Site-Selective Acylation of Natural Products with BINOL-Derived Phosphoric Acids

Article abstract of DOI:10.1021/acscatal.9b03535

The site-selective acylation of a steroidal natural product 19-hydroxydehydroepiandrosterone catalyzed by 1,1′-Bi(2-napthol)-derived (BINOL) chiral phosphoric acids (CPAs) is described. Systematic variation and multivariate linear regression analysis reve

Full text of DOI:10.1021/acscatal.9b03535

Letter
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 9794−9799
Site-Selective Acylation of Natural Products with BINOL-Derived
Phosphoric Acids
Junqi Li,†,#,§,⊥ Samantha Grosslight,‡,§ Scott J. Miller,*,# Matthew S. Sigman,*,‡
and F. Dean Toste*,†
†Department of Chemistry, University of California, Berkeley, California 94720, United States
‡Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
#Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: The site-selective acylation of a steroidal natural
product 19-hydroxydehydroepiandrosterone catalyzed by 1,1′-
Bi(2-napthol)-derived (BINOL) chiral phosphoric acids
(CPAs) is described. Systematic variation and multivariate
linear regression analysis reveal that the same steric parameters
typically needed for high enantioselectivity with this class of
CPAs are also required for site-selectivity in this case. Density
functional theory calculations identify additional weak CH−π
interactions as contributors to site discrimination. We further
report a rare example of site-selective acylation of phenols
through the evaluation of naringenin, a flavonoid natural product, using CPA catalysis. These results suggest that BINOL-
derived CPAs may have broader applications in site-selective catalysis.
KEYWORDS: site-selective catalysis, acylation, chiral phosphoric acids, modeling, noncovalent interactions
acylation of two natural products using BINOL-derived CPAs
hiral phosphoric acids (CPAs) and phosphates based on
Cthe BINOL scaffold have been used extensively for a as catalysts and demonstrate that the same catalyst features
myriad of asymmetric transformations,1 indicating their ability
characteristically required for high enantioselectivity also
enable high site-selectivity.
to effectively induce significant energetic differences between
diastereomeric transition states across different reaction
manifolds. Similarly, site-selective functionalization of natural
products requires significant energetic differentiation between
structurally distinct transition states, with the additional
challenge of overcoming innate selectivity.2 Despite their
successful employment as asymmetric catalysts, there have
been limited cases of using BINOL-derived phosphoric acids in
selective natural product modifications. Notably, Nagorny and
co-workers demonstrated that CPAs are capable of distinguish-
ing between different alcohols on polyketide antibiotics for
site-selective glycosylation,3 and others have reported that
CPAs can be effective for site-selective acetalizations of
compounds with more than one hydroxyl group.4 Other
classes of organocatalysts have been used in both enantio- and
site-selective acyl transfers, such as peptides,5,6 borinic7 and
boronic acids,8 covalent scaffolding catalysts,9 and benzote-
tramisoles.10 Chiral metal complexes have also been
employed.11 These precedents suggest that the same catalyst
features enabling asymmetric induction may be translated to
site-recognition in complex molecule settings. Furthermore,
site-selective functionalization with CPAs may be achievable
through strategic manipulation of the noncovalent substrate−
catalyst interactions known to be crucial for asymmetric
induction with CPAs.12 Herein, we report the site-selective
We first examined the site-selective acylation of 19-
hydroxydehydroepiandrosterone (1, 19-OH-DHEA), a ster-
oidal natural product with a hydrocarbon backbone. Evaluation
of the acylation of 1 under common acylating conditions
revealed that the secondary and primary alcohols in the
neopentyl framework have comparable innate reactivity (Table
1, entries 1−2).
Inspired by Takasu’s report on the kinetic resolution of
alcohols catalyzed by BINOL-derived phosphoric acids,13,14 we
subjected 1 to acidic acylating conditions under the influence
of catalyst 5a (Ar = 2,4,6-tricyclohexylphenyl, TCYP), which
led to an increase in selectivity, from 1.2:1 to 8.5:1 in favor of
acylation of the secondary alcohol.15 In this case, the chirality
of the catalyst influences reactivity and selectivity−both the
(S)-enantiomer of the catalyst 5b and an achiral counterpart,
5c, gave lower selectivity (Table 1, entries 3−5). Notably, 5b is
also a less active catalyst, giving a lower yield of the acylated
products compared with 73% yield with the “matched” catalyst
5a. Further optimization of the reaction conditions resulted in
a 15:1 selectivity when catalyst 5a was used (Table 1, entry 6).
Received: August 19, 2019
Revised: September 19, 2019
© XXXX American Chemical Society
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Previous computational models of CPA-catalyzed trans-
formations have highlighted the contribution of steric bulk
proximal to the phosphoric acid moiety to high enantiose-
lectivity.1a,12d,e,17b,c,19−21 To develop a model for under-
standing the importance of this catalyst feature in site-selective
acylation, we first investigated several CPA catalyzed acylation
mechanisms using DFT transition-state calculations (see
Supporting Information for details). From these calculations,
the most energetically favored pathway proceeded by a
bifunctional activation of acetic anhydride and substrate
simultaneously by the CPA as depicted within Figure 1C.
Using these computational results and inspiration from
previous structural descriptions of enantioselective CPA
transformations, we propose that catalysts without adequate
proximal bulk resulted in a less-defined catalyst pocket (Figure
1, 5d−5m). This in turn provides minimal energetic
distinction between the transition states leading to 2 and 3
(Figure 1C, top).1a,20 In contrast, the presence1a,19 of bulky
groups shape the catalyst pocket such that differences arise
upon association of each alcohol to the phosphoric acid. In
considering the acylation of the primary alcohol, steric
interactions with the bulky groups on the catalyst reduce the
number of low-lying productive conformations. This effect is
less pronounced when the secondary alcohol associates with
the phosphoric acid, such that there are more productive
conformations that avoid steric interactions with 2,6-
substituents (Figure 1C, bottom).
An interesting trend emerged from the data obtained within
this particular case as a function of variation of R3 group on
observed site-selectivity. Although incorporating R3 substitu-
ents is generally beneficial for site-selectivity as indicated from
the R3L term in the MLR analysis, the effect varied depending
on the type of substituent. Aryl groups at R3 resulted in a
dramatic improvement in site-selectivity (5n vs 5q−5s), while
alkyl groups provided a modest enhancement (5n vs 5o). We
hypothesized that the differences in selectivity were the result
of attractive NCIs between the remote R3-phenyl substituent
in 5q and the substrate, which are not captured by the Sterimol
term in the model. Additionally, we reasoned that these NCIs
should be present to a greater extent in the transition state
leading to 2 than in the transition state leading to 3. To probe
this hypothesis, we performed transition state analysis on the
acylation reaction using 5q and a truncated 1 (see Supporting
Information for computational methods). Multiple low-lying
TS leading to products 2 and 3 are present. Boltzmann
averaging of all TS leading to the formation of 2 and 3 resulted
in a computed selectivity of 1.4 kcal/mol, consistent with the
experimental results observed (Figure 2, 1.84 kcal/mol, see
Supporting Information for details).22 The relative abundance
and strength of attractive NCIs between the relevant sites of
interaction within TS2 and TS1 were then assessed using
second-order perturbation theory (Supporting Informa-
tion).21,23 We found that CH−π interactions between the π
system of the R3-phenyl of 5q and the C−H of the substrate
are more abundant within TS2 than in TS1 (Supporting
Information).
Table 1. Reaction Optimization for the Site-Selective
Acylation of 19-OH-DHEA, 1
a
entry
conditions
2: 3: 4 (% yields)
2: 3
1
2
3
4
5
6
Ac2O, DMAP, NEt3, rt
20: 24: 21
24: 20: 21
56: 7: 10
13: 5: 1
29: 8: 6
34.7: 2.3: 1.8
0.8: 1
1.2: 1
8.5: 1
2.9: 1
3.4: 1
15: 1
Ac2O, DPP (25 mol %), rt
Ac2O, 5a (10 mol %), rt
Ac2O, 5b (10 mol %), rt
Ac2O, 5c (10 mol %), rt
Ac2O, 5a (10 mol %), 4 °C
b
a
Yields were determined by HPLC at 214 nm with N-phenyl-
b
acetamide as internal standard. Average of two runs. DPP =
diphenylphosphoric acid, rt = room temperature.
Because site-selectivity is determined by the relative energy
barriers of the two competing acylation pathways originating
from the two alcohols,16 we reasoned that multivariate linear
regression (MLR) analysis previously adopted for studying
BINOL-derived phosphoric acid-catalyzed enantioselective
reactions12d,17 could be applied here to identify catalyst
features contributing to site-selectivity. Thus, we evaluated
the acylation reaction with a panel of catalysts containing
different substitution patterns at the R1-R3 positions from
which we identified catalysts giving site-selectivities of up to
50:1 (Figure 1A).
To define the catalyst parameters important for selectivity,
density functional theory (DFT) optimizations were per-
formed for the catalyst panel at the M06-2X/def2-TZVP level
of theory.12d,17 From these optimized geometries, we collected
steric and electonic parameters including Sterimol values,
natural bond orbital (NBO) charges, and infrared (IR)
vibrations (see Supporting Information for all parameters
collected).18,19 Comparing the collected parameters to the
measured site-selectivity using a stepwise linear regression
algorithm revealed a statistical correlation (R2 = 0.92, intercept
= 0.07) with the terms R1B1, the R3L, and the NBOP charge
(Figure 1B). The NBOp parameter is likely describing the
hydrogen bonding capacity between the catalyst (phosphoric
acid) and substrate (the primary or secondary alcohol),
because the NBOp and NBOO measures are colinear (see
Supporting Information for additional models). The minimum
width of the R1 substituent, R1B1, points to the importance of
having bulky groups proximal (R1 and R1′ positions) to the
phosphoric acid moiety. The length of the R3 substituent, R3L,
describes the importance of functionalization at the remote
(R2, R3) positions for fine-tuning of site-selectivity.20 An
absence of these features resulted in lower selectivity (Figure
1). These same parameters were also present in previous MLR
analyses of CPA-catalyzed enantioselective transformations,
indicating that simliar catalyst features required for high
enantioselectivity12e,17c are also beneficial for high site-
selectivity in this case.
We next investigated the influence that the hydrocarbon
framework of 1 has on site-selectivity. To examine this, 6, a
derivative of 1 in which the alkene was removed by
hydrogenation, was synthesized and subjected to acylation
with the optimized conditions using catalyst 5q. A substantial
decrease in selectivity was observed (8.8:1 for 6 vs 28.1:1 for 1,
Scheme 1). This result prompted us to use TS analysis to
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Figure 1. (A) Panel of CPAs tested and selectivities obtained. (B) MLR model for site-selective acylation. (C) Rationale for site-selectivity using
catalysts with small proximal substituents (top, R1 = R1′ = H) and large proximal substituents (bottom, R1 = R1′ ≠ H).
assess if this diminished selectivity resulted from weaker or
less-abundant NCI’s between the R3-phenyl of 5q and 6. The
calculated TS reproduced the experimental selectivity well
(experimental ΔΔG‡ 1.1 kcal/mol, computed ΔΔG‡ 1.0 kcal/
mol). The TS leading to 7 and 8 either completely lack or
contain limited weak interactions with the R3-phenyl of 5q
(Supporting Information). These results indicate that subtle
changes in the conformation of the substrate can significantly
affect the attractive noncovalent interactions needed for site-
selectivity, highlighting the challenges associated with achiev-
ing site-selectivity in complex molecules.24
As a final step, we sought to expand BINOL-derived CPA-
catalyzed site-selective acylation to a different class of natural
products with a drastically different framework. Derivatives of
flavanoids are under study to optimize their wide range of
biological activities,25 but few examples exist for catalyst- or
reagent-controlled26 site-selective O-functionalization of phe-
nols.27 We thus targeted the acylation of naringenin, a
triphenol-containing flavonoid. Previous literature reports on
the acylation and alkylation of narigenin28 and related
flavonoids29 with various acyl halides30 leverages the higher
acidity of the phenol para to the ketone to achieve site-
selectivity (pKa of C7-OH = 7.5, pKa of C4′−OH = 8.4).31
Consistent with this, we found that acylation of 9 under basic
conditions is highly selective for the formation of 11 (Table 2,
entry 1). Because the mechanism of CPA-catalyzed acylation
does not likely involve deprotonation of the phenol prior to
acylation (see Supporting Information), we hypothesized that
acylation with phosphoric acids could provide a different
selectivity profile. Indeed, using diphenylphosphoric acid
(DPP) as the catalyst reverses the selectivity, albeit with low
reactivity (Table 2, entry 2, 18% yield of acylated products). A
higher temperature is required for acylation of the phenols
compared with alcohols (45 °C vs 4 °C), but both reactivity
and site-selectivity can be enhanced with catalysts 5k and 5u.
Significant catalyst control of site-selectivity was achieved using
the catalyst containing 3,3′-substituents with the bulkiest
groups in the 2,3,4,6- positions, giving a selectivity of 7.0:1 for
10 (catalyst 5u, entry 5).
In summary, BINOL-based chiral phosphoric acids have
enabled the site-selective acylation of a diol-containing
steroidal natural product. MLR analysis reveals that the same
catalyst features that create a defined catalyst pocket required
for high enantioselectivity are also required for site-selectivity
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acylation catalyzed by CPAs, we achieved a rare example of
site-selective acylation of phenols in a flavonoid natural
product. Collectively, these findings suggest that this class of
catalysts may have broader applications in site-selective
catalysis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b03535.
■
S
Experimental details, procedures, compound character-
ization data, computational details, and copies of NMR
spectra of new compounds (PDF)
X-ray crystallographic data for 6 (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: fdtoste@berkeley.edu.
*E-mail: sigman@chem.utah.edu.
*E-mail: scott.miller@yale.edu.
■
Figure 2. Transition-state structures for the formation of 2 (TS 2,
top) and 3 (TS1, bottom). The energies presented are for these TS,
demonstrating the underestimated selectivity observed when compar-
ing the lowest-energy TS. Geometries were obtained at a ω-B97XD/
6-31G* level of theory and single-point energies from M06-2X/def2-
SVP.
ORCID
Junqi Li: 0000-0003-0336-2544
Scott J. Miller: 0000-0001-7817-1318
Matthew S. Sigman: 0000-0002-5746-8830
F. Dean Toste: 0000-0001-8018-2198
Present Address
Scheme 1. Acylation of Saturated Steroid 6
⊥J.L.: Department of Chemistry, Iowa State University, Ames,
Iowa 50011, United States
Author Contributions
§J.L., S.G.: These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Table 2. Site-Selective Acylation of Naringenin
S.J.M., M.S.S., and F.D.T. are grateful to the National Institute
of General Medical Sciences of the National Institutes of
Health for support (GM121383 and GM118190). We thank
Aaron Featherston (Yale) for the large-scale synthesis of a
catalyst intermediate, and Dr. Brandon Q. Mercado for solving
the X-ray crystal structure of 6. We thank Dr. Jolene P. Reid for
her expertise and assistance. We also thank Sophia Robinson
(Utah) and Dr. Hyung Yoon (Yale) for their insight.
Computational resources were provided by the Center for
High Performance Computing at the University of Utah.
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10: 11: 12 (% yields)
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(15) A competition experiment between a 1:1 molar ratio of
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acetate. See Supporting Information for experimental details.
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