Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additions to Oxetanes

Article abstract of DOI:10.1021/jacs.0c03991

A precisely designed chiral squaramide derivative is shown to promote the highly enantioselective addition of trimethylsilyl bromide (TMSBr) to a broad variety of 3-substituted and 3,3-disubstituted oxetanes. The reaction provides direct and general access to synthetically valuable 1,3-bromohydrin building blocks from easily accessed achiral precursors. The products are readily elaborated both by nucleophilic substitution and through transition-metal-catalyzed cross-coupling reactions. The enantioselective catalytic oxetane ring opening was employed as part of a three-step, gram-scale synthesis of pretomanid, a recently approved medication for the treatment of multidrug-resistant tuberculosis. Heavy-atom kinetic isotope effect (KIE) studies are consistent with enantiodetermining delivery of bromide from the H-bond-donor (HBD) catalyst to the activated oxetane. While the nucleophilicity of the bromide ion is expected to be attenuated by association to the HBD, overall rate acceleration is achieved by enhancement of Lewis acidity of the TMSBr reagent through anion abstraction.

Full text of DOI:10.1021/jacs.0c03991

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Communication
Highly Enantioselective, Hydrogen-Bond-
Donor Catalyzed Additions to Oxetanes
Daniel A. Strassfeld, Zachary K. Wickens, Elias Picazo, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 May 2020
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Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additions
to Oxetanes
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Daniel A. Strassfeld‡, Zachary K. Wickens‡, Elias Picazo, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
Supporting Information Placeholder
ABSTRACT: A precisely designed chiral squaramide derivative is shown to promote the highly enantioselective addition of
trimethylsilyl bromide (TMSBr) to a broad variety of 3-substituted and 3,3-disubstituted oxetanes. The reaction provides
direct and general access to synthetically valuable 1,3-bromohydrin building blocks from easily accessed achiral precursors.
The products are readily elaborated both by nucleophilic substitution and through transition-metal-catalyzed cross-coupling
reactions. The enantioselective catalytic oxetane ring opening was employed as part of a 3-step, gram-scale synthesis of preto-
manid, a recently-approved medication for the treatment of multi-drug-resistant tuberculosis. Heavy-atom kinetic isotope
effect (KIE) studies are consistent with enantiodetermining delivery of bromide from the H-bond-donor (HBD) catalyst to the
activated oxetane. While the nucleophilicity of the bromide ion is expected to be attenuated by association to the HBD, overall
rate acceleration is achieved by enhancement of Lewis acidity of the TMSBr reagent through anion-abstraction.
A. catalysis of SN1-type substitution via anion abstraction
Chiral anion-binding catalysis has emerged as a powerful
strategy for enantioselective additions to cationic interme-
diates through their non-covalent association to catalyst-
R*
generation of a catalyst-
associated ion pair
N
H
N
H
E
X
E Nu
+
X M
bound spectator anions.1,2 In most applications identified to
date, the chiral catalyst-anion complex mediates stereoin-
duction in the addition of an external nucleophile (Figure
1A). An interesting variation to the anion-binding catalysis
concept arises when the catalyst-bound anion also acts as
the nucleophile in the enantiodetermining bond construc-
tion.3,4 At least in principle, such an approach can provide
more precise control over stereoselectivity through specific
association of both nucleophile and electrophile to the chi-
ral catalyst. However, H-bonding from the catalyst would
also be expected to attenuate the reactivity of the nucleo-
phile relative to an uncatalyzed, racemic pathway.5 This fun-
damental reactivity challenge can be circumvented if the
catalyst also promotes the generation of the reactive ion-
pair, as demonstrated elegantly by Gouverneur3f,g in the
specific context of phase-transfer reactions of alkali metal
fluorides (Figure 1B). Following the recent discovery that
H-bond donors such as chiral squaramides can activate silyl
triflates via anion binding to promote enantioselective
transformations,6 we were drawn to an alternative and pos-
sibly general approach to catalysis of nucleophile delivery
by applying the anion-binding principle to activation of
Lewis acids bearing nucleophilic counterions. Anion ab-
straction from the promoter should result in enhanced
Lewis acidity, providing a general platform to access highly-
reactive, cationic, electrophilic intermediates ion paired
with a catalyst-bound nucleophilic anion (Figure 1C).
+
Nu
X
M
external addition of nucleophile
(enantiocontrol through catalyst-
electrophile interaction only)
E
Nu
M
B. phase-transfer catalysis of substitution via nucleophile delivery
R*
E
X
X
M
E
enantiocontrol through
direct catalyst association to both
nucleophile and electrophile
N
H
N
H
E
Nu
+
Nu M(solid)
Nu
C. this work: addition via Lewis acid activation/nucleophile delivery
enantiocontrol through
direct catalyst association to both
nucleophile and electrophile
R*
N
H
N
H
E
+
Nu
M
E Nu
M
rate enhancement due to
increased Lewis acidity through
anion abstraction
M
Nu
E
Figure 1. (A) Conventional approach to anion-binding ca-
talysis in which the catalyst binds a spectator anion. (B)
Alternative reactive mode in anion-binding catalysis
involving delivery of the bound anionic nucleophile to a
cationic electrophile. Hydrogen bonding attenuates the
reactivity of the nucleophile, but rate acceleration has been
achieved via phase-transfer catalysis. (C) Catalyst-pro-
moted ionization of an anionic nucleophile from a neutral
Lewis acid-nucleophile complex allows for H-bond donor
catalyzed anion delivery.
We chose to explore the anion-binding effect on nucleo-
phile-bearing Lewis acids in the context of additions of
TMSBr to prochiral oxetanes (Fig. 2A). Enantioselective
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ring-opening of 3-substituted oxetanes provides a route to
to provide products bearing fully substituted stereocenters
(1q–v) with moderate-to-high enantioselectivity.
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valuable 3-carbon chiral building blocks from simple, syn-
thetically-accessible precursors.7 Several examples of enan-
tioselective openings of 3-susbtituted oxetanes with intra-
molecular nucleophiles have been identified.8,9 However,
more generally applicable highly enantioselective reactions
involving intermolecular nucleophilic addition are limited
to two pioneering examples from Sun and coworkers in-
volving chiral phosphoric acid-catalyzed addition of mer-
captobenzothiazole and HCl.10 Here we report the
successful application of a chiral squaramide catalyst to
promote the ring-opening addition of TMSBr to prochiral
oxetane substrates with unprecedented substrate scope.
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Figure 2. A) Model reaction: enantioselective opening of
oxetanes with TMSBr. B) Catalyst screening data for a series
of arylpyrrolidino squaramides.
The addition of TMSBr to 3-phenyloxetane (1a) was
selected as a model reaction.11 Squaramide hydrogen-bond-
donor catalysts6,12 bearing a 2-arylpyrrolidino amide were
identified as particularly effective, with the the aryl
substituent having a marked effect on enantioselectivity
and reproducibility (Fig. 2B). Systematic reaction and
catalyst development (Fig. S1–S5) led to the identification
of 9-phenanthryl squaramide 3a as the optimal catalyst for
the synthesis of silylated bromohydrin 2a, catalyzing its
formation in quantitative yields and with 96-98% e.e. over
>20 runs.13
Squaramide 3a was found to catalyze the opening of a
broad range of 3-subsituted and 3,3-disubstituted oxetanes
in high levels of e.e. (Figure 3). With 3-aryl oxetanes, both
electron donating and withdrawing substituents could be
introduced, with only ortho substitution impacting enanti-
oselectivity adversely (1a–h). Weakly Lewis basic func-
tional groups such as nitriles (1f) and esters (1g) had no
deleterious effect on the reaction, and aryl ether spectator
groups remained intact (1h). Oxetanes bearing protected
alcohol and amine functionality (1i–m) as well as simple
saturated alkyl groups (1n‐p) all underwent reaction with
high enantioselectivity. The reaction could even be ex-
tended successfully to certain 3,3'-disubstituted oxetane
substrates, which underwent stereoselective ring opening
Figure 3. Isolated yield and enantiomeric enrichments
measured for the asymmetric oxetane opening at 0.4 mmol
scale. See SI for details on methods for e.e. determination,
reproducibility studies, and the assignment of absolute con-
figuration. a Isolated as a 12.5 : 1 ratio of ROTMS to ROH
product. b 48-hr reaction time. c –25 °C. d 72-hr reaction time.
e 7.5 mol% 3a. f –65 °C.
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Alkyl bromide 2a was examined as a model substrate for
The oxetane-opening methodology presents an interest-
ing alternative to well-established synthetic strategies for
accessing three-carbon chiral building blocks based on
glycidol or epichlorohydrin derivatives (Figure 4B).18 In
particular, the identity of the C2 group can be set in the
prochiral oxetane substrate, thereby avoiding potentially
multi-step late-stage functional-group manipulations re-
quired in routes involving epoxide ring-opening. This ad-
vantage is illustrated in the synthesis of the recently ap-
proved tuberculosis drug pretomanid19 (Figure 4C), which
was prepared previously by Reider, Sorensen and cowork-
ers in an elegant 5-step route from enantioenriched (R)-3-
chloro-1,2-propanediol.20a Readily accessible oxetane 1w
underwent highly enantioselective ring-opening to yield
TMS-protected bromohydrin 2w in 98% e.e.21 Gratifyingly,
2-chloro-4-nitroimadzole, which was identified in the
Reider and Sorensen synthesis as a non-explosive alterna-
tive to 2,4-dinitroimidazole,20a underwent alkylation by 2w
with complete regioselectivity followed by SNAr annulation
to yield the desired product. Both intermediates were
formed in sufficient purity to be carried forward without
purification, and only a recrystallization of the final product
was required to access analytically-pure pretomanid (10) in
>99% e.e. The synthetic route avoids protecting-group ma-
nipulation steps and provides access to pretomanid in just
3 steps.
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potential product derivatizations (Fig. 4A) and was found to
undergo facile substitution with azide, cyanide, and thio-
phenolate nucleophiles. Recent advances in transition-
metal-catalyzed cross-coupling chemistry14 provide further
opportunities for product elaborations; for example, we
found that 2a engaged effectively in cobalt-catalyzed aryla-
tions.15 Moreover, the polarity of the electrophilic alkyl bro-
mide could be inverted either by copper-catalyzed boryla-
tion,16 or through metal-halogen exchange, allowing 2a to
function as the nucleophilic partner in a C(sp2)–C(sp3) cross
coupling.17 Overall, the diverse range of products that can
be accessed directly from 2a illustrates the synthetic versa-
tility of these chiral bromohydrin building blocks.
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Figure 5. One-pot competition KIE between 1a and 13C2‐
1a. A primary KIE of 1.126(9) was measured, indicating that
oxetane silylation must be reversible, supporting enanti-
odetermining bromide delivery.
Figure 4. A) Product elaborations: all reported yields are
for the entire sequence of reactions starting from 1a a)
standard reaction conditions with 0.4 mmol 1a; b) NaCN; c)
NaN3; d) NaSPh; e) p-TolMgBr, Co(acac)3, TMEDA; f) B2Pin2,
CuCl, Xantphos, t-BuOK; g) NaI in MeCN then solvent swap
to Et2O, t-BuLi, ZnCl2, Pd(dppf)Cl2, R-I. See SI for detailed
procedures. B) Glycidol- and oxetane-based strategies to C3
chiral derivatives. C) Gram-scale synthesis of pretomanid:
As an initial step toward establishing the basis for exquis-
ite enantiocontrol in oxetane ring-opening reactions with
squaramide 3a, we endeavored to determine whether bro-
mide delivery was indeed the enantiodetermining step as
proposed at the outset of reaction development. To address
this question, the 12C / 13C KIE at the site of bromide attack
was determined through analysis of starting material recov-
ered at partial conversion from a one-pot competition be-
tween doubly labeled oxetane 13C2-1a and unlabeled isotop-
ologue 1a (Fig. 5).22 If bromide-promoted ring opening
were substrate-committing, and thus, enantiodetermining,
a primary KIE consistent with C–O bond cleavage would be
expected. In contrast, if a step preceding ring opening such
as oxetane silylation were irreversible then only a small,
secondary KIE would be anticipated. Irreversible silylation
Ar
= 4-(trifluoromethoxy)phenyl h) 4-(trifluormeth-
oxy)benzyl bromide (1.2 equiv.), NaH (1.2 equiv.), 2-Me-
THF (1.0 M), 60 °C, 12 hr; i) 3a (2 mol%), TMSBr (1.1
equiv.), t-BuOMe (0.25 M), –80 °C, 24 hr; j) 2-chloro-4-ni-
troimidazole (2.0 equiv.), Et3N (2.1 equiv.), NaI (1.0 equiv.)
DMF (0.25 M), 115 °C, 24 hr, then cool to 23 °C and add
MeOH (1.0 M) and NaOH (5.0 equiv.), 30 min.
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(1) (a) Doyle, A. G.; Jacobsen, E. N. Small-molecule H-bond donors
would not necessarily preclude enantiodetermining bro-
mide delivery, but it would allow for the possibility that si-
lylation of 1a was enantiodetermining.23 Subjection of a
mixture of 1a and 13C2-1a to the catalytic reaction condi-
tions led to the observation of a large, primary KIE (k12/k13
= 1.126(9)), fully consistent with reversible silylation and
enantioselectivity-determining bromide delivery (see SI for
full details of the KIE studies).
In conclusion, the chiral squaramide-catalyzed addition
of TMSBr to 3-aryl, 3-alkyl, and 3-heteroatom substituted
oxetanes as well as certain 3,3-disubstituted oxetanes pro-
vides a general enantioselective synthesis of protected 1,3-
bromohydrin derivatives. The products of these reactions
can be elaborated through a variety of nucleophilic substi-
tution reactions, and the utility of the method is illustrated
in the 3-step, gram-scale synthesis of the TB drug preto-
manid. Heavy-atom KIE studies are consistent with enanti-
odetermining bromide delivery by the catalyst to an acti-
vated oxetane. This strategy overcomes the intrinsic deacti-
vation of nucleophiles that accompanies association with an
H-bond donor and holds promise as a broadly applicable ap-
proach to asymmetric catalysis of addition reactions.
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3
4
5
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in asymmetric catalysis. Chem. Rev. 2007, 107, 5713-5743. (b)
Brak, K.; Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew.
Chem., Int. Ed. 2013, 52, 534-561.
(2) Chiral Brønsted acids have also been employed effectively to
generate analogous chiral ion-pair intermediates through associa-
tion of protonated species to the conjugate base of the chiral acid
catalyst. For a recent reviews see ref. 1b and: Parmar, D.; Sugiono,
E.; Raja, S.; Rueping, M. Complete field guide to asymmetric BINOL-
phosphate derived Bronsted acid and metal catalysis: history and
classification by mode of activation; Bronsted acidity, hydrogen
bonding, ion pairing, and metal phosphates. Chem. Rev. 2014, 114,
9047-9153.
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(3) (a) Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N.
Scaleable catalytic asymmetric Strecker syntheses of unnatural α-
amino acids. Nature 2009, 461, 968-970. (b) Zuend, S. J.; Jacobsen,
E. N.; Mechanism of amido-thiourea catalyzed enantioselective
imine hydrocyanation: transition state stabilization via multiple
non-covalent interactions. J. Am. Chem. Soc. 2009, 131, 15358-
15374. (c) Birrell, J. A.; Desrosiers, J.-N.; Jacobsen, E. N. Enantiose-
lective acylation of silyl ketene acetals through fluoride anion-
binding catalysis. J. Am. Chem. Soc. 2011, 133, 13872-13875. (d) De,
C. K.; Mittal, N.; Seidel, D. A dual-catalysis approach to the asym-
metric Steglich rearrangement and catalytic enantioselective addi-
tion of O-acylated azalactones to isoquinolines. J. Am. Chem. Soc.
2011, 133, 16802-16805. (e) Jarvis, C. L.; Hirschi, J. S.; Vetticatt, M.
J.; Seidel, D. Catalytic enantioselective synthesis of lactams through
formal [4+2] cycloaddition of imines with homophthalic anhy-
dride. Angew. Chem., Int. Ed. 2017, 56, 2670-2674. (f) Pupo, G.;
Ibba, F.; Ascough, D. M. H.; Vicini, A. C.; Ricci, P.; Christensen, K. E.;
Pfeifer, L.; Morphy, J. R.; Brown, J. M.; Paton, R. S.; Gouverneur, V.
Asymmetric nucleophilic fluorination under hydrogen bonding
phase-transfer catalysis. Science 2018, 360, 638-642. (g) Pupo, G.;
Vicini, A. C.; Ascough, D. M. H.; Ibba, F.; Christensen, K. E.; Thomp-
son, A. L.; Brown, J. M.; Paton, R. S.; Gouverneur, V. Hydrogen bond-
ing phase-transfer catalysis with potassium fluoride: enantioselec-
tive synthesis of β-fluoroamines. J. Am. Chem. Soc. 2019, 141, 2878-
2883.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental and characterization data of catalyst and
substrate syntheses, procedures and analytical data for
enantioselective reactions, procedure and analytical data
for product elaborations, details of KIE experiment (PDF)
Crystallographic data for 26a (derivative of 2a) (CIF)
Crystallographic data for 26o (derivative of 2o) (CIF)
Crystallographic data for 2t (CIF)
(4) Nucleophilic attack by catalyst-bound anions on neutral elec-
trophiles is frequently proposed in reactions catalyzed by bifunc-
tional hydrogen-bond donors. See ref. 4a and 4b for representative
mechanistic studies, and ref. 4c for an example of halide delivery in
a hydrochlorinative aziridine opening. (a) Hamza, A.; Schubert, G.;
Soos, T.; Papai, I. Theoretical studies on the bifunctionality of chiral
thiourea-based organocatalysts: competing routes to C-C bond
formation. J. Am. Chem. Soc. 2006, 128, 13151-13160. (b) Izzo, J. A.;
Myshchuk, Y.; Hirschi, J. S.; Vetticatt, M. J. Transition state analysis
of an enantioselective Michael addition by a bifunctional thiourea
organocatalyst. Org. & Biomol. Chem. 2019, 17, 3934-3939. (c)
Mita, T.; Jacobsen, E. N. Bifunctional asymmetric catalysis with hy-
drogen chloride: enantioselective ring opening of aziridines cata-
lyzed by a phosphinothiourea. Synlett 2009, 10, 1680-1684.
(5) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemis‐
try; University Science Books: Sausalito, CA, 2006: pp 643-646.
(6) (a) Banik, S. M.; Levina, A.; Hyde, A. M.; Jacobsen, E. N. Lewis
acid enhancement by hydrogen-bond donors for asymmetric catal-
ysis. Science 2017, 10, 761-764. (b) Wendlandt, A. E.; Vangal, P.; Ja-
cobsen, E. N. Quaternary stereocenters via an enantioconvergent
catalytic SN1 reaction. Nature 2018, 556, 447-451.
Crystallographic data for 26u (derivative of 2u) (CIF)
AUTHOR INFORMATION
Corresponding Author
*jacobsen@chemistry.harvard.edu
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support for this work was provided by the NIH
through GM043214 and a postdoctoral fellowship to Z.K.W.
We thank Dr. E. E. Kwan for discussions regarding the KIE
studies, and Dr. S.-L. Zheng for X-ray data collection and
structure determination.
REFERENCES
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(7) (a) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Muller, K.;
enantioselective
catalysis:
Cu(I)/bisazaferrocene-catalyzed
1
2
3
4
5
6
7
8
Carreira, E. M. Oxetanes as versatile elements in drug discovery
and synthesis. Angew. Chem., Int. Ed. 2010, 49, 9052-9067. (b)
Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parilla, I.;
Schuler, F.; Rogers-Evans, M.; Müller, K. Oxetanes in drug discov-
ery: structural and synthetic insights. J. Med. Chem. 2010, 53, 3227-
3246. (c) Ahmad, S.; Yousaf, M.; Mansha, A.; Rasool, N.; Zahoor, A.
F.; Hafeez, F.; Rizvi, S. M. A. Ring-opening reactions of oxetanes: a
review of methodology development and synthetic applications.
Synth. Comm. 2016, 46, 1397-1416. (d) Bull, J. A.; Croft, R. A.; Davis,
O. A.; Doran, R.; Morgan, K. F. Oxetanes: recent advances in synthe-
sis, reactivity, and medicinal chemistry. Chem. Rev. 2016, 116,
12150-12233.
(8) (a) Loy, R. N.; Jacobsen, E. N. Enantioselective intramolecular
openings of oxetanes catalyzed by (salen)Co(III) complexes: access
to enantioenriched tetrahydrofurans. J. Am. Chem. Soc. 2009, 131,
2786-2787. (b) Chen, Z.; Wang, B.; Wang, Z.; Zhu, G.; Sun, J. Complex
bioactive alkaloid-type polycycles through efficient catalytic asym-
metric multicomponent aza-Diels-Alder reactions of indoles with
oxetane as directing group. Angew. Chem., Int. Ed. 2013, 52, 2027-
2031. (c) Chen, Z.; Wang, Z.; Sun, J. Catalytic enantioselective syn-
thesis of tetrahydroisoquinolines and their analogues bearing a C4
stereocenter: formal synthesis of (+)-(8S,13R)-cyclocelabenzine.
Chem. Eur. J. 2013, 19, 8426-8430. (d) Wang, Z.; Chen, Z.; Sun, J.
Catalytic asymmetric nucleophilic openings of 3-substituted ox-
etanes. Org. & Biomol. Chem. 2014, 12, 6028-6032. (e) Yang, W.;
Sun, J. Organocatalytic enantioselective synthesis of 1,4-dioxanes
and other oxa-heterocycles by oxetane desymmetrization. Angew.
Chem., Int. Ed. 2016, 55, 1868-1871. (f) Zhang, R.; Guo, W.; Duan,
M.; Houk, K. N.; Sun, J. Asymmetric desymmetrization of oxetanes
for the synthesis of chiral tetrahydrothiophenes and tetrahydrose-
lenophenes. Angew. Chem., Int. Ed. 2019, 58, 18055-18060. An en-
antioselective ring expansion of 3-substituted oxetanes has also
been developed: (g) Yin, Q.; You, S-L. Asymmetric chlorination/ring
expansion for the synthesis of α-quaternary cycloalkanones. Org.
Lett. 2014, 14, 1810-1813.
(9) Several enantioselective reactions have also been developed
that employ 2-substituted oxetanes as substrates for ring expan-
sion: (a) Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R. Asymmetric
induction in carbenoid reactions by means of a dissymmetric
copper chelate. Tet. Lett. 1966, 7, 5239-5244. (b) Nozaki, H.;
Takaya, H.; Moritui, S.; Noyori, R. Homogeneous catalysis in the
decomposition of diazo compounds by copper chelates:
asymmetric carbenoid reactions. Tetrahedron 1968, 24, 3655-
3669. (c) Ito, K.; Katsuki, T. Asymmetric carbene C-O insertion
reaction using optically active bipyridine-copper complex as a
catalyst. Ring expansion of oxetanes to tetrahydrofurans. Chem.
Lett. 1994, 23, 1857-1860. (d) Ito, K.; Yoshitake, M.; Katsuki, T.
Enantioselective synthesis of trans-whisky lactone by using newly
developed asymmetric ring expansion reaction of oxetane as a key
step. Chem. Lett. 1995, 24, 1027-1028. (e) Ito, K.; Yoshitake, M.;
Katsuki, T. Enantiospecific ring expansion of oxetanes:
stereoselective synthesis of tetrahydrofurans. Heterocycles 1996,
42, 305-317. (f) Ito, K.; Fukuda, T.; Katsuki, T. A new methodology
for efficient construction of 2,7-dioxabicyclo[3.3.0]octane
derivatives. Synlett 1997, 4, 387-389. (g) Ito, K.; Fukuda, T.;
Katsuki, T. A new enantiospecific approach to the bislactone
structure: formal syntheses of (+)-avenaciolide and (-)-
isoavenaciolide. Heterocycles 1997, 46, 401-411. (h) Lo, M. M.-C.;
Fu, G. C. Applications of planar-chiral heterocycles in
asymmetric expansion of oxetanes to tetrahydrofurans.
Tetrahedron 2001, 57, 2621-2634. (i) Guo, B.; Schwarzwalder, G.;
Njardarson, J. T. Catalytic ring expansion of vinyl oxetanes:
asymmetric synthesis of dihydropyrans using chiral counterion
catalysis. Angew. Chem., Int. Ed. 2012, 51, 5675-5678.
(10) (a) Wang, Z.; Chen, Z.; Sun, J. Catalytic enantioselective inter-
molecular desymmetrization of 3-substituted oxetanes. Angew.
Chem., Int. Ed. 2013, 52, 6685-6688. (b) Yang, W.; Wang, Z.; Sun, J.
Enantioselective oxetane ring opening with chloride: unusual use
of wet molecular sieves for the controlled release of HCl. Angew.
Chem., Int. Ed. 2016, 55, 6954-6958. For pioneering examples of
moderately enantioselective intermolecular oxetane openings
with organolithium reagents, see: (c) Mizuno, M.; Kanai, M.; Iida, A.;
Tomioka, K. Chiral ligand controlled enantioselective opening of
oxirane and oxetane. Tet. Asymm. 1996, 7, 2483-2484. (d) Mizuno,
M.; Kanai, M.; Iida, A.; Tomioka, K. An external chiral ligand con-
trolled enantioselective opening of oxirane and oxetane by organ-
olithiums. Tetrahedron 1997, 53, 10699-10708.
(11) Kricheldorf, H. R.; Morber, G.; Regel, W. Syntheses of alkyl
bromides from ethers and bromotrimethylsilane. Synthesis 1981,
5, 383-384.
(12) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral squaramide
derivatives are excellent hydrogen bond donor catalysts. J. Am.
Chem. Soc. 2008, 130, 14416-14417.
(13) Variability in the e.e. was observed to be catalyst-dependent
and traced to the effect of adventious water. The addition of up to
4 mol% of H2O or other protic additives had little effect on the
enantioselectivity of ring opening of 1a catalyzed by 3a (Fig. S6
entries 1 and 2, Fig. S7 entry 1), but higher loadings of protic
additives led to decreases in enantioselectivity ranging from
moderate (Fig. S6 entries 3 and 4, Fig. S7 entry 2) to significant (Fig.
S7 entry 3). The effect of catalytic amounts of HBr and the unqiue
features that allow 3a to catalyze the transformation with
consistently high levels of e.e. are the subject of ongoing study, and
will be discussed in a separate report.
(14) (a) Luh, T-Y.; Leung, M-K.; Wong, K.-T. Transition metal-cata-
lyzed activation of aliphatic C-X bonds in carbon-carbon bond for-
mation. Chem. Rev. 2000, 100, 3187-3204. (b) Netherton, M. R.; Fu,
G. C. Nickel-catalyzed cross-couplings of unactivated alkyl halides
and pseudohalides with organometallic compounds. Adv. Synth.
Catal. 2004, 346, 1525-1532. (c) Frisch, A. C.; Beller, M. Catalysts
for cross-coupling reactions with non-activated alkyl halides. An‐
gew. Chem., Int. Ed. 2004, 44, 674-688. (d) Terao, J.; Kambe, N.
Transition metal-catalyzed C-C bond formation reactions using al-
kyl halides. Bull. Chem. Soc. Jpn. 2006, 79, 663-672. (e) Cahiez, G.;
Moyeux, A. Cobalt-catalyzed cross-coupling reactions. Chem. Rev.
2010, 110, 1435-1462.
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10
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12
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14
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16
17
18
19
20
21
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24
25
26
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35
36
37
38
39
40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) Cahiez, G.; Chaboche, C.; Duplais, C.; Moyeux, A. A new efficient
catalytic system for the chemoselective cobalt-catalyzed cross-cou-
pling of aryl Grignard reagents with primary and secondary alkyl
bromides. Org. Lett. 2009, 11, 277-280.
(16) Ito, H.; Kubota, K. Copper(I)-catalyzed boryl substitution of
unactivated alkyl halides. Org. Lett. 2012, 14, 890-893.
(17) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in transition
metal (Pd,Ni,Fe)-catalyzed cross-coupling reactions using alkyl-or-
ganometallics as reaction partners. Chem. Rev. 2011, 111, 1417-
1492.
(18) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. Catalytic Asymmetric Epoxidation and Kinetic
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Resolution: Modified Procedures Including in Situ Derivatization. J.
Shaopei, C.; Keeler, E. L. Nitro-[2,1-b]imidazopyran Compounds
and Antibacterial Uses Thereof. U.S. Patent 6087358, 2000. (c)
Orita, A.; Miwa, K.; Otera, J. Integration of Solventless Reaction in a
Multi-Step Process: Application to an Efficient Synthesis of PA-824.
Adv. Synth. Catal. 2007, 349, 2136-2144. (d) Thompson, A. M.;
Blaser, A.; Anderson, R. F.; Shinde, S. S.; Franzblau, S. G.; Ma, Z.;
Denny, W. A.; Palmer, B. D. Synthesis, Reduction Potentials, and An-
titubercular Activity of Ring A/B Analogues of the Bioreductive
Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihy-
dro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J. Med. Chem. 2009,
52, 637-645. (e) Thompson, A. M.; O’Connor, P. D.; Marshall, A. J.;
Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.;
Chatelain, E.; Wan, B.; Franzblau, S. G.; Ma, Z.; Cooper, C. B.; Denny,
W. A. Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phe-
noxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A
New Lead for Visceral Leishmaniasis. J. Med. Chem. 2018, 61, 2329-
2352.
(21) The catalytic reaction was found to slow down on larger scale,
but this could be compensated for by increasing the concentration
to 0.25 M. The basis for the dependence of rate on reaction scale is
related to the effect of adventitious water noted in ref. 13 and will
be discussed fully in a separate report.
(22) The one-pot intermolecular competition experiment is the
only option that allows accurate and diagnostic determination of
the KIE in this system. For a lucid discussion of the applications of
intramolecular, one-pot, and two-pot competition KIE experiments
see: Simmons, E. M.; Hartwig, J. F. On the Interpretation of Deuter-
ium Kinetic Isotope Effects in C—H Bond Functionalizations by
Transition Metal Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066-
3072.
1
2
3
4
5
6
7
8
Am. Chem. Soc. 1987, 109, 5765-5780. (b) Hanson, R. M. The Syn-
thetic Methodology of Nonracemic Glycidol and Related 2,3-Epoxy
Alcohols. Chem. Rev. 1991, 91, 437-475. (c) Tokunaga, M.; Larrow,
J. F.; Kakiuchi, F.; Jacobsen, E. N. Asymmetric Catalysis with Water:
Efficient Kinetic Resolution of Terminal Epoxides by Means of Cat-
alytic Hydrolysis. Science 1997, 277, 936-938. (d) Furrow, M. E.;
Schaus, S. E.; Jacobsen, E. N. Practical Access to Highly Enantioen-
riched C-3 Building Blocks via Hydrolytic Kinetic Resolution. J. Org.
Chem. 1998, 63, 6776-6777. (e) Kasai, N.; Suzuki, T.; Furukawa, Y.
Chiral C3 epoxides and halohydrins: Their preparation and syn-
thetic application. J. Mol. Cat. B: Enzymatic 1998, 4, 237-252. (f)
Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K.
B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. Highly Selective Hy-
drolytic Kinetic Resolution of Terminal Epoxides Catalyzed by Chi-
ral (salen)CoIII Complexes. Practical Synthesis of Enantioenriched
Terminal Epoxides and 1,2-Diols. J. Am. Chem. Soc. 2002, 124,
1307-1315. (g) Larrow, J. F.; Hemberger, K. E.; Jasmin, S.; Kabir, H.;
Morel, P. Commercialization of the hydrolytic kinetic resolution of
racemic epoxides: toward the economical large-scale production of
enantiopure epichlorohydrin. Tet. Asymm. 2003, 14, 3589-3592.
(h) Larrow, J. F.; Quigley, P. F. Industrial Applications of the Jacob-
sen Hydrolytic Kinetic Resolution Technology. In Comprehensive
Chirality; Carreira, E. M., Yamamoto, H., Eds.; Elsevier: Amsterdam,
2012; Vol. 9, pp 129−146. (i) Singh, G. S.; Mollet, K.; D’hooghe, M.;
De Kimpe, N. Epihalohydrins in Organic Synthesis. Chem. Rev.
2013, 113, 1441-1498.
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60
(19) TB Alliance: News: FDA Approves New Treatment for Highly
Drug-Resistant Forms of Tuberculosis (August 14, 2019).
https://www.tballiance.org/news/fda-approves-new-treatment-
highly-drug-resistant-forms-tuberculosis (accessed April 11,
2020).
(23) For an example where substrate activation rather than anion
delivery is proposed to be enantiodetermining, see ref. 3b.
(20) (a) Marsini, M. A.; Reider, P. J.; Sorensen, E. J. A Concise and
Convergent Synthesis of PA-824. J. Org. Chem. 2010, 75, 7479-
7482. For other syntheses of pretomanid see: (b) Baker, W. R.;
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