Oxazole Synthesis by Sequential Asmic-Ester Condensations and Sulfanyl-Lithium Exchange-Trapping

Article abstract of DOI:10.1021/acs.orglett.1c00288

Oxazoles are rapidly assembled through a sequential deprotonation-condensation of Asmic, anisylsulfanylmethylisocyanide, with esters followed by sulfanyl-lithium exchange-trapping. Deprotonating Asmic affords a metalated isocyanide that efficiently traps esters to afford oxazoles bearing a versatile C-4 anisylsulfanyl substituent. Interchange of the anisylsulfanyl substituent is readily achieved through a first-in-class sulfur-lithium exchange-electrophilic trapping sequence whose versatility is illustrated in the three-step synthesis of the bioactive natural product streptochlorin.

Full text of DOI:10.1021/acs.orglett.1c00288

pubs.acs.org/OrgLett
Letter
Oxazole Synthesis by Sequential Asmic-Ester Condensations and
Sulfanyl−Lithium Exchange−Trapping
Louis G. Mueller, Jr., Allen Chao, Embarek Alwedi, Maanasa Natrajan, and Fraser F. Fleming*
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ABSTRACT: Oxazoles are rapidly assembled through a sequential
deprotonation−condensation of Asmic, anisylsulfanylmethylisocyanide,
with esters followed by sulfanyl−lithium exchange−trapping. Deproto-
nating Asmic affords a metalated isocyanide that efficiently traps esters to
afford oxazoles bearing a versatile C-4 anisylsulfanyl substituent.
Interchange of the anisylsulfanyl substituent is readily achieved through
a first-in-class sulfur−lithium exchange−electrophilic trapping sequence
whose versatility is illustrated in the three-step synthesis of the bioactive
natural product streptochlorin.
socyanides have a rich history as versatile precursors to
The versatile isocyanide building block Asmic (anisyl-
I
peptidomimetic pharmacophores1 and bioactive hetero-
sulfanylmethylisocyanide, 5)12 provides an attractive solution
for assembling and selectively accessing substituted oxazoles
(Scheme 2). Deprotonating Asmic (5) followed by trapping
cycles.2 The privileged status of isocyanides stems from the
carbene-like reactivity of the terminal isocyanide carbon;3 the
isocyanide carbon provides a 1,1-connection point in bond
constructions that span multicomponent reactions4 to
transition metal catalyzed insertions5 to cycloadditions.6
Isocyanide-based cycloadditions provide a concise route to
oxazoles via a highly efficient deprotonation−condensation−
cyclization sequence (Scheme 1).7 Most formal [3 + 2]
Scheme 2. Asmic-Based Synthesis of Oxazoles
Scheme 1. [3 + 2]-Isocyanide Cycloaddition Route to
Oxazoles
with esters is shown to generate anisylsulfanyl-substituted
(AnS) oxazoles 6 that engage in a first-in-class sulfur−lithium
exchange−trapping to afford C-4 substituted oxazoles 7.
Optimizing the deprotonation and condensation of Asmic
with esters proved remarkably straightforward (Scheme 3).
Lithiation13 of Asmic with BuLi followed by addition of an
ester efficiently generated a suite of aliphatic or aromatic
anisylsulfanyl-substituted oxazoles (Scheme 3, 9a−9d and 9f−
9h, respectively). Intercepting lithiated Asmic with α-methyl-γ-
butyrolactone gave the hydroxy-oxazole 9e. Trapping lithiated
Asmic with a benzyl-protected indole-3-carboxylate gave the 5-
indoyl-oxazole 9h that contains the core scaffold found in the
fungicidal pimprinine natural products.14
cycloadditions of alkylisocyanides involve deprotonation
adjacent to the isocyanide to create a formal 1,3-dipole (1
→ 2, Scheme 1).8 Nucleophilic addition of anion 2 to carbonyl
electrophiles installs an electron pair in a 1,5-relationship to the
carbenoid isocyanide carbon 3 triggering cyclization and a
series of proton transfers to generate an oxazole (3 → 4).
The isocyanide [3 + 2] cycloaddition route to oxazoles9
requires an electron-withdrawing group adjacent to the
isocyanide to enable an otherwise difficult α-deprotonation
(Scheme 1).10 The electron-withdrawing group is beneficial if
required in the target, or readily removed, but otherwise adds
steps for conversion into the types of substituents found in
bioactive oxazoles.11 A significant advance would be realized
with an exchangeable C-4 substituent (4) to overcome
processing of the vestigial electron-withdrawing group.
Exploratory forays to substitute the anisylsulfanyl group
focused on selective cleavage of the sulfur-oxazole bond in
Received: January 25, 2021
Published: February 3, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00288
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1500−1503
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a
Scheme 3. Oxazole Synthesis by Asmic-ester Condensation
Scheme 4. BH3-Promoted Sulfanyl−Lithium Exchange−
a
Trapping
a
General Procedure: A THF solution of BH3·THF (1.1−1.2 equiv)
was added to a rt, THF solution of 14 (1.0 equiv) that was, after 30−
40 min, cooled to −78 °C. BuLi (1.75−2.2 equiv) was added
followed, after 30−40 min, by the electrophile (1−2 equiv). After
warming to rt, a 1:1 mixture of EtOH and 1 M HCl was added, and
after 16 h, the crude mixture was concentrated and then extracted
with EtOAc to afford a crude material that was chromatographed to
a
General procedure: Addition of BuLi (1.05−1.1 equiv) to a −78 °C,
a
THF solution of Asmic was followed, after 5−10 min, by the neat
ester (1.1 equiv). After 1−2 h, the reaction was allowed to warm to rt,
and after 1−2 h, saturated, aqueous NH4Cl was added, to give, after
afford the pure oxazole. An exchange stannylation−protodestanny-
lation sequence afforded 11a in 95% yield.
b
workup and chromatography, the pure oxazole. 2.0 equiv of LDA
protonation of 10 afforded 11f whereas exchange−trapping
with aldehydes or carbon dioxide afforded the corresponding
oxazoles 11g−i.
The anisylsulfanyl−lithium exchange is envisaged to occur
through a chelation-assisted attack of BuLi on the BH3-
complexed oxazole (13, Scheme 5). Complexation of BuLi to
were used to deprotonate Asmic.
preference to the sulfur-anisyl bond. Raney-nickel hydro-
genolysis15 (10 → 11a) provided a route to reductively
exchange the C-4 anisylsulfanyl group (eq 1) whereas exchange
Scheme 5. Sulfanyl−Lithium Exchange Mechanism
processes via catalytic coupling16 or sulfur−lithium exchange
processes identified the latter as more promising.17 After some
optimization, a selective exchange was achieved with the TIPS-
protected oxazole 1018 as a prototype (Scheme 4); critical for
the success was complexation of the oxazole with BH3.19
Borane complexation likely reduces the electron density in the
oxazole 12 to favor a selective BuLi-initiated sulfanyl-lithium
exchange. Operationally, the sequential addition of BH3·THF,
BuLi,20 and an electrophile afforded a range of substituted
oxazoles (Scheme 4). Electrophilic bromination with
BrCl2CCCl2Br followed by addition of saturated, aqueous
NH4Cl afforded bromooxazole 11b,21 whereas a more acidic
workup with ethanolic-HCl afforded the desilylated, debory-
lated bromooxazole 11c. The iodination of 10 to afford 11d
was achieved through a highly unusual reverse lithium−iodine
exchange with iodoacetonitrile serving as the electrophilic
iodine source.22 Trapping with Bu3SnCl afforded the
stannyloxazole 11e that was isolated as the stable BH3
complex;23 an analogous reaction with Me3SnCl afforded a
stannyloxazole that was particularly susceptible to proto-
destannylation, providing oxazole 11f (95% yield) after
exposure to acetic acid. Halooxazoles and stannyl oxazoles
similar to 11b−e are used as coupling partners for the
synthesis of complex oxazoles.24 The direct exchange−
the methoxy group25 facilitates the nucleophilic attack on
sulfur to generate the sulfuranylide26 14 either as a transition
structure en route to the lithiated oxazole 15 or as the
nucleophile; no exchange occurs on similar substrates in the
absence of an o-methoxy group.27,12b Electrophilic trapping at
C-4 followed by acid-promoted deborylation affords the
oxazole 11.28
The versatility of the Asmic-addition−exchange strategy was
illustrated via a three-step synthesis of the bioactive agent
streptochlorin (Scheme 6, 18).29 Deprotonation of Asmic (5)
followed by trapping with the indole carboxylate 16 gave
oxazole 9i. TIPS protection of 9i with KHMDS and TIPSOTf
followed by sulfanyl−lithium exchange, trapping with hexa-
chlorethane, and global deprotection efficiently gave strepto-
chlorin (18).
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Scheme 6. Asmic-Exchange Synthesis of Streptochlorin
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AUTHOR INFORMATION
Corresponding Author
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Authors
Louis G. Mueller, Jr. − Department of Chemistry, Drexel
University, Philadelphia, Pennsylvania 19104, United States
Allen Chao − Wistar Institute, Philadelphia, Pennsylvania
19104, United States
Embarek Alwedi − Merck Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0002-7031-2427
Maanasa Natrajan − Department of Chemistry, Drexel
University, Philadelphia, Pennsylvania 19104, United States
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(18) Prepared by silylation of 9f; see the Supporting Information for
details.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00288
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Drexel University is gratefully acknowl-
edged as are discussions with Dr. Caleb Holyoke, Jr. (Drexel
University).
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