Enantioselective Silver-Catalyzed Cascade Synthesis of Fused Lactone and Lactam Oxazolines

Article abstract of DOI:10.1021/acs.orglett.8b02383

A new and highly stereoselective cascade reaction between isocyanoacetate esters and α-hydroxy and α-amino ketones has been developed. A cinchona alkaloid derived aminophosphine/silver(I) catalyst complex promoted the reaction and enabled the ready synthesis of fused bicyclic γ-lactone and γ-lactam oxazolines with high enantiocontrol (up to 99% ee).

Full text of DOI:10.1021/acs.orglett.8b02383

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Silver-Catalyzed Cascade Synthesis of Fused
Lactone and Lactam Oxazolines
†
́
Raquel de la Campa, Ruben Manzano, Paul Calleja, Sam R. Ellis, and Darren J. Dixon*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: A new and highly stereoselective cascade reaction between isocyanoacetate esters and α-hydroxy and α-amino
ketones has been developed. A cinchona alkaloid derived aminophosphine/silver(I) catalyst complex promoted the reaction and
enabled the ready synthesis of fused bicyclic γ-lactone and γ-lactam oxazolines with high enantiocontrol (up to 99% ee).
ascade reactions constitute an important resource
efficient tool to rapidly build complex molecular
Scheme 1. Proposed Cascade Reaction of Isocyanoacetates
and α-Hydroxy or α-Amino Ketones
C
architectures from simple starting materials while reducing
processing times and avoiding the need for isolation of
intermediate compounds.1,2 In particular, the enantioselective
synthesis of heterocycles via cascade processes has attracted
considerable interest from the synthetic community. In this
context, inspired by the seminal works of Hayashi, Ito, and
Sawamura,3 our group has developed enantioselective silver-
catalyzed reactions of isocyanoacetates with aldehydes,
ketones, and ketimines to afford enantioenriched oxazolines4
and imidazolines (Scheme 1a).5 The catalyst system, formed
from a quinine-derived aminophosphine ligand and a silver(I)
salt, is able to coordinate the isocyanoacetate and electrophile
simultaneously to promote cyclization to the corresponding
heterocycle in a highly enantiocontrolled fashion.5a Analogous
enantioselective transformations have been reported using Ag
and other metals such as Cu and Ni.6
As part of our research program into the development of
new enantioselective complexity-generating reactions, we
considered a multistage, one-pot cascade process between
isocyanoacetates and ketones possessing pendant nucleophilic
moieties, such as a hydroxy or an amino group. We envisaged
that a chiral silver/ligand complex might initially catalyze an
enantioselective aldol-type reaction which, following cycliza-
tion, would result in oxazoline formation.
At this stage, the pendant nucleophilic group would then be
positioned to react with the adjacent ester functionality to
afford fused bicyclic γ-lactone or γ-lactam oxazolines
possessing a fully substituted β-carbon atom (Scheme 1b).
Such cascade products would have the potential to be readily
converted into α-amino-β-hydroxy-γ-lactones or -γ-lactams
and, therefore, could be considered as masked polyhydroxy-
lated α-amino acids, which can be found in many biologically
active antibacterial7 and antifungal8 drugs. Although several
stereoselective syntheses of polyhydroxylated α-amino acids
and derivatives have been reported,9,10 a general enantiose-
lective synthesis of β,γ-dihydroxy-α-amino acid precursors to
date has not been realized, and herein we wish to report our
findings.
Received: July 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02383
Org. Lett. XXXX, XXX, XXX−XXX

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Preliminary studies to assess the feasibility of this cascade
concept were performed employing 2-hydroxyacetophenone
2a and methyl isocyanoacetate 3 as the model system. Building
on our previous work,4,5 a range of silver salts, aminophosphine
ligands, and other reaction parameters were investigated.
Pleasingly, under previously reported conditions (Table 1,
With the optimized conditions established, the scope of the
cascade reaction was explored using methyl isocyanoacetate 3
and a variety of 2-hydroxy ketones 2 (Scheme 2). The reaction
Scheme 2. Scope of the Enantioselective Cascade Synthesis
a
of Fused Bicyclic γ-Lactone and γ-Lactam Oxazolines
Table 1. Optimization of the Cascade Synthesis of Fused
a
Bicyclic γ-Lactone Oxazolines
d
change in
conditions
5a/6a
c
ee of 5a
(%)
b
b
entry
5a (%) 6a (%)
ratio
1
2
3
4
5
6
7
8
none
CH2Cl2
MeOH
−40 °C
0 °C
Ag2CO3
AgOAc (5 mol %)
1b
55
36
50
46
50
52
54
40
25
46
43
24
36
16
23
20
74:26
52:48
54:46
72:28
69:31
73:27
67:33
66:34
99
91
14
94
95
96
92
e
96
f
9
10
no Ag2O
no 1a
f
11
R = Et (4)
53
35 (7)
63:37
99
a
Conditions: isocyanoacetate 3 (0.35 mmol), α-hydroxy ketone 2a
(1.1 equiv), Ag2O (2.5 mol %), and ligand 1a (5 mol %) in EtOAc (2
b
mL) at −20 °C for 16 h. Yield of isolated product after flash column
c
1
chromatography. Ratio of 5a and 6a was determined by H analysis
d
of the crude reaction mixture Enantiomeric excess of 5a was
determined by HPLC analysis on a chiral stationary phase.
e
f
Enantiomeric product (3aS,6aR)-5a was formed. No reaction.
entry 1) employing Ag2O and the quinine-derived amino-
phosphine ligand 1a, the cis-fused bicyclic γ-lactone oxazoline
(3aR,6aS)-5a was formed as the major product in good yield
with excellent enantioselectivity (99% ee). In addition,
monocyclic oxazoline 6a was isolated as a minor reaction
side product.11 EtOAc proved to be optimal as the solvent,
with lower yields and enantioselectivities being obtained in
other solvents (entries 2 and 3), while changing the
temperature (entries 4 and 5) or silver salt (entries 6 and 7)
offered no improvement. Importantly, use of the pseudoe-
nantiomeric aminophosphine ligand 1b led to formation of the
enantiomeric product (3aS,6aR)-5a with excellent enantiose-
lectivity (96% ee, entry 8). Control reactions demonstrated
that both Ag2O and the aminophosphine ligand were required,
as no reaction occurred in their absence (entries 9 and 10
respectively). The reaction performed similarly well using ethyl
isocyanoacetate 4, with the product being formed in
comparable yield and enantioselectivity (99% ee, entry 11)
to the reaction with 3.
a
Conditions: methyl isocyanoacetate 3 (0.35 mmol), α-hydroxy
ketone 2 (1.1 equiv), Ag2O (2.5 mol %), and ligand 1a (5 mol %) in
EtOAc (2 mL) at −20 °C. Yields given are of isolated product after
flash column chromatography. 5/6 ratios were determined by 1H
NMR analysis of the crude reaction mixture. Enantiomeric excess of 5
was determined by HPLC analysis on a chiral stationary phase. Values
in parentheses represent the reaction with ligand 1b generating the
b
enantiomeric product. AgOAc (5 mol %) and 1a (10 mol %) were
used.
proceeded with several para-substituted 2-hydroxyacetophe-
nones possessing either electron-withdrawing or -donating
groups, 2b−d, and the corresponding fused γ-lactone oxazo-
lines (5b−d) were obtained as the major products with good
product selectivity (5/6 ratio) and excellent enantioselectiv-
ities (97−99% ee). The use of meta-substituted 2-hydrox-
yacetophenone 2e afforded the bicyclic product 5e with similar
B
DOI: 10.1021/acs.orglett.8b02383
Org. Lett. XXXX, XXX, XXX−XXX

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levels of enantiocontrol as compared to 5d. Importantly, the
use of ortho-substituted 2-hydroxyacetophenones 2f−i was
well-tolerated, and bicyclic oxazolines 5f−i were obtained with
higher product selectivity (90:10 to 96:4) and yield compared
to their corresponding meta or para equivalents. The products
were also obtained with excellent enantioselectivity (90−99%
ee).
1-Acetonaphthone derivative 2j was an excellent substrate
and afforded the cis-fused γ-lactone oxazoline 5j with excellent
product selectivity (>98:2) and with good enantioselectivity.
Heteroaromatic ketone 2k also engaged in this reaction,
affording oxazoline 5k with good enantioselectivity, albeit with
minimal diastereocontrol in the initial aldol reaction.
Interestingly, sterically hindered alcohols such as the tertiary
alcohol 2l performed well, with 5l being obtained with
excellent enantioselectivity. The reaction could be readily
extended to obtain bicyclic lactams, with the corresponding cis-
fused γ-lactam oxazoline product (5m) being obtained from
the aniline-derived acetophenone 2m with good enantiocon-
trol. In addition, enantiomeric products of 5a−m could be
prepared by employing pseudoenantiomeric aminophosphine
ligand 1b with similar (albeit reduced) yields and enantiose-
lectivities in most cases.
The absolute configuration of product 5g (obtained using
ligand 1a) was established by single-crystal X-ray diffraction
analysis12 and was in agreement with previous observations;5a
other products were assigned by analogy.
The absolute configuration of monocyclic oxazolines 6 was
assigned by chemical correlation; treatment of 6e and ent-6e
with DBU afforded bicyclic oxazolines 5e and ent-5e in 10%
and 6% ee, respectively, presumably through epimerization
adjacent to the ester and concomitant cyclization. See the
Supporting Information for further details.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02383.
■
S
All experimental details, copies of NMR spectra, and
HPLC data (PDF)
Accession Codes
CCDC 1542388 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
*E-mail: darren.dixon@chem.ox.ac.uk.
ORCID
́
Ruben Manzano: 0000-0001-7290-3979
Sam R. Ellis: 0000-0003-1412-113X
Darren J. Dixon: 0000-0003-2456-5236
Present Address
†(R.M.) Department of Organic Chemistry II, University of
the Basque Country (UPV/EHU), P.O. Box 644, 48080
Bilbao, Spain.
Notes
The authors declare no competing financial interest.
The versatility of the fused γ-lactone oxazoline bicyclic
products was demonstrated by subjecting 5d to acidic
methanolic conditions, which afforded functionally dense and
stereochemically defined α-amino-β-hydroxy-γ-lactone 8 with-
out erosion of enantiopurity (Scheme 3).
ACKNOWLEDGMENTS
■
The authors thank the EC for IEFs to R.C. (PIEF-GA-2012-
329689) and to R.M. (PIEF-GA-2013-627232). S.R.E. is
supported by the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1),
generously supported by AstraZeneca, Diamond Light Source,
Defence Science and Technology Laboratory, Evotec, Glax-
oSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda,
Scheme 3. Application to the Synthesis of α-Amino-β-
Hydroxy-γ-Lactones
́
UCB, and Vertex. We thank Dr. Angel Fuentes and Heyao
Shi (University of Oxford) for X-ray structure determination
and Dr. Amber L. Thompson and Dr. Kirsten E. Christensen
(Oxford Chemical Crystallography Service) for X-ray mentor-
ing and help.
REFERENCES
■
In summary, we have developed a highly enantioselective
synthesis of fused γ-lactone and γ-lactam oxazolines from
isocyanoacetate pronucleophiles and α-hydroxy or α-amino
ketones, respectively. One carbon−carbon bond, two carbon−
heteroatom bonds, and two stereogenic centers of the bicyclic
product were created through a cascade reaction employing a
silver(I)/aminophosphine catalyst system. Application to the
synthesis of α-amino-β-hydroxy-γ-lactones was also demon-
strated. Work to apply these findings to other enantioselective
cascade reactions is ongoing in our laboratory, and the results
will be disclosed in due course.
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DOI: 10.1021/acs.orglett.8b02383
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DOI: 10.1021/acs.orglett.8b02383
Org. Lett. XXXX, XXX, XXX−XXX