Ring-Strain-Enabled Catalytic Asymmetric Umpolung C-O Bond-Forming Reactions of 1,2-Oxazetidines for the Synthesis of Functionalized Chiral Ethers

Article abstract of DOI:10.1021/acs.orglett.0c01916

An unprecedented catalytic asymmetric umpolung C-O bond-forming reaction of N-nosyl 1,2-oxazetidines with β-keto esters has been achieved in the presence of a chiral phase-transfer catalyst, allowing access to a range of highly functionalized chiral ethers bearing quaternary and no adjacent stereogenic centers with high yields, excellent enantioselectivities, and diastereoselectivities (up to 97percent ee and 20:1 dr). These versatile products could be flexibly transformed into biologically important chiral fused and spiro morpholines in two steps.

Full text of DOI:10.1021/acs.orglett.0c01916

pubs.acs.org/OrgLett
Letter
Ring-Strain-Enabled Catalytic Asymmetric Umpolung C−O Bond-
Forming Reactions of 1,2-Oxazetidines for the Synthesis of
Functionalized Chiral Ethers
Binyu Wu, Jinggang Yang, Min Gao, and Lin Hu*
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ABSTRACT: An unprecedented catalytic asymmetric umpolung
C−O bond-forming reaction of N-nosyl 1,2-oxazetidines with β-
keto esters has been achieved in the presence of a chiral phase-
transfer catalyst, allowing access to a range of highly functionalized
chiral ethers bearing quaternary and no adjacent stereogenic
centers with high yields, excellent enantioselectivities, and
diastereoselectivities (up to 97% ee and 20:1 dr). These versatile
products could be flexibly transformed into biologically important
chiral fused and spiro morpholines in two steps.
We are interested in the synthetic chemistry of 1,2-
mall strained ring compounds have emerged as versatile
Sbuilding blocks for chemical synthesis due to their intrinsic oxazetidines because these small strained compounds are also
easily accessible, highly reactive, and yet sufficiently stable.7−9
More impressively, they could function as an unusual oxygen
high energies that could be harnessed to create a large
spectrum of synthetically important transformations.1 For
reagent. The N−O bond in this compressed four-membered
structure is remarkably distorted and polarized, rendering the
oxygen atom electrophilic toward the carbon nucleophiles.
Therefore, functionalized N,O-containing ether compounds
could be accessed from these reagents via an unconventional
umpolung C−O bond-forming strategy. Traditionally, ethers
were overwhelmingly constructed via C−O bond-forming
reactions of nucleophilic oxygens with electrophilic carbon
centers. In contrast, formation of the C−O bonds from the
corresponding carbon nucleophiles and electrophilic oxygen
reagents has received much less attention (Scheme 1b).10 In
particular, an asymmetric catalytic umpolung C−O bond-
forming reaction for the synthesis of chiral ether compounds
has not been reported yet.11
Herein, we report an unprecedented catalytic asymmetric α-
alkoxylation reaction of β-keto esters with N-nosyl 1,2-
oxazetidines in the presence of a chiral phase-transfer catalyst,
allowing access to a range of chiral ether products bearing
quaternary and no adjacent stereogenic carbon centers with
high yields, excellent enantioselectivities (up to 97% ee), and
diastereoselectivities (>20:1 dr) under mild conditions
instance, the well-established ring-opening reactions of cyclo-
propanes,2 cyclobutanes,3 oxiranes,1e oxetanes,1f and oxazir-
idines1g as well as their catalytic asymmetric variants4 are the
representative examples of the strain-enabled transformations
in chemical synthesis. On the other hand, the heterocyclic 1,2-
oxazetidines are also structurally unique, featured in nitrogen
and oxygen atoms within a compact four-membered ring.
According to the calculation results, their ring strain energy
(25.2 kcal/mol)5 is even higher than that of the three-
membered oxaziridine analogues (22.9 kcal/mol)6 (Scheme
1a). Surprisingly, compared to the well-documented chemistry
of oxaziridines, the reaction profiles of these four-membered
homologues have been rarely investigated. To the best of our
knowledge, only three isolated examples have been reported to
date.7 In 2015, the group of Bode7a utilized the chiral N-Fmoc-
protected 1,2-oxazetidine amino acid as a powerful serine-
forming ligation reagent for the chemical synthesis of complex
peptides (up to 100 residues). Meanwhile, in 2015, Orentas7b
also reported that N-tosyl or Boc-protected 1,2-oxazetidines
could react with aryl organometallic reagents to form a series of
functionalized ether products via distinctive bond disconnec-
tions. Quite recently, Loh7c reported that N-tosyl-protected
1,2-oxazetidine was able to participate in the cobalt-catalyzed
C−C bond cleavage and concomitant C−H activation
reactions with heteroarenes to afford various aminomethylated
and hydroxymethylated products. These elegant examples
indicate that 1,2-oxazetidines are highly valuable synthons and
potentially the rich source for the discovery of new reactions.
Received: June 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01916
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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Scheme 1. Background and Our Research Synopsis
(Scheme 1c). Moreover, these versatile products could be
flexibly transferred into structurally diverse chiral-fused
morpholines and spiro morpholin-3-ones in two steps. Such
heterocyclic scaffolds are prevalent in many biologically
important natural products and drugs.12
Table 1. Optimization of the Catalytic C−O Bond-forming
a
Reaction Conditions
We commenced our investigation by selecting tert-butyl
indanone carboxylate 1a and N-Boc 1,2-oxazetidine 2a as the
model substrates for the ring-opening reaction. Unfortunately,
no reaction occurred under various organic base and phase-
transfer catalyst conditions (Table 1, entries 1−3). This was
probably due to the low reactivity of 2a. Then, 1,2-oxazetidine
2b bearing a more electron-withdrawing Ts group on nitrogen
was evaluated for the ring-opening reaction; however, the
desired C−O bond-forming product 3 was produced with low
yield under phase-transfer catalytic conditions (Table 1, entries
4 and 5). To further improve the reaction, N-nosyl 1,2-
oxazetidine 2c was next examined. This compound was more
reactive but more prone to decompose under strong basic
conditions. Only a trace amount of 3a was detected when
subjecting 2c and 1a to the KOH and TBAB catalytic
conditions. Interestingly, the reaction still proceeded efficiently
under the less basic Na2CO3 condition, and the yield of the 3a
was improved to 32%. However, a significant amount of an
unexpected side product 4 was also isolated as a major product
(Table 1, entries 6 and 7). Apparently, development of a
catalytic C−O bond-forming reaction of N-protected 1,2-
oxazetidine is a formidable challenge, which confronts not only
the reactivity and but also the chemoselectivity issues.
a
Reaction conditions: 1a (0.12 mmol), 2 (0.1 mmol), catalyst (10
mol %), and base (0.2 mmol, if required) in indicated solvent and at
indicated temperature. Determined by H NMR analysis. Isolated
yield. Determined by HPLC analysis.
b
c
1
d
In spite of the low chemoselectivity obtained from the
reaction of compound 2c, its higher reactivity encouraged us to
further explore the ring-opening reaction of this compound
with 1a under chiral phase-transfer catalyst conditions.13 To
our surprise and delight, in the presence of chiral catalyst 5a
and weak base Na2CO3, the reaction between 2c and 1a
selectively provided the target compound 3a as major product
in 59% yield and 49% ee. Although the chemoselectivity was
still not satisfactory (3a/4a = 2.5:1), the major product from
this reaction was strikingly reversed for the first time. More
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importantly, when the temperature was decreased to 0 °C, the
chemo- and enantioselectivities of the reaction were further
improved to 5:1 and 56% ee, respectively (Table 1, entries 8−
10). At this stage, other cinchona alkaloid-derived phase-
transfer catalysts were then screened. Catalysts 5b−g with
increased conformational rigidity steadily improved chemo-
and enantioselectivities as well as the yield of the reaction
(Table 1, entries 11−16). Upon further optimization, we
finally identified a conformationally more rigid catalyst 5h,
which successfully catalyzed the reaction of 1a and 2c with
good yield (80%), excellent chemeoselectivity (>20:1), and
enantioselectivity (93% ee) at 0 °C (Table 1, entry 17). The
absolute configuration of product 3a was confirmed to be S
based on the X-ray crystallographic analysis, and a plausible
model of the transition state to explain the stereochemical
outcome was proposed (see the Supporting Information for
details).
ee, regardless of the electronic and steric properties of these
substituents (Table 2, 3a−l). Substrate 1j bearing a strongly
electron-donating N,N-dimethylamino group, which was
normally sensitive under oxidative reaction conditions, was
compatible with current conditions and provided product 3j in
67% yield and 96% ee. Owing to the lower acidic α-proton in
this substrate, a stronger base Cs2CO3 had to be used to
promote the C−O bond-forming reaction with 2c. Meanwhile,
substrates 1k−l bearing strongly electron-withdrawing groups
also engaged in the ring-opening reactions well and afforded
products 3k−l in 90% ee. Moreover, substrates bearing
different 4- and 6-substituents on the phenyl ring also
consistently afforded the ether products with more than 90%
ee (Table 2, 3m−t). Interestingly, when installing the N,N-
dimethylamino group at the 4- or 6-position on the phenyl
ring, substrates 1o and 1t still underwent the C−O bond-
forming reactions very well using weaker Na2CO3 as the base
and provided yields and enantioselectivities even higher than
those of the other substrates (Table 2, 3o and 3t).
Furthermore, substrates with naphthalene and a heteroar-
omatic framework were also well-tolerated under the current
catalytic system and gave excellent results in terms of chemical
yields and enantioselectivities (Table 2, 3u,v).
With optimal reaction conditions in hand, the scope of the
reaction was then evaluated. As summarized in Table 2, this
a
Table 2. Substrate Scope for Reactions of 1 with 2c
We also tested other nucleophiles for the reaction (Table 2,
3w−y). Replacing the tert-butyl with a smaller ethyl group in
indanone carboxylate dramatically reduced the enantioselec-
tivity of the reaction (93% ee for 3a vs 73% ee for 3w),
whereas no reaction happened when using simple tert-butyl
cyclopentanone carboxylate as the nucleophile. However, the
cyanoacetate substrate was still reactive under the standard
conditions, giving product 3y in 65% yield and 21% ee.
We are interested in extending of the scope of the new
reaction to the substituted N-nosyl 1,2-oxazetidines, which will
allow the synthesis of the challenging N,O-containing chiral
ether products possessing multiple and no adjacent stereogenic
carbon centers. However, we are uncertain whether the
substituted N-nosyl 1,2-oxazetidines with different absolute
configurations could be compatible with the above catalytic
systems, as matched and mismatched relationships between
the catalyst and chiral substrates often encountered in many
catalytic reactions.
To examine the tolerance of the chiral four-membered
substrates, N-nosyl 3-methyl 1,2-oxazetidines (R)-6a and (S)-
6a were individually treated with 1a in the presence of 10 mol
% of 5h under the standard conditions. To our delight, both
reactions smoothly offered the desired products 7a and 7b
with good yields and excellent diastereoselectivities (20:1 dr,
Table 3). Similarly, chiral 1,2-oxazetidines (R)-6b and (S)-6b
bearing a hindered 3-isopropyl substituent were also tolerated
and produced products 7c and 7d with good yields and
excellent diastereoselectivities (20:1 dr). Our further explora-
tion revealed that this diastereoselective catalytic reaction was
quite general. Both enantiomers of a scope of chiral 3-alkyl- or
3-aryl-substituted N-nosyl 1,2-oxazetidines were all well-
tolerated, uniformly affording the stereodivergent ether
products with high diastereoselectivities. For comparison,
achiral catalyst TBAB only afforded the products with very
low diastereoselectivities (Table 3, 7a−j).
a
Reaction conditions: 1 (0.24 mmol), 2c (0.2 mmol), 5h (10 mol %),
and 20% aq Na2CO3 (0.4 mmol) in toluene (2 mL) at 0 °C for 72 h.
b
The absolute configuration of 3a was determined to be the S; see the
c
Supporting Information for details. 1.0 equiv of 50% aq Cs2CO3 was
used. Reaction was carried out at room temperature. Reaction was
run for 7 days.
d
e
new reaction was quite general. A range of highly function-
alized N,O-containing chiral ether compounds could be
smoothly constructed in good to excellent yields and excellent
enantioselectivities (55−96% and 90−97% ee). Substrates
bearing various 5-substituted groups on the phenyl ring
uneventfully afforded the ether products with more than 90%
In addition, due to the disfavored steric hindrance, C4-
substituted substrates such as N-nosyl 4-phenyl 1,2-oxazeti-
dines (R)-6f and (S)-6f were considered to be challenging for
this reaction. However, by slightly modifying the reaction
conditions to stronger K3PO4 base, these compounds were still
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Table 3. Substrate Scope for the Reactions of 1a with 1,2-
Oxazetidines 6
Scheme 3. Synthetic Applications of Compound 3a
a b
,
>20:1), respectively. Notably, the former provided a cis-fused
morpholine skeleton, whereas the latter afforded a trans one.
Both of their relative stereochemistries were unambiguously
confirmed by the nuclear Overhauser effect or X-ray
crystallographic analysis. It should also be noted that the
stereochemically complex tricyclic compound 10 bearing two
adjacent quaternary carbon centers is a challenging structural
motif, which has never been previously prepared. On the other
hand, the ester functionality in compound 3a could also be
utilized for the construction of chiral spiro morpholine
skeletons. Accordingly, 3a was smoothly transformed into
spiro morpholin-3-one 11 in 50% overall yield and 92% ee
after two simple steps of reductive cyclization and oxidation
operations. Collectively, structurally diverse chiral morpholines
could be readily accessed from 1,2-oxazetidines in three steps.
In conclusion, we have developed an unprecedented highly
enantio- and diastereoselective catalytic ring-opening reaction
of N-nosyl 1,2-oxazetidines with indanone carboxylates in the
presence of a chiral phase-transfer catalyst. Enabled by the
unique electrophilic oxygen reactivity of 1,2-oxazetidines, a
wide range of a highly functionalized N,O-containing chiral
ether compounds bearing quaternary and no adjacent
stereogenic carbon centers, which are difficult to access from
conventional approaches,16 could be effectively constructed
with high yields and stereoselectivities (up to 97% ee and 20:1
dr) from the current catalytic asymmetric umpolung reactions.
Additionally, synthetic utility of these versatile products has
also been demonstrated by the concise synthesis of structurally
diverse chiral-fused and spiro morpholine skeletons in two
steps. Further applications of such unique strained reagents to
other transformations will be reported in due course.
a
Conditions: 1a (0.24 mmol), 6 (0.2 mmol), 5h or TBAB (10 mol
%), and 20% aq Na2CO3 (0.4 mmol) in toluene (2 mL) at 0 °C for 72
b
c
1
h. Value of dr was determined by H NMR analysis. The absolute
configuration of 7f was determined to be (S,S); see the Supporting
Information for details. 2.0 equiv of 50% aq K3PO4 was used.
d
able to offer the products 7k and 7l with 4:1 and 5:1 dr,
respectively (Table 3, 7k−l). It should be noted that such
hindered chiral ether products bearing two adjacent quaternary
and tertiary carbons are normally difficult to prepare from
conventional methods.14
To explore the practicality of the newly developed
transformation, a gram-scale reaction between 1a and 2c was
carried out under the standard conditions. By reducing the
catalyst loading to 5 mol %, the reaction still performed well on
a 5 mmol scale and afforded 1.7 g of product 3a in 71% yield
and 93% ee (Scheme 2).
Scheme 2. Gram-Scale Synthesis of Compound 3a
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01916.
To demonstrate the synthetic utility of the functionalized
ether products, we carried out the asymmetric synthesis of the
structurally diverse chiral morpholines.15 We envision that the
terminal amino and two different carbonyl functionalities in
compound 3a provide convenient handles for the rapid
construction of this class of heterocycles. As shown in Scheme
3, 3a was converted into the tricyclic compound 8 with 95%
yield and 93% ee via a one-step deprotection of the nosyl
group and a simultaneous cyclization process. Then, this
versatile imine intermediate could stereoselectively react with
NaBH3CN and alkynyl lithium reagents to give chiral
morpholines 9 and 10 with high diastereoselectivities (dr
Experimental procedures and characterization data for
all of the products (PDF)
Accession Codes
CCDC 1949872−1949874 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
D
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Yu, S.-J.; Kong, L.-H.; Li, X.-W. Rhodium(III)-Catalyzed Coupling of
Arenes with Cyclopropanols via C−H Activation and Ring Opening.
ACS Catal. 2016, 6, 647−651. (e) Davis, D. C.; Walker, K. L.; Hu, C.;
Zare, R. N.; Waymouth, R. M.; Dai, M. Catalytic Carbonylative
Spirolactonization of Hydroxycyclopropanols. J. Am. Chem. Soc. 2016,
138, 10693−10699.
AUTHOR INFORMATION
■
Corresponding Author
Lin Hu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical Sciences,
Chongqing University, Chongqing 401331, P.R. China;
orcid.org/0000-0002-8600-965X; Email: lhu@cqu.edu.cn
(3) For representative examples, see: (a) Murakami, M.; Amii, H.;
Ito, Y. Selective Activation of Carbon−Carbon Bonds Next to a
Carbonyl Group. Nature 1994, 370, 540−541. (b) Murakami, M.;
Ashida, S.; Matsuda, T. Eight-Membered Ring Construction by [4 + 2
+ 2] Annulation Involving β-Carbon Elimination. J. Am. Chem. Soc.
2006, 128, 2166−2167. (c) Ishida, N.; Ikemoto, W.; Murakami, M.
Cleavage of C−C and C−Si σ-Bonds and Their Intramolecular
Exchange. J. Am. Chem. Soc. 2014, 136, 5912−5915. (d) Seiser, T.;
Cramer, N. Rhodium-Catalyzed C−C Bond Cleavage: Construction
of Acyclic Methyl Substituted Quaternary Stereogenic Centers. J. Am.
Chem. Soc. 2010, 132, 5340−5342. (e) Ko, H.-M.; Dong, G.
Cooperative Activation of Cyclobutanones and Olefins Leads to
Bridged Ring Systems by a Catalytic [4 + 2] Coupling. Nat. Chem.
2014, 6, 739−744. (f) Zhou, X.; Dong, G. (4 + 1) vs (4 + 2):
Catalytic Intramolecular Coupling between Cyclobutanones and
Trisubstituted Allenes via C−C Activation. J. Am. Chem. Soc. 2015,
137, 13715−13721.
Authors
Binyu Wu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P.R. China
Jinggang Yang − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P.R. China
Min Gao − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, School of Pharmaceutical
Sciences, Chongqing University, Chongqing 401331, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01916
Notes
(4) For representative examples, see: (a) Pohlhaus, P. D.; Johnson, J.
S. Enantiospecific Sn(II)- and Sn(IV)-Catalyzed Cycloadditions of
Aldehydes and Donor-Acceptor Cyclopropanes. J. Am. Chem. Soc.
2005, 127, 16014−16015. (b) Parsons, A. T.; Johnson, J. S. Catalytic
Enantioselective Synthesis of Tetrahydrofurans: A Dynamic Kinetic
Asymmetric [3 + 2] Cycloaddition of Racemic Cyclopropanes and
Aldehydes. J. Am. Chem. Soc. 2009, 131, 3122−3123. (c) Seiser, T.;
Cramer, N. Enantioselective C−C Bond Activation of Allenyl
Cyclobutanes: Access to Cyclohexenones with Quaternary Stereo-
genic Centers. Angew. Chem., Int. Ed. 2008, 47, 9294−9297.
(d) Zhang, Q.-W.; Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.; Zhao, Y.-M.;
Gu, P.; Chen, Z.-M. Brønsted Acid Catalyzed Enantioselective
Semipinacol Rearrangement for the Synthesis of Chiral Spiroethers.
Angew. Chem., Int. Ed. 2009, 48, 8572−8574. (e) Zhang, E.; Fan, C.-
A.; Tu, Y.-Q.; Zhang, F.-M.; Song, Y.-L. Organocatalytic Asymmetric
Vinylogous α-Ketol Rearrangement: Enantioselective Construction of
Chiral All-Carbon Quaternary Stereocenters in Spirocyclic Diketones
via Semipinacol-Type 1,2-Carbon Migration. J. Am. Chem. Soc. 2009,
131, 14626−14627.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from NSFC (21871032),
Fundamental Research Funds for the Central Universities
(2018CDQYYX0041), Chongqing Research Program of Basic
Research and Frontier Technology (cstc2017jcyjAX0375), and
Venture & Innovation Support Program for Chongqing
Overseas Returnees (cx2017013).
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