Allenoates in Enantioselective [2+2] Cycloadditions: From a Mechanistic Curiosity to a Stereospecific Transformation

Article abstract of DOI:10.1021/jacs.8b10008

Identification of a novel catalyst-allenoate pair allows enantioselective [2+2] cycloaddition of α-methylstyrene. To understand the origin of selectivity, a detailed mechanistic investigation was conducted. Herein, two competing reaction pathways are proposed, which operate simultaneously and funnel the alkenes to the same axially chiral cyclobutanes. In agreement with the Woodward-Hoffmann rules, this mechanistic curiosity can be rationalized through a unique symmetry operation that was elucidated by deuteration experiments. In the case of 1,1-diarylalkenes, distal communication between the catalyst and alkene is achieved through subtle alteration of electronic properties and conformation. In this context, a Hammett study lends further credibility to a concerted mechanism. Thus, extended scope exploration, including β-substitution on the alkene to generate two adjacent stereocenters within the cyclobutane ring, is achieved in a highly stereospecific and enantioselective fashion (33 examples, up to >99:1 er).

Full text of DOI:10.1021/jacs.8b10008

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Allenoates in Enantioselective [2+2] Cycloadditions: From a
Mechanistic Curiosity to a Stereospecific Transformation
Johannes. M. Wiest,‡ Michael L. Conner,‡ and M. Kevin Brown*
Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, Indiana 47405, United States
S
* Supporting Information
ABSTRACT: Identification of a novel catalyst−allenoate pair
allows enantioselective [2+2] cycloaddition of α-methylstyr-
ene. To understand the origin of selectivity, a detailed
mechanistic investigation was conducted. Herein, two
competing reaction pathways are proposed, which operate
simultaneously and funnel the alkenes to the same axially
chiral cyclobutanes. In agreement with the Woodward−
Hoffmann rules, this mechanistic curiosity can be rationalized
through a unique symmetry operation that was elucidated by
deuteration experiments. In the case of 1,1-diarylalkenes,
distal communication between the catalyst and alkene is achieved through subtle alteration of electronic properties and
conformation. In this context, a Hammett study lends further credibility to a concerted mechanism. Thus, extended scope
exploration, including β-substitution on the alkene to generate two adjacent stereocenters within the cyclobutane ring, is
achieved in a highly stereospecific and enantioselective fashion (33 examples, up to >99:1 er).
Scheme 1. Enantioselective Arylcyclobutane Synthesis
INTRODUCTION
■
Construction of multiple stereocenters in a single event has
become an increasingly important strategy to build molecular
complexity in an efficient and economical way. Arguably, one
of the most powerful methods to achieve such a transformation
is the Diels−Alder reaction.1 It is generally postulated that the
aforementioned reaction involves a symmetry-allowed cyclic
transition state as predicted by the Woodward−Hoffmann
rules.2 Consequently, the reaction can be performed in a
stereospecific fashion, allowing the generation of all possible
isomers from the respective E- or Z-alkenes. Despite significant
advances in the realm of enantioselective Diels−Alder
reactions,3 the analogous, concerted [2+2] cycloaddition of
alkenes has remained a challenge. Particularly, methods that
utilize activated olefins are especially difficult. In contrast to the
Diels−Alder reaction, recent methods to construct enantioen-
riched arylcyclobutanes by [2+2] cycloaddition often proceed
through stepwise processes, resulting in decreased reaction
selectivity (Scheme 1a).4,5 With respect to Lewis acid catalyzed
examples, gold complexes have been utilized to activate
alkynes6 or allenes7 to achieve enantioselective cycloaddition
with highly activated styrene derivatives. In addition, copper
and zinc have been used with electron rich arylalkenes to give
cyclobutanes with good control of enantioselectivity.8 Alter-
natively, chiral amines can be used to assemble cyclobutanes
via ionic intermediates.9 Photochemical methods10 often
exhibit increased tolerance for electron-poor styrenes, but
generally involve excited state biradical intermediates, which
lead to either stereoconvergence10f or erosion of diastereose-
lectivity.10g Overall, only a few examples,9a report good
stereospecificity through trapping of reactive intermediates at
low temperatures.
Received: September 14, 2018
© XXXX American Chemical Society
A
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To address this problem, we recently focused our efforts on
rendering alkene-allenoate cycloadditions enantioselective.11
Based on several reports in the literature,11b,12 alkene-allenoate
cycloadditions appear to be concerted and therefore stereo-
specific in nature, which provides a unique opportunity for an
in-depth study (Scheme 1b). Herein, we report the
enantioselective [2+2] cycloaddition of α-methylstyrene
through identification of a novel alkene-allenoate pair. This
method does not only enable catalytic enantioselective
formation of quaternary carbon centers13 but also exemplifies
how elucidation of reaction mechanism can go hand in hand
with expansion of scope. Ultimately, we propose models that
reliably explain the observed selectivity for a range of activated
alkenes in this unique [2+2] cycloaddition.
while providing higher reaction selectivity. Significant improve-
ments in both reaction yield and enantioselectivity was
observed when more electron deficient 3,5-(CF3)2-C6H3
catalyst 2e was examined in the reaction (entry 7).
Interestingly, utilizing the same catalyst with benzyl allenoate
resulted in a smaller increase in enantioselectivity (compare
entries 1 and 8).
Mechanism. To account for the observed enantiomer
obtained in the reaction we propose that upon binding of the
Lewis basic carbonyl oxygen to the Lewis acidic boron atom,14
the orientation of the allenoate may be fixed by a putative C−
H···O hydrogen bonding interaction (Scheme 2a).15 As the
Scheme 2. Model for Enantioselectivity
RESULTS AND DISCUSSION
■
Optimization. We initially envisioned accessing cyclo-
butanes bearing a quaternary center by using activated 1,1-
disubstituted alkenes (e.g., α-methylstyrene). Preliminary data
suggested that the identity of the allenoate ester has a
significant influence on modulating reactivity as well as
selectivity.12d As such, investigations of various allenoates 1
were undertaken (Table 1).
Table 1. Reaction Optimization
b
c
Entry
XR
Ar
Yield
er
1
2
3
4
5
6
7
8
OBn (1a)
OCH2CF3 (1b)
SBn (1c)
SBn (1c)
SBn (1c)
SBn (1c)
SBn (1c)
OBn (1a)
Ph (2a)
Ph (2a)
Ph (2a)
3,5-(CH3)2-C6H3 (2b)
3,5-(tBu)2-C6H3(2c)
3,5-(OMe)2-C6H3 (2d)
3,5-(CF3)2-C6H3 (2e)
3.5-(CF3)2-C6H3 (2e)
95%
46%
72%
71%
90%
56%
96%
87%
78:22
76:24
81:19
90:10
80:20
87:13
96:4
86:14
a
b
See the Supporting Information for experimental details. Determi-
nation by 1H NMR of the crude reaction mixture utilizing a calibrated
standard. Determined by HPLC analysis using a chiral column.
c
Changing from benzyl (1a) to the more reactive 2,2,2-
trifluoroethyl ester (1b) under our previously optimized
reaction conditions resulted in decreased yield, due to
competitive polymerization of the starting materials under
the reaction conditions (Table 1, compare entries 1 and 2). We
next examined the use of thiobenzyl allenic ester 1c in the
reaction and were pleased to find a slight increase in reaction
selectivity, albeit with decreased overall yield (compare entries
1 and 3). Confident that reaction yield could be improved
through catalyst control, we studied modifications of the
diarylprolinol scaffold. Whereas increasing the steric size of the
aryl groups from phenyl (2a) to xylyl (2b) provided a
significant increase in reaction selectivity, further increase to
sterically bulkier 3,5-(tBu)2-C6H3 catalyst 2c resulted in a
substantially less selective reaction (compare entries 3−5).
Investigation of more electron rich aryl groups (i.e., entry 6,
2d) resulted in a marked decrease in overall reaction yield
bottom face of the allenoate is effectively blocked by the large
aryl groups of the catalyst, approach of the alkene may only
occur from the top face. Additionally, the sterically large
phenyl group of the alkene is oriented distal to the large
catalyst−substrate complex. Conveniently, the planar character
of the phenyl group thereby also minimizes steric interaction
with the protruding C−H bond of the allene, resulting in two
plausible transition states (Scheme 2a, TS-A1 and TS-B1) for
alkene approach.
We propose a concerted, asynchronous [π2s+(π2s+π2s)]
cycloaddition in which the direction of rotation of the electron
deficient allenic π-bond is dictated by the Woodward−
Hoffmann rules (indicated by the blue arrows).2,16 Because
B
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of the unusual symmetry of the system, both transition states
lead to the same enantiomer. The absolute configuration of the
cycloadduct 3c was proven through hydrolysis of the thioester
and subsequent analysis of the corresponding carboxylic acid 4
via X-ray diffraction.17 To distinguish TS-A1 and TS-B1, cis-β-
deutero-α-methylstyrene 5 was subjected to the reaction
conditions (Scheme 2b). To our surprise, the cycloadduct 6
was obtained as an 83:17 Z:E mixture suggesting that both
pathways are operating. Accordingly, trans-β-deutero-α-meth-
ylstyrene 7 furnished cyclobutane 8 as a 86:14 Z:E mixture.
Assignment of the respective E- and Z-isomers was achieved
through derivatization and subsequent NOE analysis of the
respective tertiary alcohol 9 (see Supporting Information for
details). Thus, we were able to deduce TS-A1 to be
energetically favored, which can be explained by the alkene
being distal to the bulky boroaryl group of the catalyst. In
addition, the cycloaddition was highly stereospecific, as
indicated by the two different pairs of products generated
from the respective cis- and trans-deuteroalkene. This suggests
a concerted mechanism, which was not necessarily to be
expected considering the stabilization of a potential benzylic
carbocation in a stepwise process.
Scheme 3. Distal Differentiation of 1,1-Biarylalkenes
To gain further insight into the reaction mechanism, we
became interested in differentiating 1,1-biaryl alkenes based on
their steric and/or electronic properties (Scheme 3a). Herein,
only one aryl ring is in conjugation with the π-system, resulting
in substantial steric differentiation of the two aryl groups
(Scheme 3a, TS-A2). We propose preferential reaction occurs
with the more reactive conformer of alkene (TS-A2, X = more
electron donating than Y), providing an excellent setting to
undertake a more detailed Hammett study. Electronically
differentiated biaryl alkenes 10 were evaluated in the reaction.
Moderate to good yields were obtained depending on the
electronic properties of the biarylalkenes. In agreement with
our model, increased disparity between the two aryl groups
resulted in improved reaction enantioselectivity (products
11a−11f). We found a good correlation between log(er) and
σ+ with a ρ value <1, suggesting the build-up of positive charge
in the transition state in a less sensitive fashion than the parent
SN1 reaction.18 This correlates with a concerted, highly
asynchronous cycloaddition. According to the regression
equation obtained from the small training set used for the
Hammett study, an enantiomeric ratio of 92:8 was predicted
for alkene 12 bearing two electronically altered rings19 (herein
Δσ+ was obtained from the parent σ+ values for para-CF3 and
para-OMe).18 When 12 was subjected to the reaction
conditions, cycloadduct 13 was obtained in 58% yield and
92:8 er highlighting the potential of this type of enantiodis-
crimination (Scheme 3b). Proof of absolute stereochemistry
was achieved by hydrolysis of product 13 and X-ray analysis of
the respective biarylcyclobutanecarboxylic acid 14.
Scope. With a catalyst system that allowed for the
cycloaddition of activated alkenes in hand, we examined the
substrate scope of the reaction (Scheme 4). α-Methylstyrene
underwent [2+2] cycloaddition in 93% yield and 96:4 er
(product 3c) on gram scale (5.26 mmol) with no loss in
reaction selectivity. Increasing the steric size of the α-
substituent was investigated and proceeds with high
enantioselectivity (products 3d and 3e). High chemoselectivity
for the activated alkene in the presence of an unactivated
alkene was observed to provide 3e in 72% yield and 96:4 er,
with no trace of cycloadducts derived from the reaction of the
unactivated olefin. Several steric and electronic perturbations
of the aromatic ring have been investigated (products 3f−3l).
The cycloaddition proceeded in good yield with sterically
encumbered (product 3f), halogenated (products 3h and 3j),
and electron-poor (products 3i and 3j) vinyl arenes.
Spirocyclic cyclobutane derivatives can also be accessed from
the requisite 1,1-disubstituted olefin in good yield and high
To further probe our hypothesis, differentially substituted
1,1-biaryl olefin 15 was synthesized and examined in the
reaction (Scheme 3c). As the aryl groups of this alkene possess
more similar electronic properties, the rotation of one aryl
group out of conjugation is primarily driven by adverse
intramolecular steric interactions. We hypothesized the ortho-
tolyl group would preferentially rotate out of plane to minimize
1,3-allylic strain (TS-A3, Scheme 3c), thus providing a similar
steric environment as proposed in TS-A2. Gratifyingly, 16 was
obtained in 48% yield and 89:11 er, lending support to our
mechanistic hypothesis.
C
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Scheme 4. 1,1-Disubstituted Alkene Substrate Scope*
Scheme 5. Catalyst Induced Periselectivity
a
b
Isolated yield of cycloaddition product(s). Determined by 1H
c
NMR analysis of the crude reaction mixture. Enantiomeric ratio
determined through HPLC analysis with a chiral column. 20 was
d
*
All reactions run with 5 equiv of alkene on a 0.25 mmol scale. Yields
obtained as a ∼9:1 mixture of regioisomers. Absolute stereochemistry
of 20 tentatively assigned.
reported are the average of two experiments. Enantiomeric ratios
determined through HPLC analysis with a chiral column Absolute
a
stereochemistry of 17 and 3o tentatively assigned. Reactions run at
−20 °C.
moderate for this reaction. We assume that upon binding of
allenoate 1c to catalyst 2e, the internal π-bond (Scheme 5a,
marked in gray in TS-A4) is sufficiently blocked by the large
boroaryl group of the catalyst, leaving the distal π-bond
(marked in red in TS-A5) more readily accessible for [2+2]
cycloaddition.20 It should be noted that our system comple-
ments previous reports on Diels−Alder reactions between
allenoates and cyclic dienes.14b,21,22 α-Substitution, as imposed
by 2,3-dimethylbutadiene (21), significantly improved the
enantioselectivity while preserving the high level of peri-
selectivity (Scheme 5b, product 22).
Application to β-Substitution. The potential to generate
two adjacent stereocenters piqued our curiosity to further
study β-substitution of the alkene starting materials and test
our proposed models. We initiated this survey with cyclic
alkene 23. Gratifyingly, the reaction proceeded in good yield,
regioselectivity, and with excellent enantioselectivity, but
resulted in the formation of both alkene isomers (Scheme 6,
Z-24 and ent-E-24) in a 69:31 ratio. Separation by column
chromatography revealed Z-isomer Z-24 as the major product.
In accordance with the deuteration experiment and as a
consequence of β-substitution on the alkene, the two TS do
not lead to the same absolute configuration within the
cyclobutane ring (see Scheme 6a, TS-A6 and TS-B2). To
verify this hypothesis, Z-24 and ent-E-24 were individually
transformed to ketone 25 by oxidative cleavage using a
modified Lemieux−Johnson oxidation.23 As expected, 25
revealed opposite absolute configuration indicated by opposite
optical rotation.
enantioselectivity (product 3k and 3l). Heterocycles bearing
weakly basic heteroatoms, such as thiophene, were also
tolerated (product 3l). In some cases, dropping the temper-
ature improved the yield by decreasing the rate of alkene
polymerization. Interestingly, enynes underwent cycloaddition
without any interference of the alkyne moiety yielding 3m and
3n in moderate yield and excellent enantioselectivity.
Replacement of the aryl group with a cyclohexyl group
resulted in substantial decrease in enantioselectivity, demon-
strating that the aryl group is necessary to obtain highly
enantioenriched products (Scheme 4, compare products 17
and 3c). Substitution at the α-position was also essential for
successful reaction, as styrene itself performed poorly in terms
of reactivity and selectivity under several reaction conditions
(product 3o, see Supporting Information for further details).
Partial polymerization of styrene presumably accounts for the
low yield, whereas low enantioselectivities for 17 and 3o can be
rationalized by lack of steric differentiation with the protruding
C−H bond of the allene.
To further expand the reaction scope, we investigated
commodity dienes, such as isoprene (18), in the cycloaddition
reaction (Scheme 5). Initially, when EtAlCl2 was used as a
Lewis acid, low periselectivity was observed, favoring Diels−
Alder product 20. In stark contrast to EtAlCl2, catalyst 2e
allowed for >99:1 selectivity favoring [2+2] cycloadduct 19.
The reaction also occurred with high chemoselectivity, as only
the more substituted alkene of isoprene underwent cyclo-
addition; however, the observed enantioselectivity was only
D
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Scheme 6. Initial Study on Trisubstituted Alkenes
Table 2. Stereospecific [2+2] Cycloadditions
a
K2OsO4·2H2O, NaIO4, 2,6-lutidine (1,4-dioxane,H2O) rt, 6 h.
Acyclic trisubstituted alkenes should, based on our
mechanistic study, undergo cycloaddition in a concerted,
stereospecific fashion. To demonstrate the utility of such an
attribute, different pairs of acyclic E- and Z-alkenes were
subjected to the optimized conditions (Table 2). As seen for
alkene 23, modest E/Z selectivity was observed for Z-alkenes;
however, the respective cyclobutanes 27a and 27b were
formed with very high enantioselectivity (entries 1 and 2, the
respective TS-A6 and TS-B2 from Scheme 6 are likely
operating and explain the observed selectivity for alkenes 26a
and 26b). Gratifyingly, no detectable amounts of the
diastereomeric product originating from a nonstereospecific
process was observed (compare entry 1 and 3). Interestingly,
E-alkenes (entries 3−7) performed significantly better in terms
of E/Z selectivity of products. Considering the two transition
states TS-A7 and TS-B3, this is not surprising because TS-A7
encounters a substantial steric interaction between the E-β-
substituent and the boroaryl group, whereas TS-B3 is less
affected by this substituent pointing away from the large
boroaryl group (see Scheme 7a for details). Thus, E-isomeric
cyclobutanes were formed almost exclusively from E-alkenes;
however, product 27c (entry 3) was obtained with low
enantioselectivity even when the temperature was decreased to
−20 °C. A modest improvement was accomplished by
exchanging catalyst 2c with 2a to provide the desired product
in 90:10 er. Interestingly, when benzyl allenoate 1a was used
instead of its thio-analog 1c, good enantioselectivity was
achieved while maintaining the high level of E/Z selectivity
(entry 4). Steric bulk, as imposed by ethyl groups on their
respective positions (alkene 26d and 26e), was well tolerated
giving products 27e and 27f in good yield and enantiose-
lectivity. Finally, cyclic alkene 26f proceeded in 88% yield and
94:6 er with thiobenzyl allenic ester 1c. Its absolute
stereochemistry was unambiguously determined by X-ray
diffraction of the respective pentabromophenyl ester 28 and
was found to be in agreement with the proposed models
(Scheme 7b).
a
Determination by 1H NMR of the crude reaction mixture utilizing a
calibrated standard. Reactions run under optimized conditions using
b
catalyst 2e. Yields reported of pure major isomer as average of two
experiments. Enantiomeric ratio of the major isomer (see Supporting
c
d
Information for er of minor isomers). Reactions run at −20 °C.
e
Combined yield of both isomers in parentheses.
Scheme 7. TS for E-Alkenes
CONCLUSION
■
In summary, a method for enantioselective [2+2] cyclo-
additions of activated alkenes with allenoates has been
developed. Supported by mechanistic evidence, this reaction
resembles a rare example of a concerted, enantioselective
[2+2] cycloaddition with activated alkenes. As such, its
potential to generate molecular complexity, with precise
control of stereochemistry, makes the reaction especially
E
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Ohashi, M.; Ogoshi, S. Nickel-Catalyzed Enantioselective Synthesis of
Cyclobutenes via [2+2] Cycloaddition of α,β-Unsaturated Carbonyls
with 1,3-Enynes. Synthesis 2016, 48, 2789. (b) Kossler, D.; Cramer, N.
Neutral chiral cyclopentadienyl Ru(II)Cl catalysts enable enantiose-
lective [2+2]-cycloadditions. Chem. Sci. 2017, 8, 1862.
attractive toward the synthesis of cyclobutane containing
targets.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b10008.
■
S
́
(6) García-Morales, C.; Ranieri, B.; Escofet, I.; Lopez-Suarez, L.;
Obradors, C.; Konovalov, A. I.; Echavarren, A. M. Enantioselective
Synthesis of Cyclobutenes by Intermolecular [2+2] Cycloaddition
with Non-C2 Symmetric Digold Catalysts. J. Am. Chem. Soc. 2017,
139, 13628.
Crystallographic data for C13H14O2 (CIF)
Crystallographic data for C22H17Br5O2 (CIF)
Experimental procedures, analytical data for all new
compounds (PDF)
(7) (a) Teller, H.; Flugge, S.; Goddard, R.; Furstner, A.
̈ ̈
Enantioselective Gold Catalysis: Opportunities Provided by Mono-
dentate Phosphoramidite Ligands with an Acyclic TADDOL
Crystallographic data for C20H17F3O3 (CIF)
́
Backbone. Angew. Chem., Int. Ed. 2010, 49, 1949. (b) Gonzalez, A.
Z.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Toste, F. D.
Phosphoramidite Gold(I)-Catalyzed Diastereo- and Enantioselective
Synthesis of 3,4-Substituted Pyrrolidines. J. Am. Chem. Soc. 2011, 133,
5500. (c) Teller, H.; Corbet, M.; Mantilli, L.; Gopakumar, G.;
̈
Goddard, R.; Thiel, W.; Furstner, A. One-Point Binding Ligands for
Asymmetric Gold Catalysis: Phosphoramidites with a TADDOL-
AUTHOR INFORMATION
Corresponding Author
*brownmkb@indiana.edu
ORCID
■
Related but Acyclic Backbone. J. Am. Chem. Soc. 2012, 134, 15331.
M. Kevin Brown: 0000-0002-4993-0917
́
́
́
(d) Suarez-Pantiga, S.; Hernandez-Díaz, C.; Rubio, E.; Gonzalez, J. M.
Intermolecular [2+2] Reaction of N-Allenylsulfonamides with Vinyl-
arenes: Enantioselective Gold(I)-Catalyzed Synthesis of Cyclobutane
Author Contributions
‡J.M.W. and M.L.C. contributed equally to this work.
́
Derivatives. Angew. Chem., Int. Ed. 2012, 51, 11552. (e) Mauleon, P.
Notes
Gold-Catalyzed Intermolecular Enantioselective [2+2] Cycloaddi-
tions of Sulfonylallenamides and Styrenes. ChemCatChem 2013, 5,
2149. (f) Wang, Y.; Zhang, P.; Liu, Y.; Xia, F.; Zhang, J.
Enantioselective gold-catalyzed intermolecular [2+2] versus [4+2]-
cycloadditions of 3-styrylindoles with N-allenamides: observation of
interesting substituent effects. Chem. Sci. 2015, 6, 5564. (g) Jia, M.;
Monari, M.; Yang, Q.-Q.; Bandini, M. Enantioselective gold catalyzed
dearomative [2+2]-cycloaddition between indoles and allenamides.
Chem. Commun. 2015, 51, 2320.
(8) (a) Hu, J.-L.; Feng, L.-W.; Wang, L.; Xie, Z.; Tang, Y.; Li, X.
Enantioselective Construction of Cyclobutanes: A New and Concise
Approach to the Total Synthesis of (+)-Piperarborenine B. J. Am.
Chem. Soc. 2016, 138, 13151. (b) Kang, T.; Ge, S.; Lin, L.; Lu, Y.; Liu,
X.; Feng, X. A Chiral N,N′-Dioxide−ZnII Complex Catalyzes the
Enantioselective [2+2] Cycloaddition of Alkynones with Cyclic Enol
Silyl Ethers. Angew. Chem., Int. Ed. 2016, 55, 5541.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Indiana University and the National Institutes of
Health (R01GM110131) for financial support. The Deutsche
Forschungsgemeinschaft (WI 4933/1-2) is acknowledged for
postdoctoral fellowship support to J.M.W.
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