Kinetic Resolution of Tertiary Allylic Alcohols: Highly Enantioselective Access to Cyclic Ethers Bearing an α-Tetrasubstituted Stereocenter

Article abstract of DOI:10.1021/acs.orglett.1c01110

A chiral phosphoric acid-catalyzed kinetic resolution of tertiary allylic alcohols was developed to provide structurally valuable enantioenriched 2,2-disubstituted tetrahydrofurans, tetrahydropyrans, and oxepane. A variety of tertiary allylic alcohols were resolved with selectivity factors of ≤120. A tertiary allylic carbocationic intermediate mediates the enantioselective intramolecular substitution to achieve high regio- and enantioselectivity. A gram-scale reaction with low catalyst loading and subsequent transformations of the recovered alcohols and products demonstrated the utility of this method.

Full text of DOI:10.1021/acs.orglett.1c01110

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Letter
Kinetic Resolution of Tertiary Allylic Alcohols: Highly
Enantioselective Access to Cyclic Ethers Bearing an
α‑Tetrasubstituted Stereocenter
Chao-Huan Zhang, Qing Gao, Meng Li, Jian-Fei Wang, Chuan-Ming Yu, and Bin Mao*
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ABSTRACT: A chiral phosphoric acid-catalyzed kinetic resolution of tertiary allylic alcohols was developed to provide structurally
valuable enantioenriched 2,2-disubstituted tetrahydrofurans, tetrahydropyrans, and oxepane. A variety of tertiary allylic alcohols were
resolved with selectivity factors of ≤120. A tertiary allylic carbocationic intermediate mediates the enantioselective intramolecular
substitution to achieve high regio- and enantioselectivity. A gram-scale reaction with low catalyst loading and subsequent
transformations of the recovered alcohols and products demonstrated the utility of this method.
he enantioselective construction of structurally diverse
stitution of inherently unreactive allylic alcohols,11 a major
limitation is stereoelectronic interactions that create a poorly
defined stereochemical environment in the proposed acyclic
precursors of α-tertiary allylic alcohols.12 Nevertheless, such a
reaction is of great interest because it would lead to regio- and
stereocontrolled tertiary C−O bond formation from O-
nucleophiles. Pioneering work by Rueping and co-workers
showed that enantioselective asymmetric allylic alkoxylation of
phenol derivatives could be achieved through activation of the
allylic alcohol motif into a π-allylic cationic species by a chiral
Brønsted acid (Scheme 1a).13 On the basis of chiral BINOL-
derived phosphoric acids14 as privileged precursors of chiral
anions15 to render enantioselective allylic substitution,13,16 we
hypothesized that the bifunctional character of Brønsted acid
catalysts would provide access to π-allylic carbocationic
intermediates by activation of tertiary allylic alcohols and
direct stereoselective nucleophilic attack on the intermediate
tertiary carbocation. This would form an achiral allyl cation
and a chiral phosphate counterion with the concomitant
1
Toxacyclic frameworks such as tetrahydrofurans (THFs)
and tetrahydropyrans (THPs)2 bearing an α-tertiary stereo-
center at the C2 position is important because these motifs
occur in a variety of medicinally relevant agents and
biologically active natural products.3 Several distinct trans-
formations have been developed for such targets, including
[3+2] cycloadditions,4 alkene functionalizations,5 oxa-Michael
reactions,6 and others.7 A general method for the direct
catalytic substitution of tertiary alcohols8 through a dehy-
drative path has remained elusive, despite the enantioselective
formation of α-tetrasubstituted oxacycles with water as the sole
byproduct. A major difficulty is that unfavorable steric
hindrance from the highly congested carbon center usually
interferes with the SN2 reaction, whereas the alternative SN1
reaction proceeds through a carbocation intermediate,
resulting in partial or total loss of stereochemical integrity.8b
Thus, the catalytic asymmetric functionalization of tertiary
alcohols to furnish O-heterocycles bearing tetrasubstituted
stereogenic centers remains a formidable challenge.9
Asymmetric allylic substitution reactions have been exten-
sively investigated for constructing carbon−carbon and
carbon−heteroatom bonds.10 Substantial achievements have
been reported by treatment of tertiary alcohols with allylic
derivatives equipped with a leaving group using organometallic
allylic species as the key intermediates. Despite more atom
economical progress toward catalytic enantioselective sub-
Received: March 31, 2021
https://doi.org/10.1021/acs.orglett.1c01110
© XXXX American Chemical Society
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A

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the challenges of spatial differentiation and steric congestion.
There are few approaches for the KR of tertiary alcohols by
virtue of the nucleophilicity of the alcohols.16d,19 Moreover,
dehydrative functionalization is a long-standing problem for
the KR of tertiary alcohols, mainly because of the poor leaving
ability of the hydroxy group and the difficulty of stereo-
control.20 The only example of intramolecular dehydrative
cyclization for the KR of tertiary alcohols, albeit with a
relatively limited scope, was made by Yang and co-workers,
who employed chiral phosphoric acid catalysis on tertiary 2-N-
acylamido allylic alcohols (Scheme 1b).21,22 We report herein
an intramolecular asymmetric allylic substitution for the highly
enantioselective KR of various acyclic diols bearing tertiary
allylic alcohol moieties under chiral phosphoric acid catalysis
(Scheme 1c). This approach enables asymmetric access to
structurally and stereochemically diverse saturated oxygenated
heterocycles.
Scheme 1. Approaches to Oxacyclic Frameworks via CPA-
Catalyzed Enantioselective Intramolecular Allylic
Substitution
We evaluated various chiral phosphoric acids in the
asymmetric allylic alkylation of racemic tertiary allylic alcohol
1a (Table 1). Treatment with 10 mol % TRIP (A1) and
activated 4 Å molecular sieves (MS) in dichloromethane at
ambient temperature achieved the KR of tertiary alcohol 1a
with exclusive regioselectivity but a low selectivity factor (s =
3),23 providing tetrahydrofuran 2a in an enantiomeric ratio
(er) of 70:30, and recovered starting material 1a with a
68.5:31.5 er (Table 1, entry 1). Of the phosphoric acids
screened (entries 1−6), the reaction time was significantly
decreased using sterically bulky chiral phosphoric acid A4 [s =
9 (entry 6)]. Halogenated solvents improved selectivity
(entries 6−9). Increasing the amount of 4 Å MS slightly
improved the enantiomeric ratio of tetrahydrofuran 2a (entry
10). Notably, the reaction proceeded even at 5 °C, at which
temperature the s factor was improved to 16, albeit with a
removal of water to incorporate the requisite stereochemistry
for cycloetherification and form the enantioenriched α-
tetrasubstituted cyclic ethers.
Kinetic resolution (KR) is a powerful tool for constructing
enantioenriched alcohols.17 Catalytic KR capable of delivering
tertiary alcohols with high enantioselectivity is much less
common than that for chiral secondary alcohols18 because of
a
Table 1. Selected Optimization Strategies
b
c
c
d
entry
catalyst
solvent
t (h)
conversion (%)
er of (R)-1a
er of (S)-2a
s
1
2
3
4
5
6
7
8
A1
B1
C1
A2
A3
A4
A4
A4
A4
A4
A4
A4
A4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
n-hexane
DCE
DCE
DCE
DCE
DCE
28
96
96
72
45
9
96
96
12
12
120
72
72
48
49
47
52
48
52
52
50
52
51
50
54
53
68.5:31.5
63.5:36.5
54:46
63.5:36.5
79:21
84:16
65:35
55:45
86:14
86:14
88:12
95:5
95:5
70:30
64:36
54.5:45.5
62.5:37.5
81:19
82:18
64:36
55:45
83:17
3
2
1
2
8
9
2
1
10
12
16
22
27
9
e
e
e
e
10
11
12
13
85:15
87.5:12.5
88:12
,
f
−
g
−
h
90:10
a
Unless otherwise noted, reactions were run with 1a (0.05 mmol) and a catalyst (10 mol %) in a solvent (4 mL) with 4 Å MS (50 mg) at 25 °C.
b
c
d
Conversion (C) = ees/(ees + eep). The er values were determined by HPLC analysis with a chiral stationary phase. s = ln[(1 − C)(1 − ees)]/
e
f
g
h
ln[(1 − C)(1 + ees)]. Using 75 mg of 4 Å MS. At 5 °C. Using 15 mol % catalyst. Using 5 mL of DCE (1,2-dichloroethane).
B
https://doi.org/10.1021/acs.orglett.1c01110
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Letter
longer reaction time (entry 11). The best selectivity [s = 27
(entry 13)] was achieved at a catalyst loading of 15 mol % and
a lower substrate concentration.
Scheme 3. Substrate Scope of the Substituents of the
Tertiary Alcohol Moiety and the Diol Chain Lengths
a
The scope of the KR reaction for different substituents at the
allylic position of the 1,4-diol was then evaluated (Scheme 2).
Scheme 2. Substrate Scope of Substituents at the Allylic
a
Position of the 1,4-Diols
a
Unless otherwise noted, reactions were run with 1 (0.05 mmol) and
(R)-A4 (15 mol %) in 1,2-dichloroethane (5 mL) with 4 Å MS (75
mg) at 5 °C. Isolated yields are given. The er values were determined
b
c
by HPLC analysis with a chiral stationary phase. At −10 °C. At −25
d
e
°C. At 0 °C. At 20 °C.
a
Unless otherwise noted, reactions were run with racemic diols (0.05
mmol) and (R)-A4 (15 mol %) in 1,2-dichloroethane (5 mL) with 4
Å MS (75 mg) at 5 °C. Isolated yields are given. The er values were
The KR of substrates 1b−1i was achieved with good
conversion and high selectivity (s = 17−80), regardless of
the electronic nature of the substituents. The absolute
configurations of the products were assigned as S by analogy
to that of product 2c, whose structure was unambiguously
confirmed by X-ray crystallography. Enantioenriched alcohol
1c was established to be in the R configuration with chemical
correlation into (R)-2c (see the Supporting Information for
details), thereby confirming that the intramolecular substitu-
tion of tertiary allylic alcohols proceeds with retention of
configuration. Increased steric bulk in the allylic substituents
(1j and 1k) led to slightly decreased selectivity. Substrates
bearing heterocycles were also well-tolerated; 3-indolyl- and 2-
thienyl-substituted allylic alcohols 1l and 1m had excellent
selectivity (s = 29−50). Incorporation of a 2-cyclohexenyl
group at the allylic position, however, resulted in a decreased s
factor, indicating that resonance stabilization in the allyl system
is crucial for selectivity.
b
determined by HPLC analysis with a stationary phase. At −25 °C.
c
d
e
f
At −10 °C. At 0 °C. At 20 °C. At 35 °C.
limitations of the KR were further investigated through the
incorporation of an alkyl substituent at the carbinol center.
Notably, when R2 was an alkyl group (3l−3o), the reaction
afforded both enantiomers with good enantioselectivities.
Analogous to 1,4-diols, 1,5-diols smoothly underwent dehy-
drogenative coupling to afford tetrahydropyrans with a
tetrasubstituted stereogenic center (5a−5c) in high yields
and with good selectivities (s = 22−48). The KR of 1,6-diol 7
was also attempted; however, it had a moderate s factor. Trace
amounts of 1,3-diene were detected in the crude reaction
mixture, indicating that β-H elimination was promoted by the
chiral phosphoric acid. The identical strategy also allows for
the kinetic resolution of 1,3-diol, providing 2H-1-pyran
derivative 10 with a high level of chiral recognition (s = 60)
(Scheme 4).24
We next examined the substituents of the tertiary alcohol
moiety (Scheme 3). A variety of α-aryl and α-heteroaryl
alcohols (3a−3j) reacted smoothly to afford the corresponding
products with excellent enantioselectivity and high s factors (s
= 21−120). A chiral secondary alcohol substituent was also
well-tolerated, resulting in excellent diastereoselectivity of
2,2,5-trisubstituted tetrahydrofuran 4k. The scope and
To evaluate the utility of this method, KR of racemic 1d was
performed on a gram scale. The reaction was conducted at 0
°C, and the catalyst loading of (R)-A4 could be decreased to 5
mol % while still providing a comparable s factor and
C
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Scheme 4. Kinetic Resolution of 1,3-Diol
Scheme 6. Relationship between the Reaction Rate (K) and
the σ Value of the Substituent R
a
enantioselectivities for (R)-1d and (S)-2d (Scheme 5a). A
series of transformations were then carried out to demonstrate
Scheme 5. Gram-Scale Reaction and Derivations of Chiral
Products
a
The reactions were performed using ( )-3 (0.025 mmol) and
( )-1d (0.025 mmol) and stopped at ∼30% conversion. The results
are the average of four runs. ρ is the slope of the line.
disubstituted tetrahydrofurans demonstrated the synthetic
utility of this method.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01110.
Full experimental details, characterization data, and
1
the synthetic utility of the products. Cyclization of resolved
(R)-1d with subsequent lactonization readily produced
enantiopure butyrolactone 11 with a 97:3 er. Treatment of
(R)-1d with MsCl under basic conditions yielded (R)-2d,
providing an enantiodivergent path for the asymmetric
synthesis of both enantiomers of 2d. Further elaboration
afforded 12, a key intermediate of VLA-4 antagonists, in high
yield with retained enantioselectivity (Scheme 5b).25 Primary
alcohol 13 was readily obtained from the reaction of (S)-4d
with potassium osmate followed by NaBH4 reduction. The
iodination of 13 and subsequent nucleophilic substitution of a
sodium triazole salt provided 14, which is one of the core
structures of the antifungal drug posaconazole (Scheme 5c).26
A Hammett analysis with a series of tertiary α-aryl alcohols
bearing para or meta substituents was carried out to
experimentally evaluate the mechanism. Substrates with
electron-donating substituents reacted at faster rates, possibly
providing enhanced stabilization for the resulting tertiary allylic
carbocationic intermediate (Scheme 6). In addition, only a
trace amount of the desired product was obtained from a
tertiary (Z)-allylic alcohol, indicating geometrical selectivity
toward the olefinic substrate in the metal-free asymmetric
allylic alkylation (see the Supporting Information for details).
In summary, we have developed an efficient KR of tertiary
allylic alcohols through organocatalytic asymmetric allylic
alkylation. High selectivity was achieved by employing a chiral
phosphoric acid as the catalyst, and a range of enantiomerically
pure cyclic ethers bearing tetrasubstituted stereocenters, as well
as enantioenriched tertiary allylic alcohols, were obtained with
excellent regio- and enantioselectivities. The reaction was also
conducted on a preparative scale, and the elaboration of 2,2-
copies of H and 13C spectra and HRMS data for all
products (PDF)
Accession Codes
CCDC 2056090 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Bin Mao − Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou 310014, P. R. China; orcid.org/
0000-0003-3699-9197; Email: maob@zjut.edu.cn
Authors
Chao-Huan Zhang − Collaborative Innovation Center of
Yangtze River Delta Region Green Pharmaceuticals, Zhejiang
University of Technology, Hangzhou 310014, P. R. China;
orcid.org/0000-0003-1348-6065
Qing Gao − Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou 310014, P. R. China
Meng Li − Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou 310014, P. R. China
Jian-Fei Wang − College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
D
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(10) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You,
S.-L. Iridium-catalyzed asymmetric allylic substitution reactions.
Chem. Rev. 2019, 119, 1855−1969.
(11) For selected reviews of the enantioselective allylic substitution
of allylic alcohols, see: (a) Sundararaju, B.; Achard, M.; Bruneau, C.
Transition metal catalyzed nucleophilic allylic substitution: activation
of allylic alcohols via π-allylic species. Chem. Soc. Rev. 2012, 41,
4467−4483. (b) Butt, N. A.; Zhang, W. Transition metal-catalyzed
allylic substitution reactions with unactivated allylic substrates. Chem.
Soc. Rev. 2015, 44, 7929−7967.
Chuan-Ming Yu − College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China; orcid.org/0000-0002-1345-0778
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01110
Notes
The authors declare no competing financial interest.
(12) (a) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M.
Asymmetric Brønsted acid catalysis: enantioselective nucleophilic
substitutions and 1,4-additions. Angew. Chem., Int. Ed. 2008, 47, 593−
596. (b) Görbe, T.; Lihammar, R.; Bäckvall, J.-E. Heterogeneous acid-
catalyzed racemization of tertiary alcohols. Chem. - Eur. J. 2018, 24,
77−80.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (NSFC) (21676252 and
21606200), the Zhejiang Provincial NSFC (LY19B020010),
and the starting fund of Zhejiang University of Technology.
(13) Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. Chiral organic
contact ion pairs in metal-free catalytic asymmetric allylic
substitutions. J. Am. Chem. Soc. 2011, 133, 3732−3735.
REFERENCES
■
(14) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete field
guide to asymmetric BINOL-phosphate derived Brønsted acid and
metal catalysis: history and classification by mode of activation;
Brønsted acidity, hydrogen bonding, ion pairing, and metal
phosphates. Chem. Rev. 2014, 114, 9047−9153.
(15) For selected reviews of asymmetric counteranion-directed
catalysis, see: (a) Brak, K.; Jacobsen, E. N. Asymmetric ion-pairing
catalysis. Angew. Chem., Int. Ed. 2013, 52, 534−561. (b) Mahlau, M.;
List, B. Asymmetric counteranion-directed catalysis: concept,
definition, and applications. Angew. Chem., Int. Ed. 2013, 52, 518−
533.
(1) Ghosh, A. K.; Anderson, D. D. Tetrahydrofuran, tetrahydropyr-
an, triazoles and related heterocyclic derivatives as HIV protease
inhibitors. Future Med. Chem. 2011, 3, 1181−1197.
(2) Nasir, N. M.; Ermanis, K.; Clarke, P. A. Strategies for the
construction of tetrahydropyran rings in the synthesis of natural
products. Org. Biomol. Chem. 2014, 12, 3323−3335.
(3) Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T.
From oxiranes to oligomers: architectures of U.S. FDA approved
pharmaceuticals containing oxygen heterocycles. J. Med. Chem. 2018,
61, 10996−11020.
(4) Trost, B. M.; Bringley, D. A. Enantioselective synthesis of 2,2-
disubstituted tetrahydrofurans: Palladium-catalyzed [3 + 2] cyclo-
additions of trimethylenemethane with ketones. Angew. Chem., Int. Ed.
2013, 52, 4466−4469.
(16) (a) Wang, P. S.; Zhou, X. L.; Gong, L. Z. An organocatalytic
asymmetric allylic alkylation allows enantioselective total synthesis of
hydroxymetasequirin-A and metasequirin-B tetramethyl ether diac-
etates. Org. Lett. 2014, 16, 976−979. (b) Zhuang, M.; Du, H. Chiral
Brønsted acid catalyzed enantioselective intermolecular allylic
aminations. Org. Biomol. Chem. 2014, 12, 4590−4593. For
enantioselective allylic substitution of 2-amidoallylic alcohol, see:
(c) Rajkumar, S.; Wang, J.; Zheng, S.; Wang, D.; Ye, X.; Li, X.; Peng,
Q.; Yang, X. Regioselective and enantioselective synthesis of β-indolyl
cyclopentenamides by chiral anion catalysis. Angew. Chem., Int. Ed.
2018, 57, 13489−13494. (d) Rajkumar, S.; He, S.; Yang, X. Kinetic
resolution of tertiary 2-alkoxycarboxamido-substituted allylic alcohols
by chiral phosphoric acid catalyzed intramolecular transesterification.
Angew. Chem., Int. Ed. 2019, 58, 10315−10319.
(5) (a) Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. Catalytic
asymmetric bromoetherification and desymmetrization of olefinic 1,3-
diols with C2-symmetric sulfides. J. Am. Chem. Soc. 2014, 136, 5627−
5630. (b) Cheng, Y. F.; Liu, J. R.; Gu, Q. S.; Yu, Z. L.; Wang, J.; Li, Z.
L.; Bian, J. Q.; Wen, H. T.; Wang, X. J.; Hong, X.; Liu, X. Y. Catalytic
enantioselective desymmetrizing functionalization of alkyl radicals via
Cu(i)/CPA cooperative catalysis. Nat. Catal. 2020, 3, 401−410.
(c) Hopkins, B. A.; Garlets, Z. J.; Wolfe, J. P. Development of
enantioselective palladium-catalyzed alkene carboalkoxylation reac-
tions for the synthesis of tetrahydrofurans. Angew. Chem., Int. Ed.
2015, 54, 13390−13392. (d) Tsuji, N.; Kennemur, J. L.; Buyck, T.;
(17) (a) Pellissier, H. Catalytic non-enzymatic kinetic resolution.
Adv. Synth. Catal. 2011, 353, 1613−1666. (b) Pellissier, H. Recent
developments in non-enzymatic catalytic oxidative kinetic resolution
of secondary alcohols. Tetrahedron 2018, 74, 3459−3468.
̀
Lee, S.; Prévost, S.; Kaib, P. S. J.; Bykov, D.; Fares, C.; List, B.
Activation of olefins via asymmetric Brønsted acid catalysis. Science
2018, 359, 1501−1505.
̌
(6) Lu, Y.; Zou, G.; Zhao, G. Asymmetric intramolecular oxa-
Michael reactions to tetrahydrofurans/2H-pyrans catalyzed by
primary−secondary diamines. ACS Catal. 2013, 3, 1356−1359.
(7) (a) Lee, S.; Bae, H. Y.; List, B. Can a ketone be more reactive
than an aldehyde? Catalytic asymmetric synthesis of substituted
tetrahydrofurans. Angew. Chem., Int. Ed. 2018, 57, 12162−12166.
́
(18) Kim, J. H.; Coric, I.; Palumbo, C.; List, B. Resolution of diols
via catalytic asymmetric acetalization. J. Am. Chem. Soc. 2015, 137,
1778−1781.
(19) For selected examples of kinetic resolution of tertiary alcohols,
see: (a) Lu, S.; Poh, S. B.; Siau, W. Y.; Zhao, Y. Kinetic resolution of
tertiary alcohols: highly enantioselective access to 3-hydroxy-3-
substituted oxindoles. Angew. Chem., Int. Ed. 2013, 52, 1731−1734.
(b) Greenhalgh, M. D.; Smith, S. M.; Walden, D. M.; Taylor, J. E.;
Brice, Z.; Robinson, E. R. T.; Fallan, C.; Cordes, D. B.; Slawin, A. M.
Z.; Richardson, H. C.; Grove, M. A.; Cheong, P. H.-Y.; Smith, A. D. A
C = O···isothiouronium interaction dictates enantiodiscrimination in
acylative kinetic resolutions of tertiary heterocyclic alcohols. Angew.
Chem., Int. Ed. 2018, 57, 3200−3206. (c) Rajkumar, S.; Tang, M.;
Yang, X. Chiral phosphoric acid catalyzed kinetic resolution of 2-
amido benzyl alcohols: asymmetric synthesis of 4H-3,1-benzoxazines.
Angew. Chem., Int. Ed. 2020, 59, 2333−2337. (d) Zheng, W. F.;
Zhang, W.; Huang, C.; Wu, P.; Qian, H.; Wang, L.; Guo, Y. L.; Ma, S.
Tetrasubstituted allenes via the palladium-catalysed kinetic resolution
of propargylic alcohols using a supporting ligand. Nat. Catal. 2019, 2,
997−1005. (e) Seliger, J.; Dong, X.; Oestreich, M. Kinetic resolution
of tertiary propargylic alcohols by enantioselective Cu-H-catalyzed Si-
(b) Monasterolo, C.; Muller-Bunz, H.; Gilheany, D. G. Very short
̈
highly enantioselective Grignard synthesis of 2,2-disubstituted
tetrahydrofurans and tetrahydropyrans. Chem. Sci. 2019, 10, 6531−
6538.
(8) (a) Gualandi, A.; Rodeghiero, G.; Cozzi, P. G. Catalytic
stereoselective SN1-type reactions promoted by chiral phosphoric
acids as Brønsted acid catalysts. Asian J. Org. Chem. 2018, 7, 1957−
1981. (b) Lanke, V.; Marek, I. Stereospecific nucleophilic substitution
at tertiary and quaternary stereocentres. Chem. Sci. 2020, 11, 9378−
9385.
(9) For selected example on the Brønsted acid catalyzed asymmetric
̌
́
O-alkylation of racemic secondary alcohol, see: Coric, I.; Kim, J. H.;
Vlaar, T.; Patil, M.; Thiel, W.; List, B. Brønsted acid catalyzed
asymmetric SN2-type O-alkylations. Angew. Chem., Int. Ed. 2013, 52,
3490−3493.
E
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Organic Letters
pubs.acs.org/OrgLett
Letter
O coupling. Angew. Chem., Int. Ed. 2019, 58, 1970−1974. (f) Qu, S.;
Smith, S. M.; Laina-Martín, V.; Neyyappadath, R. M.; Greenhalgh, M.
D.; Smith, A. D. Isothiourea-catalyzed acylative kinetic resolution of
tertiary α-hydroxy esters. Angew. Chem., Int. Ed. 2020, 59, 16572−
16578. (g) Liao, K.; Gong, Y.; Zhu, R.; Wang, C.; Zhou, F.; Zhou, J.
Highly enantioselective CuAAc of functional tertiary alcohols
featuring an ethynyl group and their kinetic resolution. Angew.
Chem., Int. Ed. 2021, 60, 8488−8493.
(20) For selected examples of the stereocontrolled nucleophilic
substitution over tertiary alcohol-derived carbocations, see: (a) Pronin,
S. V.; Reiher, C. A.; Shenvi, R. A. Stereoinversion of tertiary alcohols
to tertiary-alkyl isonitriles and amines. Nature 2013, 501, 195−199.
(b) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Enantioselective formation
of all-carbon quaternary stereocenters from indoles and tertiary
alcohols bearing a directing group. Angew. Chem., Int. Ed. 2015, 54,
1910−1913.
(21) For recent review of the CPA-catalyzed kinetic resolution, see:
Liu, W.; Yang, X. Recent advances in (dynamic) kinetic resolution
and desymmetrization catalyzed by chiral phosphoric acids. Asian J.
Org. Chem. 2021, 10, 692.
(22) Pan, Y.; Jiang, Q.; Rajkumar, S.; Zhu, C.; Xie, J.; Yu, S.; Chen,
Y.; He, Y.; Yang, X. Kinetic resolution of 2-N-acylamido tertiary allylic
alcohols: asymmetric synthesis of oxazolines. Adv. Synth. Catal. 2021,
363, 200−207.
(23) The s values have been reported to the nearest integer when s <
50 or the nearest 10 for larger values (s = 50−200). For good practice
concerning the use of the s value, see: Greenhalgh, M. D.; Taylor, J.
E.; Smith, A. D. Best practice considerations for using the selectivity
factor, s as a metric for the efficiency of kinetic resolutions.
Tetrahedron 2018, 74, 5554−5560.
(24) The absolute configuration of 10 remained undetermined
because an SN1-type mechanism via chiral contact ion-pair catalysis
and an alternative enantioselective SN2′ substitution pathway were
both possible.
(25) Doherty, G. A.; Yang, G. X.; Borges, E.; Chang, L. L.; MacCoss,
M.; Tong, S.; Kidambi, U.; Egger, L. A.; McCauley, E.; Van Riper, G.;
Mumford, R. A.; Schmidt, J. A.; Hagmann, W. K. Substituted
tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific
VLA-4 antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 1501−1505.
(26) Teske, K. A.; Dash, R. C.; Morel, S. R.; Chau, L. Q.; Wechsler-
Reya, R. J.; Hadden, M. K. Development of posaconazole-based
analogues as hedgehog signaling pathway inhibitors. Eur. J. Med.
Chem. 2019, 163, 320−332.
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on April 30, 2021. Changes
were made to the enantiomeric ratios on page two of the
document, and the corrected version was reposted on May 3,
2021. Scheme 6 was replaced, and the corrected version was
reposted on May 4, 2021.
F
https://doi.org/10.1021/acs.orglett.1c01110
Org. Lett. XXXX, XXX, XXX−XXX