounds
containing an α-carbonyl quaternary center was recently
utilized as a key intermediate in the synthesis of novel
pantothenamide analogues displaying promising antiplasmoi-
dal activity.19 We continued to optimize the reaction
conditions, and a solvent screen revealed TFE to be essential
D
synthetic organic chemistry,1,2 materials science,3 and bio-
conjugation.4 Accordingly, molecules that bear a bridging bond
between opposite carbon or nitrogen atoms such as
[1.1.1]propellane, bicyclo[1.1.0]butanes (BCBs), or 1-
azabicyclo[1.1.0]butanes have emerged as a privileged class
of compounds.5 Owing to their relative destabilization, arising
from bond length and bond angle distortions, torsional strain,
and nonbonded as well as transannular steric interactions,6
these “spring-loaded“7 compounds display π-bond-type behav-
ior towards nucleophiles, electrophiles, and radicals.5 Such
versatile reactivity is especially desirable in the field of
medicinal chemistry where they are commonly used to install
the bicyclo[1.1.1]pentane, cyclobutane, and azetidine moieties,
motifs which serve as bioisosteres in the development and
modification of pharmaceuticals.8
Since Baran’s fundamental work on C−N bond formation by
a strain-release approach,9 chemists’ interest in utilizing the
unique properties of these molecules has been renewed.10,11 In
2019, the group of Aggarwal expanded the toolbox of BCB
chemistry by carbopalladation of the central C−C σ-bond of
BCB boronate complexes triggered by a 1,2-metalate
rearrangement (Figure 1a). Subsequent cross-coupling gave
access to valuable difunctionalized cyclobutyl boronates.12 To
overcome the inherent electrophilic reactivity of electron-
deficient BCBs, Gryko and co-workers reported a formal
polarity-reversal approach. Co(I)-catalysis allowed the gen-
eration of nucleophilic radicals upon light-induced homolysis
of the intermediate Co(III)−alkyl species. These radicals could
be coupled with electrophiles to afford disubstituted cyclo-
butanes (Figure 1b).13 Besides these inspiring examples,
transition metal catalyzed transformations involving BCBs
remain scarce.14 Wipf and co-workers hinted at the various
mechanistic pathways of reactions of BCBs that might be
enabled by the application of transition metal catalysis. They
showed that nitrogen-tethered BCBs could undergo a Rh(I)-
Received: April 1, 2021
Published: May 11, 2021
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a
for the reaction outcome, with other solvents leading to low
yields or no reactivity (entries 2−4). Variation of the
temperature did not improve the yield (entries 5−7). We
examined different bases, including Na2CO3, KOAc, NaOAc,
and K3PO4, which all resulted in diminished yields (entries 8−
11). To our delight, the use of 2.0 equiv of BCB ester 2a
delivered the desired product in 82% yield with perfect
diastereoselectivity and E-selectivity (entry 12). Subsequent
control experiments showed that the rhodium catalyst was
essential for the reaction, and an absence of base led to a
decreased yield (entries 13 and 14).
Table 1. Optimization of the Reaction Conditions
entry
solvent
TFE
DCE
1,4-dioxane
HFIP
TFE
TFE
TFE
TFE
TFE
additive
T
dr
yield
1
2
3
4
5
6
7
8
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
Na2CO3
KOAc
NaOAc
K3PO4
CsOAc
CsOAc
−
60 °C
60 °C
60 °C
60 °C
rt
40 °C
80 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
>20:1
−
60%
traces
−
8%
9%
40%
47%
28%
55%
49%
30%
82%
−
−
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
−
9
10
11
12
TFE
TFE
TFE
TFE
b
c
13
14
TFE
>20:1
52%
a
Reactions were performed on a 0.10 mmol scale with
[Cp*Rh(CH3CN)3](SbF6)2 as the catalyst. Yields and diastereomeric
ratios (dr) were determined by LC-UV using 1-fluoronaphthalene as
the internal standard. The E-isomer was observed exclusively in all
b
c
cases. 2.0 equiv of 2a. No catalyst. HFIP = hexafluoroisopropanol. rt
= room temperature.
4ua, the diminished yield was attributed to the strong
coordinating properties of the sulfur atom. Notably, meta-
substituted oxime ethers could be successfully applied and
reacted with perfect site selectivity (4va, 4wa). Similar
reactivity was observed for disubstituted substrates that
provided the products in moderate to good yields with
outstanding selectivities (4xa, 4ya). We were delighted that
even an ortho-substituted oxime ether was suitable in the
developed strain-release reaction despite the high steric
congestion (4za). In addition to the broad functional group
tolerance, several BCB esters could be applied. Ethyl and
isobutyl esters gave the corresponding products (4ab, 4ac) and
gratifyingly, a Weinreb amide was also reactive in this protocol
(4ad). In terms of the aldehyde scope, we examined alkyl as
well as aryl aldehydes. However, only trace amounts of product
were observed in these cases (see the Supporting Information
for further details). The relative configuration of the stereo-
centers was unambiguously assigned by X-ray crystallographic
analysis of a derivative of sulfone 4sa that was obtained after
esterification and subsequent debenzylation (see the Support-
ing Information for further details).
In addition, to further illustrate the synthetic value of this
protocol we sought to convert the products into valuable β-
lactones.20 Indeed, compound 4aa was successfully debenzy-
lated and hydrogenated under reducing conditions using Pd/C
as the catalyst (Figure 2). The resulting carboxylic acid 5 was
then transformed into the corresponding α-quaternary β-
lactone 6 (PyBOP, NEt3) in good yield and without the
observation of isomerization. NOE experiments confirmed the
stereochemistry indicated.
Figure 1. Transition metal catalyzed reactions of BCBs. (a) C−C σ-
bond carbopalladation. (b) Photochemical polarity reversal via Co(I)-
catalysis. (c) Rh(I)-catalyzed cycloisomerization. (d) This work:
diastereoselective formation of quaternary carbon centers by twofold
C−C bond cleavage. FG = functional group. TFE = 2,2,2-
trifluoroethanol.
With the optimized conditions in hand, we set out to explore
the substrate scope of the strain-release reaction and started
with the exploration of the arene scope (Table 2). Halides
were well tolerated and delivered the corresponding products
in good yields and with excellent diastereo- and E-selectivities
(4ba−4da, 4wa). Triflate and ester substituents underwent the
reaction smoothly and the products were isolated in moderate
to good yields (4ea−4ga). Substrates bearing electron-
donating functionalities, such as methoxy, phenol, and Boc-
protected amino groups (4ha−4ja), could also be employed
and furnished the products in moderate to very good yields. In
addition, sterically demanding alkyl and aryl substituents were
tolerated as well (4ka, 4la). We continued to investigate
naphthalene (4ma) and thiophene (4na) derivatives and were
pleased to obtain the respective products in moderate to good
yields with perfect diastereoselectivity, E-selectivity, and site
selectivity in favor of the more accessible or more reactive
position, respectively. A wide range of electron-deficient
functional groups, including cyano, nitro, trifluoromethyl,
trifluoromethoxy as well as sulfonyl, sulfamoyl, and a
challenging sulfenyl moiety were well tolerated and afforded
the desired products in moderate to very good yields with
excellent selectivities (4oa−4ua). In the case of the thioether
Furthermore, the respective epimer could be accessed
complementarily under Mitsunobu conditions (see the
Supporting Information for further details).
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a
Table 2. Scope of the Strain-Release Construction of Quaternary Carbon Centers
a
Standard reaction conditions: 1 (0.20 mmol, 1.0 equiv), 2 (0.40 mmol, 2.0 equiv), 3 (0.40 mmol, 2.0 equiv), [Cp*Rh(CH3CN)3](SbF6)2 (5 mol
%), CsOAc (30 mol %), TFE (0.10 M), 60 °C, 16 h. Diastereomeric ratios and site selectivities were determined by LC-UV of the crude reaction
mixture. All products were obtained exclusively as the E-isomer. See the Supporting Information for full experimental details.
b
c
d
[Cp*Rh(CH3CN)3](SbF6)2 (10 mol %) was used. Performed on 1.00 mmol scale. >20:1 site selectivity. Tf = trifluoromethylsulfonyl. Cy =
cyclohexyl.
rate-determining step (Figure 3a).21 Moreover, two-compo-
nent experiments were performed under the optimized
reaction conditions (Figure 3b). In the absence of aldehyde
3, olefinated product 7 was obtained in 19% yield. In contrast,
omission of BCB ester 2a led to selective addition of the
organometallic species generated to aldehyde 3 yielding
alcohol 8. These results suggest that a stepwise mechanism
of an initial rearrangement-olefination and subsequent aldol-
type addition might be operative. Nevertheless, when olefin 7
and aldehyde 3 were exposed to the standard conditions, the
desired product 4aa was obtained in low yield and with a
decreased dr of 7:1 (Figure 3c). A stepwise mechanism is
therefore unlikely to proceed. In addition, we conducted an
isomerization experiment of BCB ester 2a under the conditions
developed to examine whether a rhodium catalyzed diene
isomerization might be part of the catalytic cycle.14a However,
no isomers were detected and 2a was recovered in 83% yield
(see the Supporting Information for further details). Based on
these experiments and literature known mechanistic character-
istics of Cp*Rh(III)-catalyzed C−H activation,22 we propose
the following catalytic cycle (Figure 3d): The catalytically
Figure 2. Synthesis of an α-quaternary β-lactone. Ar = 2-(C(Me)
=NOMe)-C6H4.
In order to get insight into the underlying reaction
mechanism a preliminary series of mechanistic experiments
was conducted (Figure 3). First, the kinetic isotope effect was
determined by two parallel experiments. A KIE value of 1.2
indicates that the C−H activation might not be involved in the
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Communication
by twofold C−C bond cleavage. The reaction proceeds under
mild conditions and tolerates a wide range of common
functional groups. The products could be further transformed
into valuable α-quaternary β-lactones. The high diastereose-
lectivity was rationalized by mechanistic investigations that
suggest a catalytic cycle proceeding through a key C−C σ-
bond insertion, followed by a β-carbon elimination and a
subsequent allylation via a six-membered transition state. This
method exhibits a rare example of transition metal catalysis in
the field of BCB chemistry and showcases the diversity of
reactivity pathways accessible to these strained compounds.
Ultimately, we believe that this work will inspire researchers to
further explore the potential of these fascinating molecules in
transition metal catalysis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03492.
■
sı
Experimental and details (PDF)
Accession Codes
CCDC 2070494 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Frank Glorius − Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Munster, 48149 Munster, Germany;
̈ ̈
orcid.org/0000-0002-0648-956X; Email: glorius@uni-
muenster.de
Authors
Tobias Pinkert − Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Munster, 48149 Munster, Germany
Mowpriya Das − Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Munster, 48149 Munster, Germany
Malte L. Schrader − Organisch-Chemisches Institut,
Westfälische Wilhelms-Universität Munster, 48149 Mu
Germany
̈
̈
̈
̈
̈
̈
nster,
Figure 3. Mechanistic investigations and proposed catalytic cycle.
[Cp*Rh(III)] = [Cp*Rh(CH3CN)3](SbF6)2.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03492
Notes
active species I is generated from the catalyst precursor
[Cp*Rh(CH3CN)3](SbF6)2 and CsOAc by ligand exchange.
Oxime ether 1 coordinates to the metal center, and rhodacycle
II is formed by C−H activation. BCB ester 2 associates to the
metal center and inserts into the Rh−C bond to give Rh−
cyclobutyl species III. This intermediate undergoes β-carbon
elimination to generate IV, that is transformed into π-allyl
species VI via a syn-β-hydride elimination-reinsertion sequence
through diene V. This species isomerizes to the corresponding
σ-allyl intermediate before adding to aldehyde 3 via chairlike
transition state VII,17g which leads to the observed stereo-
chemistry. Finally, protodemetalation delivers product 4 and
closes the catalytic cycle to regenerate the active species I.
In conclusion, we have developed a highly diastereoselective
and E-selective three-component protocol for the construction
of quaternary carbon centers via strain-release from BCB esters
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Roman Kleinmans, Dr. Frederik Sandfort, Dr. J.
Luca Schwarz, Dr. Andreas Lerchen, Toryn Dalton, Tobias
Wagener (all WWU), Mariusz Milewski, and Prof. Karol Grela
(both University of Warsaw) for helpful discussions; Dr. Klaus
Bergander for NMR analysis; and Dr. Constantin G. Daniliuc
and Birgit Wibbeling for X-ray crystallographic analysis.
Financial support from the Deutsche Forschungsgemeinschaft
(Leibniz Award, SFB 858) is gratefully acknowledged.
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