Enantioselective Kinetic Resolution/Desymmetrization of Para-Quinols: A Case Study in Boronic-Acid-Directed Phosphoric Acid Catalysis

Article abstract of DOI:10.1002/adsc.201900816

A chiral phosphoric acid-catalyzed kinetic resolution and desymmetrization of para-quinols operating via oxa-Michael addition was developed and subsequently subjected to mechanistic study. Good to excellent s-factors/enantioselectivities were obtained over a broad range of substrates. Kinetic studies were performed, and DFT studies favor a hydrogen bonding activation mode. The mechanistic studies provide insights to previously reported chiral anion phase transfer reactions involving chiral phosphate catalysts in combination with boronic acids. (Figure presented.).

Full text of DOI:10.1002/adsc.201900816

COMMUNICATIONS
DOI: 10.1002/adsc.201900816
Enantioselective Kinetic Resolution/Desymmetrization of Para-
Quinols: A Case Study in Boronic-Acid-Directed Phosphoric Acid
Catalysis
Banruo Huang,+a Ying He,+a Mark D. Levin,a Jaime A. S. Coelho,a, b
Robert G. Bergman,a and F. Dean Tostea,*
a
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 (USA)
Phone: 1-510-642-2850
E-mail: fdtoste@berkeley.edu
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
b
+
These authors contributed equally to this work
Manuscript received: July 4, 2019; Revised manuscript received: September 3, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900816
catalyst, affording cyclization of a boronic acid
Abstract: A chiral phosphoric acid-catalyzed ki-
netic resolution and desymmetrization of para-
monoester intermediate (Figure 1B).[4]
In our own report,[3] we hypothesized that the
quinols operating via oxa-Michael addition was
boronic acid forms an intermediate hemiester which
developed and subsequently subjected to mechanis-
serves as the corresponding directing group. Because
tic study. Good to excellent s-factors/enantioselec-
tivities were obtained over a broad range of
the CAPT fluorination chemistry requires the use of
heterogeneous conditions, support for this hypothesis
substrates. Kinetic studies were performed, and
derived from the observation of hemiester formation
DFT studies favor a hydrogen bonding activation
under conditions lacking the insoluble components,
mode. The mechanistic studies provide insights to
with no test for kinetic relevance of the intermediate
previously reported chiral anion phase transfer
possible.[5] In order to gain more mechanistic insight,
reactions involving chiral phosphate catalysts in
we sought a homogeneous model reaction to enable
combination with boronic acids.
kinetic analysis. By examining oxa-Michael addition
rather than fluorination, the insoluble reagent could be
Keywords: asymmetric catalysis; chiral phosphoric
excluded. As such, we developed a chiral phosphoric
acid; reaction mechanisms; kinetics; directed reactiv-
acid-catalyzed kinetic resolution /desymmetrization of
ity; oxa-Michael addition
quinol derivatives (Figure 1C).[6–9] The homogeneity of
the reaction mixtures allowed us to examine the kinetic
relevance of alcoholÀ boronic acid condensation. These
Chiral Anion Phase Transfer (CAPT) Catalysis has studies have enabled the gathering of some new
proven to be a powerful strategy for achieving insights into the nature of reactions involving
asymmetric induction.[1,2] A central hypothesis in this boronicÀ acid-directed chiral phosphoric acid catalysis.
catalytic manifold is the use of suitable H-bonding
We began our investigation by examining the
directing groups which have empirically proven crucial reaction of quinol rac-1a with phenylboronic acid
to obtain high selectivity in these transformations.[1h] (Table 1). Routine optimization identified (R)-TCYP as
Along these lines, our group recently reported the the optimal catalyst (Table 1, entry 6) (replacing (R)-
fluorination of allylic alcohols via the in situ gener- TCYP with (R)-TRIP gives s=21)[10] and toluene as
ation of boronic acid-derived directing groups (Fig- the optimal solvent for kinetic resolution.[10,11] Various
ure 1A).[3] This work was in turn inspired by a 2008 arylboronic acids were examined, culminating in the
report from Falck and co-workers, in which a formal identification of 1-naphthylboronic acid as the optimal
enantioselective oxa-Michael addition of hydroxide boron reagent, affording a significant increase in
was achieved by employing a bifunctional organo- selectivity (s=23). A key finding was the discovery
that implementation of 1-naphthyl boroxine in place of
Adv. Synth. Catal. 2019, 361, 1–8
1
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Figure 2. A) Initial rate-(R)-TRIP catalyst loading plot; B)
Reaction plot of [4a] under saturation of 3e.
1
(4a) by H-NMR spectroscopy.[12] However, no dis-
crete observable new species were formed, and no
detectable changes in the spectra were found as the
concentration of each species was varied.
This lack of observable association between the
substrate and boroxine was surprising given our
previous observation of quantitative condensation of
boroxine with primary allylic alcohols.[5] In order to
gain further insight, a series of kinetic experiments
were performed. Unfortunately, kinetics conducted
under typical reaction stoichiometries were found at
extended reaction times to deviate from simple integer-
order behavior.[10,13] To simplify the analysis, the
method of initial rates was employed, along with
flooding conditions in one or more substrates. Under
flooding in boroxine, an order in (R)-TRIP deviating
Figure 1. A) Boronic acid monoester as an in stiu directing
group for CAPT enantioselective fluorination of allylic alcohols
(CPA=chiral phosphoric acid); B) Oxa-Michael addition of
boronic acid monoester promoted by push/pull-type catalyst; C)
Kinetic resolution of para-quinols via complexation of in situ
directing group and phosphate.
from linearity was observed, with reasonable fits
1
its boronic acid analogue decreased the required obtained to either = order or saturation kinetics
2
reaction time and afforded an improved s factor of 27 (Figure 2A). In order to distinguish these possibilities,
in the presence of only 2 mol% catalyst at room the diffusion constants of both (R)-TRIP and the O-
temperature for 24 h. This trend of increased enantio- methylated analogue were measured by DOSY (dif-
selectivity and increased rate held across a variety of fusion ordered spectroscopy), affording nearly indis-
boronic acid/boroxine pairs, including phenylboroxine tinguishable diffusion constants.[10] These experiments
and m-tolylboroxine (Table 1).
indicated that the phosphoric acid catalyst is likely
With optimized conditions in hand, we next ex- monomeric under the reaction conditions, excluding
plored the scope of the kinetic resolution (Table 2). the possibility of 1= order.[14]
2
Various α-substitutents (R1), β-substituents (R2), and γ-
For the remaining components, under the pseudo-
substituents were tolerated with varying levels of zero order conditions, first-order dependence on the
selectivity, including various alkyl, unsaturated, and substrate concentration (Figure 2B) was observed. The
heteroaromatic groups. The protocol was also found to boroxine exhibited kinetic behaviour deviating from
apply well in the desymmetrization of prochiral p- first order which could be modelled as first-order
quinols (Table 2). Two representative substrates were dependence on the concentration of monomeric
examined under conditions similar to the optimized arylboron.[10] Taken together, this kinetic behavior
kinetic resolution protocol. Gratifyingly, the reaction indicates a preequilibrium to form boronic acid ester
proceeded smoothly to yield the corresponding diols in before the involvement of chiral phosphoric acid.
88% and 85% ee, respectively.
The 1H-NMR spectroscopy of the mixtures of TRIP
As noted above, the homogeneity of these reactions and boroxine 3e reveals a concentration dependent
enabled a closer examination of the mechanism. shift in the resonances of the phosphoric acid, with
Initially, we were drawn to the observation that the partial decoalesence of the signals achieved upon
boroxine hydration state affects both rate of the cooling to 217 K.[10,16,17] A DFT study at the B3LYP-
reaction and its enantioselectivity, suggesting that D3/def2-TZVPP/SMD(toluene)//B3LYP/6-31G(d) lev-
formation of boronic acid esters of the substrate may el of theory suggests that the most likely candidate for
be relevant. We began our investigation by examining the associated complex is the mixed phosphoric/
association between the boroxine and the substrate
Adv. Synth. Catal. 2019, 361, 1–8
2
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 1. Key Influence of Boron Reagent Hydration State on Reaction Selectivity.[a]
[a] Reaction conditions: rac-1a (0.2 mmol), (R)-TCYP (2 or 5 mol%), Boronic acid or Boroxine (0.7 equiv.), solvent (2.0 mL), rt for
24 or 48 h;
1
[b] Determined by H-NMR using internal standard;
[c] Determined by chiral phase HPLC; Selectivity factor (s) was calculated according ln[(1-C)(1À eeSM)/1-C](1+eeSM)].[10]
boronic anhydride (vide infra).[10] This association
complex is potentially kinetically relevant.[15]
Finally, KIE experiments were conducted using 4a
labelled at the vinylic CÀ H bonds. A separate pot
experiment showed a clear inverse secondary KIE
(Scheme 1), indicating that oxa-Michael addition is the
rate-limiting step, either concerted with catalyst associ-
ation or as a discrete second step following reversible
catalyst association.[10,18,19] Initial Michael addition
followed by esterification is likely inconsistent with
the exclusively observed syn diastereoselectivity and
the observation that methylation of the hydroxyl group
of 4a shuts down reactivity altogether, with no
conversion observed over 72 h.[10]
Scheme 1. Separate-pot kinetic isotope effect.
As a whole, these data are consistent with a
mechanism involving two roles for the boroxine:
productive association with the substrate, and delete-
rious association with the catalyst (though we cannot
Adv. Synth. Catal. 2019, 361, 1–8
3
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 2. Scope for Kinetic Resolution and Desymmetrization.[a,b]
[a] Isolated yield. Absolute configuration assigned by analogy to that of 1g, which was determined to be (S) by single-crystal X-ray
diffraction.
[b] Selectivity factor (s) was calculated according ln[(1-C)(1À eeSM)/1-C](1+eeSM)].[10] For isolated yields of kinetic resolution, see
Supporting Information.
[c] 5.0 mol% of catalyst was used.
[d] Reaction time variation: 12 h.
[e] Reaction time variation: 18 h.
[f] Reaction time variation: 20 h.
conclusively rule out the possibility that the mixed phosphate, enabling high enantiocontrol.[1h,20] Further-
phosphoricÀ boronic anhydride is on-cycle).
more, preliminary evidence supporting formation of
A DFT study conducted at the B3LYP-D3/def2- mixed anhydrides between boronic and phosphoric
TZVPP/SMD(toluene)/ /B3LYP/6-31G(d) level of acids was garnered, suggesting a potentially under-
theory located four transition structures for the TRIP- appreciated role for these species. We anticipate that
catalyzed reaction. Importantly, formation of the new asymmetric transformations will be enabled by
observed major enantiomer is correctly predicted. Our the knowledge garnered herein concerning the dynam-
proposed mechanism for the overall reaction, consider- ics of this potent reagent pair.
ing all of the collected data, is shown in Scheme 2.
The lowest-energy computed transition state for oxa-
Michael addition is shown, as well as the computation-
Experimental Section
For details of instruments used and the general experimental
procedures, see the Supporting Information.
ally suggested structure for the mixed anhydride.
Based on this mechanism, we propose that the boronic
acid/boroxine effect on enantioselectivity arises from a
background reaction catalyzed by the boronic acid
(further exacerbated by catalyst inhibition by boron),
whereas the rate enhancement is a function of the
equilibrium for substrate esterification.
In conclusion, a chiral phosphoric acid-catalyzed
kinetic resolution (or desymmetrization) of para-
quinols was developed. This method provides the
access to enantioenriched para-quinols and corre-
sponding diols. Kinetic experiments are in line with
the canon of indirect experimental evidence we have
garnered over the course of our studies on the role of
H-bonding in CAPT catalysis – namely, that appropri-
ately situated H-bonding directing groups, including
in situ formed boronic acid esters, orient the chiral
General Procedure of Kinetic Resolution of Para-
Quinols
The rac-1 (0.20 mmol), 1-naphthylboroxine (0.04 mmol) and
(R)-TCYP (2.0 mol%) were added to a vial containing a stir bar.
The vial was twined with Teflon tape, toluene (2.0 ml) was
added using a syringe, and the vial was fitted with a cap. The
reaction mixture was stirred at room temperature for the
indicated time. To the mixture was added MeOH/H2O (1/1,
2.0 mL), and then KHF2 (10 eqiv.) was added and the mixture
was stirred vigorously for 5–30 min until the boronic ester was
removed as evident from TLC analysis. The aqueous phase was
separated and collected, and the organic phase was evaporated
and then re-dissolved in n-hexanes. The mixture was then
Adv. Synth. Catal. 2019, 361, 1–8
4
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Scheme 2. Proposed mechanism with calculated transition state.
washed MeOH/H2O (1/1) twice and the aqueous phase was
combined. The combined aqueous layers were then evaporated
and purified by column chromatography carefully over silica
gel affording the desired chiral p-quinols and diols. The
products were further purified by preparative TLC as necessary.
Chemistry, University of California, Berkeley (NSF CHE-
0840505).
References
[1] a) V. Rauniyar, A. D. Lackner, G. L. Hamilton, F. D.
Toste, Science 2011, 334, 1681–1684; b) H. P. Shunato-
na, N. Früh, Y.-M. Wang, V. Rauniyar, F. D. Toste,
Angew. Chem. Int. Ed. 2013, 52, 7724–7727; Angew.
Chem. 2013, 125, 7878–7881; c) A. D. Lackner, A. V.
Samant, F. D. Toste, J. Am. Chem. Soc. 2013, 135,
14090–14093; d) R. J. Phipps, K. Hiramatsu, F. D. Toste,
J. Am. Chem. Soc. 2012, 134, 8376–8379; e) R. J.
Phipps, F. D. Toste, J. Am. Chem. Soc. 2013, 135, 1268–
1271; f) A. J. Neel, J. P. Hehn, P. F. Tripet, F. D. Toste, J.
Am. Chem. Soc. 2013, 135, 14044–14047; g) Y.-M.
Wang, J. Wu, C. Hoong, V. Rauniyar, F. D. Toste, J. Am.
Chem. Soc. 2012, 134, 12928–12931; h) J. Wu, Y.-M.
Wang, A. Drljevic, V. Rauniyar, R. J. Phipps, F. D. Toste,
Proc. Natl. Acad. Sci. USA 2013, 110, 13729–13733;
i) X. Yang, R. J. Phipps, F. D. Toste, J. Am. Chem. Soc.
2014, 136, 5225–5228; j) H. M. Nelson, S. H. Reisberg,
Crystallographic Data for (S)-1g
CCDC-1950552 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We gratefully acknowledge the National Institute of Health
(R35GM118190) for financial support of this work. We thank
Dr. Andrew Neel, Dr. David Kaphan, and Dr. Richard Thorn-
bury for helpful discussions, Dr. Cynthia Hong for X-ray
crystallographic collection and analysis, Dr. Hasan Celik for
assistance with NMR experiments and Dr. Miao Zhang for
assistance with HR-MS data. DFT studies were conducted at the
Molecular Graphics and Computation Facility, College of
Adv. Synth. Catal. 2019, 361, 1–8
5
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
H. P. Shunatona, J. S. Patel, F. D. Toste, Angew. Chem.
Int. Ed. 2014, 53, 5600–5603; Angew. Chem. 2014, 126,
5706–5709; k) H. M. Nelson, J. S. Patel, H. P. Shunato-
na, F. D. Toste, Chem. Sci. 2015, 6, 170–173; l) H. M.
Nelson, B. D. Williams, J. Miró, F. D. Toste, J. Am.
Chem. Soc. 2015, 137, 3213–3216; m) A. Milo, A. J.
Neel, F. D. Toste, M. S. Sigman, Science 2015, 347,
737–743.
[8] For enantioselective synthesis of para-quinols: a) K. A.
Volp, A. M. Harned, Chem. Commun. 2013, 49, 3001–
3003; For select reports for synthesis of chiral para-
quinol derivatives, see b) W.-T. Wu, L. Zhang, S.-L.
You, Chem. Soc. Rev. 2016, 45, 1570–1580; c) Q. Gu,
Z.-Q. Rong, C. Zheng, S.-L. You, J. Am. Chem. Soc.
2010, 132, 4056–4057; d) D. M. Rubush, T. Rovis,
Synlett 2014, 25, 713–717; e) D. M. Rubush, M. A.
Morges, B. J. Rose, D. H. Thamm, T. Rovis, J. Am.
Chem. Soc. 2012, 134, 13554–13557; f) N. T. Vo, R. D.
Pace, F. O’Hara, M. J. Gaunt, J. Am. Chem. Soc. 2008,
130, 404–405; g) M. T. Corbett, J. S. Johnson, Chem.
Sci. 2013, 4, 2828–2832.
[2] For other recent reports on CAPT catalysis, see: a) Z.
Shen, X. Pan, Y. Lai, J. Hu, X. Wan, X. Li, H. Zhang, W.
Xie, Chem. Sci. 2015, 6, 6986–6990; b) F. Romanov-
Michailidis, L. Guénée, A. Alexakis, Angew. Chem. Int.
Ed. 2013, 52, 9266–9270; Angew. Chem. 2013, 125,
9436–9440; c) W. Xie, G. Jiang, H. Liu, J. Hu, X. Pan,
H. Zhang, X. Wan, Y. Lai, D. Ma, Angew. Chem. Int. Ed.
2013, 52, 12924–12927; Angew. Chem. 2013, 125,
13162–13165; d) Z. Yang, Y. He, F. D. Toste, J. Am.
Chem. Soc. 2016, 138, 9775–9778; e) E. Yamamoto,
M. J. Hilton, M. Orlandi, V. Saini, F. D. Toste, M. S.
Sigman, J. Am. Chem. Soc. 2016, 138, 15877–15880;
f) C. M. Avila, J. S. Patel, Y. Reddi, M. Saito, H. M.
Nelson, H. P. Shunatona, M. S. Sigman, R. B. Sunoj,
F. D. Toste, Angew. Chem. Int. Ed. 2017, 56, 5806–5811;
Angew. Chem. 2017, 129, 5900–5905; g) S. Biswas, K.
Kubota, M. Orlandi, M. Turberg, D. H. Miles, M. S.
Sigman, F. D. Toste, Angew. Chem. Int. Ed. 2018, 57,
589–593; Angew. Chem. 2018, 130, 598–602; h) B. Ye,
J. Zhao, K. Zhao, J. M. McKenna, F. D. Toste, J. Am.
[9] For recent reports on kinetic resolution of alcohols and
1,2-diols catalyzed by chiral phosphoric acid, see: a) T.
Yamanaka, A. Kondoh, M. Terada, J. Am. Chem. Soc.
2015, 137, 1048–1051; b) J. H. Kim, I. Čorić, C.
Palumbo, B. List, J. Am. Chem. Soc. 2015, 137, 1778–
1781; c) C. Xie, D. Bai, S.-H. Huang, X. Jia, R. Hong,
Asian J. Org. Chem. 2014, 3, 277–280; d) S. Harada, S.
Kuwano, Y. Yamaoka, K. Yamada, K. Takasu, Angew.
Chem. Int. Ed. 2013, 52, 10227–10230; Angew. Chem.
2013, 125, 10417–10420; e) K. Fujii, K. Mitsudo, H.
Mandai, S. Suga, Adv. Synth. Catal. 2017, 359, 2778–
2788; f) M. Pawliczek, T. Hashimoto, K. Maruoka,
Chem. Sci. 2018, 9, 1231–1235; g) B. Liu, J. Yan, R.
Huang, W. Wang, Z. Jin, G. Zanoni, P. Zheng, S. Yang,
Y. R. Chi, Org. Lett. 2018, 20, 3447–3450.
Chem. Soc. 2018, 140, 8350–8356; i) J. A. S. Coelho, A. [10] For detailed results, see Supporting Information.
Matsumoto, M. Orlandi, M. J. Hilton, M. S. Sigman, [11] V. Rauniyar, Z. J. Wang, H. E. Burks, F. D. Toste, J. Am.
F. D. Toste, Chem. Sci. 2018, 9, 7153–7158.
Chem. Soc. 2011, 133, 8486–8489.
[3] W. Zi, Y.-M. Wang, F. D. Toste, J. Am. Chem. Soc. 2014, [12] m-tolylboroxine (3e) and (R)-TRIP were employed in
136, 12864–12867.
[4] D. R. Li, A. Murugan A. J. R. Falck, J. Am. Chem. Soc.
2008, 130, 46–48.
place of the 1-naphthyl analogue (3f) and (R)-TCYP to
maintain homogeneity across a wider range of concen-
trations and temperatures.
[5] A. J. Neel, A. Milo, M. S. Sigman, F. D. Toste, J. Am. [13] We are unable to conclusively distinguish between
Chem. Soc. 2016, 138, 3863–3875.
product inhibition and catalyst deactivation due to our
inability to isolate the product boronic ester without
contaminating diol and/or boronic acid. In either case,
initial rate kinetics obviate any confounding rate influ-
ence.
[6] For para-quinols in complex bioactive molecules and
natural products: a) X. Wang, J. A. Porco Jr., Angew.
Chem. Int. Ed. 2005, 44, 3067–3071; Angew. Chem.
2005, 117, 3127–3131; b) J. E. Baldwin, R. M. Adling-
ton, V. W.-W. Sham, R. Marquez, P. G. Bulger, Tetrahe- [14] For dimerization of phosphoric acids: a) M. R. Monaco,
dron 2005, 61, 2353–2363; c) A. D. Patil, A. J. Freyer,
L. Killmer, P. Offen, B. Carte, A. J. Jurewicz, R. K.
Johnson, Tetrahedron 1997, 53, 5047–5060; d) J. M.
Berry, T. D. Bradshaw, I. Fichtner, R. Ren, C. H.
Schwalbe, G. Wells, E.-H. Chew, M. F. G. Stevens, A. D.
Westwell, J. Med. Chem. 2005, 48, 639–644; e) G. Stork,
J. J. La Clair, P. Spargo, R. P. Nargund, N. Totah, J. Am.
Chem. Soc. 1996, 118, 5304–5305; f) L. H. Mejorado,
T. R. R. Pettus, J. Am. Chem. Soc. 2006, 128, 15625–
15631.
D. Fazzi, N. Tsuji, M. Leutzsch, S. Liao, W. Thiel, B.
List, J. Am. Chem. Soc. 2016, 138, 14740–14749; b) J.
De Ford, F. Chu, E. V. Anslyn, Tetrahedron Lett. 1996
37, 1925–1928; c) D. F. Peppard, J. R. Ferraro, G. W.
Mason, J. Inorg. Nucl. Chem. 1958, 7, 231–244; For a
recent study of dimerization in hydrogen-bond-donor
catalysts, see: d) D. D. Ford, D. Lehnerr, C. R. Kennedy,
E. N. Jacobsen, J. Am. Chem. Soc. 2016 138, 7860–7863;
For a full derivation of the relevant rate laws and
discussion of the assumptions involved, see the support-
ing information.
[7] For recent reports on preparation of para-quinols, see
a) M. C. Carreño, M. González-López, A. Urbano, [15] For a full derivation of the relevant rate laws and
Angew. Chem. Int. Ed. 2006, 45, 2737–2741; Angew.
Chem. 2006, 118, 2803–2807; b) T. Yakura, M. Omoto,
discussion of the assumptions involved, see the support-
ing information.
Y. Yamauchi, Y. Tian, A. Ozono, Tetrahedron 2010, 66, [16] P. Thordarson, Chem. Soc. Rev. 2011, 40, 1305–1323.
5833–5840.
Adv. Synth. Catal. 2019, 361, 1–8
6
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
[17] For a discussion on the interaction between phosphoric [19] These two possibilities are kinetically indistinguishable.
acids and boronic acids, see: M. A. Martínez-Aguirre,
A. K. Yatsimirsky, J. Org. Chem. 2015, 80, 4985–4993.
[18] In principle, a post-rate-determining equilibration be-
Another possibility involves reversible oxa-Michael
addition and rate-determining enolate protonation. See
the Supporting information for details.
tween parent and deuterated substrate prior to the [20] Indeed, in the limit of protonation of the carbonyl, the
enantiodetermining step is possible, but the observation
of a separate-pot KIE indicates that CÀ O bond formation
occurs before the turnover-limiting step. For a discussion
on KIE interpretation, see: E. M. Simmons, J. F. Hartwig,
Angew. Chem. Int. Ed. 2012, 51, 3066–3072; Angew.
Chem. 2012, 124, 3120–3126.
quinone electrophile can be seen as directly analogous to
previous examples of CAPT catalysis.
Adv. Synth. Catal. 2019, 361, 1–8
7
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

COMMUNICATIONS
Enantioselective Kinetic Resolution/Desymmetrization of
Para-Quinols: A Case Study in Boronic-Acid-Directed
Phosphoric Acid Catalysis
Adv. Synth. Catal. 2019, 361, 1–8
B. Huang, Y. He, M. D. Levin, J. A. S. Coelho, R. G.
Bergman, F. D. Toste*