Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self-inhibition

Article abstract of DOI:10.1002/chir.23132

Chirality plays a pivotal role in an uncountable number of biological processes, and nature has developed intriguing mechanisms to maintain this state of enantiopurity. The strive for a deeper understanding of the different elements that constitute such s

Full text of DOI:10.1002/chir.23132

Received: 30 July 2019
DOI: 10.1002/chir.23132
Revised: 13 August 2019
Accepted: 16 August 2019
R E G U L A R A R T I C L E
Design and synthesis of a stereodynamic catalyst with
reversal of selectivity by enantioselective self‐inhibition
Jan Felix Scholtes1,2 | Oliver Trapp1,2
1 Department of Chemistry, Ludwig‐
Abstract
Maximilians‐University Munich, Munich,
Chirality plays a pivotal role in an uncountable number of biological processes,
and nature has developed intriguing mechanisms to maintain this state of
enantiopurity. The strive for a deeper understanding of the different elements
that constitute such self‐sustaining systems on a molecular level has sparked
great interest in the studies of autoinductive and amplifying enantioselective
reactions. The design of these reactions remains highly challenging; however,
the development of generally applicable principles promises to have a consider-
able impact on research of catalyst design and other adjacent fields in the
future. Here, we report the realization of an autoinductive, enantioselective
self‐inhibiting hydrogenation reaction. Development of a stereodynamic cata-
lyst with chiral sensing abilities allowed for a chiral reaction product to interact
with the catalyst and change its selectivity in order to suppress its formation,
which caused a reversal of selectivity over time.
Germany
2 Max‐Planck‐Institute for Astronomy,
Heidelberg, Germany
Correspondence
Prof. Dr Oliver Trapp, Department of
Chemistry, Ludwig‐Maximilians‐
University Munich, Butenandtstr. 5‐13,
81377 Munich, Germany.
Email: oliver.trapp@cup.uni‐muenchen.de
Funding information
H2020 European Research Council,
Grant/Award Number: AMPCAT 258740;
Max‐Planck‐Gesellschaft,
Grant/Award Number: Max‐Planck‐Fel-
low; Max‐Planck‐Society; European
Research Council (ERC),
Grant/Award Number: 258740
KEYWORDS
asymmetric catalysis, autoinduction, chirality transfer, ligand design, noncovalent interaction, tropos
ligands
1 | INTRODUCTION
Even before the first experimental realization of
stereoamplification, Frank described a “mutual antago-
The basis of an autoinductive, asymmetric reaction is the
participation of the chiral product in its own formation.
This may involve the incorporation of the product into a
larger catalyst structure or catalytic activity of the product
molecules themselves.1 A self‐amplifying reaction also
necessitates occurrence of nonlinear effects,2 which can
lead to a significant growth of the enantiomeric excess
as demonstrated first by Kagan and Noyori.3-5 Along
similar lines, Mikami and coworkers applied concepts
of stereoselective activation and deactivation by combin-
ing racemic ligands with chiral coligands to induce
enantioselectivity in various transformations.6-8
nism,” where the desired reaction is assisted by the induc-
ing product and the undesired reaction is simultaneously
suppressed in order to prevent a decrease in selectivity, as
a fundamental requirement.9
The first experimental examples that combine
autoinduction and amplification were delivered by
Wynberg and Alberts and later by Wynberg and Feringa,
who observed autoinductive properties during C―C bond
formation.10,11 Danda et al12 and Shvo et al13 performed
enantioselective hydrocyanation reactions on aldehydes
incorporating the reaction products into the chiral cata-
lysts, while Figadère et al14 reported autoinductive aldol
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© 2019 The Authors. Chirality published by Wiley Periodicals, Inc.
Chirality. 2019;1–15.
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1

2
SCHOLTES AND TRAPP
reactions between 2‐trimethylsilyloxyfuran and various
aldehydes in the presence of a BINOL‐Ti catalyst. The
most prominent example is the Soai reaction, a self‐
amplifying, autocatalytic reaction in which substituted
5‐pyrimidinecarbaldehydes react with diisopropylzinc to
form the corresponding pyrimidyl alcohols. Catalyzed by
zinc complexes of the same alcohol, even very small
enantiomeric surpluses in the latter are sufficient to alkyl-
ate aldehydes with high enantioselectivities.15,16
shown that stereodynamic 3,3′‐methoxy‐2,2′‐biphenol‐
based ligands with (S)‐amino acid‐derived interaction
sites (selectors) in the 5,5′‐position can be aligned by
other (S)‐amino acid‐derived diamides to induce the
opposite stereo information during subsequent asymmet-
ric hydrogenation reactions. Diamide selectors were
found to interact in a highly enantioselective manner;
however, overly efficient binding resulted in the forma-
tion of supramolecular ligand adducts and a concurrent
loss of ligand's stereo dynamics.29,30 As a consequence,
ligands with the same biphenyl core, decorated with (S)‐
phenylalanine‐derived amido ester groups, were to be
investigated. These were believed to be able to differenti-
ate the chirality of structurally similar molecules in their
surroundings.31 Enantioselective interaction with amino
acid derivatives of the same configuration was envisioned
to induce a change of the ligand's rotameric ratio, while
not adversely affecting the fluxional nature of the
stereodynamic ligand core. In a two‐stage development
process, it was decided to (a) conduct interaction studies
with ligands and different chiral additives to evaluate
the degree of chirality transfer32,33 and subsequently (b)
apply these results to design an autoinductive, self‐
inhibiting, rhodium‐catalyzed hydrogenation reaction,
where reduction of an appropriately substituted olefin
would yield amino acid‐derived reaction products capable
of changing the catalysts selectivity.34
Recently, we developed a self‐amplifying, asymmetric
hydrogenation reaction for prochiral olefins.17 It features
a tropos biphenyl‐based ligand18-22 with a low barrier of
inversion.17,23 The ligand backbone was modified with
interaction sites for efficient noncovalent bonding,24,25
which were derived from a chiral recognition system
developed by Pirkle and Murray.26-28During the course
of the reaction, enantioselective, noncovalent interactions
between chiral reaction products and the interaction sites
on the rhodium catalyst induce changes in the complex
structure, thus enhancing the catalyst's selectivity in sub-
sequent turnovers.17 The most crucial requirements for
this system include (a) constant adaptation to changing
equilibria which is provided by the dynamic nature of
noncovalent interactions between catalyst and reaction
product, (b) the rapid incorporation of the chiral reaction
product into the reaction cycle of a comparatively slower
hydrogenation reaction, (c) the enantioselectivity of the
interaction between selector and product molecules,
which created the basis for mutual antagonism, and (d)
a fast stereochemical response during product‐selector
interaction that leads to immediate structural change in
the catalyst.
2 | MATERIALS AND METHODS
2.1 | General methods
We believed that a reaction featuring an autoinductive,
self‐inhibiting process based on the same prerequisites
would be of equal interest due to its complementary,
“inverse” nature (see Figure 1). Earlier studies have
All reactions involving the use of oxygen and/or moisture
sensitive substances were carried out in heat dried glass-
ware under an atmosphere of nitrogen or argon using
FIGURE 1 Conceptual representation of two types of autoinductive catalytic reactions that have been studied in the Trapp group and that
feature either enantioselective self‐amplification or enantioselective self‐inhibition

SCHOLTES AND TRAPP
3
standard Schlenk techniques. All chemicals were used as
received from suppliers without further purification. Col-
umn chromatography was done using silica gel (technical
grade, pore size 60 Å, 70‐230 mesh, 63‐200 μm) produced
by Sigma‐Aldrich Chemie GmbH. Thin layer chromatog-
raphy was performed on coated aluminum sheets
(Machery‐Nagel POLYGRAM SIL G/UV 254). Compo-
nents were visualized by fluorescence quenching during
irradiation with UV light (254 nm). Dry solvents were
taped from solvent purification system MB SPS‐800 and
used immediately. Dry and stabilized THF (250 ppm
butylated hydroxytoluene) was purchased from Sigma‐
Aldrich Chemie GmbH. Manual degassing of solvents, if
needed, was done by performing three consecutive
freeze‐pump‐thaw cycles. Oxygen‐free solvents were then
placed under an atmosphere of argon.
was re‐extracted with more ethyl acetate (twice with 100
mL each). Combined organic layers were washed with
brine (100 mL), dried over sodium sulfate, and evaporated
to give a yellow oil, which crystallized into an off‐white
solid upon prolonged drying in high vacuum (9.46 g,
1
22.1 mmol, 97%). H NMR (CDCl3, 598.76 MHz, 300 K):
δ = 3.88 (s, 3H), 3.93 (s, 6H), 4.43‐4.45 (m, 2H), 4.99‐
5.02 (m, 1H), 5.05‐5.09 (m, 1H), 5.71‐5.79 (m, 1H), 7.60
4
4
(d, 1H, J(H,H) = 2.0 Hz), 7.61 (d, 1H, J(H,H) = 2.0
Hz) ppm. 13C{1H} NMR (CDCl3, 150.57 MHz, 300 K): δ
= 52.2, 56.2, 74.1, 113.0, 117.5, 125.2, 125.3, 132.3, 134.0,
150.1, 152., 166.8 ppm. HRMS (ESI): m/z calcd. for
C24H30N1O8 [M + NH4]+: 460.1966; found: 460.1971.
FTIR: ṽ = 761 (s), 981 (s), 1042 (s), 1173 (s), 1222 (s),
1286 (s), 1714 (s), 2845 (w), 2870 (w), 2951 (m), 3015
(w), 3090 (w) cm−1
.
NMR spectra were recorded on Varian NMR‐System
(300, 400, and 600 MHz) and Bruker Avance III HD and
DRX (300, 400, 600, and 800 MHz). NMR shifts are given
in parts per million (ppm) and are referenced to the resid-
ual proton or carbon solvent signals.35 Multiplicity is
termed as follows: s (singlet), bs (broad singlet), d (dou-
blet), t (triplet), q (quartet), quint (quintet), sept (septet),
dd (doublet of a doublet), dt (doublet of triplet) and tt
(triplet of triplet), and m (multiplet). Assignment was
done by means of two‐dimensional experiments (1H‐1H‐
2.3 | 6,6′‐Bis (allyloxy)‐5,5′‐dimethoxy‐
[1,1′‐biphenyl]‐3,3′‐dicarboxylic acid (3)
Diester 2 (9.40 g, 21.2 mmol, 1.00 eq.) and sodium hydrox-
ide (8.50 g, 212 mmol, 10.0 eq.) were dissolved in a mix-
ture of water (110 mL) and THF (110 mL), and the
biphasic system was refluxed under vigorous stirring for
14 hours. For work‐up, THF was evaporated, and the
aqueous orange solution was acidified with conc. HCl
solution (6 M) until pH 1 was reached and a thick, white
precipitate formed. The solids were filtered off and
washed with more water to neutrality. Freeze‐drying
afforded product as a white powder (8.80 g, 21.2 mmol,
COSY, H‐13C‐HSQC, and H‐13C‐HMBC). Mass spectra
were acquired on Thermo Finnigan LTQ FT Ultra FT‐
ICR (ESI) or Thermo Q Finnigan MAT 95 (EI). For
solid‐state IR analysis, Thermo Fisher Nicolet 6700 FT‐
IR‐Spectrometer was employed, and the wavenumber of
reflectance was measured with signals being denoted as
s (strong), m (medium), w (weak), and b (broad). Elemen-
tal analysis was conducted on an Elementar vario micro
cube equipped with a thermal conductivity detector.
1
1
1
99%). H NMR (CDCl3, 800.34 MHz, 300 K): δ = 3.90 (s,
3H), 4.37 to 4.38 (m, 2H), 4.99 to 5.01 (m, 1H), 5.04 to
4
5.06 (m, 1H), 5.68 to 5.73 (m, 1H), 7.41 (d, 1H, J(H,H)
4
= 2.0 Hz), 7.57 (d, 1H, J(H,H) = 2.0 Hz), 12.91 (bs, 1H)
ppm. 13C{1H} NMR (CDCl3, 201.24 MHz, 300 K): δ =
55.9, 73.2, 112.8, 117.1, 124.3, 125.7, 131.5, 134.1, 149.0,
152.1, 166.8 ppm. HRMS (ESI): m/z calcd. for
C22H26NO8 [M + NH4]+: 432.16529; found: 432.16564.
FTIR: ṽ = 759 (s), 980 (s), 1040 (s), 1179 (s), 1218 (s),
1285 (s), 1404 (s), 1577 (s), 1677 (s), 2519 (bm), 2837
2.2 | Dimethyl 6,6′‐bis (allyloxy)‐5,5′‐
dimethoxy‐[1,1′‐biphenyl]‐3,3′‐
dicarboxylate (2)
(bm), 2970 (bm), 3063 (w) cm−1
.
This compound was prepared according to a known pro-
cedure.36 Unprotected biphenol was prepared from
37
methyl vanillate according to literature. The biphenol
2.4 | Di‐tert‐butyl 2,2′‐((6,6′‐bis (allyloxy)‐
5,5′‐dimethoxy‐[1,1′‐bi‐phenyl]‐3,3′‐
dicarbonyl)bis (azanediyl))(2S,2′S)‐bis(3‐
phenylpropanoate) (4a)
(8.00 g, 22.1 mmol, 1.00 eq.) and potassium carbonate
(30.5 g, 221 mmol, 10.0 eq.) were suspended in 2‐
butanone (250 mL). Allyl bromide (9.55 mL, 110 mmol,
5.00 eq.) was added, and the mixture was refluxed for 24
hours. All volatiles were subsequently evaporated, and
the solid residue was heated to 70°C for 1 hour under vac-
uum to remove residual allyl bromide. Solids were then
partitioned between ethyl acetate (200 mL) and water
(200 mL), layers were separated, and the aqueous layer
Dicarboxylic acid 3 (4.00 g, 9.65 mmol, 1.00 eq.) was
placed in a dried Schlenk flask with reflux condenser
and overpressure ventilation, and thionyl chloride (30
mL) was added. The mixture was refluxed for 7 hours
and turned unto a clear, brown solution within minutes.

4
SCHOLTES AND TRAPP
Subsequently, thionyl chloride was removed in vacuo,
residual solids were suspended in dry toluene (15 mL),
and all volatiles were removed again. The last two steps
were repeated another two times, and after drying, the
product was obtained as a grey solid. Allyl‐protected acid
chloride (800 mg, 4.43 mmol, 2.50 eq.) was dissolved in
dry DCM (4 mL). In a separate flask, phenylalanine tert‐
butyl ester hydrochloride (1.14 g, 4.43 mmol, 2.50 eq.)
was mixed with diisopropylethylamine (1.54 mL, 8.86
mmol, 5.00 eq.) in dry DCM (10 mL) to give a clear solu-
tion. Both mixtures were cooled in an ice bath, and the
acid chloride was subsequently added dropwise to the
selector solution. The resulting orange solution was
slowly warmed to room temperature, and stirring was
continued for 18 hours. For work‐up, the mixture was
diluted with ethyl acetate (120 mL) and subsequently
washed with HCl solution (2 M, 3 120 mL), saturated
bicarbonate solution (2 × 120 mL), and brine (120 mL),
dried over sodium sulfate and evaporated to yield the
and brine (1 × 100 mL), dried over sodium sulfate, and
evaporated on celite. Purification by column chromatogra-
phy (silica, n‐pentane:ethyl acetate 1:2, Rf = 0.4). Appro-
priate fractions were evaporated, and the residue
precipitated from ethyl acetate:n‐pentane to yield the
desired diol 5a as an off‐white powder (481 mg, 649 μmol,
1
71%). H NMR (CDCl3, 598.74 MHz, 300 K): δ = 1.39 (s,
9H), 3.13‐3.23 (m, 2H), 3.90 (s, 3H), 5.03‐5.04 (m, 1H),
6.20 (bs, 1H), 7.17‐7.23 (m, 5H), 7.27 (s, 1H), 7.30 (s, 1H),
7.39 (s, 1H) ppm. 13C{1H} NMR (CDCl3, 150.57 MHz, 300
K): δ = 55.9, 73.2, 112.8, 117.1, 124.3, 125.7, 131.5, 134.1,
149.0, 152.1, 166.8 ppm. HRMS (ESI): m/z calcd. for
C42H49N2O10 [M + H]+: 741.3382; found: 741.3391. FTIR:
ṽ = 698 (s), 1042 (s), 1086 (s), 1150 (s), 1220 (s), 1366 (s),
1487 (s), 1593 (s), 1636 (s), 1710 (s), 2933 (m), 2977 (m),
3029 (w), 3330 (bm), 3508 (bw) cm−1
.
2.6 | Di‐tert‐butyl 2,2′‐((6,6′‐bis
((diphenylphosphaneyl)oxy)‐5,5′‐
dimethoxy‐[1,1′‐biphenyl]‐3,3′‐dicarbonyl)
bis (azanediyl))‐(2S,2′S)‐bis(3‐
phenylpropanoate) (6a)
1
product as a brown powder (1.33 g, 1.62 mmol, 91%). H
NMR (CDCl3, 598.47 MHz, 300 K): δ = 1.39 (s, 9H), 3.14
to 3.26 (m, 2H), 3.89 (s, 3H), 4.35 to 4.36 (m, 2H), 4.96
to 5.05 (m, 2H), 5.05 (s, 1H), 5.70 to 5.77 (m, 1H), 7.16
to 7.28 (m, 6H), 7.43 (s, 1H) ppm. The NH protons were
not observed. 13C{1H} NMR (CDCl3, 150.57 MHz, 300
K): δ = 28.1, 28.3, 54.5, 56.1, 74.1, 82.3, 111.7, 117.5,
121.2, 127.0, 128.3, 128.8, 129.5, 132.1, 134.0, 136.7,
148.7, 152.9, 166.2, 171.6 ppm. HRMS (ESI): m/z calcd.
for C48H57N2O10 [M + H]+: 821.4008; found: 821.4026.
FTIR: ṽ = 698 (s), 982 (s), 1151 (s), 1219 (s), 1366 (s),
1537 (s), 1639 (s), 1706 (s), 2867 (w), 2935 (w), 2978 (w),
Selector‐modified diol 5a (350 mg, 472 μmol, 1.00 eq.) and
1,4‐diazabicyclo[2.2.2]octane (DABCO, 212 mg, 1.89
mmol, 4.00 eq.) were placed in a flame‐dried Schlenk
flask and dissolved in dry and degassed DCM (10 mL).
The solution was cooled in an ice bath and PPh2Cl (326
μL, 1.89 mmol, 4.00 eq.) was added. After 15 minutes,
the ice bath was removed, and stirring was continued at
room temperature for another 2 hours. For work‐up, all
volatiles were removed, and the off‐white residue was
suspended in dry, degassed, and stabilized THF (5 mL).
The suspension was filtered through an inert pad of neu-
tral alumina, and the product was eluated with more
THF. Combined fractions were evaporated to give a white
foam. Re‐precipitation from DCM:n‐pentane (4x, 1:10
mL) gave the desired phosphinite 6a as a white powder
(105 mg, 94.8 mmol, 20%). The compounds exist as two
interconverting rotamers. The minor isomer (A, Sax)
3029 (w), 3062 (w), 3344 (bm) cm−1
.
2.5 | Di‐tert‐butyl 2,2′‐((6,6′‐dihydroxy‐5,5′‐
dimethoxy‐[1,1′‐biphenyl]‐3,3′‐dicarbonyl)
bis (azanediyl))(2S,2′S)‐bis(3‐
phenylpropanoate) (5a)
The deprotection was done by a known procedure,
which was slightly modified.38 To remove the allyl
groups, substrate 4a (750 mg, 914 mmol, 1.00 eq.), palla-
dium acetate (10.2 mg, 45.7 μmol, 0.05 eq.), and (4‐
dimethylaminophenyl)‐diphenylphosphine (140 mg,
457 μmol, 0.50 eq.) were dissolved in dry ethyl acetate
(18 mL), and the suspension was stirred for 15 minutes.
The resulting solution was treated with formic acid (0.20
mL, 5.30 mmol, 5.80 eq.), and the orange mixture was
subsequently refluxed. It quickly turned brown and gas
evolved. After 2 hours, the mixture was cooled to room
temperature and diluted with ethyl acetate (80 mL). The
organic layer was washed with HCl solution (2 M, 4 ×
100 mL), saturated bicarbonate solution (3 × 100 mL)
1
shows sharp NMR signals in 31P, H, and 13C NMR spec-
tra. For the major rotamer (B, Rax), significant line broad-
ening was detected in 31P and 1H NMR spectra, and even
with concentrated samples, almost no peaks could be
1
detected in the 13C NMR spectrum. H NMR (THF‐d8,
400.22 MHz, 300 K): δ = 1.37 (s, B), 1.39 (s, A), 3.04‐
3.09 (m, A), 3.12 (bs, B), 3.14‐3.19 (m, A), 3.27 (bs, B),
3.53 (bs, B), 3.59 (s, A), 4.75‐4.81 (m, A) 4.86 (bs, B),
6.91 (bs, B), 7.04‐7.26 (m, A and B), 7.12 (m, A), 7.28‐
4
3
7.35 (m, A), 7.35 (d, J(H,H) = 1.9 Hz, A), 7.40 (d, J(H,
H) = 7.7 Hz, A), 7.48 (bs, B), 8.47 (bs, B) ppm. 13C{1H}
NMR (THF‐d8, 100.54 MHz, 300 K): δ = 27.2, 37.5, 54.4,

SCHOLTES AND TRAPP
5
54.7, 54.9, 80.5, 111.8, 121.1, 120.8, 126.3, 126.2, 127.3,
127.3, 127.4, 127.5, 127.5, 127.5, 127.9, 129.1, 129.2,
129.3, 129.5, 129.5, 129.7, 130.3, 130.5, 130.6, 130.7,
131.3, 137.7, 138.0, 142.5, 142.7, 143.0, 143.1, 147.5,
151.2, 165.0, 165.1, 170.8 ppm. 31P{1H} NMR (THF‐d8,
161.85 MHz, 300 K): δ = 118.4 (bs, 1P, B), 121.1 (s, 1P,
A), 121.1 (bs, 1P, B) ppm. HRMS (ESI): m/z calcd. for
C66H67N2O10P2 [M + H]+: 1109.4271; found: 1109.4286.
FTIR: ṽ = 694 (s), 863 (m), 1094 (s), 1152 (s), 1367 (s),
1476 (s), 1642 (s), 1707 (s), 2859 (w), 1933 (w), 2977 (w),
washed with HCl solution (2 M, 3 × 300 mL), saturated
bicarbonate solution (3 × 300 mL), and brine (1 × 300
mL), dried over sodium sulfate and evaporated to give
the product as a yellow oil, which crystallized into an
amorphous solid after prolonged drying (4.57 g, 20.7
1
mmol, 69%). H NMR (CDCl3, 800.34 MHz, 300 K): δ =
2
1.29 (s, 9H), 2.78 (bs, 1H), 2.93 (dd, 1H, J(H,H) = 13.9
3
2
Hz, J(H,H) = 7.6 Hz), 3.12 (dd, 1H, J(H,H) = 13.9 Hz,
3J(H,H) = 4.8 Hz), 4.16 (dd, 1H, J(H,H) = 7.6 Hz, J(H,
H) = 4.9 Hz), 6.13 (s, 1H), 7.24 to 7.26 (m, 3H), 7.30 to
7.32 (m, 2H) ppm. 13C{1H} NMR (CDCl3, 201.24 MHz,
300 K): δ = 28.7, 41.1, 51.1, 72.9, 127.1, 128.8, 129.8,
137.1, 172.0 ppm. HRMS (ESI): m/z calcd. for
C13H18NO2 [M + H]+: 220.1343; found: 220.1344. FTIR:
ṽ = 697 (s), 742 (s), 1089 (s), 1186 (s), 1223 (s), 1454 (s),
1528 (s), 1642 (s), 1743 (s), 2929 (m), 2968 (m), 3030
(w), 3063 (w), 3088 (w), 3225 (bs), 3335 (w), 3397 (w)
cm−1. [α]D20−56.5 (c 1%, CHCl3).
3
3
3054 (w), 3349 (bm) cm−1
.
2.7 | [Rh(6a)(COD)]BF4 (7a)
Bisphosphinite 6a (53 mg, 47.8 μmol, 1.00 eq.) and [Rh
(COD)2]BF4 (19.4 mg, 47.8 μmol, 1.00 eq.) were placed in
a flame‐dried Schlenk flask and dissolved in dry and
degassed DCM (3.5 mL). The clear orange solution was
stirred for 2 hours at room temperature and then concen-
trated to 1.0 mL. Addition of dry and degassed pentane
(10 mL) gave an orange precipitate. The supernatant solu-
tion was removed using a filter‐tipped cannula, and re‐pre-
cipitation was repeated another two times. The solids were
finally dried in high vacuum to give the desired Rh com-
plex as a yellow powder (61.0 mg, 43.4 μmol, 91%). The
compound exists as two interconverting rotamers. 31P
2.9 | Bis((S)‐1‐(tert‐butylamino)‐1‐oxo‐3‐
phenylpropan‐2‐yl) 6,6′‐bis (allyloxy)‐5,5′‐
dimethoxy‐[1,1′‐biphenyl]‐3,3′‐
dicarboxylate (4b)
Dicarboxylic acid 3 (1.00 g, 2.41 mmol, 1.00 eq.), amido
alcohol S1 (2.14 g, 9.56 mmol, 4.00 eq.), and N,N‐
dimethylaminopyridine (59.0 mg, 482 μmol, 0.20 eq.)
were mixed in dry DCM (40 mL) and cooled in an ice
bath. EDCI.HCl (1.16 g, 6.03 mmol, 2.50 eq.) was added,
and the yellow solution was left stirring to warm to
room temperature overnight. After 18 hours, the mixture
was diluted with ethyl acetate (200 mL) and subse-
quently washed with HCl solution (2 M, 3 × 180 mL),
saturated bicarbonate solution (2 × 180 mL), and brine
(180 mL), dried over sodium sulfate, and evaporated.
Purification by column chromatography (neutral alu-
mina, diethyl ether:toluene 3:1, Rf = 0.6) yielded the
1
{1H} NMR (CDCl3, 161.98 MHz, 300 K): δ = 127.91 (d, J
1
(P,Rh) = 179.9 Hz, Sax), 128.02 (d, J(P,Rh) = 181.3 Hz,
Rax) ppm. EA (CHNS): calcd. for C74H78N2O10P2RhBF4:
C: 63.17, H: 5.59, N: 1.99; found: C: 61.24, H: 5.48, N:
1.93. HRMS (ESI): m/z calcd. for C74H78N2O10P2Rh
‐ +
[M‐BF4 ] : 1319.4181; found: 1319.4175. FTIR: ṽ = 695
(s), 745 (s), 1039 (s), 1095 (s), 1154 (s), 1215 (m), 1368
(m), 1464 (m), 1585 (m), 1731 (m), 2932 (w), 1376 (w),
3031 (w), 3358 (bm) cm−1
.
2.8 | (S)‐N‐(tert‐butyl)‐2‐hydroxy‐3‐
phenylpropanamide (S1)
1
product as a white solid (1.00 g, 1.22 mmol, 50%). H
NMR (CDCl3, 598.74 MHz, 300 K): δ = 1.24 (s, 9H),
3.26 to 3.28 (m, 2H), 3.92 (s, 3H), 4.42 to 4.43 (m, 2H),
4.99 to 5.08 (m, 2H), 5.43 to 5.45 (m, 1H), 5.58 (s, 1H),
5.71 to 5.77 (m, 1H), 7.19 to 7.22 (m, 1H), 7.22 to 7.29
(S)‐3‐Phenyl lactic acid (5.00 g, 30.1 mmol, 1.00 eq.) and
hydroxybenzotriazole (4.47 g, 33.1 mmol, 1.10 eq.)
were dissolved in dry DMF (60 mL). Diisopropylethyl
amine (10.5 mL, 60.2 mmol, 2.00 eq.) was added, the
solution was cooled in an ice bath, and
3‐(Ethyliminomethyleneamino)‐N,N‐dimethylpropan‐1‐
amine hydro chloride (EDCI.HCl, 6.34 g, 33.1 mmol, 1.10
eq.) was added. After 15 minutes, all solids had dissolved,
and the solution was treated with tert‐butyl amine (3.48
mL, 33.1 mmol, 1.10 eq.). After 30 minutes at lower temper-
atures, the mixture was warmed to room temperature
again, and stirring was continued for 18 hours. The mixture
was subsequently diluted with ethyl acetate (500 mL) and
4
4
(m, 4H), 7.53 (d, 1H J(H,H) = 2.0 Hz), 7.55 (d, 1H, J
(H,H) = 2.0 Hz) ppm. 13C{1H} NMR (CDCl3, 150.57
MHz, 300 K): δ = 28.7, 38.0, 51.3, 56.2, 74.2, 75.3,
113.2, 117.7, 124.3, 125.4, 127.1, 128.5, 130.0, 132.3,
133.9, 136.2, 150.6, 152.7, 164.9, 168.0 ppm. HRMS
(ESI): m/z calcd. for C48H60N3O10 [M
+
NH4]+:
838.4273; found: 838.4279. FTIR: ṽ = 696 (s), 979 (s),
1169 (s), 1217 (s), 1657 (s), 1711 (s), 2867 (w), 2966
(w), 3029 (w), 3088 (w), 3291 (bm) cm−1
.

6
SCHOLTES AND TRAPP
product 6b as a white solid (52.0 mg, 46.9 μmol, 69%).
Traces of Ph2P(O)PPh2 (side product) still remained and
could not be removed without significant loss of product.
For some atoms, an additional signal splitting was
2.10 | Bis((S)‐1‐(tert‐butylamino)‐1‐oxo‐3‐
phenylpropan‐2‐yl) 6,6′‐dihydroxy‐5,5′‐
dimethoxy‐[1,1′‐biphenyl]‐3,3′‐
dicarboxylate (5b)
1
observed. Those signals are marked X and X′. H NMR
The deprotection was done by a known procedure,
which was slightly modified.38 To remove the allyl
groups, substrate 4b (890 mg, 1.08 mmol, 1.00 eq.), pal-
ladium acetate (12.2 mg, 54.2 μmol, 0.05 eq.), and (4‐
dimethylaminophenyl)‐diphenylphosphine (166 mg, 542
μmol, 0.50 eq.) were dissolved in dry ethyl acetate
(18 mL), and the suspension was stirred for 15 minutes.
The resulting solution was treated with formic acid
(0.24 mL, 6.29 mmol, 5.80 eq.), and the orange mixture
was subsequently refluxed. It quickly lost its color and
gas evolved. After 1 hour, the mixture was cooled to room
temperature and diluted with ethyl acetate (100 mL). The
organic layer was washed with HCl solution (2 M, 4 × 100
mL), saturated bicarbonate solution (2 × 100 mL), and
brine (1 × 100 mL), dried over sodium sulfate and evapo-
rated. The residue was precipitated from ethyl acetate:n‐
pentane to yield the desired diol 5b as an off‐white powder
(745 mg, 1.01 mmol, 93%). 1H NMR (CDCl3, 598.47 MHz,
(THF‐d8, 399.78 MHz, 300 K): δ = 1.25 (s, 9H), 3.17 (dd,
2
3
2H, J(H,H) = 14.8 Hz, J(H,H) =, 6.6 Hz), 3.63 (s, 3H),
3
5.20 (q, J(H,H) = 6.3 Hz), 6.53 (s, 1H), 7.03 to 7.32 (m,
4
15H), 7.30 (s, 1H), 7.38 (d, 1H, J(H,H) = 2.0 Hz) ppm.
13C{1H} NMR (THF‐d8, 100.54 MHz, 300 K): δ = 27.8,
37.8, 50.3, 54.9, 75.1, 75.2, 112.9, 124.4, 124.7 (J(C,P) =
4.6 Hz), 126.3 (J(C,P) = 11.4 Hz), 127.4 (J(C,P) = 7.4
Hz), 127.6 (J(C,P) = 8.3 Hz), 127.9 (J(C,P) = 4.6 Hz),
128.3 (J(C,P) = 7.4 Hz), 128.8 (J(C,P) = 5.5 Hz), 129.4,
129.5 (J(C,P) = 5.8 Hz), 129.7 (J(C,P) = 11.5 Hz), 130.3
(J(C,P) = 12.9 Hz), 130.5 (J(C,P) = 12.9 Hz), 131.3, 137.0
(J(C,P) = 11.4 Hz), 142.5 (J(C,P) = 17.8 Hz), 142.7 (J(C,
P) = 16.6 Hz), 149.0 (J(C,P) = 7.3 Hz), 151.1 ((J(C,P) =
7.4 Hz), 164.2, 167.5, 167.6 ppm. 31P{1H} NMR (THF‐d8,
161.85 MHz, 300 K): δ = 122.4 (s), 122.5 (s) ppm. HRMS
(ESI): m/z calcd. for C66H67N2O10P2 [M
+
H]+:
1109.4266; found: 1109.4248. FTIR: ṽ = 692 (s), 1166 (s),
1211 (m), 1453 (m), 1657 (s), 1723 (m), 2867 (w), 2930
3
(m), 2965 (m), 3002 (w), 3056 (w), 3291 (bm) cm−1
.
300 K): δ = 1.25 (s, 9H), 3.27 (d, 2H, J(H,H) = 5.9 Hz),
3
3.98 (s, 3H), 5.46 (t, 1H, J(H,H) = 5.9 Hz), 5.63 (s, 1H),
6.39 (s, 1H), 7.19 to 7.21 (m, 1H), 7.23 to 7.26 (m, 4H),
7.49 (d, 1H, 4J(H,H) = 1.9 Hz), 7.71 (d, 1H, 4J(H,H)
= 1.9 Hz) ppm. 13C{1H} NMR (CDCl3, 150.57 MHz, 300
K): δ = 28.7, 38.00, 51.4, 56.5, 75.0, 111.2, 121.0, 122.8,
126.4, 127.0, 128.4, 130.0, 136.3, 146.8, 148.0, 164.9, 168.2
ppm. HRMS (ESI): m/z calcd. for C42H52N3O10 [M +
NH4]+: 758.3647; found: 758.3650. FTIR: ṽ = 699 (s), 740
(m), 1039 (m), 1208 (s), 1277 (s), 1454 (m), 1669 (s), 2868
(w), 2933 (w), 2965 (m), 3027 (w), 3065 (w), 3317 (bm),
2.12 | [Rh(6b)(COD)]BF4 (7b)
Bisphosphinite 6b (33 mg, 29.8 μmol, 1.00 eq.) and [Rh
(COD)2]BF4 (9.10 mg, 22.3 μmol, 1.00 eq.) were placed
in a dried Schlenk flask and dissolved in dry and degassed
DCM (2.0 mL). The clear orange solution was stirred for 2
hours at room temperature and then concentrated to 0.5
mL. Addition of dry and degassed n‐pentane (5.0 mL)
gave an orange precipitate. The supernatant solution
was removed using a filter‐tipped cannula, and re‐precip-
itation was repeated another two times. The solids were
finally dried in high vacuum to give the desired Rh com-
plex 7b as a yellow powder (23.3 mg, 16.6 μmol, 74%). The
compound exists as two rotamers A and B. 31P{1H} NMR
3407 (w) cm−1
.
2.11 | Bis((S)‐1‐(tert‐butylamino)‐1‐oxo‐3‐
phenylpropan‐2‐yl) 6,6′‐bis
((diphenylphosphaneyl)oxy)‐5,5′‐
dimethoxy‐[1,1′‐biphenyl]‐3,3′‐
dicarboxylate (6b)
1
(CDCl3, 161.98 MHz, 300 K): δ = 129.00 (d, J(P,Rh) =
1
179.9 Hz), 129.19 (d, J(P,Rh) = 179.8 Hz) ppm. HRMS
(ESI): m/z calcd. for C68H69N3O10P2Rh [M‐COD‐BF4 +
CH3CN]+: 1252.35077; found: 1252.34933.
Selector‐modified diol 5b (50 mg, 67.5 μmol, 1.00 eq.) was
dissolved in dry, degassed, and stabilized THF (2 mL),
and triethylamine (23.5 μL, 168 μmol, 2.50 eq.) was
added. The mixture was cooled in an ice bath, and
chlorodiphenylphosphine (24.2 μL, 142 μmol, 2.10 eq.)
was added. After 2 hours, the mixture was filtered
through a filter‐tipped cannula and residual solids rinsed
with more THF (2 × 2 mL). Combined organic washings
were evaporated, and the resulting white crude product
was washed with n‐pentane (5 × 2 mL) to give the
2.13 | Di‐tert‐butyl 2,2′‐((6‐(diethylamino)‐
4,8‐dimethoxydibenzo [d,f][1,3,2]
dioxaphosphepine‐2,10‐dicarbonyl)bis
(azanediyl)) (2S,2′S)‐bis(3‐
phenylpropanoate) (16)
Selector‐modified diol 5a (100 mg, 135 μmol, 1.00 eq.) was
dissolved in dry, degassed, and stabilized THF (2 mL),

SCHOLTES AND TRAPP
7
and triethylamine (54.6 μL, 391 μmol, 2.90 eq.) was
added. The mixture was cooled in an ice bath, and
diethylaminophosphoramidous dichloride (22.5 μL, 155
μmol, 1.15 eq.) was added dropwise. The mixture was
warmed to room temperature and stirred for 18 hours.
For work‐up, the mixture was filtered through a filter‐
tipped cannula, and residual solids were rinsed with more
THF (2 × 2 mL). Combined organic washings were evap-
orated and the crude product was washed with n‐pentane
(3 × 3 mL) to give compound 16 as a white solid (87.0 mg,
103 μmol, 77%). For some atoms, an additional signal
splitting was observed. This is caused by the nonequiva-
lence of the two halves in the biphenol‐phosphoramidite,
which has been previously observed for other chiral
phosphoramidites.39,40 1H NMR (THF‐d8, 400.22 MHz,
1894.7429; found: 1894.7464. EA (CHNS): calcd. for
C100H124N6O20P2RhBF4: C: 60.61, H: 6.31, N: 4.24; found:
C: 58.42, H: 6.13, N: 4.23. FTIR: ṽ = 697 (s), 879 (m), 1022
(s), 1153 (s), 1367 (s), 1456 (m), 1527 (m), 1663 (m), 1728
(m), 2872 (w), 2933 (w), 2975 (w), 3314 (bw) cm−1
.
2.15 | Additive syntheses
The following compounds are known in literature and
were prepared accordingly: (S/R)‐2‐acetamido‐N‐methyl‐
3‐phenylpropanamide
methylpropanamide
(10),41
(12)41,
(S)‐2‐acetamido‐N‐
and (S)‐N‐(1‐(tert‐
butylamino)‐1‐oxo‐3‐phenylpropan‐2‐yl)benzamide
(13)30. In all cases where gaseous amines were supposed
to be employed, these were substituted by their respective
alcoholic solutions.
3
300 K): δ = 1.05 (t, 3H, J(H,H) = 7.0 Hz), 1.40 (s, 9H),
3
3
3.05 (dd, 2H, J(P,H) = 10.8 Hz, J(H,H) = 7.0 Hz), 3.10
2
3
(dd, 1H, J(H,H) = 13.8 Hz, J(H,H) = 8.2 Hz), 3.18 (dd,
2
3
1H, J(H,H) = 13.8 Hz, J(H,H) = 6.5 Hz), 3.87 (s, 3H),
4.78 to 4.84 (m, 1H), 7.14 to 7.18 (m, 1H), 7.23 to 7.29
(m, 4H), 7.48 to 7.49 (m, 1H), 7.58 to 7.59 (m, 1H), 7.81
to 7.84 (m, 1H) ppm. 13C{1H} NMR (THF‐d8, 100.65
MHz, 300 K): δ = 14.7, 28.1, 38.6, 38.8, 55.7, 56.2, 81.5,
2.16 | (S)‐2‐acetamido‐N‐(3,5‐
dichlorophenyl)propanamide (11)
4
4
111.9 (d, J(P,C) = 9.6 Hz), 121.0 (d, J(P,C) = 12.4 Hz),
127.3, 129.0, 130.2, 131.8, 132.0 (m), 138.6, 144.3 (m),
152.9, 166.6, 171.8 ppm. 31P{1H} NMR (THF‐d8, 162.00
(S)‐N‐Acetyl alanine (200 mg, 1.53 mmol, 1.00 eq.) was
suspended in dry DCM (5 mL). EDCI.HCl (322 mg, 1.68
mmol, 1.10 eq.) was added, and the mixture was stirred
for 15 minutes to give a clear solution. Subsequently,
3,5‐dichloroaniline (260 mg, 1.60 mmol, 1.05 eq.) was
added as a solid to give a dark purple solution from
which solids precipitated shortly after. After 16 hours,
the solids were collected by filtration. The mother liquor
was evaporated, and the residue slurried in warm aceto-
nitrile from which another batch of solids was obtained.
The combined crude product was finally dissolved in
ethyl acetate (10 mL) at 65°C and crystallized in the
freezer. This was repeated twice to give the
enantiomerically pure product as a white, crystalline
solid (150 mg, 1.53 mmol, 36%). The enantiopurity of
the compound was verified by chiral HPLC (Chiralpak
IA, hexane:isopropanol 80:20, tR = 5.10 min) and was
found to be >99% ee. 1H‐NMR (CD3OD, 600.24 MHz,
300 K): δ = 1.26 (d, 3H, 3J(H,H) = 7.0 Hz), 1.85 (s,
3H), 4.31 (dt, 1H, 3J(H,H) = 7.0 Hz, 3J(H,NH) = 6.9
Hz), 7.27 (t, 1H, 3J(H,H) = 1.8 Hz), 7.67 (d, 2H,
3J(H,H) = 1.8 Hz), 8.24 (d, 1H, 3J(NH,H) = 6.9 Hz),
10.33 (s, 1H) ppm. 13C{1H}‐NMR (CD3OD, 150.93 MHz,
300 K): δ = 17.7, 22.4, 49.3, 117.4, 122.6, 134.1,
141.3, 169.4, 172.4 ppm. HRMS (ESI): m/z calcd. for
3
MHz, 300 K): δ = 150.9 (quint, J(P,H) = 10.8 Hz) ppm.
HRMS (ESI): m/z calcd. for C46H57N3O10P [M + H]+:
842.3776; found: 842.3773. FTIR: ṽ = 697 (s), 740 (s), 843
(s), 1022 (s), 1089 (s), 1151 (s), 1366 (s), 1456 (s), 1533
(m), 1585 (m), 1640 (m), 1733 (m), 2868 (w), 2933 (w),
2974 (m), 3028 (w), 3064 (w), 3088 (w), 3330 (bm) cm−1
.
2.14 | [Rh(16)2(COD)]BF4 (17)
Phosphoramidite 16 (150 mg, 178 μmol, 1.00 eq.) and [Rh
(COD)2]BF4 (36.2 mg, 89.1 μmol, 0.50 eq.) were dissolved
in dry and degassed DCM (5 mL). The orange solution
was stirred for 18 hours and subsequently concentrated
to 0.5 mL. Addition of n‐pentane (4 mL) gave the complex
as a yellow precipitated. The supernatant solution was
removed using a filter‐tipped cannula, and the product
was re‐precipitated another two times. Subsequent drying
gave the product as a yellow powder. (141 mg, 71.1 μmol,
80%). Due to high molecular dynamics, very broad signals
1
were observed in H, 13C{1H} NMR spectra which made
peak assignment impossible. 31P{1H} NMR spectrum
shows various signals which is in line with the nature of
previously investigated Rh complexes of similar nature.17
31P{1H} NMR (CDCl3, 162.00 MHz, 300 K): δ = 137.6,
138.2, 138.6, 139.3, 140.6, 142.3, 143.7 ppm. HRMS
C11H12Cl2N2NaO2 [M
+
Na]+: 297.0168; found:
297.0170. FTIR: ṽ = 668 (s), 1153 (s), 1409 (s), 1436 (s),
1526 (s), 1586 (s), 1642 (s), 2978 (w), 3086 (w), 3117
(w), 3181 (w), 3257 (w), 3343, (m) cm−1. [α]D20‐34.9
(c 0.5%, MeOH).
‐ +
(ESI): m/z calcd. for C100H124N6O20P2Rh [M‐BF4 ] :

8
SCHOLTES AND TRAPP
with water (3 × 75 mL), and recrystallized from methanol
to yield the product as a yellow solid (21.5 g, 86.3 mmol,
62 %). H NMR (CDCl3, 400.22 MHz, 300 K): δ = 7.25
2.17 | (R)‐N‐(1‐(tert‐butylamino)‐1‐oxo‐3‐
phenylpropan‐2‐yl)benzamide (13)
1
This compound was prepared according to the same pro-
cedure as its enantiomer, which has already been
reported elsewhere.30 Analytical NMR and HR‐MS data
(s, 1H), 7.46 to 7.55 (m, 5H), 7.60 to 7.64 (m, 1H), 8.18
to 8.22 (m, 4H) ppm. 13C{1H} NMR (CDCl3, 100.65
MHz, 300 K): δ = 125.7, 128.5, 129.0, 129.1, 131.4, 131.9,
132.6, 133.4, 133.5, 133.6, 163.6, 167.8 ppm. HRMS (EI):
m/z calcd. for C16H12NO2 [M + H]+: 250.08626; found:
250.08642. FTIR: ṽ = 684 (s), 766 (s), 983 (s), 1294 (s),
20
was identical. Analytics for BOC‐protected amide: [α]D
−9.0 (c 1% in CHCl3). Analytics for amide hydrochloride:
20
[α]D20−67.3 (c 1% in CHCl3). Analytics for diamide: [α]D
1448 (s), 1651 (s), 1791 (s), 3028 (w), 3242 (w) cm−1
.
−7.2 (c 1% in CHCl3).
2.18 | (S)‐2‐acetamido‐N‐(3‐nitrophenyl)
propanamide (15)
2.20 | (Z)‐N‐(3‐(tert‐butylamino)‐3‐oxo‐1‐
phenylprop‐1‐en‐2‐yl)‐benzamide (19)
(S)‐N‐acetyl alanine (400 mg, 3.05 mmol, 1.00 eq.) was
placed in a dried Schlenk flask and suspended in dry
DCM (2 mL). The mixture was cooled in an ice bath,
and EDCI.HCl (643 mg, 3.36 mmol, 1.10 eq.) was added
as a solid. After 15 minutes, all solids had dissolved, and
3‐nitroaniline (421 mg, 3.05 mmol, 1.00 eq.) was added.
After stirring was continued for another 18 hours at room
temperature, the solution was diluted more DCM (50
mL). The organic layer was washed with HCl solution
(2 M, 3 × 50 mL), saturated bicarbonate solution (2 × 50
mL), and brine (1 × 50 mL), dried over sodium sulfate,
and evaporated. Resulting solids were recrystallized four
times from hot ethyl acetate at 60°C to give the
enantiopure product as a white powder (300 mg, 1.19
mmol, 39 %). Enantiopurity of the compound was con-
firmed by chiral HPLC (Chiralpak IE, hexane:isopropanol
Azlactone 18 (800 mg, 3.21 mmol, 1.00 eq.) was dissolved
in chloroform (20 mL). The clear solution was cooled in
an ice bath and treated with tert‐butylamine (3.37 mL,
32.1 mmol, 10.00 eq.). The clear solution was subse-
quently stirred at 40°C for 72 hours. For work‐up, all vol-
atiles were removed in vacuo, and residual off‐white
solids were recrystallized from acetone:hexane to give
the product as a white solid (702 mg, 2.18 mmol, 68%).
1H NMR (CDCl3, 400.22 MHz, 300 K): δ = 1.30 (s, 9H),
6.17 (s, 1H), 6.73 (s, 1H), 7.13 to 7.22 (m, 3H), 7.28 to
3
7.34 (m, 4H), 7.40 to 7.44 (m, 1H), 7.74 (d, 2H, J(H,H)
= 7.3 Hz), 8.08 (s, 1H) ppm. 13C{1H} NMR (CDCl3,
100.65 MHz, 300 K): δ = 28.7, 51.8, 125.3, 127.8, 128.7,
128.8, 128.9, 129.1, 131.1, 132.3, 133.2, 134.1, 165.5,
166.3 ppm. HRMS (EI): m/z calcd. for C20H22N2O2
[M]+: 322.1681; found: 322.1678. FTIR: ṽ = 688 (s), 1223
(s), 1281 (s), 1475 (s), 1627 (s), 1642 (s), 2871 (w), 2826
1
80:20, 1 mL/min, 20°C, tR = 8.3 min). H NMR (DMSO‐
3
d6, 400.33 MHz, 300 K): δ = 1.30 (d, 3H, J(H,H) = 7.1
(w), 2967 (m), 3029 (w), 3059 (m), 3238 (bm) cm−1
.
3
3
Hz), 1.87 (s, 3H), 4.37 (dq, 1H, J(H,H) = 7.1 Hz, J(H,
3
H) = 7.0 Hz), 7.60 (t, 1H, J(H,H) = 8.2 Hz), 7.89 to 7.94
3
4
2.21 | Hydrogenation experiments
(m, 2H), 8.23 (d, 1H, J(H,H) = 6.9 Hz), 8.64 (t, 1H, J
(H,H) = 2.2 Hz), 10.46 (s, 1H) ppm. 13C{1H} NMR
(DMSO‐d6, 100.66 MHz, 300 K): δ = 17.7, 22.4, 49.3,
113.3, 117.8, 125.2, 130.2, 140.1, 148.0, 169.4, 172.3 ppm.
HRMS (ESI): m/z calcd. for C22H26N6NaO8 [M + Na]+
525.1704; found: 525.1713. FTIR: ṽ = 729 (s), 740 (s),
820 (s), 1209 (s), 1294 (s), 1345 (s), 1526 (s), 1599 (s),
1647 (s), 1686 (s), 2950 (w), 3001 (w), 3103 (bm), 3136
(w), 3246 (m) cm−1. [α]880nm 20−1.3 (c 1%, MeOH).
For hydrogenation experiments with bisphosphinite cata-
lysts 7a and 7b, methyl 2‐acetamidoacrylate 8 (6.10 mg,
42.6 μmol, 20 eq. with respect to catalyst) was added to
the equilibrated mixtures from the seeding experiments
(see SI section 2.3). For hydrogenation experiments with
phosphoramidite catalyst 17 and substrate 8, a J. Young
NMR tube was charged with a 3.2 Mm stock solution of
the catalyst, as well as appropriate amounts of substrate
(20 eq.) and additive (10 eq for (S)‐ or (R)‐13, 20 eq. for
rac‐13). The catalyst was added from a stock solution.
For those experiments with catalyst 17 and olefin 19, a
catalyst stock solution of the desired concentration was
prepared and added to a J. Young NMR tube together
with the substrate, whose amount was adjusted to
account for catalyst loading of the respective reaction.
The prepared solution was transferred into a nitrogen
filled stainless steel reactor loaded with a standard NMR
2.19 | (Z)‐4‐benzylidene‐2‐phenyloxazol‐5
(4H)‐one (18)
Hippuric acid (25 g, 139 mmol, 1 eq.), benzaldehyde (21.9
g, 2.07 mmol, 1.48 eq.), sodium acetate (8.47 g, 103 mmol,
0.74 eq.), and acetic anhydride (33.0 mL, 349 mmol, 2.50
eq.) were mixed and heated to 140°C for 2 hours and yel-
low solid formed. The product was filtered off, washed

SCHOLTES AND TRAPP
9
tube and a small stirring bar. The reactor was pressurized
with hydrogen gas (50 bar in case of bisphosphinite com-
plexes, 5 bar in case of phosphoramidite complexes,
unless noted otherwise) to initiate the catalysis. The auto-
clave was reopened after one day (two days in case of low
catalyst concentrations). The solution was passed through
a short pipet filled with silica (ca. 3 cm) using ethyl ace-
tate as eluent. Evaporation gave the hydrogenation prod-
uct as a yellow oil. Enantiomeric ratio and conversion
were determined by chiral GC (compound 9: (6‐TBDMS‐
2,3‐Ac)‐β‐CD, 25 m, i.d. 250 μm, film thickness 250 nm,
prepared and coated in the Trapp group, 100‐kPa helium,
130°C, FID detection, kSubst = 4.59, kR = 6.63, kS = 8.76, α
(kS/kR) = 1.32) or chiral HPLC (compound 19: Chiralpak
IE, hexane:isopropanol: 80:20, 1 mL/min, 20°C, 254 nm,
tS = 5.3 min and tR = 5.9 min, tSubst = 15.1 min). Assign-
ment of absolute configuration was accomplished by
comparing measurements to those of previously prepared
enantiopure samples. The conversion of all hydrogena-
tion reactions was greater 99.5%, and no byproducts were
observed.
3 | RESULTS AND DISCUSSION
3.1 | Interaction studies
Initial interaction studies were to be conducted on
stereodynamic bisphosphinite ligands, as their rhodium
complexes have a rotational barrier above 80 kJ mol−1
which allows for a distinct differentiation of the two axial
isomers by NMR spectroscopy, while equilibration of the
ligand still occurs at ambient temperature.33 Further-
more, the direct relationship between rotamer distribu-
tion and enantioselectivity in asymmetric hydrogenation
reactions is known.42 Ligand synthesis was achieved by
initial oxidative coupling of methyl vanillate 1, protection
of the resulting 2,2′‐biphenol with allyl bromide and
saponification of the methyl ester groups of 2 to yield
dicarboxylic acid 3 (see Figure 2).
After introduction of the selector units by reaction of
the corresponding diacid chloride with the respective
amine hydrochloride (4a) or by Steglich esterification
(4b), palladium‐mediated deprotection of the hydroxyl
groups with formic acid gave biphenols 5a,b. Finally,
reaction with PPh2Cl afforded the bisphosphinite ligands
6a,b, which were treated with [Rh (COD)2]BF4 to give
the desired catalysts 7a,b.
FIGURE 2 Synthesis of selector‐modified rhodium catalysts 7a,b
i) PhI (OAc)2, 51%, ii) allyl bromide, K2CO3, 97%, iii) KOH, 99%, iv)
a: SOCl2, then NH3Cl‐(S)‐Phe‐OtBu, DIPEA, 91%; b: HO‐(S)Phe‐
NHtBu (S1), DMAP, EDCI·HCl, 50%, v) Pd (OAc)2, PPh2
(C6H4NMe2), HCOOH, a: 71%; b: 93% vi) a: PPh2Cl, DABCO, 20%;
b: PPh2Cl, triethylamine, 69%, vii) [Rh (COD)2]BF4, quant
asymmetric hydrogenation experiments of methyl 2‐
acetamidoacrylate 8 generated exclusively racemates.
For compound 7a, however, a weighted equilibrium of
both rotamers was found comprising a major Rax and a
minor Sax rotamer (for assignment of rotamers, see SI; cf.
Figure S3). When N‐acetyl (S)‐phenylalanine methyl
amide (S)‐10 was added to the complex in excess, a signif-
icant rotameric enrichment of Rax‐7a was observed by 31
P
NMR spectroscopy (see Figure 3). The enrichment pro-
cess took several hours and was accompanied by an
immediate low‐field shift and distinct sharpening of the
NMR signals for the increasing rotamer. Interestingly, sig-
nals representing the minor species Sax‐7a showed only a
negligible change. In the following, similar ligand enrich-
ment was also found during the addition of other amino
acid derivatives of the same configuration (see SI for spec-
tral data).
A comparison of both ligand types revealed significant
differences.34 Rh complex 7b, which was formed as a
mixture of two axial rotamers of equal amounts, could
not be influenced by addition of chiral additives (see
SI for spectral data; cf. Figure S4), and subsequent

10
SCHOLTES AND TRAPP
FIGURE 3 31P NMR spectra showing influence of N‐acetyl phenylalanine methyl amide (S)‐10 on rhodium complex 7a (4.3 mM in CDCl3).
Noncovalent interactions between the additive (10 eq.) and the ligand's interaction sites induce rotameric enrichment of Rax‐7a during re‐
equilibration over several hours at 20°C
In some cases, signal overlap and line broadening,
caused by noncovalent interactions, did not allow for an
unambiguous determination of the final rotameric distri-
bution of 7a. Therefore, hydrogenation experiments were
carried out, and stereoenriched complex mixtures were
used as catalysts in order to comparatively assess the
structural adaptation of the ligand resulting from the
noncovalent interactions (see Figure 4). The untreated
catalyst converted methyl 2‐acetamidoacrylate 8 to ala-
nine methyl ester 9 with an enantiomeric excess of 27%
ee R. All (S)‐amino acid‐derived additives were found to
align the catalyst to significantly increase its selectivity.
Additionally, enantiomeric discrimination during ligand‐
additive interaction was observed. In the presence of
(S)‐10, a strong NMR signal shift as well as significant
rotameric enrichment was observed for the major rotamer
of complex 7a and selectivity for hydrogenation of 8
increased to 56% ee R (Δee = +29%). (R)‐10, however,
induced no visible change to the catalyst, and the differ-
ence in selectivity generated during subsequent catalysis
was negligible (29% ee R, Δee = +2%). Strongest
stereoinduction was found using alanine derivatives with
electron‐deficient aromatics at the N‐terminus, Ac‐(S)‐
Ala‐NH‐(3,5‐dichlorophenyl) 11 and Ac‐(S)‐Ala‐NH‐(3‐
nitrobenzene) 15, which, after catalyst alignment, allowed
reduction of 8 with 84% ee R (Δee = +57%) and 81% ee R
(Δee = +54%), respectively, and selector‐like diamide (S)‐
13, which increased selectivity during hydrogenation to
82% ee R (Δee = +55%).
3.2 | Autoinductive hydrogenation
Following the successful demonstration of chirality trans-
fer, these results were utilized in the second phase to real-
ize an asymmetric hydrogenation reaction that is
governed by enantioselective self‐inhibition.34 Since
bisphosphinite complex 7a, discussed above, took numer-
ous hours to equilibrate in the presence of chiral addi-
tives, a rhodium complex bearing highly dynamic
phosphoramidite ligand with the same ligand core as
ligand 6a was synthesized (see Figure 5A). This com-
pound was expected to instantly adapt to a changing chi-
ral environment, due to its low barrier of rotation.17

SCHOLTES AND TRAPP
11
FIGURE 4 Hydrogenation experiments
with catalyst 7a, which was pre‐aligned
using various chiral amino acid
derivatives. Adaptation of the ligand's
rotamer ratio during interactions with
certain additives is illustrated by a
concurrent change in the catalyst's
selectivity. All reactions showed full
conversion. A detailed experimental
procedure can be found in the
experimental section.

12
SCHOLTES AND TRAPP
FIGURE 6 Stereodynamic, phosphoramidite‐bearing catalyst 17
shows a change in selectivity in presence of the S enantiomer of
additive 13. All reactions showed full conversion. A detailed
experimental procedure can be found in the SI
FIGURE 5 (A) Synthesis of stereodynamic complex 17: i)
Cl2PNEt2, NEt3, 77%, ii) [Rh (COD)2]BF4, quant. (B) Synthesis of
prochiral olefin 19 i) PhCOCl, PhCHO, NaOAc, 62%, ii) tBuNH2, 68%
With these results at hand, a first set of hydrogenation
experiments with substrate 19 using different catalyst
loadings at a constant catalyst concentration were con-
ducted. As this associates with different turnover num-
bers (TONs)43, a decreased catalyst loading results in an
Regarding the appropriate substrate for an autoinductive
reaction, good solubility as well as high stereoinductive
capacities for the corresponding hydrogenated product
was considered important. Electron‐deficient alanine
derivatives (S)‐11 and (S)‐15 were already only sparingly
soluble, and olefin analogs usually exhibit reduced solu-
bility. Consequently, phenylalanine‐derived diamide (S)‐
13 was chosen, whose olefin counterpart 19 could be con-
veniently synthesized from glycine, benzoic acid chloride,
and benzaldehyde with subsequent aminolysis in tert‐
butylamine (see Figure 5B).
As with previously investigated phosphoramidite
complexes bearing amino acid‐derived selector moieties,
compound 17 was found to produce a complex 31P NMR
spectrum indicating an equilibrium of various species
(see SI in Storch and Trapp 17 for further information).
In the presence of the enantiomers of diamide 13, again,
stereoselective interaction with the catalyst was observed
by NMR spectroscopy (see SI for spectral data; cf. Fig-
ures S1, S2 and S5). When employing these catalyst mix-
tures for the asymmetric hydrogenation of prochiral
olefin 8, a change in selectivity was found when the S
enantiomer or the racemate of 13 was present. Sole
addition of the R enantiomer gave almost no change
for the enantiomeric ratio of alanine derivative 9 (see
Figure 6). These results demonstrate that findings of
stereoselective interactions and resulting stereoinduction
concerning bisphosphinite 6a can also be applied to the
more dynamic phosphoramidite analogue 16.
FIGURE 7 Results for the reduction of olefin 19 to phenylalanine
derivative 13 using stereodynamic catalyst 17. Selectivities were
found to depend on the turnover number and the concentration of
the catalyst. The change of product ee is indicated. All reactions
showed full conversion. A detailed experimental procedure can be
found in the experimental section.

SCHOLTES AND TRAPP
13
increase in catalytic cycles, which is equivalent to higher
levels of interaction between the catalyst and an increas-
ing amount of formed product molecules. This modifies
dynamically the catalyst's structure as well as its selectivity,
which changes in course of the turn over steps, and hence
changes the enantiomeric excess of the final product over
time. The results are summarized in Figure 7. With 100
mol% catalyst, which corresponds to a TON of 1, at 5 bar
H2, selectivity for 13 was found to be 19% ee in favor of
the S enantiomer. The same outcome was observed when
the reaction was repeated with 100 bar H2 gas. This affirms
that the selectivity of the reduction is determined by the
distribution of stereo‐dictating species of compound 17
and not the result of diastereoselective catalyst activation,
ie, kinetically favored hydrogenation of cyclooctadiene
for a specific catalyst species. Decreasing the catalyst load-
ing led to a significant change in selectivity. Running the
reaction with 10 mol% catalyst (TON = 10) gave product
13 with a slightly lower excess for the S enantiomer of
10%. When 2.5 mol% and 1 mol% catalyst (TON = 40
and TON = 100, respectively) were used, a reversal of
selectivity was observed, and diamide 13 was obtained in
12% ee R and 41% ee R, respectively. This represents an
overall shift in selectivity of Δee = 60% toward the R enan-
tiomer. When a similar set of experiments was repeated
with substrate 8, however, a change of the TON always
yielded the same enantiomeric ratio of product 9, which,
similar to previously investigated amido ester 14, was
not believed to have any influence on the selectivity of
the reaction. This demonstrates that the enantioselectivity
of catalyst 17 is not inherently dependent on its TON.
However, (S)‐13, as previously established, is capable of
inducing structural change to the catalyst to alter its
selectivity. Increased production of the R enantiomer
with higher TONs thus demonstrates that the original
major enantiomer (S)‐13 triggers the enrichment of its
mirror and suppresses its own formation over the course
of the reaction.
4 | CONCLUSION
In summary, a novel (S)‐phenylalanine‐based amido ester
selector unit for noncovalent interaction has been suc-
cessfully used with a variety of differently substituted
amino acid‐derived additives to induce chirality in a
stereodynamic bisphosphinite catalyst (7a) to enhance
selectivity in the asymmetric hydrogenation of methyl 2‐
acetamidoacrylate 8. Selectivity could be increased from
27% ee R, when no additive was present, to 84% ee R
(Δee = 57%) when Ac‐(S)‐Ala‐NH‐(3,5‐dichlorophenyl)
11 was used as stereoinducing additive.
On the basis of these findings, highly stereodynamic
catalyst 17 and olefin 19, which was derived of strongly
interacting diamide PhCO‐(S)‐Phe‐NHtBu (S)‐13, were
synthesized. During asymmetric hydrogenation of this ole-
fin, it was demonstrated that the initially preferred product
enantiomer (S)‐13 interacted with the catalyst 17 to
suppress its own formation. Ongoing enantioselective
self‐inhibition leads to increased production of the R
enantiomer and selectivity changed from 19% ee S, using
100 mol% catalyst, to 41% ee R, when 1 mol% catalyst was
used (Δee = 60%). A second parameter found to influence
the catalyst's behavior was its concentration, which was
linked to weak intermolecular interactions between
selector units of different catalyst molecules. (S)‐13‐like
interaction sites align neighboring biphenyl units thus
enhancing enantioselectivity for the formation of (R)‐13
with increased concentration of catalyst 17. Ultimately,
these resultes illustrate how stereoselective self‐inhibition,
a process that controls a large number of biochemical
systems in nature, can be recreated on a molecular level.
ACKNOWLEDGEMENTS
Generous financial support by the European Research
Council (ERC) for a Starting Grant (No. 258740,
AMPCAT) and the Max‐Planck‐Society is gratefully
acknowledged.
In a following set of experiments, hydrogenations were
repeated with varying catalyst concentrations and a con-
stant catalyst loading of 10 mol%. Selectivity changed
from 23% ee S to 1% ee S (Δee = 22%) when the concentra-
tion was increased from 0.2 to 8 mM with respect to the
catalyst. This was attributed to intermolecular interac-
tions between different catalyst molecules. The interac-
tion site of one molecule acts as chiral additive to align
a neighboring biphenyl unit. This behavior was also
observed for bisphosphinite ligand 6a (see SI section 2.1
for details about ligand‐ligand interaction). An increased
presence of selector units with S configuration evoked
the same trend of change for the reaction's selectivity
compared with (S)‐13, which appears reasonable given
their structural similarity.
ORCID
Oliver Trapp https://orcid.org/0000-0002-3594-5181
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Design and synthesis of a stereodynamic catalyst
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