Outer-Sphere Control for Divergent Multicatalysis with Common Catalytic Moieties

Article abstract of DOI:10.1021/acs.joc.8b03068

We herein report two examples of one-pot, simultaneous reactions, mediated by multiple, orthogonal catalysts with the same catalytic motif. First, BINOL-derived chiral phosphoric acids (CPA) and phosphothreonine (pThr)-embedded peptides were found to be matched for two different steps in double reductions of bisquinolines. Next, two -methylhistidine (Pmh)-containing peptides catalyzed enantio- and chemoselective acylations and phosphorylations of multiple substrates in one pot. The selectivity exhibited by common reactive moieties is adjusted solely by the appended chiral scaffold through outer-sphere interactions.

Full text of DOI:10.1021/acs.joc.8b03068

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Outer-Sphere Control for Divergent
Multicatalysis with Common Catalytic Moieties
Christopher R Shugrue, Bianca R Sculimbrene, Elizabeth R. Jarvo, Brandon Q. Mercado, and Scott J. Miller
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03068 • Publication Date (Web): 04 Jan 2019
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Outer-Sphere Control for Divergent Multicatalysis with Common
Catalytic Moieties
Christopher R. Shugrue, Bianca R. Sculimbrene,†,§ Elizabeth R. Jarvo,‡,§ Brandon Q. Mercado, and
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Scott J. Miller*,§
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, United States
ABSTRACT: We herein report two examples of one pot, simultaneous reactions, mediated by multiple, orthog-
onal catalysts with the same catalytic motif. First, BINOL-derived chiral phosphoric acids (CPA) and phos-
phothreonine (pThr)-embedded peptides were found to be matched for two different steps in double reductions of
bisquinolines. Next, two p-methylhistidine (Pmh)-containing peptides catalyzed enantio- and chemoselective ac-
ylations and phosphorylations of multiple substrates in one pot. The selectivity exhibited by common reactive
moieties is adjusted solely by the appended chiral scaffold through outer-sphere interactions.
A remarkable feature of enzymes is their ability to catalyze highly selective transformations on specific
substrates, often in tandem and simultaneous pathways and in the presence of competing, reactive analytes.1 The
tuning of active sites, which often employ a similar catalytic apparatus for bond-formation, to perform diverse
molecular functions is a triumph of evolution.2 However, by comparison, chemists struggle to mimic this level of
control over the reactivities and selectivities of multiple catalysts in complex settings,3 as cross-reactivity among
diverse chemical species can intervene.4–6 While approaches toward relay catalysis have recently seen a number
of advances,7 most of these studies (1) require either sequential addition of catalysts or intermediate purification
steps, or (2) are combinations of two catalysts that are chemically distinct (i.e. hetero-combinations of metals,
photocatalysts, and organocatalysts), such that both catalysts independently mediate orthogonal transformations.8–
10 While simultaneous operations of the same catalytic species is rare, a few reports of one pot multicatalytic reac-
tions, such as with two ruthenium complexes (Figure 1A)11 and a dual imidazolidinone/proline system (Figure
1B),12 create an optimistic prognosis. These studies offer validation that a common, reactive moiety (Ru atom or
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secondary amine) can be subtly modified to function divergently in situ (i.e. oxidations vs. reductions, and imini-
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um vs. enamine catalysis).
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Figure 1. (A,B) Examples of organometallic and organocatalyst multicatalytic systems. (C,D) This work: multicatalysis with
similar catalysts.
With these precedents in mind, we sought functional divergence with catalysts of even more closely re-
lated intrinsic reactivity. We chose to assess whether (1) two Brønsted acids or (2) two Lewis bases could func-
tion in the presence of one another to perform either a tandem reaction, or a parallel processing reaction scheme,
simply through modification of the chiral scaffold appended to the catalytically competent group. The crafting of
precise outer-sphere interactions between these catalysts and their targeted substrates would be essential in as-
signing specific catalytic functions, and discriminating between competing, but fully analogous types of bond
formations.13 The approach to assigning specific catalyst-substrate interactions described below uses peptide-
based catalysts in a biomimetic manner, building on their analogy to enzymes.14 Presented herein are reports in-
volving two different families of catalysts: (1) phosphothreonine (pThr)-embedded peptides,15–18 complementary
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to BINOL-derived chiral phosphoric acid (CPA) catalysts,19,20 are explored for multicatalytic transfer hydrogena-
tion (Figure 1C); and (2) p-methylhistidine (Pmh)-containing peptides are explored for in situ parallel hydroxyl
group transfer reactions (Figure 1D).21
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Divergent, One Pot CPA Catalysis. While BINOL- and peptide-based CPA catalysts (like P1 and 1)
maintain a common catalytic phosphoric acid, their overall chiral scaffolds are distinct (Figure 2A). In our previ-
ous studies of the transfer hydrogenation of 8-aminoquinolines (2), we reported that both catalyst P1 and 1 were
highly selective, affording tetrahydroquinoline 3 in up to 94:6 e.r. and with opposite absolute stereochemical con-
figurations (Figure 2B).15 Given the utility of reduced quinoline scaffolds, we chose to probe the possibility of
sequential, high selectivity reductions with these catalysts on biologically relevant bisquinolines,22,23 such as 4,
linked through the 8-substituted urea (Figure 2C). Upon initial formation of 5, further reduction can produce a
mixture of chiral (6) and meso (7) products. Initial reactions mediated by pThr-derived P1 generated mono-
reduced 5 with 67:33 e.r. (Figure 2C–D, entry 1), a lower level of selectivity than previously observed for the
reduction of 2 to 3. Yet, further reduction of 5 to 6+7 revealed a substantial amplification of product enantiopuri-
ty, producing 6 with 95:5 e.r..24
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The combination of two subsequent chirality-generating reactions to enhance the e.r. of an asymmetric
process is a manifestation of Horeau amplification (Figure 2E).25–29 In this paradigm, e.r. may be enhanced at the
expense of d.r., as the disfavored enantiomer in the first reduction is converted to meso-7 through a second reduc-
tion. Under ideal conditions, assuming the catalyst reduces 4 and 5 with the same selectivity, the final e.r. of 6 can
be predicted by squaring the initial selectivity.30,31 Since catalyst P1 produces mono-reduced 5 in 67:33 e.r. (s1 =
2
2.0), the theoretical e.r. of 6 would be 81:19 (s1 = 4.1); thus, P1 substantially outperforms ideal Horeau amplifi-
cation estimates (95:5 e.r., s2 = 19), implying second order outer-sphere effects in the second reduction. In the
case of P1 mediated reductions of monoquinolines (2), secondary interactions between the peptide and the 8-
aminoquinoline were essential for high selectivities; and these key outer-sphere interactions presumably operate
in the reduction of these bisquinolines as well.15
Interestingly, BINOL-derived catalyst 1 produced mono-reduced 5 in higher initial e.r., 86:14 (s1 = 6.1,
Figure 2D, entry 2). Yet, upon second reduction, the e.r. of 6 minimally changes to 87:13 (s2 = 6.7), much lower
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than the Horeau expectation (s1 = 38, 97:3 e.r).32 Thus, catalyst 1 is more selective in the first reduction, while P1
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is more selective in the second. Furthermore, while P1 and 1 previously gave the opposite sense of absolute ste-
reochemistry in the reduction of monoquinoline (2 to 3; Figure 2B), both catalysts afford products with the same
sense of stereochemistry with 4.31
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Figure 2. (A) BINOL-derived and pThr-based CPAs. (B) Asymmetric transfer hydrogenation of 8-aminoquinolines with
CPAs. (C+D) Scheme and catalyst screening for CPA-mediated reductions of bisquinoline 4. (E) Kinetics diagram for this
transformation.
Given the complementarity of catalysts P1 and 1 for different steps of this bis-reduction, we wondered
whether the catalysts could be combined in one pot to mediate their respective, matched reactions with high se-
lectivity (Figure 2E). Indeed, reacting 4 in the presence of a 1:1 mixture of 1 and P1 produced 5 in 83:17 e.r., and
6 in 94:6 e.r. and 2.0:1 d.r., constituting a synergistic effect for the combined catalysts in achieving better e.r. to-
gether than in individual screens (Figure 2D, entry 3). It appears that catalyst 1 predominantly controls its
matched reduction of 4 to 5 (83:17 e.r. vs. 86:14 e.r. in individual screen). Alternatively, in the second reduction
from 5 to 6+7, the dual catalyst system outperforms individual reaction with only catalyst 1 (94:6 e.r. vs. 87:13
e.r.), indicating that P1 affords rate enhancement in the second step (1 also appears to compete to a low, but de-
tectable extent). To further elucidate the level of control exhibited by P1 on this second reduction, reactions were
performed in the presence of both P1 and ent-1. The first reduction was still controlled by ent-1, revealing 5 with
the reversed (R)-stereochemistry (28:72 e.r., Figure 2D, entry 4). However, even though (R)-5 was favored in the
first step, the second reduction results in (S,S)-6 as the major product (63:37 e.r.), revealing that P1 competes ef-
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fectively. Thus, this reversal of the stereochemical outcome between the first and second reductions elucidates the
substantial control that ent-1 and P1 have in conducting their matched reductions in a tandem process. These re-
sults imply that, despite the shared identity of the catalytic phosphoric acid of 1 and P1, reactivity can be heavily
tuned by appended chiral scaffold and specific, matched outer-sphere interactions (presumably 1 with 4 and P1
with 5).33
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Control of Pmh-Catalysts through Peptide Variation. The divergent selectivity regimes of BINOL-
and peptide-based CPAs described above allow for interpretable, catalyst-assigned outcomes in these multicata-
lytic parallel reactions, specifically due to the different, surrounding molecular architecture.1 Complementary re-
activity might not be unexpected for these two families, taking into account the dissimilar nature of the rigid
BINOL framework in comparison to the functionalized and flexible nature of peptides. Yet, we are able to docu-
ment related assignment of catalytic function based on outer-sphere tuning of common catalytic moieties with
purely peptide-based systems as well,14,34 specifically relying on Pmh-based catalysts for selective hydroxyl
group transfers.
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Figure 3. (A) Kinetic resolution of (±)-8 with P2 to yield acylated (R,R)-9. (B) Desymmetrizing phosphorylation
of inositol derivative 10 with P3. (C) One pot phosphorylation of (±)-8 and 10 revealed P3 favors reaction with
(S,S)-8, opposite to P2. (D–F) Scheme and NMR data for peptide-mediated one-pot reactions.
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Some time ago, we showed that octameric Pmh catalyst P2 facilitated the selective acylation of racemic
trans-aminoalcohol 8 with a krel > 50:1 (Figure 3A).35 With an alternative peptide backbone, Pmh peptide P3 was
reported to mediate the phosphorylation of an inositol derivative (10) with high levels of site- and enantioselectiv-
ity (>99:1 e.r.; Figure 3B).36 However, catalysts P2 and P3 gave unspectacular, or even stereodivergent selectivi-
ty when applied to the reactions for which each was unoptimized. For example, when (±)-8 and 10 were reacted
in the presence of only (PhO)2P(O)Cl and P3, phosphorylated (S,S)-12 was obtained with a krel of 1:5 (Figure
3C), the opposite stereochemistry shown with P2 for acylation. These results indicated the crucial nature of the
appended peptide sequences in tuning the selectivity of the shared Pmh residue through outer-sphere interac-
tions.35b Furthermore, these divergent reactivities gave us hope that the two catalysts could exhibit specificity for
their matched substrates in a one pot, parallel processing experiment wherein catalyst function was assigned by
the independent studies of enantioselectivity.
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Competition experiments were performed wherein substrates (±)-8 and 10 were added together in one
pot, along with both phosphorylating and acylating reagents(Figure 3D). DMAP provided a complex and intrac-
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table mixture of products by H NMR (Figure 3E).32 However, when equimolar amounts of the two Pmh-
catalysts P2 and P3 were utilized, a vastly simplified product distribution is observed (Figure 3F). Racemic ami-
noalcohol 8 was mostly consumed (>75% conversion to products), and acylated (R,R)-9 was obtained in 90:10
e.r., presumably under the control of P2. Additionally, P3 was found to phosphorylate the unreacted enantiomer
of 8, affording (S,S)-12 with 87:13 e.r.. In parallel and in situ, inositol derivative 10 was consumed more slowly
(<50% conversion to products), and phosphate 11 could be isolated with still 77:23 e.r.. Hence, despite the com-
plexity of this one pot reaction, and the conserved nature of the Pmh residue, the peptide sequences of P2 and P3
were indeed tuned to react preferentially with 8 and 10 as assigned. Since mostly acylation of (R,R)-8 and mono-
C1-phosphorylation of 10 was observed, with limited crossover reactivity seen, this example represents a striking
simplification of the reaction mixture in comparison to the outcome with DMAP, most notably observed in the
cleanliness of the crude NMR of the peptide catalytic system compared to that with DMAP (Figure 3E–F). Key
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outer-sphere interactions between the peptides and specific, assigned substrates, which are absent for DMAP, are
key to the observed selectivities.
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Multicatalytic systems are a frontier for studies of synthetically-relevant catalysis, as a myriad of selectiv-
ity issues emerge, including the efficient performance of different catalysts for different bond-forming operations
in one pot. When a common catalytic moiety is assigned aspirationally to perform a different function, the outer-
sphere of the catalyst may be called upon to achieve some of the selectivity criteria associated with these complex
reaction designs. In the examples explored above, these capabilities have been documented in two distinct reac-
tivity paradigms of considerable generality¾chiral phosphoric acid catalysis and chiral Lewis base catalysis.
Much study remains to generalize these concepts for efficient process development. Yet, a basis for optimism
seems firmly in place as examples of multicatalytic chemistry mount, and as rational control over the outer-sphere
of powerful catalytic moieties develops further.
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EXPERIMENTAL SECTION
General Information. Room temperature is defined as 21–25 °C. All reagents were purchased from
commercial sources and used as received, unless otherwise noted. Solvents used for reactions, such as methylene
chloride (CH2Cl2), tetrahydrofuran (THF), and acetonitrile (MeCN) were either obtained from a Seca Solvent Pu-
rification System by Glass Countour, in which the solvents were dried over alumina and dispended under an at-
mosphere of argon, or distilled from appropriate drying agents prior to use. For all other purposes, solvents were
used as received from commercial sources unless otherwise noted.
1H NMR spectra were recorded on 300 MHz, 400 MHz, 500 MHz, or 600 MHz Varian or Agilent spec-
trometers at ambient temperature. Samples were prepared in chloroform-d (CDCl3) and dimethyl sulfoxide-d6 (d6-
DMSO). 1H NMR data are reported as chemical shifts with multiplicity, coupling constants (J) in Hz, and integra-
tions. Proton chemical shifts are reported in ppm (d) and referenced to tetramethylsilane (TMS d 0.00 ppm) or
residual solvent (CHCl3, d 7.26 ppm, DMSO d 2.50 ppm).37 Multiplicity is reported as follows: singlet (s), broad
singlet (bs), doublet (d), doublet of doublets (dd), doublet of doublet of doublets (ddd), doublet of doublet of tri-
plets (ddt), doublet of triplets (dt), doublet of triplet of doublets (dtd), doubet of quartets (dq), triplet (t), quartet
(q), quartet of doublets (qd), pentet (p), heptet (hept), multiplet (m), and overlapping multiplets (comp). 13C NMR
spectra with broadband proton decoupling were recorded on 500 (126) MHz or 600 (151) MHz Agilent spec-
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trometers with complete proton decoupling at ambient temperature, unless otherwise noted. Carbon chemical
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shifts are reported in ppm (d) and referenced to tetramethylsilane (TMS) or solvent (CDCl3, d 77.16 ppm, d6-
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DMSO d 39.52 ppm).37 31P NMR spectra were recorded on 500 (202) MHz Agilent spectrometers with complete
proton decoupling at ambient temperature.
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Low resolution mass spectrometry (MS) was acquired on a Waters SQD2 UPLC/MS equipped with an
electrospray ionization (ESI) detector, with a Waters ACQUITY UPLC BEH C18 (1.7 µm, 2.1 x 50 mm) column.
High resolution mass spectrometry (HRMS) was conducted by the Mass Spectrometry Laboratory at the Univer-
sity of Illinois at Urbana-Champaign using a Waters Synapt G2-Si instrument equipped with a QToF mass spec-
trometer and an ESI detector.
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Infrared spectra were obtained using a Nicolet ATR/FT-IR spectrometer, and νmax (cm–1) were partially
recorded in accordance with convention. Optical rotations were recorded on a Perkin Elmer Polarimeter 341 at
the sodium D line (1.0 dm path length) at 20 °C. Analytical thin-layer chromatography (TLC) was performed us-
ing EMD Millipore silica gel 60 F254 precoated plates (0.25 mm thickness). The developed plates were visualized
by a UV lamp and/or potassium permanganate (KMnO4) stain.
Normal-phase column chromatography was performed with either silica gel 60 Å (32-63 microns) or with
a Biotage Isolera One flash purification system equipped with 15 g, 30 g, 60 g, or 120 g SNAP Ultra HP-Sphere
25 µm columns using an appropriate linear gradient of EtOAc/Hexanes. Reversed-phase column chromatography
as performed with a Biotage Isolera One flash purification system equipped with 30 g, 60 g, or 120 g SNAP KP-
C18-HS or SNAP Ultra-C18 columns with an appropriate gradient of MeCN/H2O. In some cases, 0.1% formic
acid or trifluoroacetic acid buffers were utilized.
Enantiomeric ratio (e.r.) values were acquired using both HPLC and GC. Analytical HPLC was per-
formed on both an Agilent 1100 series analytical chiral HPLC equipped with a photodiode array detector (210
nm, 230 nm, 250 nm, and 254 nm) and a Rainin SD-200 chromatograph, equipped with a single wavelength UV
detector (214 nm), were used with a Chiralpak IB column (5 µm particle size, 4.5 x 250 mm) and a Chiralcel OD
column (Alltech). Analytical GC was performed on a Hewlett-Packard 6890, employing a flame ionization detec-
tor and a Chiraldex G-TA column (Alltech).
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Double Reductions of Unsymmetrical Bisquinolines with CPAs. See Supporting Information for Fig-
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ure S1. Given this significant divergent selectivity displayed by catalysts 1 and P1, we sought to probe the effect
further with unsymmetrical bisquinoline 13, which presents the intriguing challenge of both enantio- and site-
selectivity with respect to the first reduction (14 vs. 15, Figure S2.A). In this case, amplified enantioselectivities
from this tandem process must come from either (1) a secondary kinetic resolution of the two enantiomers of 14
(Figure S2.C, blue),38 or (2) a difference in selectivity for the reduction of 15 to 16 (Figure S2.C, red), as the
Horeau-type correction of e.r. is no longer operative. Interestingly, with both catalysts P1 and 1, the initial reduc-
tion of 13 leads to mixtures of 14 and 15, despite the quite different level of substitution on each ring (Figure
S2.B). Catalyst 1 gives a nearly equivalent ratio of 14 and 15, while P1 favors 14.39 Moreover, we observe that
P1 gives similar e.r. for the first reduction of either 4 and 13 (67:33 vs. 65:35), but also produces doubly reduced
15 with lower e.r. (76:24). Catalyst 1 yields substantially lower enantioselectivities than previously observed both
at low and high conversion, and with the opposite senses of chirality as P1 for product 15. Taken together, the
observations with substrate 13 unveil further the nuanced outer-sphere interactions of catalysts 1 and P1 in the
second reduction.
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Previously Synthesized Compounds. Peptide P1 was previously synthesized and characterized in a re-
lated publication.15,16 Compound trans-2-acetamidocyclohexanol ((±)-12) was synthesized according to the meth-
od of Hawkins.40 For the syntheses and characterizations of catalyst P2 (Boc-Pmh-Val-Val-DPro-Leu-Val-Val-
OMe) and acylated 13, please see a related publication.35 Compound 2,4,6-Tribenzyl-myo-inositol (14) was syn-
thesized according to the method of Billington.41 For the syntheses and characterizations of catalyst P3 (Boc-
Pmh-Asn(Trt)-His(pBn)-Asp(tBu)-Ala-OMe) and phosphorylated 15, as well as methods for catalyst screening,
please see a related publication.36
Compound Synthesis and Characterization. Reported yields are for the preparation of analytically pure
standards. During purifications, mixed fractions were often excluded.
1,3-bis(2-methylquinolin-8-yl)urea (4). Modified from literature precedent,42 a flame dried 100 mL round
bottom flask was charged with 8-aminoquinaldine (2.00 g, 12.6 mmol, 2.10 equiv), 1,1′-Carbonyldiimidazole
(CDI, 976 mg, 6.02 mmol, 1.00 equiv), and 32 mL THF. A condenser was added on the flask and was fit with a
septum and placed under and Ar balloon. The solution was heated at 76 °C for 24 h, after which the reaction was
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cooled to room temperature and concentrated. The crude mixture was purified via normal-phase chromatography,
with a gradient eluent of 1 to 30% EtOAc/Hex. The isolated product was further crystallized from a solution of
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CH2Cl2/MeOH, resulting in pure product. Yield: 931 mg beige solid, 45% yield. H NMR (400 MHz, CDCl3) δ
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9.49 (s, 1H), 8.64 (dd, J = 7.7, 1.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.42 (dd, J = 8.1,
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1.3 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 2.81 (s, 3H). C{ H} NMR (151 MHz, CDCl3) δ 157.0, 152.4, 137.8, 136.7,
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135.0, 126.7, 126.4, 122.5, 120.0, 115.3, 25.4. IR (cm–1, neat): 3313, 1691, 1603, 1519, 1487, 1434, 1382, 1333,
1233, 1191, 1140, 1074, 827, 794, 761, 748, 714. HRMS (ESI-QToF) m/z: [M + H]+ calcd for C21H19N4O
343.1559, found 343.1558. Mp: 177–178 °C. TLC: Rf (2:1 Hex/EtOAc) 0.64, visualized with UV light.
1-(2-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-(2-methylquinolin-8-yl)urea (5). A flame dried 100 mL round
bottom flask was charged with 4 (200 mg, 0.826 mmol, 1.00 equiv), Hantzsch ester (523 mg, 2.07 mmol, 2.50
equiv), diphenyl phosphate (103 mg, 0.410 mmol, 0.500 equiv), and 17 mL CH2Cl2. The flask was fit with a sep-
tum, placed under an N2 atmosphere, and stirred for 24 h. The reaction was washed with NaHCO3 (satd, aq, 20
mL), dried over Na2SO4, filtered, and concentrated. The crude product, which was predominantly 6+7, was puri-
fied by automatic normal-phase chromatography, with a gradient eluent of 5% to 75% EtOAc/Hex to yield a
mostly pure mixture of 5 with some 6+7. The mixture was suspended in methanol, which dissolves all of 6+7 and
some of 5, and the suspended 5 was filtered to yield pure product. Yield: 12.8 mg beige solid, 4%. 1H NMR (600
MHz, d6-DMSO) δ 9.50 (s, 1H), 8.68 (s, 1H), 8.47 (dd, J = 6.1, 2.8 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.51–7.40
(comp, 3H), 7.09 (d, J = 7.7 Hz, 1H), 6.78 (d, J = 7.3 Hz, 1H), 6.52 (t, J = 7.6 Hz, 1H), 4.96 (bs, 1H), 2.80 (ddd, J
= 16.3, 11.1, 5.4 Hz, 1H), 2.75–2.67 (comp, 3H), 1.88 (dq, J = 11.9, 4.7 Hz, 1H), 1.52 – 1.41 (m, 1H), 1.19 (d, J
= 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, d6-DMSO) δ 156.7, 153.4, 137.1, 136.6, 135.5, 126.1, 126.0, 125.7,
123.5, 122.9, 122.6, 121.4, 119.2, 115.3, 114.2, 114.2, 46.6, 29.3, 26.3, 24.9, 22.3. IR (cm–1, neat):3394, 1665,
1532, 1496, 1433, 1338, 1283, 1226, 1113, 830, 756, 731. HRMS (ESI-QToF) m/z: [M + H]+ calcd for
C21H23N4O 347.1872, found 347.1872. Mp: 200–201 °C. TLC: Rf (2:1 Hex/EtOAc) 0.48, visualized with UV
light. Assay of enantiomeric purity: Enantiomers of product 5 were separated by a chiral IB column, eluting at a
flow rate of 1.0 mL/min with 2.0% EtOH/Hex. Rt[(S)-5] = 27 min; Rt[(R)-5] = 30 min.
Cis- and trans-1,3-bis(2-methyl-1,2,3,4-tetrahydroquinolin-8-yl)urea (6+7). Two reactions were setup
simultaneously: (A) A flame dried 100 mL round bottom flask was charged with 4 (75.0 mg, 0.219 mmol, 1.00
equiv), Hantzsch ester (117 mg, 0.460 mmol, 2.50 equiv), diphenyl phosphate (27.0 mg, 0.110 mmol, 0.500
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equiv), and 40 mL CHCl3. The flask was fit with a septum, placed under an Ar balloon, and stirred for 48 h. Upon
consumption of all Hantzsch ester, the reaction was washed with NaHCO3 (satd, aq, 40 mL), dried over Na2SO4,
filtered, and concentrated. The crude product was purified by automatic normal-phase chromatography, with a
gradient eluent of 5% to 75% EtOAc/Hex to yield a mostly pure mixture of 6+7. (B) A flame dried 250 mL round
bottom flask was charged with 4 (100 mg, 0.292 mmol, 1.00 equiv), Hantzsch ester (333 mg, 1.31 mmol, 4.50
equiv), diphenyl phosphate (37.0 mg, 0.146 mmol, 0.500 equiv), and 60 mL CH2Cl2. The flask was fit with a sep-
tum, placed under an Ar balloon, and stirred for 168 h. Upon consumption of all Hantzsch ester, the reaction was
washed with NaHCO3 (satd, aq, 60 mL), dried over Na2SO4, filtered, and concentrated. The crude product was
purified by automatic normal-phase chromatography, with a gradient eluent of 5% to 75% EtOAc/Hex to yield a
mostly pure mixture of 6+7. (A+B) The crude products from both (A) and (B) were combined and further puri-
fied by automatic normal-phase chromatography, with a gradient eluent of 5% to 60% EtOAc/Hex to yield pure
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product. Yield: 47.7 mg of 6+7 as a beige solid, 26%. H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 7.7 Hz, 1H),
6.89 (d, J = 7.5 Hz, 1H), 6.61 (t, J = 7.6 Hz, 1H), 6.07 (s, 1H), 3.44–3.33 (m, 1H), 2.92–2.69 (m, 2H), 1.93 (ddt, J
1
13
= 12.6, 6.1, 3.5 Hz, 1H), 1.60–1.48 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H). C{ H} NMR (151 MHz, CDCl3) δ 156.1,
140.7, 128.0, 125.1, 123.1, 121.8, 117.0, 47.3, 29.8, 26.8, 22.7. IR (cm–1, neat): 3293, 2956, 2929, 1628, 1560,
1497, 1460, 1336, 1296, 1279, 1247, 1153, 1115, 1064, 961, 742. HRMS (ESI-QToF) m/z: [M + H]+ calcd for
C21H27N4O 351.2158, found 351.2188. TLC: Rf (2:1 Hex/EtOAc) 0.29, visualized with UV light. Assay of enan-
tiomeric purity: Stereoisomers of products 6+7 were separated by a chiral IB column, eluting at a flow rate of 1.0
mL/min with 2.0% EtOH/Hex. Rt[(S,S)-6] = 33 min; Rt[meso-7] = 38 min; Rt[(R,R)-6] = 42 min.
(±)-2-acetamidocyclohexyl diphenyl phosphate [(±)-12]: A 100 mL round bottom flask was charged with
(±)-8 (200 mg, 1.27 mmol, 1.00 equiv), DMAP (8.0 mg, 0.070 mmol, 0.050 equiv), PhMe (25 mL), followed by
sequential addition of triethylamine (distilled, 173 uL, 1.24 mmol, 1.30 equiv) and diphenylchlorophosphate (251
uL, 1.15 mmol, 1.20 equiv). CH2Cl2 (20 mL) was added to aid solubility. The reaction was stirred at RT for 12 h,
followed by quenching by addition of MeOH (2 mL). The solution was concentrated and purified by flash chro-
matography, eluting with a gradient of 3% to 5% MeOH/CH2Cl2 to yield pure product. Yield: 130 mg light
1
brown oil, 26%. H NMR (500 MHz, CDCl3) δ 7.36–7.29 (comp, 4H), 7.22–7.15 (comp, 6H), 6.34 (bd, J = 7.8
Hz, 1H), 4.38–4.28 (m, 1H), 3.93–3.83 (m, 1H), 2.13 (d, J = 12.4 Hz, 1H), 2.04–1.97 (m, 1H), 1.74 (d, J = 10.3
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Hz, 1H), 1.69 (s, 3H), 1.62 (d, J = 13.1 Hz, 1H), 1.54 (qd, J = 12.7, 3.9 Hz, 1H), 1.35–1.16 (m, 2H), 1.09 (qd, J
= 12.7, 3.6 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3, for analogous C–P splitting, see a related reference43) δ
170.2, 150.5 (d, JCP = 7.5 Hz), 150.4 (d, JCP = 7.5 Hz), 129.9, 125.7 (d, JCP = 1.1 Hz), 125.6 (d, JCP = 1.0 Hz),
120.3 (d, JCP = 4.6 Hz), 120.2 (d, JCP = 4.8 Hz), 81.0 (d, JCP = 6.4 Hz), 53.6 (d, JCP = 3.3 Hz), 32.61 (d, JCP = 4.1
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Hz), 32.1, 24.2, 24.0, 23.2. P NMR (202 MHz, CDCl3) δ –10.6. IR (cm–1, thin film from CHCl3): 3300, 2940,
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2861, 1657, 1591, 1551, 1488, 1455, 1371, 1272, 1188, 1162, 1021, 952, 907, 726. HRMS (ESI-QToF) m/z: [M +
H]+ calcd for C20H24NO5PNa 412.1290, found 412.1292. TLC: Rf (9:1 CH2Cl2/MeOH) 0.33, visualized with UV
light. Assay of enantiomeric purity: Enantiomers of product 12 were separated by a chiral OD column (Alltech),
eluting at a flow rate of 0.5 mL/min with 1.5% EtOH/Hex. Rt[(S,S)-12] = 38 min; Rt[(R,R)-12] = 41 min.
1-(2-methylquinolin-8-yl)-3-(quinolin-8-yl)urea (13, see Figure S2). Modified from literature
precedent,43 a flame dried 100 mL round bottom flask was charged with 8-aminoquinoline (1.00 g, 6.93 mmol,
1.00 equiv), 1,1′-Carbonyldiimidazole (CDI, 675 mg, 4.16 mmol, 0.600 equiv), and 35 mL CH2Cl2. The solution
was fitted with a septum and Ar balloon and stirred for 2 h. Then, 8-aminoquinaldine (1.10 g,6.92 mmol, 1.00
equiv) was added, and the reaction was stirred overnight for 22 h. The solution was concentrated, yielding a mix-
ture of symmetrical urea products (including 4) and the desired unsymmetrical product (13). The mixture was
purified by automatic normal-phase chromatography, with a gradient eluent of 1 to 50% EtOAc/Hex. The isolated
product was further purified with automatic reversed-phased chromatography, eluting with a gradient of 50% to
100% MeCN/H2O to yield pure product. Yield: 409 mg white solid, 30%. 1H NMR (400 MHz, CDCl3) δ 9.53 (s,
1H), 9.44 (s, 1H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.70 (dd, J = 7.8, 1.3 Hz, 1H), 8.65 (dd, J = 7.7, 1.3 Hz, 1H),
8.19 (dd, J = 8.3, 1.7 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.53–7.45 (comp, 3H), 7.42 (dd,
1
13
J = 8.2, 1.3 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 2.82 (s, 3H). C{ H} NMR (151 MHz, CDCl3) δ 157.1, 152.4,
148.0, 138.5, 137.8, 136.7, 136.7, 135.7, 134.9, 128.3, 127.8, 126.66, 126.4, 122.6, 121.7, 120.3, 120.1, 115.4,
115.4, 25.4. IR (cm–1, neat): 3249, 1667, 1518, 1489, 1434, 1380, 1324, 1254, 1191, 1079, 820, 787, 752, 731,
708. HRMS (ESI-QToF) m/z: [M + H]+ calcd for C20H17N4O 329.1402, found 329.1401. Mp: 149–150 °C. TLC:
Rf (2:1 Hex/EtOAc) 0.63, visualized with UV light.
1-(2-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-(quinolin-8-yl)urea (14, see Figure S2). A flame dried 20
mL scintillation vial was charged with 13 (100 mg, 0.305 mol, 1.00 equiv), Hantzsch ester (193 mg, 0.762 mmol,
2.50 equiv), diphenyl phosphate (38.2 mg, 0.153, 0.500 equiv), and 6 mL CH2Cl2. The vial was flushed with Ar,
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capped, and the reaction was stirred for 24 h. The solution was washed with NaHCO3 (satd, aq, 6 mL), dried over
Na2SO4, filtered, and concentrated. The crude product, which included 13, 14, 15, and 16) was purified by auto-
matic normal-phase chromatography, with a gradient eluent of 5% to 100% EtOAc/Hex. The mostly pure product
was further purified with automatic reversed-phase chromatography, eluting with a gradient of 25% to 100%
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MeCN/H2O to yield pure product. Yield: 8.7 mg pale yellow solid, 9%. H NMR (600 MHz, CDCl3) δ 9.48 (s,
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1H), 8.66–8.59 (comp, 2H), 8.09 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.35 (dd, J
= 8.3, 4.2 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.58 (bs, 1H), 4.28
(bs, 1H), 3.44–3.39 (m, 1H), 2.90 (ddd, J = 16.7, 11.4, 5.4 Hz, 1H), 2.81 (dt, J = 16.3, 4.5 Hz, 1H), 1.94 (ddt, J =
12.5, 6.1, 3.4 Hz, 1H), 1.60 (qd, J = 11.8, 4.9 Hz, 1H), 1.15 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 154.9, 148.0, 141.1, 138.7, 136.3, 135.6, 128.3, 128.1, 127.6, 125.6, 123.0, 121.4, 121.2, 120.2, 116.7,
115.4, 47.3, 29.8, 27.0, 22.6. IR (cm–1, neat): 3270, 2923, 1644, 1542, 1488, 1423, 1382, 1327, 1284, 1252, 1221,
1115, 1102, 822, 787, 746. HRMS (ESI-QToF) m/z: [M + H]+ calcd for C20H21N4O 333.1715, found 333.1715.
Mp: 149–150 °C. TLC: Rf (2:1 Hex/EtOAc) 0.40, visualized with UV light. Assay of enantiomeric purity: Enan-
tiomers of product 14 were separated by a chiral IB column, eluting at a flow rate of 1.0 mL/min with 10%
EtOH/Hex. Rt[(S)-14] = 15 min; Rt[(R)-14] = 17 min.
1-(2-methylquinolin-8-yl)-3-(1,2,3,4-tetrahydroquinolin-8-yl)urea (15, see Figure S2). A flame dried 20
mL scintillation vial was charged with 13 (100 mg, 0.305 mol, 1.00 equiv), Hantzsch ester (193 mg, 0.762 mmol,
2.50 equiv), diphenyl phosphate (38.2 mg, 0.153, 0.500 equiv), and 6 mL CH2Cl2. The vial was flushed with Ar,
capped, and the reaction was stirred for 24 h. The solution was washed with NaHCO3 (satd, aq, 6 mL), dried over
Na2SO4, filtered, and concentrated. The crude product, which included 13, 14, 15, and 16) was purified by auto-
matic normal-phase chromatography, with a gradient eluent of 5% to 100% EtOAc/Hex. The mostly pure product
was further purified with automatic reversed-phase chromatography, eluting with a gradient of 25% to 100%
MeCN/H2O, with a 0.1% formic acid buffer (aq), to yield mostly pure 15 as a colorless oil. Yield not reported.
Compound 15 was a minor regioisomer of this reaction, and it was difficult to obtain and purify preparative
amounts of material for characterization. The product was assigned for conversion measurements by UPLC/MS
by a mostly pure NMR. 1H NMR (400 MHz, CDCl3, mostly pure) δ 9.49 (s, 1H), 8.49 (dd, J = 7.7, 1.4 Hz, 1H),
7.94 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 (d, J =
7.7 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 5.97 (s, 1H), 4.41 (bs, 1H), 3.39–3.26 (m, 2H),
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2.83 (t, J = 6.4 Hz, 2H), 2.49 (s, 3H), 2.01–1.83 (m, 2H). In particular, an observed singlet for the C2 methyl
group helps to differentiate this compound from 14. UPLC/MS (ESI) m/z: [M + H]+ calcd for C20H21N4O 333.17,
found 333.35.
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1-(2-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-3-(1,2,3,4-tetrahydroquinolin-8-yl)urea (16, see Figure S2).
A flame dried 4 mL scintillation vial was charged with 13 (20.0 mg, 0.0600 mol, 1.00 equiv), Hantzsch ester
(38.0 mg, 0.150 mmol, 2.50 equiv), diphenyl phosphate (7.50 mg, 0.0300, 0.500 equiv), and 1.25 mL CH2Cl2.
The vial was flushed with Ar, capped, and the reaction was stirred for 24 h. The solution was washed with Na-
HCO3 (satd, aq, 1.5 mL), dried over Na2SO4, filtered, and concentrated. The crude product, which included 13,
14, 15, and 16) was purified by automatic normal-phase chromatography, with a gradient eluent of 5% to 100%
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EtOAc/Hex to yield pure product. Yield: 5.6 mg beige solid, 28%. H NMR (400 MHz, CDCl3) δ 7.05–7.00
(comp, 2H), 6.92–6.84 (comp, 12H), 6.67–6.57 (comp, 2H), 6.23–6.15 (comp, 2H), 3.41–3.33 (m, 1H), 3.33–3.27
(m, 2H), 2.89–2.79 (m, 1H), 2.79–2.71 (comp, 2H), 1.98–1.94 (m, 1H), 1.94–1.86 (comp, 2H), 1.62–1.48 (m,
1H), 1.22 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 155.9, 140.5, 128.2, 125.1, 123.4, 123.4,
122.1, 121.8, 117.4, 117.0, 47.4, 42.1, 29.9, 27.2, 26.8, 22.6, 21.9. IR (cm–1, neat): 3318, 2930, 1630, 1604, 1529,
1472, 1328, 1302, 1232, 1190, 1104, 1026, 744. HRMS (ESI-QToF) m/z: [M + H]+ calcd for C20H25N4O
337.2028, found 337.2022. Mp: >200 °C. TLC: Rf (2:1 Hex/EtOAc) 0.22, visualized with UV light. Assay of en-
antiomeric purity: Enantiomers of product 16 were separated by a chiral IB column, eluting at a flow rate of 1.0
mL/min with 10% EtOH/Hex. Rt[(S)-16] = 11 min; Rt[(R)-16] = 12 min.
Determination of Absolute Stereochemistry of 5+6. In our previous study of the reduction of mono-
quinoline 2 to 3, P1 and 1 gave opposite absolute stereochemical configurations, yet generate the same enantio-
mers in the reduction of 4. To probe this intriguing reversal, the absolute stereochemistry of enantioenriched 6
was sought. Unfortunately, numerous attempts to grow a single crystal of 5 or 6, in addition to a number of relat-
ed compounds, proved futile. However, the absolute stereochemistry of 3 had been determined in our previous
study,15 and we wondered whether this could be converted into a derivative of 6. As such, (R)-TRIP (1) was uti-
lized to facilitate the HEH-mediated reduction of 17 to (R)-18 (Figure S3A). The secondary amine of (R)-18 was
next dimethylated, and the primary amine was deprotected and dimerized with CDI to yield a mixture of (R,R)-19
and meso-20. Intriguingly, the observed e.r. and dr (98:2 e.r., 4.26:1 dr) are similar to the predicted values from
squaring the selectivity of the initial reduction (89:11 e.r., s = 8.1), which would give s2 = 65, 98:2 e.r., 4.10 d.r.,
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representing ideal Horeau kinetics for asymmetric amplification. Upon dimethylation of enantioenriched 6, from
reduction of 4 with (R)-TRIP (1), chiral-19 proved to have bis-(S) stereochemistry (Figure S2B). Hence, while
P1 processes both monoquinoline 2 and bisquinoline 4 with the same absolute stereochemistry of reduction, 1
shows enantiodivergence, representing another intriguing complementary feature of these two catalyst systems.
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Benzyl (2-methylquinolin-8-yl)carbamate (17, see Figure S3A). A flame dried 100 mL round bottom
flask was charged with 8-aminoquinaldine (1.00 g, 6.23 mmol, 1.00 equiv), 25 mL THF, and 6.3 mL NaHCO3
(satd, aq). The vessel was cooled to 0 °C, followed by addition of benzyl chloroformate dropwise (948 µL, 6.64
mmol, 1.05 equiv). The reaction was allowed to warm to rt slowly, and stirred overnight for 18 h. Upon comple-
tion of the reaction, the reaction was concentrated, redissolved in CH2Cl2 (20 mL), and washed with NaHCO3
(satd, aq, 20 mL). The organics were dried over Na2SO4, filtered, and concentrated. The crude material was puri-
fied by automatic normal-phase chromatography, with a gradient eluent of 5% to 100% EtOAc/Hex to yield pure
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product. Yield: 1.454 g beige solid, 79%. H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.42 (s, 1H), 8.00 (d, J =
1
13
8.4 Hz, 1H), 7.54–7.33 (m, 7H), 7.29 (d, J = 8.4 Hz, 1H), 5.31 (s, 2H), 2.71 (s, 3H). C{ H} NMR (151 MHz,
CDCl3) δ 157.2, 153.5, 137.5, 136.3, 136.3, 134.0, 128.7, 128.5, 128.4, 126.2, 126.1, 122.5, 120.5, 114.6, 67.0,
25.2. IR (cm–1, neat): 3357, 1723, 1604, 1573, 1521, 1492, 1455, 1434, 1383, 1339, 1311, 1237, 1192, 1109,
1023, 978, 862, 797, 748. HRMS (ESI-QToF) m/z: [M + H]+ calcd for C18H17N2O2 293.1290, found 293.1288.
Mp: 79–80 °C. TLC: Rf (4:1 Hex/EtOAc) 0.50, visualized with UV light.
(R)-Benzyl (2-methyl-1,2,3,4-tetrahydroquinolin-8-yl)carbamate (18). The (R)-stereochemistry was as-
signed in analogy to a similar substrate from a previous study.15 A flame dried 20 mL scintillation vial was
charged with 17 (121 mg, 0.413 mmol, 1.00 equiv), Hantzsch ester (261 mg, 1.03 mmol, 2.50 equiv), and catalyst
[(A) diphenyl phosphate (52.0 mg, 0.250 mmol, 0.500 equiv); (B) (R)-TRIP (1, 12.0 mg, 0.0159 mmol, 4 mol%)].
The vial was flushed with argon, charged with 8.5 mL CH2Cl2, capped, and stirred for 48 h. Upon completion, the
reaction was washed with NaHCO3 (satd, aq, 10 mL), with the aqueous layer being reextracted with CH2Cl2 (10
mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude material was purified
by automatic normal-phase chromatography, with a gradient eluent of 5% to 100% EtOAc/Hex to yield a mixture
of 18 and oxidized HEH byproduct (HEox). For reaction (B), the crude material was used in the next step without
further purification assuming full yield. For reaction (A), the crude material was further purified by two automatic
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reversed-phase chromatography columns, eluting with a gradient of 30% to 100% MeCN/H2O and 50% to 85%
MeCN/H2O, both with a 0.1% formic acid buffer (aq). The protonated product was dissolved in 2 mL CH2Cl2 (2
mL) and washed with 2 mL NaHCO3 (satd, aq), dried over Na2SO4, filtered, and concentrated to yield pure 18 as
a colorless oil. Yield not reported. 1H NMR (500 MHz, CDCl3) δ 7.47–7.31 (comp, 5H), 7.16 (bs, 1H), 6.87 (d, J
= 7.4 Hz, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.34 (bs, 1H), 3.41–3.31 (m, 1H), 2.90–2.71 (m, 2H), 1.93 (ddt, J = 11.9,
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5.6, 3.1 Hz, 1H), 1.54 (ddt, J = 16.7, 12.0, 5.2 Hz, 1H), 1.23 (d, J = 6.0 Hz, 3H). C{ H} NMR (126 MHz, d6-
DMSO, 60 °C) δ 154.2, 137.8, 136.7, 128.1, 127.5, 125.4, 122.5, 122.4, 121.3, 115.2, 65.5, 46.4, 28.9, 26.0, 21.7.
IR (cm–1, thin film from CHCl3): 3315, 2930, 1697, 1608, 1498, 1453, 1330, 1218, 1065, 1020, 982, 909, 728.
HRMS (ESI-QToF) m/z: [M + H]+ calcd for C18H21N2O2 297.1603, found 297.1603. TLC: Rf (4:1 Hex/EtOAc)
0.32, visualized with UV light. Assay of enantiomeric purity: Enantiomers of product 18 were separated by a chi-
ral IB column, eluting at a flow rate of 1.0 mL/min with 15% EtOH/Hex. Rt[(S)-18] = 6.0 min; Rt[(R)-18] = 6.5
min.
Cis- and trans-1,3-bis(1,2-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)urea (19+20). Preparation from 6:
Modified from literature precedent,44 a flame dried 4 mL scintillation vial was charged with 6 (16.7 mg, 0.0476
mmol, 1.00 equiv), 0.75 mL MeCN, and formaldehyde (37% aq soln, 29.0 µL, 0.357 mmol, 7.50 equiv). Sodium
cyanoborohydride (22.0 mg, 0.357 mmol, 7.50 equiv), handled entirely in a well ventilated fume hood or capped
vials, was added quickly to the reaction. The vessel was fitted with a septum, pierced with a cannula leading to a
solution of NaHCO3 (satd, aq) to neutralize any HCN. Glacial acetic acid (10 µL) was added, and the reaction was
allowed to stir for 1 h, after which more glacial acetic acid (10 µL) was added. The reaction was stirred overnight
for 18 h, after which the mixture was slowly added to a solution of NaHCO3 (satd, aq, 20 mL). This mixture was
extracted with CH2Cl2 (20 mL x 2), and the combined organics were dried over Na2SO4, filtered, and concentrat-
ed. The crude product was purified by automatic normal-phase chromatography, with a gradient eluent of 5% to
100% EtOAc/Hex, followed by automatic reversed-phase chromatography, with a gradient eluent of 30% to
100% MeCN/H2O, finally followed by normal-phase chromatography with a gradient eluent of 1% to 40%
EtOAc/Hex to yield 10.8 mg of 19+20 as a white solid (60% yield). Preparation from 17: Modified from litera-
ture precedent,44,45 a 100 mL round bottom flask containing crude 18+HEox (assumed 0.413 mmol of 18, 1.00
equiv) was charged with 3.0 mL MeCN and formaldehyde (37% aq soln, 168 µL, 2.07 mmol, 5.00 equiv). Sodi-
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um cyanoborohydride (130 mg, 130 mmol, 5.00 equiv), handled entirely in a well ventilated fume hood or capped
vials, was added quickly to the reaction. The vessel was fitted with a septum, pierced with a cannula leading to a
solution of NaHCO3 (satd, aq) to neutralize any HCN. Glacial acetic acid (123 µL) was added, and the reaction
was allowed to stir for 15 min. A thick sludge formed; as such 2.0 mL of additional MeCN was added. The reac-
tion was stirred overnight for 18 h, after which the mixture was slowly added to a solution of NaHCO3 (satd, aq,
100 mL). This mixture was extracted with CH2Cl2 (100 mL x 2), and the combined organics were dried over
Na2SO4, filtered, and concentrated. The crude product was purified by automatic normal-phase chromatography,
with a gradient eluent of 5% to 100% EtOAc/Hex, followed by automatic reversed-phase chromatography, with a
gradient eluent of 25% to 100% MeCN/H2O, with a 0.1% formic acid buffer (aq). The protonated product was
dissolved in 2 mL CH2Cl2 (2 mL) and washed with 2 mL NaHCO3 (satd, aq), dried over Na2SO4, filtered, and
concentrated to yield 25.0 mg of mostly pure 21, which was taken forward to the next step without further purifi-
cation. A 10 mL round bottom containing 21 was charged with 0.75 mL MeOH and 0.75 mL THF. The vessel
was fitted with a septum, which was pierced by a balloon of H2, connected to a needle; and H2 was bubbled
through the solution. The reaction was stirred at rt overnight for 20 h, after which the crude mixture was filtered
through a plug of celite, eluting with MeCN and MeOH. The solution was concentrated to yield 14 mg of mostly
pure 22, which was taken forward to the next step without further purification. A 4 mL scintillation vial contain-
ing 22 (14.0 mg, 0.0805 mmol, 1.00 equiv) was charged with 0.5 mL THF, followed by 1,1′-Carbonyldiimidazole
(CDI, 31.0 mg, 0.191 mmol, 2.4 equiv), which was added portionwise over the course of 1 day. The vial was
capped and heated at 70 °C for 96 h. Upon completion, the reaction was concentrated and purified by automatic
normal phase chromatography, with a gradient eluent of 1% to 40% EtOAc/Hex, yielding pure product. Yield:
7.0 mg of 19+20 as a white solid, 4% yield from 17, 4 steps. 1H NMR (400 MHz, CDCl3) δ 7.73 (t, J = 6.8 Hz,
1H), 7.29–7.23 (m, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 3.09 (qd, J = 6.7, 3.5 Hz, 1H), 2.78–
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2.72 (m, 2H), 2.54 (d, J = 3.3 Hz, 3H), 2.04–1.88 (m, 1H), 1.69–1.50 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H). C{ H}
NMR (151 MHz, CDCl3) δ 153.6, 138.9, 138.7, 132.7, 129.9, 124.1, 123.0, 123.0, 118.4, 54.1, 54.0, 41.2, 40.6,
24.5, 24.3, 22.0, 19.2. IR (cm–1, thin film from CH2Cl2): 3272, 2966, 2928, 1654, 1602, 1535, 1468, 1411, 1379,
1315, 1220, 1191, 771. HRMS (ESI-QToF) m/z: [M + H]+ calcd for C23H31N4O 379.2498, found 379.2497. TLC:
Rf (4:1 Hex/EtOAc) 0.17, visualized with UV light. Assay of enantiomeric purity: Enantiomers of products 19+20
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were separated by a chiral IB column, eluting at a flow rate of 1.0 mL/min with 2.0% EtOH/Hex. Rt[(S,S)-19]
=14 min; Rt[20] =15 min; Rt[(R,R)-19] = 16 min.
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General Procedures for Catalyst Screening. Bisquinoline reduction. A flame dried 5 mL scintillation
vial was charged with substrate (4 or 13; 0.0600 mmol, 1.00 equiv), Hantzsch ester (38.0 mg, 0.150 mmol, 2.50
equiv), catalyst (DPP, P1, or 1; 0.0120 mmol, 0.200 equiv), and 1.25 mL CH2Cl2. The vial was flushed with Ar,
capped, and stirred for 24 h. After conclusion of the reaction, the conversion was measured by LC/MS. The reac-
tion was washed with NaHCO3 (satd, aq, 1.0 mL), the aqueous layer was reextracted with 2 mL CH2Cl2, and the
combined organics were dried over Na2SO4, filtered, and concentrated. The crude product, which was purified by
automatic normal-phase chromatography, with a gradient eluent of 5% to 75% EtOAc/Hex to yield mono-reduced
products (5, 14, or 15), plus di-reduced products (6+7 that were inseparable, or 16). The e.r. and dr of both iso-
lates were measured by HPLC. All reported results are the average of ³ 2 trials.
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Monoquinoline reduction (from literature precedent15): An oven dried 4 mL vial equipped with a stir bar
was charged with catalyst (0.00600 mmol, 0.100 equiv), quinoline 17 (17.6 mg, 0.0600 mmol, 1.00 equiv), and
Hantzsch ester (38.0 mg, 0.150 mmol, 2.5 equiv.). The vial was flushed with Ar, charged with 1.25 mL CH2Cl2,
capped, and stirred for 24 h. The reaction was quenched by addition of NaHCO3 (1 mL), with the aqueous layer
being reextracted with CH2Cl2 (2 mL). The combined organics were dried with Na2SO4, filtered, and concentrated
to yield crude product. This was taken up in CDCl3 to determine conversion via 1H NMR and e.r. by HPLC. Re-
ported values are the average of 2 trials. With P1 as catalyst, 18 was produced in 92% conv., 59:41 e.r.; with 1 as
catalyst, 18 was produced in 99% conv., 11:89 e.r..
One-pot site- and enantioselective acylations and phosphorylations. Substrates 10 (14.3 mg, 0.0318
mmol, 1.00 equiv) and (±)-8 (5.0 mg, 0.032 mmol, 1.0 equiv) were dissolved in PhMe (3 mL). Solutions of cata-
lyst P3 (0.7 mg, 6*10–4 mmol, 2 mol%) and P2 (0.6 mg, 6*10–4 mmol, 2 mol%) were added, followed by triethyl-
amine (distilled, 56 µL, 0.40 mmol, 13 equiv). Acetic anhydride (18 µL, 0.19 mmol, 6.0 equiv) and diphenylchlo-
rophosphate (40 µL, 0.19 mmol, 6.0 equiv) were then added in rapid succession. After 1 h, an aliquot (1.5 mL) of
the reaction was quenched with methanol (0.75 mL) and the solvent was removed in vacuo. Product distribution
was monitored by 1H and 31P NMR spectroscopy (see Figure 3). Products were separated and analyzed by HPLC
and GC as detailed below. Separation of reaction products: Reaction products 9, 11, and 12 were separated by
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normal phase HPLC employing a YMC PVA-Sil column (Waters), eluting at a flow rate of 10 mL/min with the
following gradient ramp from Hex to 6.5% iPrOH/Hex over 40 min. Rt(9+12) = 27 min; Rt(11) = 30 min. Assay of
enantiomeric purity (11): Enantiomers of product 11 were separated by chiral HPLC employing a Chiralcel OD
column (Alltech), eluting at a flow rate of 0.5 mL/min with 30% EtOH/Hex. Rt[11(3-P)] = 11.5 min; Rt[11(1-P)]
= 12.5 min.46 Separation of reaction products: Reaction products 9 and 12 were separated by chiral HPLC em-
ploying an L-Leucine column (Regis), eluting at a flow rate of 0.5 mL/min with 15% EtOH/Hex. Rt(12) = 16.8
min; Rt(9) = 20.3 min. Assay of enantiomeric purity (9): Enantiomers of product 9 were separated by chiral GC
employing a 30m Chiraldex G-TA column (Alltech). Conditions: temperature = 135 °C; flow rate = 60 psi.
Rt[(R,R)-9] = 12.0 min; Rt[(S,S)-9] = 12.8 min.35 Assay of enantiomeric purity (12): Enantiomers of product 12
were separated by a chiral OD column (Alltech), eluting at a flow rate of 0.5 mL/min with 1.5% EtOH/Hex.
Rt[(S,S)-12] = 38 min; Rt[(R,R)-12] = 41 min.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Further commentary on Horeau amplification.
Study of CPA-mediated reduction of an unsymmetric bisquinoline
Schemes for substrate synthesis and testing
Tables for conversion dependence of enantioselectivities reduction of bisquinolines
HPLC and UPLC/MS traces for catalytic reductions
X-ray crystallographic data for compounds (±)-5 and (±)-14
Crystallographic data are deposited with the Cambridge Crystallographic Data Centre under the accession num-
bers CCDC 1882216 and 1882217.
AUTHOR INFORMATION
Corresponding Author
*E-mail: scott.miller@yale.edu
ORCID
Christopher R. Shugrue: 0000-0002-3504-9475
Elizabeth R. Jarvo: 0000-0002-2818-4038
Scott J. Miller: 0000-0001-7817-1318
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Present Addresses
†
BRS: Department of Chemistry, College of the Holy Cross, Worcester, Massachusetts 01610-2395, United
States.
‡ERJ: Department of Chemistry, University of California, Irvine, California 92697-2025, United States.
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Notes
§ERJ, BRS, SJM: Earlier work in this study was performed at the Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467-3860.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Institutes of Health (NIH R01-GM096403). We also thank Takeda for
research support. We graciously thank Angela Lin for assistance in the synthesis of compounds for this study. The
earliest work in this project was supported by the National Institutes of Health and the National Science Founda-
tion. C.R.S. thanks the National Science Foundation Graduate Research Fellowship Program for funding
(DGE1122492).
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