Rhodium-Catalyzed Asymmetric Conjugate Alkynylation/Aldol Cyclization Cascade for the Formation of α-Propargyl-β-hydroxyketones

Article abstract of DOI:10.1021/acs.orglett.8b00153

A rhodium-catalyzed conjugate alkynylation/aldol cyclization cascade was developed. Densely functionalized cyclic α-propargyl-β-hydroxyketones were synthesized with simultaneous formation of a C(sp)-C(sp³) bond, a C(sp³)-C(sp³) bond, as well as three new contiguous stereocenters. The transformation was achieved with excellent enantio- and diastereoselectivities using BINAP as the ligand. The synthetic utility of the newly installed alkynyl moiety was exhibited by subjecting the products to an array of derivatizations.

Full text of DOI:10.1021/acs.orglett.8b00153

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Asymmetric Conjugate Alkynylation/Aldol
Cyclization Cascade for the Formation of α‑Propargyl-β-
hydroxyketones
Ken-Loon Choo and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed conjugate alkynylation/
aldol cyclization cascade was developed. Densely function-
alized cyclic α-propargyl-β-hydroxyketones were synthesized
with simultaneous formation of a C(sp)−C(sp3) bond, a
C(sp3)−C(sp3) bond, as well as three new contiguous
stereocenters. The transformation was achieved with excellent
enantio- and diastereoselectivities using BINAP as the ligand.
The synthetic utility of the newly installed alkynyl moiety was exhibited by subjecting the products to an array of derivatizations.
aldol cascade to furnish β-hydroxyketones (Scheme 1B,C).5a,b
atalytic asymmetric tandem transformations represent an
Cefficient approach to construct complex molecular In contrast, a single report by Nishiyama detailed the use of
alkynyl nucleophiles as the initiator under ruthenium catalysis,
affording α-propargyl-β-hydroxyketones with moderate enan-
tio- and diastereoselectivity (Scheme 1D).6
scaffolds via the sequential formation of multiple bonds and
stereocenters, without the need to isolate intermediates.1 This
strategy makes tandem transformations attractive from an
economical and environmental standpoint. An example is the
transition-metal-catalyzed conjugate addition/electrophilic trap-
ping cascade, which is initiated by a Michael addition. A
nucleophilic metal enolate intermediate A is generated, which
subsequently undergoes electrophilic trapping (Scheme 1A).2
Hydride,3 alkyl,4 and aryl5 species have been employed as
nucleophilic partners for this class of transformation. Hayashi
and Krische concurrently demonstrated the use of a rhodium
catalyst with an arylboron reagent for the conjugate arylation/
Alkynes are versatile synthetic building blocks capable of
undergoing a wide array of manipulations.7 Over the past
decade, extensive effort has been devoted to developing
transition-metal-catalyzed methods to introduce an alkyne
moiety enantioselectively to prochiral carbonyls through the
formation of C(sp)C(sp3) bonds.8,9 Rhodium catalysis has
been recently reported to enable the enantioselective conjugate
alkynylation of α,β-unsaturated carbonyls.9 Seminal work by
Hayashi showed that judicious selection of chiral, bulky
bisphosphine ligands was key to mitigate the propensity for
alkyne homodimerization (Scheme 2A).9b Recent develop-
ments in this area culminated with the use of easily accessible,
bulky alkynyl(diphenyl)carbinol as the alkynylating reagent to
achieve the desired transformation (Scheme 2B).9e
Scheme 1. Conjugate Addition/Electrophilic Trapping
Cascade
We envisioned that rhodium could function as a suitable
catalyst for the conjugate alkynylation/aldol cascade for the
Scheme 2. Rhodium-Catalyzed Enantioselective Conjugate
Alkynylation
Received: January 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
simultaneous formation of a C(sp)C(sp3) bond and a
C(sp3)C(sp3) bond. Applying literature conditions for the
rhodium-catalyzed enantioselective alkynylations9b,f to the
model substrate 1a and alkyne 2a in the presence of chiral
bisphosphine ligands furnished the desired α-propargyl-β-
hydroxyketones 3a with three contiguous stereocenters
(Table 1). No significant effect on yield or enantioselectivity
Scheme 3. Keto-enone Substrate Scope
a
Table 1. Chiral Ligand Screening
b
c
d
entry
ligand
(S)-BINAP
yield (%)
dr
ee (%)
1
2
3
4
5
>99 [83]
96 [83]
>99 [83]
90 [78]
>20:1
>20:1
>20:1
>20:1
>20:1
95
94
(S)-TolBINAP
(R)-segphos
−95
−95
−95
(R)-DMM-segphos
(R)-DTBM-segphos
>99 [87]
a
b
1
Reactions conducted on 0.2 mmol scale. Yields determined by H
NMR spectroscopic analysis of the crude reaction mixture using 1,3,5-
trimethylbenzene as the internal standard. Isolated yields are reported
a
b
c
in square brackets. Determined by 1H NMR spectroscopic analysis of
All dr > 20:1. See the Supporting Information for unreactive
c
d
e
f
d
substrates. With [Rh(cod)Cl]2. 72 h reaction time. With 2b. With
[Rh(C2H4)2Cl]2.
the crude reaction mixture. ee values are determined by HPLC
analysis on a chiral stationary phase. nd = not determined. coe = cis-
cyclooctene.
of 89−99% ee and diastereoselectivity of >20:1 for all reactive
substrates tested.11
was observed when variants of the BINAP and segphos classes
of ligands were examined (entries 1−5). A solvent screen
indicated toluene as the optimal solvent.10 Furthermore, a high
degree of diastereocontrol was observed in all cases.
While investigating the alkyne substrate scope, we observed
that the reactivity of the transformation was contingent upon
having sufficient steric bulk flanking the propargylic carbon
(Scheme 4). Due to extensive homo-dimerization of the alkyne,
the reaction completely halted when unsubstituted or
monosubstituted aryl was present on the alkyne. Nevertheless,
reactivity was restored when 2,6-dimethylphenyl acetylene was
used (3o). Linear alkyls, cyclohexyl, as well as heterocycles such
as tetrahydropyran and Boc-protected piperidine were also
coupled in this fashion (3o−t). Furthermore, a biologically
relevant moiety containing multiple existing stereocenters such
as the dihydrocholesterol scaffold can be coupled efficiently
with excellent diastereoselectivity (3u,v). Finally, polycyclic
products can be furnished via this transformation with high
enantioselectivities and modest yields (3w,x).
To demonstrate the synthetic versatility of the alkyne
functional unit, derivatization of α-propargyl-β-hydroxyketone
3a was studied (Scheme 5). An alternative method to
synthesize products bearing a phenyl acetylene moiety can be
accomplished using a one-pot deprotection/Sonogashira
coupling process. A 4-bromobenzene ring was appended to
the alkyne to generate 4. The absolute stereochemistry of 3a
was unambiguously established by single X-ray crystallography
of ent-4, and the stereochemistry of the other products was
assigned by analogy.12 Deprotection of the triisopropylsilyl
group in the presence of CuI afforded the terminal alkyne 5,
With BINAP as the optimal ligand, the keto-enone substrate
scope was explored (Scheme 3). Substrates bearing a methyl or
phenyl substituent on the enone afforded the desired products
in high yields and enantioselectivities (3a,b). The reaction was
amenable to scale up (3 mmol) to give 3a with a comparable
yield and enantioselectivity of 89% and 97% ee, respectively.
Product 3c containing a highly crowded tertiary alcohol was
furnished with good yield. Diminished reactivity was observed
when the enone moiety bears electron-deficient aryl rings (3e−
g), which was consistent with the decrease in nucleophilicity of
the enolate intermediate that was formed. Conversely, electron-
rich aryl rings on the ketone moiety decreased the yield due to
lower electrophilicity (3h,i). Phenyl groups on both the enone
and the ketone moieties exhibited slightly diminished reactivity
(3k). Products containing a benzofuran moiety (3l) or 5,6-
fused rings with four contiguous stereocenters (3m) were
furnished successfully. In addition, a trisubstituted tetrahy-
dropyran (3n) was obtained, albeit with low yield. However,
substrates bearing an acrylate moiety or an ester secondary
electrophile did not produce any cyclized product. Similarly,
cyclization did not occur to form either five or seven-membered
rings when the tether length of the keto-enone substrate was
varied.10 Regardless, the reaction displayed an enantioselectivity
B
DOI: 10.1021/acs.orglett.8b00153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
hydrogenation yielded 8. Lastly, silver-mediated halo-hydration
produced α-bromoketone 9 at moderate yield.
Scheme 4. Alkyne Substrate Scope
Based on detailed mechanistic studies on rhodium-catalyzed
conjugate additions reported by Hayashi13 and the precedence
established by Krische on rhodium-catalyzed conjugate
arylation/aldol cyclization,5c a plausible mechanism for the
conjugate alkynylation/aldol cyclization was proposed (Scheme
6). The catalytic cycle starts with the coordination of the
Scheme 6. Proposed Mechanism
rhodium catalyst to the propargyl alkoxide followed by β-
carbon elimination to generate rhodium−alkynyl species B
while extruding benzophenone. Alkynylrhodation of enone 1a
forms (oxa-π-allyl)rhodium intermediate C. Chelation of the
oxygen atoms by rhodium in a favorable six-membered
Zimmerman−Traxler-type transition state dictates the syn-
relationship of the two groups.14 Finally, cyclization followed by
protonation provides the desired product 3. Depending on the
substrate, proto-demetalation of C occurred to give side
product D at 8−20% yields.
a
b
c
All dr > 20:1. With 1.5 equiv of alkyne. With 1.3 equiv of alkyne.
72 h reaction time.
d
Scheme 5. Product Derivatizations
In summary, an asymmetric rhodium-catalyzed conjugate
alkynylation/aldol cyclization cascade was developed to
synthesize highly functionalized cyclic α-propargyl-β-hydrox-
yketones with multiple contiguous stereocenters. Excellent
enantio- and diastereoselectivities of 89−99% ee and dr > 20:1
were observed. The appended alkyne functional group
exhibited potential for further useful synthetic manipulations.
This reaction also demonstrated the possible use of
alkynylrhodation as the initiating step for other widely studied
rhodium-catalyzed cascades.5g,15
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.8b00153.
Experimental procedures, optimization, characterization,
and X-ray data (PDF)
Accession Codes
which could be further functionalized. It was presumed that
CuI prevents epimerization by chelating the oxygen atoms.
Terminal alkyne 5 underwent copper-catalyzed 1,3-dipolar
cycloaddition smoothly with benzyl azide to form benzyl
triazole 6. Additionally, partial hydrogenation with Lindlar’s
catalyst and quinoline afforded alkene 7, while complete
CCDC 1590594 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.8b00153
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
55, 9007. (e) Wang, Z.-X.; Bai, X.-Y.; Yao, H.-C.; Li, B.-J. J. Am. Chem.
AUTHOR INFORMATION
■
Soc. 2016, 138, 14872. (f) Sanz-Marco, A.; Blay, G.; Munoz, M. C.;
̃
Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
ORCID
Pedro, J. R. Chem. - Eur. J. 2016, 22, 10057. (g) Wang, Z.-X.; Bai, X.-
Y.; Li, B.-J. Synlett 2017, 28, 509. (h) Bai, X.-Y.; Zhang, W.-W.; Li, Q.;
Li, B.-J. J. Am. Chem. Soc. 2018, 140, 506.
(9) (a) Nishimura, T.; Katoh, T.; Takatsu, K.; Shintani, R.; Hayashi,
T. J. Am. Chem. Soc. 2007, 129, 14158. (b) Nishimura, T.; Guo, X.-X.;
Uchiyama, N.; Katoh, T.; Hayashi, T. J. Am. Chem. Soc. 2008, 130,
1576. (c) Nishimura, T.; Sawano, T.; Hayashi, T. Angew. Chem., Int.
Ed. 2009, 48, 8057. (d) Fillion, E.; Zorzitto, A. K. J. Am. Chem. Soc.
2009, 131, 14608. (e) Dou, X.; Huang, Y.; Hayashi, T. Angew. Chem.,
Int. Ed. 2016, 55, 1133. (f) Zhi, Y.; Huang, J.; Liu, N.; Lu, T.; Dou, X.
Org. Lett. 2017, 19, 2378.
Ken-Loon Choo: 0000-0001-7745-5458
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Toronto (U of T), Alphora
Research, Inc., and the Natural Science and Engineering
Research Council (NSERC) for financial support. We thank
Umicore and Johnson Matthey for the generous donation of
rhodium catalysts. We thank Dr. Alan Lough (U of T) for
single-crystal X-ray analysis of 4. We thank Dr. M. Wegmann
(U of T) and Y. Jang (U of T) for fruitful discussions.
(10) See the Supporting Information.
(11) Alkyne 2b was used in cases where the product co-elutes with
the benzophenone byproduct during flash column chromatography.
(12) ent-4 was synthesized from ent-3a, which was synthesized during
the optimization process when (R)-segphos was used as the chiral
ligand.
(13) (a) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J.
Am. Chem. Soc. 2002, 124, 5052. (b) Kina, A.; Iwamura, H.; Hayashi,
T. J. Am. Chem. Soc. 2006, 128, 3904.
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DOI: 10.1021/acs.orglett.8b00153
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