Practical and Modular Construction of C(sp3)-Rich Alkyl Boron Compounds

Article abstract of DOI:10.1021/jacs.0c11964

Alkyl boronic acids and esters play an important role in the synthesis of C(sp3)-rich medicines, agrochemicals, and material chemistry. This work describes a new type of transition-metal-free mediated transformation to enable the construction of C(sp3)-rich and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry. The strategic significance of this approach, with alkyl boronic acids as linchpins, is demonstrated through various downstream functionalizations of the alkyl boron compounds. This two-step concurrent cross-coupling approach, resembling formal and flexible alkyl-alkyl couplings, provides a general entry to synthetically challenging high Fsp3-containing drug-like scaffolds.

Full text of DOI:10.1021/jacs.0c11964

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Practical and Modular Construction of C(sp3)‑Rich Alkyl Boron
Compounds
Yangyang Yang,∥ Jet Tsien,∥ Ayala Ben David, Jonathan M. E. Hughes, Rohan R. Merchant,*
and Tian Qin*
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ABSTRACT: Alkyl boronic acids and esters play an important role in the synthesis of C(sp3)-rich medicines, agrochemicals, and
material chemistry. This work describes a new type of transition-metal-free mediated transformation to enable the construction of
C(sp3)-rich and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional
group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage
functionalization of scaffolds relevant to medicinal chemistry. The strategic significance of this approach, with alkyl boronic acids as
linchpins, is demonstrated through various downstream functionalizations of the alkyl boron compounds. This two-step concurrent
cross-coupling approach, resembling formal and flexible alkyl−alkyl couplings, provides a general entry to synthetically challenging
high Fsp3-containing drug-like scaffolds.
ways, leading to nonmodular, linear processes and detracting
from overall efficiency.
INTRODUCTION
■
Convergence and modularity are the key driving forces in the
development of modern organic chemistry methodologies for
the synthesis of complex molecules in both industry and
academia. Recent developments in medicinal chemistry,
showcasing the improved physiochemical and pharmacokinetic
profiles of compounds with higher Fsp3 (fraction of sp3 carbon
atoms), have resulted in an increased emphasis on sp3-rich
moieties.1 This trend toward “increasing saturation” calls for a
modular and versatile platform to form these C(sp3)−C(sp3)
bonds. Over the past century, addition of alkyl organometallics,
such as Grignard reagents, to electrophiles (carbonyls, imides,
Michael acceptors, etc.) represents one of the most reliable
approaches to construct C(sp3)−C(sp3) bonds.2 Additionally,
transition-metal-mediated cross-coupling, a “go-to” approach
to access a diverse chemical space,3 has more recently enabled
the construction of a variety of C(sp3)−C(sp3) bonds.
However, this process remains a very challenging undertaking4
owing to the propensity of intermediary metal−alkyl
complexes to undergo β-hydride elimination.5 As such,
complex hydrocarbons are often assembled in “roundabout”
With the increasing demand for the construction of C(sp3)−
C(sp3) bonds in mind, we envisioned an alternate approach to
access C(sp3)-rich scaffolds via the preparation of an alkyl
boronic acid intermediate that can be subsequently employed
in further transformations. The alkyl boronic acid would
function as a linchpin, allowing for stitching together of a
variety of C(sp3) scaffolds and heteroatoms (Figure 1A). The
ability to access such an alkyl boron reagent would provide a
powerful functional handle, allowing for a myriad of down-
stream functionalizations, including single- and two-electron
transfer pathways, and 1,2-metalate rearrangements.6 To this
end, radical precursors (such as halides, pseudohalides, redox-
Received: November 15, 2020
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A

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Figure 1. Alkylboron synthesis enabled by transition-metal-free mediated alkyl−alkyl coupling. (A) Alkyl boronic acids as useful intermediates for
synthesis of C(sp3)-rich scaffolds. (B) State-of-art synthesis of alkyl boron compounds and our modular approach toward alkylboron synthesis. (C)
Alkyl boronic acid represents a more stable boronic acid in comparison with benzyl and allylic boronic acid. (D) Identification of a viable
sulfonylhydrazone and reaction conditions to achieve the cross-coupling to access tertiary boronic ester.
17
active esters, and pyridinium salts),7 olefins,8 ate complexes,9
organolithium reagents,10 α-boryl carbanion/radical,11 and
diazo compounds12 have been demonstrated to be powerful
precursors to such alkyl boron species (Figure 1B). Given the
advantages of boron intermediates in chemical synthesis,
development of new practical and efficient methodologies to
construct boron compounds are highly sought after. By
leveraging the unique reactivity of the sulfone (VI) →
sulfinate(IV) reduction, herein we showcase that readily
available alkyl sulfonylhydrazones (from aldehydes or ketones)
and alkyl boronic acids can be directly utilized to access
sterically congested alkyl boron compounds in the absence of
air-sensitive base or explosive reagents. This strategy would
thus allow for modular and convergent construction of
sterically hindered C(sp3)−C(sp3) bonds.
Valdes, and co-workers previously demonstrated the
coupling of alkyl tosyl hydrazones with aryl/vinyl boronic
acids in the presence of mild base to forge the C(sp3)−C(sp2)
linkage (Figure 1B). In this seminal transformation, they
propose formation of an alkyl boronic acid intermediate, which
is spontaneously eliminated via protodeboronation17 or
intramolecular trapping by a cyano- or azide in a classic five-
or six-membered ring transition state.18,19 The isolation of the
intermediate alkyl boronic acid was not reported in any of
these communications. While the lability of benzylic and allylic
boronic acids likely leads to the observed protodeboronation,
we presumed nonbenzylic alkyl boronic acids would be more
stable under these conditions (K2CO3, dioxane at 100 °C). To
that end, the stability of a series of alkyl boronic acids were
́
́
evaluated under Barluenga−Valdes conditions (Figure 1C).
Here we describe a general, operationally friendly, modular,
and scalable method for synthesis of C(sp3)-rich alkyl boronic
esters. The transformation is exemplified through the synthesis
of >110 alkyl boronic esters, including the late-stage
derivatization of bioactive molecules and synthetic applications
to rapidly access pharmaceutically relevant targets.
Gratifyingly, although the benzylic (3) and allylic (4) boronic
acids decomposed rapidly (<10 min) under these conditions,
simple primary, secondary, and tertiary alkyl boronic acids (5−
7) demonstrated remarkable stability (>5 h) to the basic and
high temperature conditions. On the basis of our results, we
surmised that direct access to complex alkylboronic acids 2
could be achieved in a simple and modular fashion from the
readily available sulfonylhydrazone and alkylboronic acid
building blocks via 1,2-metalate rearrangement of zwitterion
intermediate 1. With this hypothesis in mind, we subjected
alkyl tosylhydrazone 8 and cyclopentyl boronic acid 9 to the
RESULTS AND DISSCUSSION
■
Identification of Sulfonylhydrazone for Boron-Pre-
served Coupling. The literature is replete with examples of
sulfonylhydrazones serving a variety of different roles in
synthesis, from the venerable Bamford−Stevens reduction13
and Eschenmoser−Tanabe fragmentation,14 to both transition-
metal-mediated15 and transition-metal-free cross-couplings.16
In the latter regard, the breakthrough report by Barluenga,
́
Barluenga−Valdes conditions (Figure 1D, entry 2) and
observed that tertiary boronic ester 10 was observed in only
19% yield, with the majority of the mass balance resulting in
decomposition of 8 to an uncharacterized complex mixture.
B
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Figure 2. Scope of the cross-coupling between alkyl sulfonylhydrazones and alkyl boronic acids or alkyl trifluoroborate salts. Reaction conditions
(denoted by superscript labels): (a) Sulfonylhydrazone 16 (1.0 equiv), RB(OH)2 17 (3.0 equiv), Cs2CO3 (3.0 equiv) in chlorobenzene (0.1−0.2
M) heated at 100 °C for 5 h; then pinacol (5.0 equiv) was added and stirred at 100 °C for another 1 h. (b) In situ hydrolysis of potassium
alkyltrifluoroborates: RBF3K 18 (3.0 equiv), BSA (6.0 equiv), and H2O (9.0 equiv) in chlorobenzene (0.1−0.2 M) heated at 100 °C for 1 h. (c) In
situ formation of sulfonylhydrazone. 15 (1.0 equiv), MesSO2NHNH2 (1.0 equiv), chlorobenzene at 80 °C for 1 h. (d) Starting material is an E/Z
mixture. (e) Add glycol (5.0 equiv) instead of pinacol. (f) At 5 mmol scale. (g) Diastereomeric ratio is undetermined. See the Supporting
Information for experimental details. BSA = bis(trimethylsilyl)acetamide.
We hypothesized that the sulfonylhydrazone with sterically
hindered or electron-withdrawing substitutions could provide a
mild approach to access the proposed intermediate 1.
Subsequent optimization of sulfonylhydrazone, base, solvent,
and temperature (summarized in Figure 1D; see the
Supporting Information for additional details) resulted in the
identification of optimal conditions, which employ mesitylsul-
fonyl hydrazone, cesium carbonate, and chlorobenzene to
afford coupling product 10 in 88% isolated yield (96% GC
yield, entry 1). The combination of using mesitylsulfonyl
hydrazone with cesium carbonate as the base was found to be
the key, with any deviation from these optimized conditions,
C
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Figure 3. Late-stage derivatization to access alkyl boronic ester building blocks for enabling structure−activity relationship efforts. Superscripts
denote reaction conditions: (a) Sulfonylhydrazone 16 (1.0 equiv), RB(OH)2 17 (3.0 equiv), Cs2CO3 (3.0 equiv) in chlorobenzene (0.1−0.2 M)
heated at 100 °C for 5 h; then pinacol (5.0 equiv) was added and stirred at 100 °C for another 1 h. (b) In situ hydrolysis of potassium
alkyltrifluoroborates: RBF3K 18 (3.0 equiv), BSA (6.0 equiv), and H2O (9.0 equiv) in chlorobenzene (0.1−0.2 M) heated at 100 °C for 1 h. (c)
Diastereomeric ratio is undetermined. (d) At 5 mmol scale. See the Supporting Information for experimental details.
such as using an alternative sulfonylhydrazone (entry 3), base
(entries 4 and 5), or solvent (entries 6 and 7) led to reduced
yields or unreacted starting material. Employing 1.5 equiv of
boronic acid 9 (entry 8) or using different temperatures also
afforded product 10 (entries 12 and 13), albeit in lower yields.
It is noteworthy that converting the initially generated
alkylboronic acid to the corresponding pinacol ester was
unexpectedly challenging (e.g., 0% yield for compound 74, vide
infra), presumably due to the steric hindrance of the generated
tertiary boronic acid (entry 10). However, after further
optimization, it was found that heating at 100 °C with pinacol
(entry 1) or using ethylene glycol as a condensation reagent
(entry 11)20 enabled efficient boronic ester formation.
Notably, despite sulfonylhydrazone 8 being easy to prepare
and bench-stable (usually isolated as a crystalline solid by
filtration), an in situ protocol was developed to enable
functionalization of the starting ketone 13 in one pot (entry
16), resulting in comparable results to the optimized
procedure. Additionally, procedures (entries 14 and 15) that
employ the more stable (and commercial) potassium
alkyltrifluoroborate 12 as a cross-coupling partner were also
developed.21 As a current limitation, pinacol boronic esters are
not competent as coupling partners in this transformation (see
the Supporting Information for detailed substrate limitations).
Scope of the Alkyl Boronic Esters. With the optimal
conditions in hand, the robustness of this cross-coupling
reaction was demonstrated through the preparation of over 80
substrates (Figure 2A−D). The substrate scope of this
methodology was initially evaluated with a variety of functional
groups on both sulfonylhydrazone and boronic acid coupling
partners (Figure 2A). Of note, the nitro group (20), iodide
(21), bromide (24), silyl (25), tertiary amines (31 and 32),
alkyne (37), olefins (38−41), electron-rich heterocycles (33,
42, and 43), and electron-deficient heterocycles (34−36) are
all compatible with this transformation. Additionally, this
transformation was competent for a range of acidic proton-
containing substrates, such as phenols (22), anilines (23 and
28), unprotected indoles (33), alkyl alcohols (26), carboxylic
acids (27), and alkyl amines (29).22 Therefore, the relatively
mild conditions and excellent chemoselectivity of this
transformation enables access to products that would be either
be difficult or impossible to prepare via other known
methodologies, including organolithium-promoted 1,2-metal-
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Figure 4. Strategic synthetic application. See the Supporting Information for experimental details. TBC = 4-tert-butylcatechol.
ate rearrangement and transition metal catalysis (one- or two-
electron).23
aldehyde-derived sulfonylhydrazone to afford the desired alkyl
boronic esters in good yields. The structure of compound 56
was unambiguously confirmed by single crystal X-ray analysis.
As a testament to the efficiency of this transformation at
enabling access to sterically hindered linear, tertiary alkyl
boronic esters, 22 compounds with diverse substitution
patterns were prepared and are delineated in Figure 2C
Figure 2B demonstrates the construction of the C(sp3)−
C(sp3) bond as a means to synthesize a broad range of
secondary alkyl boronic esters. Primary (44, 46, 52, 53, and
55), branched (45 and 54), and cyclic (47, 48−51, and 56)
secondary boronic acids were successfully coupled with an
E
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(57−78). Anisylacetone-derived sulfonylhydrazone was re-
acted with seven different alkyl boronic acids and alkyltri-
fluoroborate salts to access a series of tertiary alkyl boronic
esters (57−61, 63, and 64). Of particular note are the tertiary
1-adamantyl- (63) and tert-butyl- (64) trifluoroborate salts,
which served as viable coupling substrates for the formation of
very hindered C(sp3)−C(sp3) bonds. The sulfonylhydrazone
derived from a more hindered piperidyl ketone also coupled
smoothly with a variety of alkylboronic acids to deliver boronic
ester products 65−72 and 74−78. This transformation was not
limited to methyl ketone-derived sulfonylhydrazones, and was
also compatible with additional α-substitutions on the ketone
(75 and 78). In the case of transition-metal-mediated
stereospecific coupling,24 the stereocenter on a chiral
nucleophile readily racemizes via one-electron or metal hydride
pathways, thereby leading to erosion in stereochemical fidelity.
In contrast, the mechanistic details of this transformation,
which involve a direct transition-metal-free 1,2-metalate
rearrangement on boron, enables the coupling of a chiral
alkyl boronic acid25 (73) with complete stereochemical
fidelity. Due to the highly sterically encumbered nature of
some of the alkyl boronic acid substrates, ethylene glycol was
selected as a more efficient trapping reagent (74 and 75) in
lieu of pinacol.
In Figure 2D, a wide range of sulfonylhydrazones derived
from cyclic ketones were investigated (79−99). A variety of
four- to seven-membered ring systems, including azetidine
(79−81), cyclobutane (82−84), azaspiro[3.3]-heptane (85
and 86), cyclopentane (87−89), pyrrolidine (90), thiane (10),
tetrahydropyran (91 and 95), piperidine (92−94), cyclo-
hexane (96), cycloheptane (97), azabicyclo[3.3.1]nonane
(98), and norbornane (99) underwent cross-coupling
smoothly with primary and secondary alkyl boronic acids.
The transformation exemplifies excellent diastereomeric
specificity, with the stereochemistry of the starting alkyl
boronic acid transferred to the product with complete fidelity
(86 and 95).
methyl cyclopropyl group, a tert-butyl bioisostere, was also
compatible in the coupling (107 and 108).28 In contrast to
one-electron approaches, where rapid ring opening is observed
when a radical is generated adjacent to strained ring systems
(such as 1-methyl cyclopropyl and BCPs),29 this cross-
coupling demonstrates remarkable tolerance in preserving
these motifs (106−108).
Given the prevalence of steroids as biologically active
scaffolds, functionalization of a variety of steroids was targeted.
Both ketone (109−112) and boronic acid (113) derived
steroidal coupling partners delivered products in synthetically
useful yields. Among which, the resultant highly sterically
encumbered boronic acids from estrone (109) and pregnane-
20-one (110) were trapped by ethylene glycol, while pinacol
was used in the cases of lithocholic acidic derivatives (111−
113).
The modularity of this approach and ability to rapidly
generate a “library” of complex alkyl boronic esters from simple
building blocks was exemplified in the late-stage functionaliza-
tion of nitrogen atom-rich pentoxifylline, a commonly used
medication to treat peripheral arterial disease. As shown in
Figure 3C, a variety of primary (119−123) and secondary
(116−118) alkyl motifs, including medicinally relevant
heterocycles such as pyridine (126) and piperidine (124),
were introduced with good to excellent yields. Notably, estrone
and pentoxifylline, two distinct and structurally complex
molecules, could be linked together (122) in excellent yield.
Historically, alkyl boronic acids have been primarily
regarded as versatile synthetic building blocks. However,
more recently, their unique biological activity has attracted
medicinal chemists’ attention for incorporation into drug
candidates.30 One such example is the bicyclic alkyl boronic
acid 127 reported by Merck and Co., Inc., as a human arginase
inhibitor to enhance cancer immunotherapy.31 Notably, any
transposition of the boronic acid motif itself would typically
require a de novo route for each new analog during structure−
activity relationship (SAR) exploration. However, this method-
ology now enables the late-stage derivatization of an advanced
boronic acid intermediate, such as 128, in a single step.
Strategic Applications via Alkyl Boronic Acid and
Ester Functionalizations. As illustrated in Figure 4, the
strategic impact of this methodology shines in its ability to
combine the modular synthesis of any alkyl boronic acid with
the power of boronic acids to serve as one of the most versatile
functional groups. This synergistic application of two highly
modular and complexity generating transformations opens up
limitless possibilities for rapid synthesis of complex druglike
scaffolds.32 First, as shown in Figure 4A, to address the
limitations of transition-metal-catalyzed cross-couplings to
access hindered C(sp3)−C(sp3) bonds (vide supra), a cross-
coupling/reductive protodeboronation sequence was devel-
oped.33 This formal alkyl−alkyl cross-coupling provides a
modular approach to access a variety of unfunctionalized
C(sp3)−C(sp3) bonds. Starting from ketones, these targets
have traditionally been prepared via olefination followed by
hydrogenation (vide infra) or Grignard addition followed by
deoxygenation. Such multistep routes typically rely on often
difficult to access reagents and harsh conditions, while the
sequential coupling shown in this context has combined our
2e− coupling with 4-tert-butylcatechol (TBC)-mediated mild
radical protodeboronation conditions.33 This modular and
highly functional group tolerant protocol proceeds in one pot
from alkyl sulfonylhydrazones 16 and alkyl boronic acids,
A number of these substrates in Figure 2 were accessed
using the in situ protocol from the corresponding aldehyde or
ketone or via the in situ hydrolysis of the potassium alkyl
trifluoroborate salts, highlighting the synthetic practicality of
this method. This operationally simple reaction was also
scalable and provided comparable yields on 5 mmol scale
couplings (93 and 118, vide infra).
Synthesis of Alkyl Bioisostere-Containing Boronic
Esters and Late-Stage Derivatization. The synthetic
applicability of this modular cross-coupling is showcased by
straightforward preparation of a variety of alkyl bioisostere-
containing boronic ester building blocks (Figure 3A). Alkyl
bioisosteres such as cubanes, bicyclo[1.1.1]pentanes (BCPs)
and cyclopropanes, have been shown to improve drug
candidates’ physiochemical and pharmacokinetics properties26
and as such, new methods for their installation and
functionalization are highly sought after.27 To this end,
boronic acids derived from BCP and cubane trifluoroborate
salts,7c,d reacted smoothly with linear ketone- (100−102) and
aldehyde- (103) derived sulfonylhydrazones to afford the
expected coupling products in good yields. Excellent results
were also observed for the introduction of BCPs onto the C4-
position of the pharmaceutically relevant piperidine scaffold
(104 and 105). Moreover, a sulfonylhydrazone derived from
highly sterically encumbered BCP ketone also coupled readily
with cyclobutyl boronic acid (106). In a similar vein, the 1-
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allowing direct access to a range of C(sp3)−C(sp3) bonds, with
varied substitution patterns and functional groups (130−136).
Therefore, this approach represents a formal cross-coupling
between primary (130) or secondary (131−136) alkyl
electrophiles with either primary (132−135), secondary
(130 and 131), or tertiary (136) nucleophiles (boronic esters)
and enables the formation of C(sp3)−C(sp3) bonds that could
not be accessed by the state-of-the-art transition metal
catalysis.
The final case study (Figure 4E) is drawn from the patent
literature, wherein medicinal chemists at Taisho Pharmaceut-
ical were interested in the azaspiroalkanes 159 and 160 as
intermediates toward GPR119 agonists.40 Although both
analogs have a similar alkyl chain spacer with the only
difference being the identity of the azaspiro fragment, step-
intensive de novo approaches (6−8 steps) were required to
access each target from the its corresponding azaspiro ketones
(157 and 158). Using the cross-coupling/radical protodeboro-
nation protocol, late-stage and modular installation of either of
the azaspiro fragments could be achieved from a common
intermediate, allowing for a streamlined and divergent route to
both targets 159 and 160.
As showcased in Figures 2−4, starting from readily available
and bench-stable starting materials, this operationally simple
method allows for the rapid and modular preparation of a
variety of complex, C(sp3)-rich alkyl boronic esters. In addition
to providing access to pharmaceutically relevant building
blocks, this transformation harnesses the versatility of alkyl
boron compounds to delineate a novel template that simplifies
retrosynthetic planning and enables structure−activity relation-
ships (SAR) of lead candidates. As such, numerous
applications of this methodology can be anticipated in both
academia and industry for rapidly accessing boronic acid
derivatives and forging C(sp3)−C(sp3) bonds that were
previously inaccessible.
Additionally, versatile alkyl boronic acid intermediates (e.g.,
138) can be parlayed into diverse structures through distinct
modes of reactivity (Figure 4B). For example, the in situ
oxidation of boronic acid 138 led to the alcohol (139) in high
yield. This transformation mimics the classical Grignard
addition into ketone, but it obviates the requirement of a
strong organometallic reagent. One intriguing feature of this
methodology is that the products are also viable coupling
partners. Therefore, iterative coupling to build complex sp3-
rich scaffolds can be realized through sequential addition of
different sulfonylhydrozones. As illustrated in Figure 4B(c), in
situ generated alkyl boronic acid 138 was treated with a second
sulfonylhydrazone to generate two new C(sp3)−C(sp3) bonds.
Subsequent trapping with pinacol enables isolation of the
iterative coupling product (141) in good yield. In addition to
2e− functionalizations of 138, under treatment with a radical
initiator or oxidant, the alkylboronic acid acts as a radical
progenitor to generate an alkyl radical, which could then
participate in sequential radical cross-couplings. This is
showcased by subsequent fluorination (140),34 photomediated
alkynylation (142),35 and Minisci-type radical addition (143
and 144)36 from in situ alkyl boronic acid 138. They can also
be transformed to the more stable trifluoroborate salt (145),
which are themselves valuable substrates for radical trans-
formations via photoinduced electron transfer.37
The synthesis of F-BCP analogs (151−153) in Figure 4C
provides a template for a general synthetic strategy to enable
the programmable construction of fully substituted quaternary
carbon centers from ubiquitous alkyl carboxylic acids. Starting
from the carboxylic acid oxidation state, sequential installation
of three distinct fragments via (1) nucleophilic addition of
alkyl lithium to Weinreb-amide, (2) cross-coupling with alkyl
boronic acid (148−150), and (3) Zweifel olefination38 of
boronic esters to vinyl carbamate afforded the desired products
(151−152) with complete control and selectivity.
Monofluorinated myristic acid analogs such as 155 are useful
probes in the study of membrane topology due to the high
sensitivity of 19F NMR.39 The previous approach to 155
required a 6-step linear synthetic sequence starting from 1,2-
decanediol 155 (Figure 4D), with several protecting group and
redox manipulations that were dictated by the functional group
incompatibility of n-butyl Grignard reagents with alcohols or
carboxylic acids. In contrast, a much simpler retrosynthetic
template emerges using this cross-coupling strategy, wherein all
three partners could be stitched together in one step without
redox or protecting group manipulations. Starting from 10-
oxocapric acid (154), cross-coupling with n-butyl boronic acid,
followed by in situ deborylative fluorination of the intermediate
alkyl boronic acid provides monofluorinated fatty acid 155 in
47% yield. This demonstrates a real-life example where the
power of a successive cross-coupling strategy with broad
functional group tolerance allows for rapid and modular
generation of C(sp3)-rich scaffolds.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11964.
Detailed experimental procedures, and characterization
data for all compounds (PDF)
Crystallographic information for 56 (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
Rohan R. Merchant − Department of Discovery Chemistry,
Merck & Co., Inc., South San Francisco, California 94080,
United States; orcid.org/0000-0002-5472-8780;
Email: rohan.merchant@merck.com
Tian Qin − Department of Biochemistry, The University of
Texas Southwestern Medical Center, Dallas, Texas 75390,
United States; orcid.org/0000-0001-7225-3224;
Email: tian.qin@utsouthwestern.edu
Authors
Yangyang Yang − Department of Biochemistry, The University
of Texas Southwestern Medical Center, Dallas, Texas 75390,
United States
Jet Tsien − Department of Biochemistry, The University of
Texas Southwestern Medical Center, Dallas, Texas 75390,
United States
Ayala Ben David − Department of Biochemistry, The
University of Texas Southwestern Medical Center, Dallas,
Texas 75390, United States
Jonathan M. E. Hughes − Department of Process Research
and Development, Merck & Co., Inc., Rahway, New Jersey
07065, United States
Complete contact information is available at:
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Author Contributions
∥Y.Y. and J.T. contributed equally to this work.
Funding
Financial support for this work was provided by the Robert A.
Welch Foundation (Grant I-2010−20190330) and the Eugene
McDermott Scholar Endowed Scholarship. Green Fellow
supported an undergraduate fellowship to A.B.D.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Feng Lin (UTSW) for assistance with NMR
spectroscopy; Hamid Baniasadi (UTSW) for HRMS; Vincent
Lynch (UT-Austin) and Delphine Gout (UT-Arlington) for X-
ray crystallographic analysis; Prof. Uttam Tambar (UTSW) for
chiral HPLC instrument access. We are grateful to Professors
Joseph Ready (UTSW), Uttam Tambar (UTSW), Patrick Fier
(Merck), Cedric Hugelshofer (Merck), James Roane (Merck)
for feedback on this manuscript.
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