Synthesis of Proline Analogues via Rh-Catalyzed Asymmetric Conjugate Addition

Article abstract of DOI:10.1021/acscatal.0c04648

An enantio- and diastereoselective Rh-catalyzed conjugate addition reaction for the synthesis of proline analogues is reported. A high-throughput experimentation campaign was used to identify an efficient chiral catalyst which was able to afford the desired products in high yield and with high levels of diastereo- and enantioselectivity. This method was used to afford a range of 3-substituted proline derivatives from readily available dehydroproline electrophiles and boronic acid nucleophiles.

Full text of DOI:10.1021/acscatal.0c04648

pubs.acs.org/acscatalysis
Letter
Synthesis of Proline Analogues via Rh-Catalyzed Asymmetric
Conjugate Addition
Emma K. Edelstein,* Danica A. Rankic, Caroline C. Dudley, Spencer E. McMinn,
and Donovon A. Adpressa
Cite This: ACS Catal. 2021, 11, 743−749
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An enantio- and diastereoselective Rh-catalyzed
conjugate addition reaction for the synthesis of proline analogues is
reported. A high-throughput experimentation campaign was used to
identify an efficient chiral catalyst which was able to afford the desired
products in high yield and with high levels of diastereo- and
enantioselectivity. This method was used to afford a range of 3-
substituted proline derivatives from readily available dehydroproline
electrophiles and boronic acid nucleophiles.
KEYWORDS: rhodium, 1,4-addition, high-throughput experimentation, proline, unnatural amino acids
he incorporation of noncanonical amino acids into
peptides and proteins can alter a variety of physical and
T
biochemical properties, thus influencing the structure and
function of the peptide or protein itself.1 The ability to alter
these parameters has become of importance to biomedical
fields in recent years with the increase of nonsmall molecule
modalities including peptides, peptidomimetics, antibodies,
and hybrid molecules as therapeutics.2 Through the incorpo-
ration of non-native amino acid building blocks, one can
introduce structural diversity, influence function, and introduce
drug-like properties to chemical matter within these less
traditional modality classes. Among the amino acids, proline
offers unique utility due to its pyrrolidine backbone that is
capable of forming a tertiary amide bond upon incorporation
into peptides, which results in conformational rigidity that can
alter secondary protein structure.3 Consequently, analogues of
proline have been used to impart changes in function and
physiochemical properties of peptides and other biomole-
cules.4
Other than acting as proline replacements, pyrrolidine-based
heterocycles are ubiquitous as structural constituents of natural
products,5 organocatalysts,6 and small molecules.7 trans-3-
Substituted proline frameworks in particular have been utilized
in the discovery and development of CDK9,8 Rho Kinase,9 and
peptide-base HCV protease10 inhibitors (Figure 1). Thus, the
expedient, robust, and stereoselective synthesis of proline
derivatives are of interest to the synthetic community and
biomedical fields alike.
Whereas racemic syntheses of trans-3-substituted proline
have been demonstrated,11 only few enantioselective routes
exist.12 Such methods can provide reliable stereocontrol;
however, multiple functional group interconversions are
Figure 1. Inhibitors containing trans-3-substituted proline scaffolds.
required to isolate the desired deprotected amino acid from
a more functionalized scaffold. These sequences become
prohibitively long when a large set of building blocks with
Received: October 26, 2020
Revised: December 23, 2020
Published: December 31, 2020
© 2020 The Authors. Published by
American Chemical Society
https://dx.doi.org/10.1021/acscatal.0c04648
ACS Catal. 2021, 11, 743−749
743

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
variable 3-position substitutions are desired, such as for
structure activity relationship (SAR) exploration in the context
of a medicinal chemistry program. It was in this vein that we
sought to develop an enantioselective, direct, and modular
synthesis of trans-3-substituted prolines.
impressive number of substrates, to the best of our knowledge
its use for the synthesis of enantioenriched α-amino acids has
been limited to deyhydroalanine derivatives.15 Dehydroproline
starting materials offer additional complications as both the α
and β-carbons are prochiral, and therefore, contiguous
stereocenters need to be set with control upon 1,4-addition
in order to achieve both a diastereo- and enantioselective
transformation. Although there are some examples of Rh-ACA
on 5-membered exocyclic Michael acceptors, achieving high
levels of enantio- and diastereoselectivity are highly substrate
dependent, and examples are limited to electron-deficient
alkenes, highlighting the challenges of such an approach.16 We
began our investigations by first determining if an achiral Rh-
catalyst could facilitate conjugate addition of a boronic acid to
dehydroproline 1 (Table 1).
We were encouraged by the reported Cu-catalyzed addition
of Grignard reagents to dehydroproline (Scheme 1).13 This
Scheme 1. Metal-Catalyzed Conjugate Addition Reactions
with Dehydroproline Derivatives
After investigating several achiral Rh-catalysts and reaction
conditions, we found that 5 mol % Rh(nbd)2BF4 in toluene
with aqueous base at 60 °C could catalyze the conjugate
addition of phenylboronic acid to 1 to provide 2 as a 14:1 dr
trans:cis mixture (Table 1, entry 1). We then turned to
investigate chiral ligands commonly used in Rh-ACA to afford
the enantioenriched product. Attempts to use (R)-BINAP
(L1) with different rhodium catalysts resulted in 1:1 dr, and
moderate enantioinduction was observed (entries 2 and
4).3,17,18 Chiral diene ligands could be used to afford a
stereoselective reaction but required the use of a Rh-catalyst
that did not give a background reaction (Table 1, entry 3).
Using Ph-bod (L2)19 resulted in improved yield and
enantioselectivities, however, low diastereoselectivity slightly
favoring the desired trans-isomer was observed (entry 5).
DOLEFIN20 (L3) gave slightly improved dr in low yield and
low enantioselectivity (entry 6). Since these initial results
showed that catalyst and ligand choice can have a dramatic
effect on the diastereo- and enantiomeric outcome of the
transformation, we aimed to survey a broader scope of ligands.
Because of the abundance of bisphosphine ligands with vastly
different steric and electronic properties, many of which have
been applied to other Rh-catalyzed transformations,21 we
began our study with different classes of these ligands. In order
to examine a large array of ligands as quickly and efficiently as
possible, we pursued a high throughput experimentation
(HTE) campaign assessing 96 chiral bidentate phosphine
ligands in parallel.22 Analysis of the crude reaction mixtures
with SFC informed on relative amounts, diastereomeric ratio,
method allows for the synthesis of the desired scaffolds
through the diversification of a starting material that is readily
available from L-proline, albeit in racemic fashion or modest ee
(70%) with chiral auxiliary. Equipped with the knowledge that
dehydroproline electrophiles are reactive in metal-catalyzed
1,4-addition reactions, we sought to develop an enantiose-
lective variation of this process to access the desired products
and address the limitations of prior art. Herein we report a Rh-
catalyzed asymmetric conjugate addition (Rh-ACA) of
commercially available and shelf-stable organoboron reagents
to prochiral electrophiles toward this effort (Scheme 1).
Rhodium complexes are commonly used as catalysts for
enantioselective 1,4-addition.14 They can undergo trans-
metalation under mild conditions with readily commercially
available and air-stable organoboron reagents which precludes
the need to use sensitive and functional group intolerant
organometallic reagents. Despite Rh-ACA’s application to an
a
Table 1. Preliminary Results
entry
[Rh]
ligand
LCAP of 2 (%)
dr (trans:cis)
ee (%) (trans)
ee (%) (cis)
1
2
3
4
5
6
Rh(nbd)2BF4
Rh(nbd)2BF4
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
-
L1
-
L1
L2
L3
94
52
<5
54
78
17
14:1
1:1
-
1:1
2.2:1
3:1
-
66
-
69
89
47
-
96
-
96
91
nd
a
Reactions were performed on 0.3 mmol scale. Liquid chromatography area percent (LCAP) determined by UPLC. dr and ee determined by SFC.
744
https://dx.doi.org/10.1021/acscatal.0c04648
ACS Catal. 2021, 11, 743−749

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Figure 2. HTE screen of chiral bidentate phosphine ligands. (a) conditions used. (b) Hits from HTE screen. (c) results from HTE screen.
Reactions were performed on 8 μmol scale. Ratio of 2:internal standard (IS) was determined by integration of SFC peaks and normalized. ee and dr
were determined by SFC. Alkylbisphosphines include ligands from the DIPAMP, BisP*, and miniPhos classes. Biarylbisphosphines include ligands
from the BINAP, BIPHEP, Segphos, Garphos, and BINAM classes. Spirocyclic bisphosphines include ligands from the SDP and SKP classes.
Ferrocene-based bisphosphines include ligands from the Josiphos, ferrolane, Walphos, JAFAphos, and Twinphos classes. See Supporting
Information for details.
and enantioenrichment of the desired product. A summary of
the HTE campaign is shown in Figure 2.
well as Me-Duphos (L8), Et-Duphos (L9), and iPr-Duphos
(L10). Ph-BPE (L7)25 was the best performing ligand overall,
affording the trans-diastereomer of product 2 in high yield and
>95% ee. Both enantiomers of this ligand are readily available,
allowing for the synthesis of both D- and L-proline analogues
depending on the enantiomer of ligand used. Moving forward,
we used the commercially available Ph-BPE-Rh complex,
which gave comparable results to that observed in our screen
and precludes the need to complex metal and ligand,
simplifying the reaction setup.26 With the optimal catalyst in
hand, we sought to optimize the reaction conditions (see
Supporting Information) and explore the substrate scope
(Table 2).
Ligands from several classes gave appreciable conversion to
the desired product in varying levels of diastereo- and
enantioselectivity, although only a few ligands were able to
afford the desired product in >60% yield and >60% ee (shaded
region). With the bisphosphine ligands surveyed, the trans
isomer was consistently observed to be the major diastereomer.
Of the 96 ligands screened, the best performing ligands were
from the BPE/DuPhos ligand class (Figure 2, L4−L11, shown
in red).23 P-Chiral ligand QuinoxP* (L12, shown in orange)
also performed well, although it gave slightly diminished dr
(13:1) compared with the BPE/DuPhos ligands (all >15:1
dr).24 Within the BPE and Duphos class, increasing
enantioselectivities were observed with increased steric bulk
of the alkyl-R group at the expense of product yield. This trend
is seen with Me-BPE (L4), Et-BPE (L5), and iPr-BPE (L6), as
We found the reaction to be general, and a variety of
aromatic boronic acid nucleophiles were reactive under the
reaction conditions to give the desired products in good yield
with high dr and ee. The reaction could also be performed on
745
https://dx.doi.org/10.1021/acscatal.0c04648
ACS Catal. 2021, 11, 743−749

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
¶
Table 2. Substrate Scope
¶
Isolated yields of the diastereomeric mixtures are reported. dr determined by crude 1H NMR (reported as trans:cis ratio). ee determined by SFC
a
after purification. ee of only the major diastereomer is reported unless otherwise shown. Reactions were performed on 0.3−0.5 mmol scale. 4.0
mmol (1 g scale) with 0.5 mol % catalyst. R-BF3K used instead of R-B(OH)2. R-B(pin) used instead of R-B(OH)2. R-B(neo) used instead of R-
B(OH)2. Collected as mixture of product and remaining starting material. Yield after HPLC purification. Cs2CO3 (2.0 equiv), dioxane [0.2 M],
H2O (10.0 equiv), 100 °C. Achiral catalyst conditions: Rh(nbd)2BF4 (3.0 mol %), 2 M K3PO4 (2.0 equiv), dioxane [0.2 M], 60 °C.
b
c
d
e
f
g
h
gram-scale with 0.5 mol % catalyst while still maintaining high
efficiency. Under optimized conditions, different organoboron
reagents such as the boronic acid, potassium trifluoroborate
salt, and pinacol and neopentyl esters were all competent
nucleophiles to afford 2 in high yield and selectivity. The
reaction was tolerant to substitution on the ester, although
slight variations in yield, dr, and ee were observed to give
products 3, 4, and 5. Replacing the ester for a benzylamide was
also tolerated to afford 6, indicating the potential for this
method to be used toward the late stage-functionalization
(LSF) of peptides.27
746
https://dx.doi.org/10.1021/acscatal.0c04648
ACS Catal. 2021, 11, 743−749

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Nitrogen protecting groups such as CBz and Boc (7) are
tolerated; however, a N-nosylate-protected substrate did not
afford product (not shown). Simple carbon-substituted
benzene rings afforded products 8, 9, 10, and 11 all with
good selectivity. The reaction was successful with function-
alized boronic acids as well. Using p-OMe and p-CF3-
substituted phenylboronic acids yielded 12 and 13. Organo-
boron nucleophiles bearing functional group handles such as
halides or nitriles, allowing for further elaboration, were also
tolerated in the reaction to afford products 14, 15, 16, 17, and
18. Heterocyclic boronic acids also performed well in the
reaction to afford compounds 19, 20, 21, and 22, although
using quinolinyl nucleophiles resulted in lower yields and
products with lower ee (23 and 24).
a large array of chiral ligands that identified a highly efficient
and selective catalyst, and the optimized conditions were
general, achieving good to excellent ee and drs for a variety of
substrates. This transformation was suitable for the mod-
ification of a variety of dehydroamino ester derivatives,
showcasing the robustness of the reaction and its potential
for late-stage functionalization of complex biological targets,
which is currently under further exploration. This method can
be used as a reliable synthetic tool for the synthesis of
analogues of both L- and D-amino acids and other substituted
pyrrolidine scaffolds to enable the exploration of novel
chemical matter.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c04648.
■
sı
Under standard reaction conditions, however, reactivity was
not observed with pyridyl organoboron reagents. Because these
are important structural motifs in the context of pharmaceuti-
cally relevant chemical matter, we felt it was important to
attempt to engage these nucleophiles in the reaction. We found
more forcing conditions (dioxane as solvent, heating to 100
°C) were necessary for product formation. Increased yield was
observed with increasing the boronic acid loadings to 3 equiv,
using Cs2CO3 as base, and lowering the H2O loading to 10
equiv. With these modifications to the reaction protocol, we
were able to obtain products 25−28 in synthetically useful
yields. In certain cases, with the 4-pyridyl substituted
nucleophiles, low levels of diastereo- and enantioinduction
were observed (25, 26, and 27).28 Despite the diminished
selectivity, these products are challenging to prepare otherwise.
Sterically encumbered substrates (29 and 30) gave low
yields under our standard reaction conditions because of
consumption of the organoboron reagent in an undesired
protodeboronation pathway.14a Whereas background reactions
can cause protodeboronation, a competing protonation of a
Rh(I)-aryl intermediate after transmetalation may contribute
to the composition as well. With simple hydrocarbon boronic
acid nucleophiles, we observed that protodeboronation only
occurred in the presence of the Ph-BPE-Rh catalyst. This Rh-
catalyzed protodeboration pathway becomes more competitive
with sterically bulky substrates, likely because of the substrate
(1) being unable to bind to a more hindered Rh-center. Higher
yields of racemic mixtures of product were observed with these
substrates with Rh(nbd)2BF4 to give the results shown. The
reaction with cyclohexenyl boronic acid to give 31 was also low
yielding under the optimized reaction conditions, but good
yield of the racemate was obtained with the achiral catalyst.29
To gain a better understanding of the high diastereose-
lectivities observed in the reaction, several additional experi-
ments were performed. When single stereoisomer cis-2 is
subjected to the standard reaction conditions, trans-2 is not
detected, indicating that epimerization is not responsible for
the observed diastereomeric ratios. DFT calculations show the
difference between the ground state energies of trans-2 and cis-
2 (ΔG) is approximately 0.18 kcal/mol, equating to a 1.3:1 dr
at 60 °C (see Supporting Information). Furthermore, when
single stereoisomer trans-2 is subjected to basic conditions,
erosion of the diastereomeric ratio is observed, indicating that
the diastereoselectivity seen in the catalytic transformation is
kinetically driven.30
Instrumental information, optimization details, detailed
experimental procedures, absolute stereochemistry de-
termination, and product characterization (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Emma K. Edelstein − Department of Process Research and
Development, Merck & Co., Inc., Boston, Massachusetts
02115, United States; orcid.org/0000-0002-2413-3831;
Email: emma.edelstein@merck.com
Authors
Danica A. Rankic − Department of Process Research and
Development, Merck & Co., Inc., Boston, Massachusetts
02115, United States; orcid.org/0000-0002-7326-8900
Caroline C. Dudley − Department of Process Research and
Development, Merck & Co., Inc., Boston, Massachusetts
02115, United States
Spencer E. McMinn − Department of Discovery Chemistry,
Merck & Co., Inc., Boston, Massachusetts 02115, United
States
Donovon A. Adpressa − Department of Process Research and
Development, Merck & Co., Inc., Boston, Massachusetts
02115, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c04648
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Shaoguang Zhang for assistance with the high-
throughput chiral ligand screen. We thank Aaron Sather,
Michael Ardolino, Thomas Lyons, Emily Corcoran, Kelsey
Poremba, Matthew Maddess, and L.-C. Campeau for helpful
conversation, advice, and guidance during the preparation of
this manuscript. We would also like to acknowledge the
internship program which C.C.D. participated in.
We have developed a highly stereoselective Rh-ACA for the
modular synthesis of trans-3-aryl proline derivatives, a chemical
space which is difficult to access efficiently with current
methods. High-throughput experimentation was used to screen
REFERENCES
■
(1) (a) Neumann-Staubitz, P.; Neumann, H. The Use of Unnatural
Amino Acids to Study and Engineer Protein Function. Curr. Opin.
747
https://dx.doi.org/10.1021/acscatal.0c04648
ACS Catal. 2021, 11, 743−749

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
Struct. Biol. 2016, 38, 119−128. (b) Young, T. S.; Schultz, P. G.
Beyond the Canonical 20 Amino Acids: Expanding the Genetic
Lexicon. J. Biol. Chem. 2010, 285, 11039−11044. (c) Zhang, W. H.;
Otting, G.; Jackson, C. J. Protein Engineering with Unnatural Amino
Acids. Curr. Opin. Struct. Biol. 2013, 23, 581−587. (d) van
Maarseveen, J. H.; Back, J. W. Re-Engineering the Genetic Code:
Combining Molecular Biology and Organic Chemistry. Angew. Chem.,
Int. Ed. 2003, 42, 5926−5928. (e) Li, X.; Liu, C. C. Biological
Applications of Expanded Genetic Codes. ChemBioChem 2014, 15,
2335−2341. (f) Lang, K.; Chin, J. W. Cellular Incorporation of
Unnatural Amino Acids and Bioorthogonal Labeling of Proteins.
Chem. Rev. 2014, 114, 4764−4806. (g) Ngo, J. T.; Tirrell, D. A.
Noncanonical Amino Acids in the Interrogation of Cellular Protein
Synthesis. Acc. Chem. Res. 2011, 44, 677−685. (h) Zheng, S.; Kwon, I.
Manipulation of Enzyme Properties by Noncanonical Amino Acid
Incorporation. Biotechnol. J. 2012, 7, 47−60.
(6) Zhou, Z. S.; Flohr, A.; Hilvert, D. An Antibody-Catalyzed Allylic
Sulfoxide−Sulfenate Rearrangement. J. Org. Chem. 1999, 64, 8334−
8341.
̀
(7) (a) Damour, D.; Herman, F.; Labaudiniere, R.; Pantel, G.;
Vuilhorgne, M.; Mignani, S. Synthesis of Novel Proline and ψ-Lactam
Derivatives as Non-Peptide Mimics of Somatostatin/Sandostatin®.
Tetrahedron 1999, 55, 10135−10154. (b) Larsen, A. M.;
́
̇
Venskutonyte, R.; Valades, E. A.; Nielsen, B.; Pickering, D. S.;
Bunch, L. Discovery of a New Class of Ionotropic Glutamate
Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-
Carboxyphenyl)-pyrrolidine-2-carboxylic Acid. ACS Chem. Neurosci.
2011, 2, 107−114. (c) Micheli, F.; Di Fabio, R.; Marchioro, C.
Asymmetric Synthesis of Some Substituted-3-Phenyl Prolines. Farm-
aco 1999, 54, 461−464. (d) Cheng, T.-J. R.; Chan, T.-H.; Tsou, E.-L.;
Chang, S.-Y.; Yun, W.-Y.; Yang, P.-J.; Wu, Y.-T.; Cheng, W.-C. From
Natural Product-Inspired Pyrrolidine Scaffolds to the Development of
New Human Golgi α-Mannosidase II Inhibitors. Chem. - Asian J.
2013, 8, 2600−2604.
́
(2) Valeur, E.; Gueret, S. M.; Adihou, H.; Gopalakrishnan, R.;
Lemurell, M.; Waldmann, H.; Grossmann, T. N.; Plowright, A. T.
New Modalities for Challenging Targets in Drug Discovery. Angew.
Chem., Int. Ed. 2017, 56, 10294−10323.
(8) Dey, J.; Deckwerth, T. L.; Kerwin, W. S.; Casalini, J. R.; Merrell,
A. J.; Grenley, M. O.; Burns, C.; Ditzler, S. H.; Dixon, C. P.; Beirne,
E.; Gillespie, K. C.; Kleinman, E. F.; Klinghoffer, R. A. Voruciclib, a
Clinical Stage Oral CDK9 Inhibitor, Represses MCL-1 and Sensitizes
High-Risk Diffuse Large B-cell Lymphoma to BCL2 Inhibition. Sci.
Rep. 2017, 7, 18007.
(3) For a review see: Mothes, C.; Caumes, C.; Guez, A.; Boullet, H.;
́
Gendrineau, T.; Darses, S.; Delsuc, N.; Moumne, R.; Oswald, B.;
Lequin, O.; Karoyan, P. 3-Substituted Prolines: From Synthesis to
Structural Applications, from Peptides to Foldamers. Molecules 2013,
18, 2307−2327.
(9) Acetta, A.; Capelli, A. M.; Rancati, F.; Bhalay, G.; Cheguillaume,
A. J. F. A.; Edwards, C.; Tisselli, P. Tyrosine Analogues Derivatives as
Rho-Kinase Inhibitors. Patent WO2019048479A1. March 14, 2019.
(10) Perni, R. B.; Farmer, L. J.; Cottrell, K. M.; Court, J. J.;
Courtney, L. F.; Deininger, D. D.; Gates, C. A.; Harbeson, S. L.; Kim,
J. L.; Lin, C.; Lin, K.; Luong, Y.-P.; Maxwell, J. P.; Murcko, M. A.;
Pitlik, J.; Rao, B. G.; Schairer, W. C.; Tung, R. D.; Van Drie, J. H.;
Wilson, K.; Thomson, J. A. Inhibitors of Hepatitis C Virus NS3·4A
Protease. Part 3: P2 Proline Variants. Bioorg. Med. Chem. Lett. 2004,
14, 1939−1942.
(4) (a) Armishaw, C.; Jensen, A. A.; Balle, T.; Clark, R. J.; Harpsøe,
K.; Skonberg, C.; Liljefors, T.; Strømgaard, K. Rational Design of α-
Conotoxin Analogues Targeting α7 Nicotinic Acetylcholine Recep-
tors: Improved Antagonistic Activity by Incorporation of Proline
Derivatives. J. Biol. Chem. 2009, 284, 9498−9512. (b) Jackson, D. Y.;
Quan, C.; Artis, D. R.; Rawson, T.; Blackburn, B.; Struble, M.;
Fitzgerald, G.; Chan, K.; Mullins, S.; Burnier, J. P.; Fairbrother, W. J.;
Clark, K.; Berisini, M.; Chui, H.; Renz, M.; Jones, S.; Fong, S. Potent
α4β1 Peptide Antagonists as Potential Anti-Inflammatory Agents. J.
Med. Chem. 1997, 40, 3359−3368. (c) Jacquot, Y.; Broutin, I.; Miclet,
(11) Waid, P. P.; Flynn, G. A.; Huber, E. W.; Sabol, J. S. Constrained
Amino Acids. An Approach to the Synthesis of 3-Substituted Prolines.
Tetrahedron Lett. 1996, 37, 4091−4094.
́
E.; Nicaise, M.; Lequin, O.; Goasdoue, N.; Joss, C.; Karoyan, P.;
Desmadril, M.; Ducruix, A.; Lavielle, S. High Affinity Grb2-SH3
Domain Ligand Incorporating Cβ-Substituted Prolines in a Sos-
Derived Decapeptide. Bioorg. Med. Chem. 2007, 15, 1439−1447.
(d) Quancard, J.; Karoyan, P.; Lequin, O.; Wenger, E.; Aubry, A.;
Lavielle, S.; Chassaing, G. Prolinoamino Acids as a Tool to Stabilize
β-Turns with the Side Chain of Natural Amino Acids. Tetrahedron
Lett. 2004, 45, 623−625. (e) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd,
N. D.; Moeller, K. D. Conformational Probes for Elucidating the
Nature of Substance P Binding to the NK1 Receptor: Initial Efforts to
Map the Phe7-Phe8 Region. Bioorg. Med. Chem. Lett. 1998, 8, 1679−
1682. (f) Zaminer, J.; Brockmann, C.; Huy, P.; Opitz, R.; Reuter, C.;
́
́
(12) (a) Rios, R.; Ibrahem, I.; Vesely, J.; Sunden, H.; Cordova, A.
Organocatalytic Asymmetric 5-Hydroxypyrrolidine Synthesis: a
Highly Enantioselective Route to 3-Substituted Proline Derivatives.
Tetrahedron Lett. 2007, 48, 8695−8699. (b) Liu, Y.; Usui, A.;
Shirakawa, S.; Maruoka, K. Catalytic Asymmetric Synthesis of 3-
Substituted Proline Derivatives by Using Phase-Transfer-Catalyzed
Conjugate Addition. Asian J. Org. Chem. 2012, 1, 180−186.
̈
(13) Huy, P.; Neudorfl, J.-M.; Schmalz, H.-G. A Practical Synthesis
of Trans-3-Substituted Proline Derivatives through 1,4-Addition. Org.
Lett. 2011, 13, 216−219.
(14) For reviews, see: (a) Fagnou, K.; Lautens, M. Rhodium-
Catalyzed Carbon−Carbon Bond Forming Reactions of Organo-
metallic Compounds. Chem. Rev. 2003, 103, 169−196. (b) Hayashi,
T.; Yamasaki, K. Rhodium-Catalyzed Asymmetric 1,4-Addition and
Its Related Asymmetric Reactions. Chem. Rev. 2003, 103, 2829−2844.
(c) Heravi, M. M.; Dehghani, M.; Zadsirjan, V. Rh-Catalyzed
Asymmetric 1,4-Addition Reactions to α,β-Unsaturated Carbonyl
and Related Compounds: an Update. Tetrahedron: Asymmetry 2016,
27, 513−588. (d) Sakai, M.; Hayashi, H.; Miyaura, N. Rhodium-
Catalyzed Conjugate Addition of Aryl- or 1-Alkenylboronic Acids to
Enones. Organometallics 1997, 16, 4229−4231. (e) Takaya, Y.;
Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. Rhodium-
Catalyzed Asymmetric 1,4-Addition of Aryl- and Alkenylboronic
Acids to Enones. J. Am. Chem. Soc. 1998, 120, 5579−5580. (f) Tian,
P.; Dong, H.-Q.; Lin, G.-Q. Rhodium-Catalyzed Asymmetric
Arylation. ACS Catal. 2012, 2, 95−119.
Beyermann, M.; Freund, C.; Muller, M.; Oschkinat, H.; Kuhne, R.;
̈ ̈
Schmalz, H.-G. Addressing Protein−Protein Interactions with Small
Molecules: A Pro-Pro Dipeptide Mimic with a PPII Helix
Conformation as a Module for the Synthesis of PRD-Binding
Ligands. Angew. Chem., Int. Ed. 2010, 49, 7111−7115.
(5) (a) Stocking, E. M.; Martinez, R. A.; Silks, L. A.; Sanz-Cervera, J.
F.; Williams, R. M. Studies on the Biosynthesis of Paraherquamide:
Concerning the Mechanism of the Oxidative Cyclization of l-
Isoleucine to β-Methylproline. J. Am. Chem. Soc. 2001, 123, 3391−
3392. (b) Stocking, E. M.; Sanz-Cervera, J. F.; Unkefer, C. J.;
Williams, R. M. Studies on the Biosynthesis of Paraherquamide.
Construction of the Amino Acid Framework. Tetrahedron 2001, 57,
5303−5320. (c) Tan, L. T.; Cheng, X. C.; Jensen, P. R.; Fenical, W.
Scytalidamides A and B, New Cytotoxic Cyclic Heptapeptides from a
Marine Fungus of the Genus Scytalidium. J. Org. Chem. 2003, 68,
8767−8773. (d) Bhat, C.; Tilve, S. G. Recent Advances in the
Synthesis of Naturally Occurring Pyrrolidines, Pyrrolizidines and
Indolizidine Alkaloids Using Proline as a Unique Chiral Synthon. RSC
Adv. 2014, 4, 5405−5452. (e) O’Hagan, D. Pyrrole, Pyrrolidine,
Pyridine, Piperidine and Tropane Alkaloids. Nat. Prod. Rep. 2000, 17,
435−446.
(15) (a) Reetz, M. T.; Moulin, D.; Gosberg, A. BINOL-Based
Diphosphonites as Ligands in the Asymmetric Rh-Catalyzed
Conjugate Addition of Arylboronic Acids. Org. Lett. 2001, 3, 4083−
4085. (b) Chapman, C. J.; Wadsworth, K. J.; Frost, C. G.
Enantioselective Rhodium-Catalysed Addition of Boronic Acids
using C2-Symmetric Aryl Diphosphite Ligands. J. Organomet. Chem.
748
https://dx.doi.org/10.1021/acscatal.0c04648
ACS Catal. 2021, 11, 743−749

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
̈
2003, 680, 206−211. (c) Hargrave, J. D.; Bish, G.; Kohn, G. K.; Frost,
C. G. Rhodium-Catalysed Conjugate Addition of Arylboronic Acids
to Enantiopure Dehydroamino Acid Derivatives. Org. Biomol. Chem.
2010, 8, 5120−5125. (d) Navarre, L.; Darses, S.; Genet, J. P. Tandem
1,4-Addition/Enantioselective Protonation Catalyzed by Rhodium
Complexes: Efficient Access to α-Amino Acids. Angew. Chem., Int. Ed.
2004, 43, 719−723. (e) Navarre, L.; Martinez, R.; Genet, J.-P.;
Darses, S. Access to Enantioenriched α-Amino Esters via Rhodium-
Catalyzed 1,4-Addition/Enantioselective Protonation. J. Am. Chem.
Soc. 2008, 130, 6159−6169.
Rhodium and Palladium Catalysis: Complementary Electrophilic and
Nucleophilic Arylation. Chem. Commun. 2007, 3903−3905. (c) Key,
H. M.; Miller, S. J. Site- and Stereoselective Chemical Editing of
Thiostrepton by Rh-Catalyzed Conjugate Arylation: New Analogues
and Collateral Enantioselective Synthesis of Amino Acids. J. Am.
Chem. Soc. 2017, 139, 15460−15466. (d) Le, D. N.; Hansen, E.;
Khan, H. A.; Kim, B.; Wiest, O.; Dong, V. M. Hydrogenation Catalyst
Generates Cyclic Peptide Stereocentres in Sequence. Nat. Chem.
2018, 10, 968−973.
(28) The addition of pyridine to a successful reaction is detrimental
to conversion, although it has little effect on the stereochemical
outcome; Adding two equivalents of pyridine to a reaction with
phenylboronic acid as the substrate causes diminished conversion
(50% conversion to 2), but only slightly eroded dr of 2 (15:1) is
observed and high ee (96% ee) is maintained.
(29) Use of chiral diene ligand L2 for the synthesis of 30 and 31
resulted in lower conversions and products with low dr.
(30) When single stereoisomer trans-2 is subjected to 1 equiv of
LiOMe in MeOH/THF at 60 °C for 5 h, approximately 35%
saponification is observed, and the resulting 65% of material has
epimerized to give 4.2:1 trans-2:cis-2.
(16) (a) Hayashi, T.; Senda, T.; Ogasawara, M. Rhodium-Catalyzed
Asymmetric Conjugate Addition of Organoboronic Acids to Nitro-
alkenes. J. Am. Chem. Soc. 2000, 122, 10716−10717. (b) Belyk, K. M.;
Beguin, C. D.; Palucki, M.; Grinberg, N.; DaSilva, J.; Askin, D.;
Yasuda, N. A Rapid Catalytic Asymmetric Synthesis of 1,3,4-
Trisubstituted Pyrrolidines. Tetrahedron Lett. 2004, 45, 3265−3268.
(c) Dziechciejewski, W. J.; Weber, R.; Sowada, O.; Boysen, M. M. K.
Cycloalkene Carbonitriles in Rhodium-Catalyzed 1,4-Addition and
Formal Synthesis of Vabicaserin. Org. Lett. 2015, 17, 4132−4135.
(17) Mothes, C. Prolino Amino Acides Substitues en Position 3.
Syntheses, Applications Structurales et Pharmacologiques dans le
Developpement D’inhibiteurs D’interactions Peptide-Proteine et Proteine-
Proteine; Universite Pierre et Marie Curie: Paris, France, 2009.
(18) In 2009, the Karoyan group showed in a single example that 1
was reactive towards Rh-ACA with potassium phenyltrifluoroborate
and [Rh(OH)COD]2/(S)-BINAP at high temperatures in methanol
to afford 2 in 65% yield as a racemate. See refs 3,17.
́
̀
́
́
́
́
́
(19) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. A Chiral
Chelating Diene as a New Type of Chiral Ligand for Transition Metal
Catalysts: Its Preparation and Use for the Rhodium-Catalyzed
Asymmetric 1,4-Addition. J. Am. Chem. Soc. 2003, 125, 11508−11509.
(20) (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.
(21) Tang, W.; Zhang, X. New Chiral Phosphorus Ligands for
Enantioselective Hydrogenation. Chem. Rev. 2003, 103, 3029−3070.
(22) (a) Shevlin, M. Practical High-Throughput Experimentation for
Chemists. ACS Med. Chem. Lett. 2017, 8, 601−607. (b) Krska, S. W.;
DiRocco, D. A.; Dreher, S. D.; Shevlin, M. The Evolution of Chemical
High-Throughput Experimentation To Address Challenging Prob-
lems in Pharmaceutical Synthesis. Acc. Chem. Res. 2017, 50, 2976−
2985.
(23) (a) Burk, M. J. C2-Symmetric Bis(phospholanes) and Their
Use in Highly Enantioselective Hydrogenation Reactions. J. Am.
Chem. Soc. 1991, 113, 8518−8519. (b) Burk, M. J.; Feaster, J. E.;
Harlow, R. L. New Electron-Rich Chiral Phosphines for Asymmetric
Catalysis. Organometallics 1990, 9, 2653−2655. (c) Burk, M. J.;
Feaster, J. E.; Harlow, R. L. New Chiral Phospholanes; Synthesis,
Characterization, and Use in Asymmetric Hydrogenation Reactions.
Tetrahedron: Asymmetry 1991, 2, 569−592.
(24) Imamoto, T.; Sugita, K.; Yoshida, K. An Air-Stable P-Chiral
Phosphine Ligand for Highly Enantioselective Transition-Metal-
Catalyzed Reactions. J. Am. Chem. Soc. 2005, 127, 11934−11935.
(25) Pilkington, C. J.; Zanotti-Gerosa, A. Expanding the Family of
Phospholane-Based Ligands: 1,2-Bis(2,5-diphenylphospholano)-
ethane. Org. Lett. 2003, 5, 1273−1275.
(26) CAS number for (R,R)-enantiomer: 528565-84-6. CAS number
for (S,S)-enantiomer: 849950-53-4.
(27) (a) Bogart, J. W.; Bowers, A. A. Dehydroamino Acids:
Chemical Multi-Tools for Late-Stage Diversification. Org. Biomol.
Chem. 2019, 17, 3653−3669. (b) Chapman, C. J.; Matsuno, A.; Frost,
C. G.; Willis, M. C. Site-Selective Modification of Peptides Using
749
https://dx.doi.org/10.1021/acscatal.0c04648
ACS Catal. 2021, 11, 743−749