Enantioselective Synthesis of Quaternary Δ4- and Δ5-Dehydroprolines Based on a Two-Step Formal [3+2] Cycloaddition of α-Aryl and α-Alkyl Isocyano(thio)acetates with Vinyl Ketones

Article abstract of DOI:10.1002/chem.201703526

A divergent synthesis of optically active quaternary Δ⁴- and Δ⁵-dehydro prolines is developed based on the first catalytic enantioselective conjugate addition of α-substituted isocyano(thio)acetates to vinyl ketones that is general for both α-aryl and α-alkyl isocyano(thio)acetates. The new tetrasubstituted C?N stereocenter is formed without the need of any metal salt due to a bifunctional tertiary amine/squaramide catalyst, featuring a bulky polyaryl sidearm and an unusually short squaramide diamide H???H interatomic distance in the solid state.

Full text of DOI:10.1002/chem.201703526

A Journal of
Accepted Article
Title: Enantioselective Synthesis of Quaternary Δ4- and Δ5-
Dehydroprolines Based on a Two-Step Formal [3+2]
Cycloaddition of α-Aryl and α-Alkyl Isocyano(thio)acetates with
Vinyl Ketones
Authors: Amaiur Odriozola, Mikel Oiarbide, and Claudio Palomo
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To be cited as: Chem. Eur. J. 10.1002/chem.201703526
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Enantioselective Synthesis of Quaternary 4- and 5-
Dehydroprolines Based on a Two-Step Formal [3+2]
Cycloaddition of -Aryl and -Alkyl Isocyano(thio)acetates with
Vinyl Ketones
Amaiur Odriozola, Mikel Oiarbide and Claudio Palomo*
Dedication ((optional))
Abstract: A divergent synthesis of optically active quaternary both
4- and 5-dehydro prolines is developed based on the first catalytic
enantioselective
conjugate
addition
of
-substituted
isocyano(thio)acetates to vinyl ketones that is general for both-aryl
and -alkyl isocyano(thio)acetates. The new tetrasubstituted C–N
stereocenter is formed without the need of any metal salt by the
action of a bifunctional tertiary amine/squaramide catalyst featuring a
bulky polyaryl sidearm and an unusually short squaramide diamide
H–H interatomic distance in the solid state.
The -carboxy-pyrrolidine units, generically referred to as
prolines, are widespread within natural products and biologically
active substances and bear considerable interest in peptide
chemistry.[1] In this context, -substituted (quaternary) prolines
constitute a particularly relevant subclass owing to their unique
structural biases and much attention has been paid to their
stereoselective synthesis.[2] One major, thoroughly investigated
convergent approach to the enantioselective synthesis of these
heterocyclic systems relies on the catalytic [3+2] cycloaddition
reaction between azomethine ylides and electrondeficient olefins
(Figure 1a, left).[3] In contrast, the catalyst-controlled formal [3+2]
cycloaddition involving -isocyanoacetates and olefins (Scheme
1a, right), which also affords the pyrrolidine system through
concomitant formation of the N–C2 and C4-C5 bonds, has been
much less developed.[4] Most studies on catalytic
enantioselective cycloadditions of -isocyanoacetates involve
very reactive olefins, such as maleimides,[5] nitroalkenes,[6] -
unsaturated -keto esters,[7] methyleneindolinones[8] and
allenoates,[9] and require, with a few exceptions,[6,8] combined
metal/Brønsted base catalysis. Generalization of this type of
cooperative catalysis is often hampered by the problem of Lewis
acid/amine base self-quenching, which leads to catalyst
deactivation and deleterious reaction stereocontrol, especially
during formation of quaternary stereocenters.[10] In this context, a
sole example of cycloaddition involving simple vinyl ketones as
the reaction partner has been reported so far, affording the
corresponding dehydroproline adducts with moderate (52–74%
ee, R= H) or poor (36% ee, R= Me, Et) enantioselectivity.[11]
Scheme 1. Convergent approaches to enantioenriched quaternary proline
derivatives.
We were intrigued by the possibility of triggering the -
isocyanoacetate-olefin addition reaction through an alternative
organocatalytic activation mode whereby the bifunctional
catalyst would activate both the donor and acceptor reaction
components in a manner similar to that assumed for the metal-
mediated process (model II vs. I, Figure 1). Eventually, the
absence of
a metal catalyst might also slow down the
subsequent intramolecular cyclization step[12] (III) thus allowing
-protonation to occur preferentially (IV) leading to adduct A.
Upon these assumptions, a divergent access to 4,5- and 1,5-
dehydroprolines B and C from the common intermediate A
would be conceivable (Scheme 1c), resulting in a substantial
enlargement of product scope. The challenge here is to perform
the 1,4-addition reaction leading to A efficiently and with good
enantiocontrol.[13] Indeed, the relatively low carbon acidity of
most -substituted isocyanoacetates has caused that catalytic
conjugate additions have been carried out with highly reactive
acceptors only,[14] remaining the conjugate addition to simple
vinyl ketones undocumented so far. Another serious limitation in
scope concerns the isocyanoacetate component, with
[a]
Prof. C. Palomo, Prof. M. Oiarbide, A. Odriozola
Departamento de Química Orgánica I
Universidad del País Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastián, Spain
Fax: (+34) 943015270
E-mail: claudio.palomo@ehu.es
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201703526
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in the presence (10 mol%) of a selection of benchmark
bifunctional Brønsted base organocatalysts.[17] From this initial
screening,[18] the known catalyst C1[19] proved to be superior in
terms of reaction conversion and enantioselectivity. As shown in
Table 1, attempts to improve the result using catalysts C2, which
has proven to be effective in difficult to control stereoselective
reactions,[20] were unfruitful giving adduct 3Aa in good yield but a
poor 56% ee. We then decided to explore the more sterically
demanding gem-diaryl catalysts C3, C4 and C5, and the
gem,gem-(bis)diaryl congener C6, which could be easily
prepared through modification of the meta mono- and diester
group(s) of the aniline fragment via Grignard technology.18 We
presumed that the bulky polyaryl moiety near the squaramide
Figure 1. Idealized dual activation modes (left) and reaction pathways (right)
in the presence or absence of a metal.
essentially all asymmetric organocatalytic reactions hitherto
reported dealing with -aryl substituted isocyanoacetates.[15]
Besides these deficiencies, another significant challenge
concerns the control of stereochemistry during the generation of
the quaternary carbon center.[16] Herein we report the first
enantioselective conjugate addition of both -aryl and-alkyl
isocyano(thio)acetates to vinyl ketones enabled by bifunctional
Brønsted base catalysts, ultimately resulting in a new approach
to enantioenriched quaternary dehydroproline products of type B
and C.
framework might prevent catalyst self-aggregation,
a
phenomenon that affects hydrogen-bond accepting substrate
recognition.21 Gratifyingly, each catalyst provided clean reaction
with essentially complete conversion, while the highest
selectivities were obtained with the bulkiest catalysts C5 and C6
(92% and 95% ee, respectively). In this respect, the X-ray
structure analysis data of crystallized C6 are worth of mention.
The interatomic diamide H…H distance in C6 is unusually short
(2.446 Å) as compared with the typical values previously
reported for related squaramide catalysts (2.85 Å[19c, 21]), and
get closer to that found for the parent thiosquaramides.[22] On the
other hand, squaramide units in the solid structure of C6 do not
self-aggregate through dual hydrogen bonding as is generally
assumed. Instead, both N―H bonds of each squaramide unit
point toward the quinoline nitrogen of a contiguous molecule.[18]
It is likely that these features, probably induced by the bulky
polyaryl sidearm in C6, would also prevail in solution and impact
the catalytic behaviour. For comparison, catalyst C7[23] was also
tested, resulting in lower reactivity and efficiency (14 h, 80%
conversion, 74% ee) probably due to its lower solubility. Further
experiments involving 1A and catalyst C6 showed that the
stereochemical outcome of the reaction appears to be
independent of the enone partner. As data in Table 2 show, both
Table 1. Reaction of -cyanoacetates 1 with enones 2 and catalyst screening
for the reaction of 1A with 2a to give 3Aa.[a]
Table 2. Scope of the conjugate addition of 1 to vinyl ketones 2 catalyzed by
C6.[a]
[a] Reactions conducted on a 0.1 mmol scale in 0.2 mL CH2Cl2 (molar ratio
of 1A/2a/catalyst 1:2:0.1). Data refer to reaction conversion at 14 h unless
otherwise specified. Ee´s determined by chiral HPLC.
[a] Reactions conducted on a 0.2 mmol scale in 0.4 mL CH2Cl2 (molar ratio of
1/2/catalyst 1:2:0.05) at room temperature, unless otherwise stated. Yields of
isolated product after column chromatography. Enantioselectivity determined
by chiral HPLC. [b] 2 mol% of C6 used (reaction run for 36 h).
The investigation was initiated by studying the reaction of -
phenyl tert-butyl isocyanoacetate 1A with methyl vinyl ketone 2a
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alkyl- and aryl-vinyl ketones 2a–f upon reaction with 1A provided
adducts 3Aa–f with good isolated yields and ee’s up to 98%.
The reaction also worked quite well with respect the
isocyanoacetate component. Thus, each 1B, 1C and 1D reacted
with the corresponding vinyl enone 2 to give products 3Be, 3Ca,
3Cd, and 3Dd with yields within the 80–90% range and ee
values greater than 96%. Nonetheless, o-substituted aryl
isocyanoacetates 1E/1F as well as alkyl isocyanoacetates
were not competent reaction partners. On the other hand,
methyl acrylate, a less reactive Michael acceptor as compared
to vinyl ketones, was not effective in this reaction regardless the
catalyst employed. However, reactions of '-hydroxy enone 2g,
an acrylate surrogate recently introduced by us,[24] with 1A–D
proceeded smoothly to give the corresponding adducts 3Ag,
3Bg, 3Cg and 3Dg in good yields and excellent
enantioselectivity. For these reactions a 5 mol% catalyst loading
was systematically employed, although both selectivity and yield
remained essentially the same using 2 mol% catalyst only
(products 3Ac and 3Dd).
Next, the inability of -alkyl isocyanoacetates to react under the
above conditions was addressed by using the corresponding
thioesters instead, and assuming that thioesters are generally
more acidic than oxoesters. At the outset, however, it was not
clear whether-alkyl isocyanoacetate thioesters would be
effective donor substrates in this reaction. In fact, a few classes
of thioesters only, with inherently acidic character, e.g.
arylacetic,[25] -unsaturated carboxylic acid,[26] and malonic acid
thioesters,[27] have been successfully employed in catalytic
asymmetric carbon-carbon bond forming reactions and, as far as
we know, -substituted isocyanoacetic thioesters have never
been reported.[28] In initial attempts, we observed that the C6-
catalyzed reactions of various-alkyl isocyanoacetate thioesters
4 (Ar: Ph) with enones 2 provided the Michael adducts 7 in good
ee´s, but with formation of considerable amounts (20%–40%) of
undesired byproducts such as 10, 11 and sulfa-Michael
products.[29] In case of using thioester 5 (Ar= 1-naphthyl) and
methyl vinyl ketone, compound 11Aa was the major product
formed with no even traces of 8Aa detected. In view of these
complications,[30] some precursors of -isocyanothioesters, such
as -substituted -formamido thioesters and N-Boc -amino
acid thioesters, were also evaluated for the above reactions, but
these substrates resulted totally unreactive under the above
catalytic conditions. After some screening,[18] it was finally found
that -alkyl isocyanoacetate thioester 6A, with a di-ortho
substituted phenyl group installed (Ar= 2,6-Me2C6H3), reacted
cleanly to furnish the corresponding adduct 9A essentially as the
sole reaction product. This reactivity pattern was quite general
for an array of isocyanoacetates 6 bearing short, medium, and
longer -alkyl linear as well as branched chains. As data in
Table 3 show, upon reaction with enones 2 the corresponding
products 9 were obtained in isolated yields from good to very
good and excellent enantioselectivity, without traces of
accompanying byproducts.[31] Furthermore, as production of
compound 9Fe illustrates, the reaction can be run at 3 mmol
scale without any detriment in yield or selectivity.
Table 3. Conjugate addition of -alkylisocyanothioacetates 4–6 to vinyl
ketones 2 catalyzed by C6.[a]
The synthetic utility of the method was briefly explored as
shown in Scheme 2. For example, the oxidative cleavage of the
acyloin moiety in adduct 3Ag provided, after methylation of the
intermediate carboxylic acid, ester 12. This product is difficult to
obtain enantioselectively from a direct addition to methyl acrylate,
vide supra. Of practical interest, acetone is the only carbon by-
product formed during this two-step transformation. Product 12
could be transformed into the pyroglutamate ester 13 in good
yield. On the other hand, mild acid hydrolysis of adducts 3Ad
and 3Dd, followed by spontaneous cyclisation, provided the 1,5-
dehydroproline esters 14 and 15 in yields of 80% and 70%,
respectively. Exposure of these adducts to H2 over Pd on
charcoal proceeded with concomitant cleavage of the benzylic
CN bond to give the corresponding -disubstituted -amino
esters 16 and 17. Conversely, when 1,5-dehydroproline esters
18 and 19, obtained from 3Aa and 3Ab as above, were
submitted to the same hydrogenation conditions, pyrrolidines 20
and 21 were produced with almost perfect stereocontrol at the
newly generated stereocenter (dr>20:1).[32] The absolute
configuration of compounds 13 and 22 was determined by X-ray
single crystal structure analysis[33] and that of the remaining
adducts by analogy assuming a uniform reaction mechanism.
[a] Reactions conducted on a 0.1 mmol scale in 0.2 mL CH2Cl2 (molar ratio
of thioester/2/catalyst 1:2:0.1). Yields of isolated product after column
chromatography. Enantioselectivity determined by chiral HPLC. [b] reaction
run for 3 days. [c] about 30% of product 10 formed. [d] 3 equiv. of 2d used.
[e] About 35% of product 11 formed. [f] with catalyst C1.[g] Reaction run for
2 days. [h] Reaction run at 3 mmol scale using 1.3 equiv of 2e.
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10.1002/chem.201703526
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Finally, it was gratifying to observe that adducts 3Aa, 3Ab, 3Af,
3Ca and 3Dd upon treatment with 10 mol% each DBU and AgF
led to 4,5-dehydroprolines 23–27 in very good yields through a
clean cyclization and isomerization process. Other bases
examined for this process, i.e. Et3N and iPr2EtN, were also
effective but longer reaction times were required for completion,
whereas in the absence of silver salts the reactions did not
proceed.[34] Importantly, using this approach prolines with an -
alkyl substituent may now be produced, as illustrated with
compounds 28 and 29 derived from 9Ae.
Acknowledgements
Support has been provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
(GV grant No IT-628-13), and Ministerio de Economía y
Competitividad (MEC Grant CTQ2016-78487-C2), Spain. A.O.
thanks UPV/EHU for a fellowship. We also thank SGIker
(UPV/EHU) for providing NMR, HRMS, and X-Ray facilities.
Keywords: asymmetric synthesis • organocatalysis • prolines •
Brønsted bases • conjugate additions.
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In conclusion, we report here a new divergent synthesis of
quaternary - and -dehydroprolines with broad substitution
patterns based on a catalytic enantioselective two-step formal
[3+2] cycloaddition of -substituted isocyano(thio)acetates with
vinyl ketones. Key for success is the development, for the first
time, of isocyanoacetic acid thioesters as donor reagents in
asymmetric synthesis and the design of a new subtype of
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a
sterically
congested polyaryl side-arm. We anticipate that these two key
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10.1002/chem.201703526
Chemistry - A European Journal
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base-promoted ketene formation. The identity of byproducts was
confirmed by comparison with authetic samples.
[30] Potential problems arising from the use of thioesters, such as ketene
formation and acyl transfer processes, have been previously noted.
See reference 25b.
[18] See the Supporting Information for details.
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example, whilst N-phenyl maleimide hardly reacts with -benzyl
isocyanoacetate methyl ester under Brønsted base catalysis (ref 14c),
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C6, RT, overnight) to provide the corresponding adduct in 70% isolated
yield, albeit as a mixture of diastereomers (dr= 70:30, 68%/80% ee).
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[33] CCDC 1555683 (catalyst C6), CCDC 1555682 (compound 13) and
CCDC 1555684 (compound 22) contain the supplementary
crystallographic data for this paper. These data can be obtained from
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif. See the Supporting Information
for details.
[22] Recently, bifunctional thiosquaramides have been described as efficient
catalysts with the two NH hydrogen atoms positioned for the two
rotamers 2.43 Å and 2.64 Å apart, respectively. See: M. Rombola, C. S.
[34] AgNO3, AgOTf and AgOAc were also tested as alternative silver source,
but among them only the latter was effective.
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10.1002/chem.201703526
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COMMUNICATION
Entry for the Table of Contents
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COMMUNICATION
Amaiur Odriozola, Mikel Oiarbide,
Claudio Palomo*
Page No. – Page No.
Enantioselective Synthesis of
Quaternary 4- and 5-
Dehydroprolines Based on a Two-
Step Formal [3+2] Cycloaddition of -
Aryl and -Alkyl
Double game: A bifunctional Brønsted base catalyst promotes the reaction of both
-aryl and -alkyl isocyano(thio)acetates with vinyl ketones, opening a divergent
access to quaternary either 4- or 5-dehydroprolines with high enantioselectivity.
Isocyano(thio)acetates with Vinyl
Ketones.
This article is protected by copyright. All rights reserved.