C-H Functionalization Approach for the Synthesis of Chiral C2-Symmetric 1,5-Cyclooctadiene Ligands

Article abstract of DOI:10.1021/acs.orglett.9b03764

Chiral cyclooctadiene (COD) derivatives are readily prepared by rhodium-catalyzed allylic C-H functionalization of COD. Either mono- or difunctionalization of COD is possible generating the products in high yield, diastereoselectivity and enantioselectivi

Full text of DOI:10.1021/acs.orglett.9b03764

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
C−H Functionalization Approach for the Synthesis of Chiral
C2‑Symmetric 1,5-Cyclooctadiene Ligands
Bowen Zhang, Michael R. Hollerbach, Simon B. Blakey,* and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: Chiral cyclooctadiene (COD) derivatives are
readily prepared by rhodium-catalyzed allylic C−H function-
alization of COD. Either mono- or difunctionalization of COD
is possible generating the products in high yield, diaster-
eoselectivity and enantioselectivity. The double C−H
functionalization generates C2-symmetric COD derivatives
with four new stereogenic centers in >99% ee, which can be
readily converted to a series of chiral COD ligands.
Preliminary evaluations revealed that the COD ligands can be used in rhodium-catalyzed asymmetric arylation of cyclohex-
2-enone, leading to the conjugate addition products in up to 76% ee.
synthesis of C2-symmetric COD derivatives 7, with four
stereogenic centers. Furthermore, we describe their derivatiza-
tion to other C2-symmetric COD derivatives 8 and their initial
evaluation as chiral ligands for rhodium-catalyzed conjugate
addition.
The motivation for this study was the realization that COD
would be an intriguing substrate to challenge catalyst-
controlled C−H functionalization by rhodium-stabilized
donor/acceptor carbenes (Scheme 2).7,8 We have recently
1,5-Cyclooctadiene (COD) is widely used as a ligand in
transition metal complexes.1 Metal−COD complexes are
useful because many are sufficiently stable to be isolated and
easily handled, often more robust than the related ethylene
complexes because of chelation. Even though the metal−COD
complexes were initially considered as stable precursors to
active catalysts, it became clear in many instances that the
COD ligand was not lost and was an integral part of the
catalytic cycle.2−4 Consequently, there became interest in
designing chiral COD ligands for chiral catalysis. The chiral
COD ligands 1 and 2 have shown considerable promise, but
their synthesis requires a multistep synthesis and a
resolution.4b This has led to the synthesis of other skipped
cyclic dienes as chiral ligands,4−6 including a number of C2-
symmetric ligands 3−6. However, all require a multistep
synthesis and most involve a racemic synthesis followed by
resolution4−6 (Scheme 1). In this paper we describe an
enantioselective C−H functionalization method for the direct
Scheme 2. Synthetic Challenge
Scheme 1. Chiral Cyclic Diene Ligands
shown that dirhodium catalysts of defined shapes are capable
of selecting between primary, secondary, and tertiary
unactivated C−H bonds.8a−e We have also shown that catalysts
can be designed that would select between different secondary
C−H bonds.8c,f,g COD was considered to be an interesting
substrate because even though the methylene sites are allylic
and relatively activated, the cis alkene would be expected to be
a competing site for cyclopropanation. Therefore, we would
need to identify a catalyst that would lead to selective C−H
functionalization instead of cyclopropanation. Then, ideally
once the mono-C−H functionalization has occurred, the
catalyst would select the C5 site for a second C−H
Received: October 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03764
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
functionalization, over the two other allylic methylene sites at
C3 and C6 to generate the COD derivative 9. For the overall
scheme to be useful we would need to be able to control the
stereochemistry of the four newly formed stereogenic centers
so that the C2-symmetric form of 7 is generated.
Scheme 4. Mono-C−H Functionalization of COD
The first stage of the study focused on the mono-C−H
functionalization reactions using the most promising catalysts
in our tool box for selective reactions at methylene sites
(Scheme 3). Rh2(S-DOSP)4 (10) is our original catalyst and
Scheme 3. Catalyst Screening
a
Larger scale reaction at 3.0 mmol of diazo compound.
the trichloroethyl ester 17, further underscoring the advantage
of the trihaloethyl esters in C−H functionalization reactions.
The trifluoroethyl derivative 19 was formed with the highest
yield and enantioselectivity and retained the high diaster-
eoselectivity. Therefore, the further studies focused on the
trifluoroethyl derivatives. A series of p-substituted aryl (20−
24) and a pyridyl derivative (25) were prepared, and they were
formed in high yield and dr, with the asymmetric induction in
the range 79−95% ee. The reaction with a meta-substituted
aryldiazoacetate gave the monoinsertion product 26 but with
decreased enantioselectivity (63% ee). We also examined the
reaction with the styryldiazoacetate, and it similarly gave an
effective reaction to form 27 in 67% yield, >30:1 dr, 88% ee.
With the vision of designing chiral COD ligands, we decided
to explore whether a double C−H functionalization could be
achieved because this could be a direct way for the synthesis of
C2-symmetric ligands. At the onset of this work, it was
considered to be a challenging C−H functionalization because
a stereoselective reaction would be required at a specific allylic
methylene site in the presence of two other allylic methylene
sites and two cis-alkenes. Nevertheless, the double C−H
functionalization turned out to be very effective (Scheme 5).
The reaction was conducted using 3 equiv of the diazo
compound at elevated temperature (40 °C), and under these
conditions the bis C−H functionalization products 28−35
were formed in good yield. All the products are produced with
very high levels of enantioselectivity (>99% ee) even though
the enantiomeric purity of the mono-C−H functionalization
products was considerably lower (72−95% ee). The enrich-
ment in the enantioselectivity, kown as the Horeau Principle,9
occurs because the minor enantiomer of the monoinsertion
product is primarily transformed into the meso diastereomer
during the second insertion. Also, imperfect asymmetric
induction of the major enantiomer of the mono insertion
product generates a diastereomer rather than an enantiomer of
the final bis C−H insertion products. Consequently 28−35 are
produced with very high enantioselectivity but with moderate
diastereoselectivity. Fortunately, the desired major diaster-
eomer is easily purified on silver-impregnated silica.
has been shown to be broadly applicable for functionalization
of activated methylene sites.7b Rh2(S-PTAD)4 (11) is an
uncrowded catalyst that can give different stereochemical
results to Rh2(S-DOSP)4 at methylene C−H functionaliza-
tion.7b Rh2(R-TPPTTL)4 (12) has shown remarkable site
selectivity for C3 over C4 C−H functionalization of
alkylcyclohexanes.8f The triphenyl-cyclopropanecarboxylates
(TPCP) derivatives generate the most sterically crowded
dirhodium tetracarboxylate catalysts. Rh2(R-p-BrTPCP)4 (13)
was the first member of this class and preferentially reacts at
less crowded C−H bonds.8a,b Rh2(R-3,5-(p-tBuC6H4)TPCP)4
(14) and Rh2(R-2-Cl-5-BrTPCP)4 (15) selectively react at the
most accessible unactivated methylene site in linear alkanes.8c,g
We have recently found that C−H functionalization with
donor/acceptor carbenes tends to proceed in higher yields
when the acceptor group is a trihaloethyl derivative.8b
Therefore, the test reaction was initially conducted with the
trichloroethyl aryldiazoacetate 16 and 2.5 equiv of COD. Most
of the catalysts gave an undefined mixture of products,
consisting of cyclopropanation, diastereomeric monoinsertion,
and likely diastereomeric and/or regioisomeric di-insertion
products (see Supporting Information for details). In contrast,
the Rh2(R-2-Cl-5-BrTPCP)4-catalyzed reaction was relatively
clean and the desired mono-C−H functionalization product 17
could be isolated in 72% yield, >30:1 dr, and 91% ee.
The scope of the reaction was then examined with a range of
aryldiazoacetates as summarized in Scheme 4. The first three
systems examined the influence of the ester functionality. The
methyl ester gave the C−H functionalization product 18 with
lower diastereoselectivity and enantioselectivity compared to
In order to understand the unprecedented site selectivity
exhibited by COD, control experiments were conducted on
B
DOI: 10.1021/acs.orglett.9b03764
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 5. Double C−H Functionalization of COD
a
Yield represents isolated yield of the pure major diastereomer. The dr was determined from the NMR of the crude reaction mixture. The minor
diastereomer is the meso compound, fully characterized for the meso diastereomer of 29. The amount of any other diastereomer is <5%. The ee
b
was determined by chiral HPLC. Larger scale reaction conducted with 0.8 mmol of COD.
related substrates using Rh2(2-Cl,5-BrTPCP)4 (15) as catalyst
(Scheme 6). 1E,5E,9E-Cyclododecatriene (36) was found to
H functionalization, and other cycloalkenes can have a very
different reactivity profile.
The bis C−H functionalization products can be further
derivatized by either ester hydrolysis, ester reduction, or
aryllithium addition, and the resulting alcohol products can be
either methylated or silylated (see Supporting Information for
details), leading to the formation of a variety of C2-symmetric
chiral COD ligands (41−49). A preliminary exploratory study
was conducted to determine if these chiral COD ligands were
compatible with rhodium-catalyzed conjugate addition of
phenylboronic acid to cyclohexenone (Scheme 7). The
reactions with all of the ligands, except for the aryl iodide
derivative 31, resulted in the formation of conjugate addition
product 50 in reasonable yield (32−84%) and variable levels of
enantioselectivity (26−76% ee). Most of the direct double C−
H insertion products gave about 30−40% ee, but some of the
ligands derived from the aryllithium addition gave higher levels
Scheme 6. Evaluation of Related Cycloalkenes
Scheme 7. Enantioselective Conjugate Addition
be an effective substrate, forming the allylic C−H functional-
ization product 37 with poor diastereoselectivity but high
enantioselectivity. The diastereomeric ratio could be altered
slightly (2:1−1:2) with different dirhodium catalysts, but no
catalyst rendered the reaction highly diastereoselective. The
reaction with cyclohexene gave a mixture of cyclopropanation
(38) and C−H functionalization products (39), ranging from
1.27:1 to 1:2.85, and the diastereoselectivity was also poor
ranging from 3.11:1 to 1:3.12 dr (see Supporting Information
for details). The reaction with cis-cyclooctene, however, was
very clean, but the only product formed was the cyclopropane
(40) (Scheme 3). These results indicate that the structural
features of COD are ideally suited for stereoselective allylic C−
C
DOI: 10.1021/acs.orglett.9b03764
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) Cooze, C.; Dada, R.; Lundgren, R. J. Direct Formic Acid
Mediated Z-Selective Reductive Coupling of Dienes and Aldehydes.
Angew. Chem., Int. Ed. 2019, 58, 12246−12251.
of enantioselectivity. The most promising ligand to date has
been 49, which resulted in the formation of 50 in 63% yield
and 76% ee.
(4) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. A Chiral
Chelating Diene as a New Type of Chiral Ligand for Transition Metal
Catalysis: Its Preparation and Use for the Rhodium-Catalyzed
Asymmetric 1,4-Addition. J. Am. Chem. Soc. 2003, 125, 11508−
11509. (b) Otomaru, Y.; Kina, A.; Shintani, R.; Hayashi, T. C2-
Symmetric Bicyclo[3.3.1]nona-2,6-diene and Bicyclo[3.3.2]deca-2,6-
diene: New Chiral Diene Ligands Based on the 1,5-Cyclooctadiene
Framework. Tetrahedron: Asymmetry 2005, 16, 1673−1679. (c) Oto-
maru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. Preparation of C2-
Symmetric Bicyclo[2.2.2]octa-2,5-diene Ligands and Their Use for
Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acids. J.
Org. Chem. 2005, 70, 2503−2508. (d) Nishimura, T.; Nagaosa, M.;
Hayashi, T. Chiral Tetrafluorobenzobarrelenes as Highly Efficient
Ligands for the Rhodium-catalyzed Asymmetric 1,4-Addition of
Arylboronic Acids. Chem. Lett. 2008, 37, 860−861. (e) Helbig, S.;
Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. Chiral
Bicyclo[3.3.0]octa-2,5-dienes as Steering Ligands in Substrate-
Dependent Rhodium-Catalyzed 1,4-Addition of Arylboronic Acids
to Enones. Adv. Synth. Catal. 2007, 349, 2331−2337. (f) Feng, C.-G.;
Wang, Z.-Q.; Tian, P.; Xu, M.-H.; Lin, G.-Q. Easily Accessible C2-
Symmetric Chiral Bicyclo[3.3.0]dienes as Ligands for Rhodium-
Catalyzed Asymmetric 1,4-Addition. Chem. - Asian J. 2008, 3, 1511−
1516.
(5) (a) Defieber, C.; Paquin, J. F.; Serna, S.; Carreira, E. M. Chiral
[2.2.2] Dienes as Ligands for Rh(I) in Conjugate Additions of
Boronic Acids to a Wide Range of Acceptors. Org. Lett. 2004, 6,
3873−3876. (b) Paquin, J. F.; Defieber, C.; Stephenson, C. R. J.;
Carreira, E. M. Asymmetric Synthesis of 3,3-Diarylpropanals with
Chiral Diene−Rhodium Catalysts. J. Am. Chem. Soc. 2005, 127,
10850−10851. (c) Paquin, J. F.; Stephenson, C. R. J.; Defieber, C.;
Carreira, E. M. Catalytic Asymmetric Synthesis with Rh−Diene
Complexes: 1,4-Addition of Arylboronic Acids to Unsaturated Esters.
Org. Lett. 2005, 7, 3821−3824. (d) Defieber, C.; Grutzmacher, H.;
Carreira, E. M. Chiral Olefins as Steering Ligands in Asymmetric
Catalysis. Angew. Chem., Int. Ed. 2008, 47, 4482−502.
In conclusion, a one-step enantioselective synthesis of C2-
symmetric chiral COD ligands was achieved by means of a
double allylic C−H functionalization of COD. This trans-
formation illustrates the capacity of C−H functionalization to
rapidly generate synthetic complexity from a simple starting
material. Initial evaluation of these chiral COD ligands along
with their derivatives revealed they were effective in the
rhodium-catalyzed asymmetric arylation of cyclohex-2-enone.9
Further studies will need to be carried out to optimize the
ligands further and to determine if they can display unique
beneficial characteristics compared to the established chiral
COD ligands.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03764.
Complete experimental procedures and compound
characterization (PDF)
Accession Codes
CCDC 1960982−1960983 and 1960993 contain the supple-
mentary 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.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hmdavie@emory.edu.
*E-mail: sblakey@emory.edu.
ORCID
(6) Nagamoto, M.; Nishimura, T. Asymmetric Transformations
under Iridium/Chiral Diene Catalysis. ACS Catal. 2017, 7, 833−847.
(7) (a) Davies, H. M. L.; Liao, K. Dirhodium Tetracarboxylates as
Catalysts for Selective Intermolecular CH Functionalization. Nat.
Rev. Chem. 2019, 3, 347−360. (b) Davies, H. M. L.; Morton, D.
Guiding Principles for Site Selective and Stereoselective Intermo-
lecular C−H Functionalization by Donor/Acceptor Rhodium
Carbenes. Chem. Soc. Rev. 2011, 40, 1857−1869.
Simon B. Blakey: 0000-0002-4100-8610
Huw M. L. Davies: 0000-0001-6254-9398
Notes
The authors declare the following competing financial
interest(s): H.M.L.D. is a named inventor on a patent entitled,
Dirhodium Catalyst Compositions and Synthetic Processes
Related Thereto (US 8,974,428, issued March 10, 2015). The
other authors have no competing financial interests.
(8) (a) Qin, C. M.; Davies, H. M. L. Role of Sterically Demanding
Chiral Dirhodium Catalysts in Site-Selective CH Functionalization
of Activated Primary CH Bonds. J. Am. Chem. Soc. 2014, 136,
9792−9796. (b) Guptill, D. M.; Davies, H. M. L. 2,2,2-Trichloroethyl
Aryldiazoacetates as Robust Reagents for the Enantioselective CH
Functionalization of Methyl Ethers. J. Am. Chem. Soc. 2014, 136,
17718−17721. (c) Liao, K. B.; Negretti, S.; Musaev, D. G.; Bacsa, J.;
Davies, H. M. L. Site-selective and Stereoselective Functionalization
of Unactivated CH Bonds. Nature 2016, 533, 230−234. (d) Liao,
K. B.; Pickel, T. C.; Oyarskikh, V. B.; Acsa, J. B.; Usaev, D. G. M.;
Davies, H. M. L. Site-selective and Stereoselective Functionalization
of Non-activated Tertiary CH Bonds. Nature 2017, 551, 609−613.
(e) Liao, K.; Yang, Y.-F.; Li, Y.; Sanders, J. N.; Houk, K. N.; Musaev,
D. G.; Davies, H. M. L. Design of Catalysts for Site-Selective and
Enantioselective Functionalization of Non-activated Primary C−H
Bonds. Nat. Chem. 2018, 10, 1048−1055. (f) Fu, J.; Ren, Z.; Bacsa, J.;
Musaev, D. G.; Davies, H. M. L. Desymmetrization of Cyclohexanes
by Site- and Stereoselective CH Functionalization. Nature 2018,
564, 395−399. (g) Liu, W.; Ren, Z.; Bosse, A. T.; Liao, K.; Goldstein,
E. L.; Bacsa, J.; Musaev, D. G.; Stoltz, B. M.; Davies, H. M. L.
Catalyst-Controlled Selective Functionalization of Unactivated C−H
Bonds in the Presence of Electronically Activated C−H Bonds. J. Am.
Chem. Soc. 2018, 140, 12247−12255.
ACKNOWLEDGMENTS
■
We thank Dr. John Bacsa (Emory University) for the X-ray
structure determination. Financial support was provided by
NSF under the CCI Center for Selective C−H Functionaliza-
tion (CHE-1700982). Funds to purchase the NMR and X-ray
spectrometers used in these studies were supported by the
NSF (CHE 1531620 and CHE 1626172).
REFERENCES
■
(1) Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to
Catalysis; University Science Books: Sausalito, CA, 2010; p 48.
(2) Hesp, K. D.; Tobisch, S.; Stradiotto, M. [Ir(COD)Cl]2 as a
Catalyst Precursor for the Intramolecular Hydroamination of
Unactivated Alkenes with Primary Amines and Secondary Alkyl- or
Arylamines: A Combined Catalytic, Mechanistic, and Computational
Investigation. J. Am. Chem. Soc. 2010, 132, 413−426.
D
DOI: 10.1021/acs.orglett.9b03764
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Vigneron, J. P.; Dhaenens, M.; Horeau, A. Nouvelle methode
pour porter au maximum la purete optique d’un produit partiellement
dedouble sans l’aide d’aucune substance chirale. Tetrahedron 1973,
29, 1055−1059. (b) D’Arrigo, P.; Feliciotti, L.; Pedrocchi-Fantoni, G.;
Servi, S. J. Org. Chem. 1997, 62, 6394−6396. (c) Heller, D.; Drexler,
H.-J.; Fischer, C.; Buschmann, H.; Baumann, W.; Heller, B. How
Long Have Nonlinear Effects Been Known in the Field of Catalysis?
Angew. Chem., Int. Ed. 2000, 39, 495−499. (d) Huo, S.; Negishi, E. A
Convenient and Asymmetric Protocol for the Synthesis of Natural
ProductsContaining Chiral Alkyl Chains via Zr-Catalyzed Asymmetric
Carboalumination of Alkenes. Synthesis of Phytol and Vitamins E and
K Org. Org. Lett. 2001, 3, 3253−3256.
(10) Chem. Archive: DOI: 10.26434/chemrxiv.10032209.v1.
E
DOI: 10.1021/acs.orglett.9b03764
Org. Lett. XXXX, XXX, XXX−XXX