Cobalt Catalysis for Enantioselective Cyclobutanone Construction

Article abstract of DOI:10.1021/jacs.7b05327

Over the past 40 years, intramolecular hydroacylation has favored five-membered rings, in preference to four membered rings. Herein, we report a catalyst derived from earth-abundant cobalt that enables preparation of cyclobutanones, with excellent regio-,

Full text of DOI:10.1021/jacs.7b05327

Communication
pubs.acs.org/JACS
Cobalt Catalysis for Enantioselective Cyclobutanone Construction
Daniel K. Kim, Jan Riedel, Raphael S. Kim, and Vy M. Dong*
Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States
*
S Supporting Information
10
endocyclic β-hydride elimination. By using first-row metals,
however, C−C bond forming reductive eliminations from D to
ABSTRACT: Over the past 40 years, intramolecular
hydroacylation has favored five-membered rings, in
preference to four membered rings. Herein, we report a
catalyst derived from earth-abundant cobalt that enables
preparation of cyclobutanones, with excellent regio-,
diastereo-, and enantiocontrol, under mild conditions (2
mol % catalyst loading and as low as 50 °C).
10,11
make small strained rings have been observed (Figure 1d).
Most relevant to our study, Bergman characterized a cobalta-
cycle (E), which upon treatment with stoichiometric FeCl3,
undergoes reductive elimination to form a cyclobutanone
11e
(
Figure 1d). Encouraged by these breakthroughs, we set out
to identify the first cobalt-catalyst capable of generating
cyclobutanones.
In our initial study, we found that commercially available
etalloenzymes can transform simple olefins into a
Co(I)-catalysts, such as Co(PPh ) Cl, result in no conversion
1
3 3
M
diverse array of cyclic natural products. For example,
an achiral building block such as geranyl pyrophosphate
undergoes ring-closing to generate a range of enantiopure
terpenoids (e.g., sabinene, limonene, camphene, and pinene)
to the desired cyclobutanone (Figure 2a). However, with
Co(PPh ) Cl, in the presence of a zinc reductant, we observe a
3
3
5
% yield and 6:1 regioisomeric ratio (rr) of 5a:6a. We postulate
(
Figure 1a). Considering Nature’s ability to construct various
2
rings via cyclases, we aim to diversify common building blocks
into different cyclic isomers, with high enantioselectivity via
3
synthetic catalysts. As an analogue to geranyl pyrophosphate,
we designed a simple model, dienyl aldehyde (1), that can be
4
accessed in one step from commercial materials. When using
Rh-catalysis, we can transform this achiral aldehyde into the
corresponding cyclopentanone (2), bicycloheptanone (3), or
cyclohexenal (4) scaffold, by tuning the ligand scaffold (Figure
3
1
b). Herein, we report a cobalt catalyst that enables ring
closing to generate the four-membered ring (5) via
enantioselective hydroacylation.
5
Hydroacylation (the addition of an aldehyde C−H bond
across an olefin or alkyne) enables C−C bond formation with
6
excellent atom economy. Most intramolecular variants provide
exclusive access to cyclopentanones in preference to cyclo-
5
butanones. However, there are two exceptions, both of which
use substrates bearing a methoxy-directing group under Rh-
7
catalysis. Fu’s method achieves an enantioenriched mixture of
four- and five-membered ketones via a parallel kinetic
̈
resolution. Aissa observed a 12% yield of the four-membered
ketone when performing a similar parallel kinetic resolution.
Rather than relying on a precious metal or a kinetic resolution,
we propose using a base-metal (Co) to overturn the usual
regioselectivity of hydroacylation to favor the more strained
ring.
Both Rh and Co are known to activate aldehyde C−H bonds
through oxidative addition to form an acyl-metal-hydride
5
,8
intermediate A (Figure 1c). From this intermediate, olefin
insertion results in an equilibrium mixture of the six- (B) and
five-membered (C) metallacycles. In general, reductive
elimination from B is thermodynamically and kinetically9
favored to generate the less strained cyclopentanone product.
Moreover, achieving reductive elimination from a five-
membered metallacycle (C) is challenging due to competitive
Figure 1. Inspiration for cobalt-based cyclase mimic.
Received: May 23, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05327
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
that the reductant transforms the Co(I)-complex into a Co(0)-
catalyst critical for reactivity. Indeed, using a well-characterized
and isolable Co(PMe ) (synthesized from CoCl , magnesium,
substrate (1) to form complex (G) prior to aldehyde C−H
bond activation by oxidative addition. The acyl-Co-hydride
intermediate (H) can isomerize by olefin insertion into the
metal-hydride bond to forge the five-membered metallacycle
(I). From here, reductive elimination forms the C−C bond to
construct the strained ring (5).
Under these mild conditions, a variety of α-aryl dienyl
aldehydes undergo isomerization to the corresponding cyclo-
butanones (Table 1). Dienyl aldehydes bearing electron-rich α-
aromatic groups (alkyls, ethers, acetals, and alcohols) ring close
in good yields and selectivities (76−93% yields, >89% ee, >10:1
dr, >10:1 rr). Substrates with electron-poor α-aromatic groups
3
4
2
and trimethylphosphine) results in a mixture of 5a and 6a in
12
1
:1 rr in 10% yield. Switching to a CoCl /reductant system,
2
as a precursor for Co(0), enabled rapid evaluation of a range of
1
3
chiral phosphine ligands. Under these conditions, we
identified a chiral ligand, (S,S)-2,4-bis(diphenylphosphino)-
pentane (BDPP), that promotes the formation of 5a in
preference to 6a. A catalyst loading of 10 mol % using diethyl
zinc as the reducing agent gave promising selectivities (10:1 dr,
10:1 rr). Moreover, by desymmetrization, we access these
motifs with 92% ee using this chiral bidentate phosphine ligand.
1
On the basis of H NMR studies, we observe evolution of
Table 1. Synthesis of Enantioenriched Cyclobutanones
ethylene and ethane gas when using diethyl zinc. This
14
observation is consistent with formation of a Co(0)-species.
The catalyst loading can be lowered to 2 mol % when switching
to activated zinc metal as a stronger reducing agent. The use of
activated zinc improves reactivity (from 24 to 4 h) and
selectivity (from 10:1 dr and rr to >20:1 dr and rr) when using
10 mol % of the catalyst.
Related protocols for Co-hydroacylation have been proposed
to occur through Co(0)/Co(II) and Co(I)/Co(III) catalytic
8
b−e
cycles.
Although both are feasible, on the basis of our
results, we propose this cyclization occurs by initial reduction of
Co(II)-chloride to a Co(0)-complex (F), with activated zinc or
diethyl zinc (Figure 2b). The Co(0)-catalyst then binds to the
a
Reaction conditions: 1 (0.1 mmol), [(S,S)-BDPP]CoCl (2 mol %),
2
b
zinc (10 mol %), MeCN (0.5 mL), 50 °C, 24 h. Gram-scale reaction
(
1a 6.40 mmol; [(S,S)-BDPP]CoCl (0.128 mmol, 2 mol %), zinc
2
(
0.640 mmol, 10 mol %), MeCN (32 mL, 0.2M), 50 °C, 24 h).
c
Robustness evaluation: Identical conditions above (a) + A [additive]
d
(
0.1 mmol, 1 equiv). Isolated yields of 5. Diastereo- and
regioisomeric ratio determined by GC-FID analysis of the unpurified
reaction mixture. Enantioselectivies determined by SFC analysis of the
purified ketone.
Figure 2. Identifying catalyst for cyclobutanones.
B
DOI: 10.1021/jacs.7b05327
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
F, Cl, and CF ) also cyclize (91−85% yield, >64% ee, >13:1 dr,
Communication
(
3
and >9:1 rr) albeit with lower enantioselectivities. Heteroaryl
thiophene, silylated phenol, and amine substrates are well
tolerated (60−92% yield, 82−95% ee, >11:1 dr, >9:1 rr). Of
note, cyclobutanone 5a was generated on gram scale without
impact on selectivity.
We imagined that an aryl group bearing a range of functional
groups could be tolerated in this transformation. To probe this
15
idea, we performed a functional group compatibility test. We
added an equivalent amount of various additives (e.g., pyridine,
phenol, amines, etc.) with aldehyde (1a) under otherwise
16
standard conditions. The cyclization to cyclobutanone (5a)
occurs smoothly in the presence of heterocycles such as
pyridines and indoles. Additives containing polar protic
functional groups such as phenols, anilines, and amides as
well as other carbonyl-containing additives such as aldehydes,
ketones, esters, and amides had little effect on the trans-
formation. The robustness screen provides a general guideline
to the selectivities and to the types of functional groups
Figure 3. Reaction evaluation of dienyl aldehyde.
olefin insertion is turnover-limiting and favors formation of the
five-membered metallacycle.
The newly formed stereocenters in our cyclobutanone
scaffold can be put to use in a number of stereoselective
reactions to build different structures (Figure 4). The reduction
15
tolerated in our reaction, although selectivities can vary
depending on where the functional group is attached. For
example, we found that the addition of morpholine additive
(A1) yielded 5a in 65% yield and 89% ee. We prepared the
analogous morpholine containing substrate (1o) and per-
formed the cyclization to provide cyclobutanone (5o) in similar
17
yield but slightly lower ee. In contrast, an aryl-bromide
containing additive (A2) and 4-bromophenyldienyl aldehyde
(1s) both underwent debromination to form biphenyl and 1a,
respectively. Our cyclization proceeds well in the presence of
known radical inhibitors such as butylated hydroxytoluene
1
8
19
(
BHT), 9,10-dihydroanthracene (DHA), and 1,1-diphenyl-
ethylene (DPE) (84% yield, 93% ee, >20:1 dr, 7:1 rr, with 94%
additive recovered). The use of TEMPO as an additive
inhibited reactivity presumably acting as an oxidant as well as a
2
0
ligand on Co.
When using deuterium-labeled aldehyde 1a-D, we observe
full incorporation of the deuteride into the α-methyl position of
the cyclobutanone product 5a-D (Figure 3a). This isotopic
labeling study provides results consistent with our proposed
mechanism (Figure 2b). When comparing the measured initial
rates of two parallel reactions between the protio-aldehyde (1a)
and deuterio-aldehyde (1a-D), we observe a primary kinetic
isotope effect of 2.7 (KIE = 2.7). When monitoring the reaction
with 1a-D as the substrate, no deuterium scrambling in the
product or the starting material was observed. The primary KIE
alongside a lack of deuterium scrambling likely points to
aldehyde C−H bond activation or olefin insertion into the Co−
H bond as the turnover-limiting step.
Figure 4. Derivatization of cyclobutanone 5a. (a) DIBAL-H; (b), L-
selectride; (c) LiHMDS, Comins’ reagent; (d) 2,4-dinitrophenylhy-
drazine, sulfuric acid; (e) vinylmagnesium bromide; (f) phenyl-
magnesium bromide; (g) isopropenylmagnesium bromide; (h) N-
bromosuccinimide; (i) 1,2-dihydrofuran, n-BuLi, then silica chroma-
tography.
By studying the scope of this cyclization, we found that regio-
isomeric ratio (rr) of 5:6 is influenced by the α-position of the
aldehyde (Figure 3b). Higher selectivity for the four-membered
versus five-membered ketone is observed with increasing size of
the α-substituent (R in Figure 3). The highest selectivity is
observed with phenyldienyl aldehyde 1a (>20:1 rr, A-value =
to the secondary alcohol can be controlled depending on choice
of the reductant. DIBAL-H adds from the more sterically
hindered face (a), whereas L-selectride adds from the less
hindered face (b). This strained ketone can be converted to an
enol-triflate suitable for cross-coupling reactions (c). A strained
ketimine can be prepared by condensation with 2,4-
dinitrohydrazine (d). New C−C bonds can be generated in a
highly diastereoselective fashion (>20:1) by using vinyl- (e) or
phenyl-Grignard (f) addition to generate the tertiary cyclo-
butanols. Taking advantage of the ring-strain, the cyclo-
butanones can undergo ring-expansion to enantioenriched
cyclopentanones with vicinal all-carbon quaternary centers by
addition of isopropenylmagnesium bromide (g) followed by
electrophilic bromination (h). Similarly, the addition of a
lithiated-dihydrofuran followed by treatment with mild acid
3
.0 for R = Ph) and the lowest selectivity is observed with
21
dienyl aldehyde 1r (1:2 rr, A-value = 0.0 for R = H). We
reason that the increased steric crowding around the metal
center promotes formation of the five-membered metallacycle
2
3
22
C over the six-membered metallacycle B. This is due to bond-
angle compression making the five-membered metallacycle C
more thermodynamically stable and kinetically accessible. Thus,
despite ring-strain, reductive elimination to form the four-
membered ring is not turnover-limiting. Therefore, we propose
C
DOI: 10.1021/jacs.7b05327
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Journal of the American Chemical Society
Communication
results in a one-carbon ring expansion to form a cyclo-
pentanone (i). This spirocyclopentanone was crystalline and a
molecular structure was unambiguously determined by X-ray
crystallography along with assignment of the absolute stereo-
chemistry of the cyclobutanone products 5a−o by analogy.
Although not depicted, the unreacted allyl-moiety could also be
used as an additional functional handle.
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(
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24
are challenging to access, especially with high enantiocontrol.
Our approach features a Co-catalyst that can isomerize a
simple, prochiral dienyl aldehyde into cyclobutanones bearing
chiral α-quaternary carbon centers, with excellent diastereo-,
regio-, and enantiocontrol. Mechanistic studies suggest a
pathway involving a Co(0)/Co(II) cycle that is triggered by
C−H bond activation. A switch from a precious metal to an
abundant base-metal enables a shift in the construction of
strained rings.
2
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05327.
■
(l) Ohashi, M.; Ueda, Y.; Ogoshi, S. Angew. Chem., Int. Ed. 2017, 56,
*
S
2
435. (m) Hu, J.; Yang, Q.; Yu, L.; Xu, J.; Liu, S.; Huang, C.; Wang, L.;
Zhou, Y.; Fan, B. Org. Biomol. Chem. 2013, 11, 2294. (n) McNally, A.;
Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129.
(o) Willcox, D.; Chappell, B. G. N.; Hogg, K. F.; Calleja, J.; Smalley, A.
P.; Gaunt, M. J. Science 2016, 354, 851.
Experimental procedures and spectral data for all new
compounds (PDF)
Crystallographic data (CIF)
(12) (a) Friedfeld, M. R.; Margulieux, G. W.; Schaefer, B. A.; Chirik,
P. J. J. Am. Chem. Soc. 2014, 136, 13178. (b) Friedfeld, M. R.; Shevlin,
M.; Hoyt, J. M.; Krska, S. W.; Tudge, M. T.; Chirik, P. J. Science 2013,
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AUTHOR INFORMATION
Corresponding Author
dongv@uci.edu
ORCID
■
*
(13) For a comprehensive list of ligands evaluated, see Supporting
Information.
1
(14) For a proposed mechanism, H NMR, and UV/vis absorption
spectra data for the formation of Co(0)-species using diethyl zinc, see
Supporting Information.
Vy M. Dong: 0000-0002-8099-1048
Notes
(15) (a) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597.
The authors declare no competing financial interest.
(b) Collins, K. D.; Ru
c) Collins, K. D.; Glorius, F. Acc. Chem. Res. 2015, 48, 619.
16) For a comprehensive list of functional groups evaluated and
̈
hling, A.; Glorius, F. Nat. Protoc. 2014, 9, 1348.
(
(
ACKNOWLEDGMENTS
■
reaction outcomes under standard reaction conditions with 1a, see
Supporting Information.
Funding provided by UC Irvine and the National Institutes of
Health (GM105938). We are grateful to Eli Lilly for a Grantee
Award. We thank Dr. Joseph W. Ziller and Jason R. Jones (UC
Irvine) and Dr. Milan Gembicky (UC San Diego) for X-ray
crystallographic analysis. We also thank Professor Yang & her
laboratory for their assistance in obtaining UV/vis absorption
spectra.
(17) For examples of robustness screens with reactions containing
enantioselectivities, see: (a) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk,
M.; Fu, G. C. Science 2016, 354, 1265. (b) Janssen-Muller, D.;
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Schedler, M.; Fleige, M.; Daniliuc, C. G.; Glorius, F. Angew. Chem., Int.
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(18) Ross, L.; Barclay, C.; Vinqvist, M. R. In PATAI’S Chemistry of
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DOI: 10.1021/jacs.7b05327
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