Highly Enantio- and Diastereoselective Catalytic Asymmetric Tamura Cycloaddition Reactions

Article abstract of DOI:10.1002/chem.201900119

The first broad-scope catalytic asymmetric Tamura cycloaddition reactions are reported. Under the influence of anion-binding bifunctional catalysis a wide range of α,β-unsaturated N-trityl imines undergo reactions with enolisable anhydrides to form highly synthetically useful α-tetralone structures with excellent enantio- and -diastereocontrol. In stark contrast to the previous literature benchmarks, doubly activated or highly electron deficient alkenes are not required. A facile two-step, high yielding sequence can convert the cycloadducts to α-haloketones (challenging to generate catalytically by other means) with the net formation of two new C?C bonds and three new contiguous stereocentres with exquisite stereocontrol. A DFT study has provided insight into the catalyst mode of action and the origins of the observed enantiocontrol.

Full text of DOI:10.1002/chem.201900119

DOI: 10.1002/chem.201900119
Communication
&
Asymmetric Catalysis
Highly Enantio- and Diastereoselective Catalytic Asymmetric
Tamura Cycloaddition Reactions
Aarꢀn Gutiꢁrrez Collar, Cristina Trujillo, and Stephen J. Connon*[a]
Abstract: The first broad-scope catalytic asymmetric
Tamura cycloaddition reactions are reported. Under the in-
fluence of anion-binding bifunctional catalysis a wide
range of a,b-unsaturated N-trityl imines undergo reactions
with enolisable anhydrides to form highly synthetically
useful a-tetralone structures with excellent enantio- and
-diastereocontrol. In stark contrast to the previous litera-
ture benchmarks, doubly activated or highly electron defi-
cient alkenes are not required. A facile two-step, high
yielding sequence can convert the cycloadducts to a-halo-
ketones (challenging to generate catalytically by other
means) with the net formation of two new CÀC bonds
and three new contiguous stereocentres with exquisite
stereocontrol. A DFT study has provided insight into the
catalyst mode of action and the origins of the observed
enantiocontrol.
The Tamura reaction between homophthalic anhydride (1) and
the activated alkyne 2 followed by loss of CO2 and aromatisa-
tion at high temperature to give naphthol 3 was discovered in
1981 (Figure 1A).[1] Shortly after, it was found that, in the pres-
ence of base, the reaction occurs under milder conditions with
doubly activated alkene substrates such as 4, to give the chiral
adduct 5.[2,3] Despite the Tamura cycloaddition finding applica-
Figure 1. The Tamura cycloaddition reaction and related lactam generation.
tion in the construction of the cores of natural products such
as (inter alia) anthraquinone antibiotics,[2] lactonamycin[4] and
dynemycin A,[5] its potential as a CÀC bond and stereocentre-
tres formed. A broad-scope catalytic asymmetric methodology
forming tool has been considerably stymied by the dearth of
catalytic asymmetric variants.
for highly enantio- and diastereoselective Tamura reactions,
which could produce malleable substituted chiral a-tetralones
(a unit prevalent in a wide range of natural products, pharma-
ceuticals and molecules of medicinal and agrichemical inter-
est,[8] of which rishirilide B[8c] and doxycycline[8e] are exemplary),
remains well beyond reach.
Very recently, Seidel, Vetticat et al.[9] demonstrated elegant
and selective Castagnoli chemistry between 1 and imine 6 cat-
alysed by thiourea 7 (Figure 1B). The authors proposed that
the catalyst binds the iminium–enolate ion pair arising from
the reaction of the basic imine with the acidic anhydride and
manages their encounter as the subsequent Mannich-type re-
action proceeds, followed by cyclisation to lactam 8.[10]
The first of these[6] (which was reported in 2014) is highly
enantio- and diastereoselective but can only be utilised for the
formation of 3,3-spirooxindole products. A second, more
recent methodology involves the reaction of a-alkyl-b-nitro-
styrenes with 1.[7] This possesses the advantage of using a
singly activated electrophile, at the cost of a narrow substrate
scope and a highly variable level of control over the stereocen-
[a] A. G. Collar, Dr. C. Trujillo, Prof. S. J. Connon
School of Chemistry Trinity Biomedical Sciences Institute
Trinity College Dublin
In the 1990s, Bulgarian researchers[11] showed that if an a,b-
unsaturated imine electrophile incorporated a bulky N-sub-
stituent, the reaction between 1 and a,b-unsaturated imines
could be (partially) diverted away from the Mannich process
and towards 1,4-conjugate addition. However, yields and/or
152-160 Pearse Street
Dublin 2 (Ireland)
E-mail: connons@tcd.ie
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/chem.201900119.
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diastereocontrol were usually poor.[12] We postulated that if
this process could be controlled, then Tamura reactions of con-
siderably broader scope involving readily available, singly acti-
vated substrates (i.e., not requiring restrictive substitution at
both alkene termini) could be brought into the orbit of asym-
metric catalysis. Herein, we report the first such broad-scope
Tamura cycloaddition reactions involving N-trityl imines of gen-
eral type 9 and anhydrides such as 1 to form stable, densely
functionalised a-tetralones 10 with excellent diastereo- and
enantiocontrol using an improved, readily prepared thiourea
catalyst (Figure 1C).[13] The reaction is unique in that it con-
structs the tetralone core with control over two new stereo-
centres in a modular way,[14] in addition to generating a highly
versatile enaminone vinylogous amide (synthetic building
blocks for heterocyclic- and target-oriented synthesis of the
first rank),[15] which we demonstrate can be readily converted
to the a-haloketone 11.
Table 1. Catalyst screening.
We began with the reaction between anhydride 1 and the
cinnamaldehyde-derived N-trityl imine 12[16] at ambient tem-
perature in MTBE in the presence of Seidel’s optimum catalyst
(i.e., 7, entry 1, Table 1). The challenge associated with devel-
oping the [1,4]-cycloaddition process (relative to the [1,2]-Cas-
tagnoli chemistry) is underlined by the formation of 13 with
32% ee (full conversion of 1) and 3:1 d.r. in favour of the syn-
diastereomer under identical conditions to those where 7 had
been reported to mediate the generation of lactam 8 with
88% ee and 19:1 d.r. A solvent screen identified toluene as a
superior solvent for the reaction, which marginally improved
both enantio- and diastereocontrol simultaneously (Table 1, en-
tries 2–6); however, stereocontrol remained some way short of
synthetically useful levels. Thus, a redesign of the catalyst
system was required.
Entry Cat. Sol.
T [8C] t [h] Conv [%][a] d.r.[b]
ee [%][c]
(syn/anti)
1
2
3
7
7
7
MTBE
MeCN
THF
RT
RT
RT
RT
RT
RT
RT
RT
RT
2
2
2
2
2
2
2
2
2
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
50
75:25
60:40
46:54
67:33
80:20
80:20
80:20
70:30
70:30
77:32
85:15
85:15
82:18
87:13
50:50
95:5
32
3
17
32
37
50
83
49
60
80
70
75
86
63
0
4
5
7
7
CH2Cl2
Et2O
6
7
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
7[d]
8
14
15
16
17
7
7
17
18
Somewhat surprisingly, removal of the electron-withdrawing
groups (which were important factors in achieving enantiocon-
trol in Seidel’s study) from the catalyst’s benzoylamide unit im-
proved product enantioselectivity considerably (catalyst 14,
Table 1, entry 7). Nagasawa-type systems,[17] which are highly
useful in anion-binding-mediated enantioselective acyl trans-
fer[18] but were less effective asymmetric catalysts in the Cas-
tagnoli chemistry,[9] served comparatively well here, catalysing
reactions with 49–80% ee and up to 70:30 d.r. (entries 8–10).
Of most interest was the observation that, of the three cata-
lysts, the bis-urea 17 easily outperformed the mixed urea-thio-
urea compound 16 and the bis-thiourea 15. At lower tempera-
tures, control over the stereocentre-forming event increased
using catalysts 7, 17 and 18 to a maximum of 86% ee (en-
tries 11–14).
9[d]
10
RT
2
11
À30
À40
À40
À40
À40
À40
À40
À40
À40
30
30
26
26
48
48
30
36
36
12[d]
13
14
15[d,e] 19
16[d]
17[d]
18[d]
14
20
21
>98
>98
>98
>98
95
75
79
96
84:16
86:14
93:7
19[d,e] 22
[a] Determined by 1H NMR spectroscopy using p-iodoanisole as an inter-
nal standard. [b] Diastereomeric ratio (determined by 1H NMR spectrosco-
py). [c] Determined by CSP-HPLC, see the Supporting Information. [d] Cat-
alyst loading of 5 mol%. [e] Reaction concentration of 0.1m.
With enantiocontrol remaining unsatisfactory, we examined
the influence of the 1,2-cyclohexanediamine-derived structural
unit on catalyst efficacy. This feature is pivotal: catalysts where
this group had been altered to either a 5-membered ring-
based- (i.e., 18) or an acyclic analogue (i.e., 19) promoted
either less selective or racemic cycloadditions, respectively
(Table 1, entries 14 and 15). Returning to the original motif,
employment of the relatively electron-rich amide 14 at À408C
provided the product in excellent ee and d.r. (entry 16). In an
attempt to exploit the finding that 17 was clearly superior to
15, we prepared and evaluated 20, the urea derivative of 14.
This catalyst did not offer advantages in terms of stereocontrol
(entry 17), which indicated that designing catalysts with anion-
binding thiourea motifs that incorporate more Lewis-basic imi-
nium ion-binding carbonyl units (see 13a) may be profitable.
Accordingly, replacement of the aromatic amide moiety with
an alkyl variant was carried out. To the best of our knowledge,
this modification has not been made previously. Gratifyingly,
the methyl amide 21 proved a small improvement over 7
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(compare entries 12 and 18), whereas its tert-butyl variant 22
(entry 19) was capable of promoting the formation of 13 with
96% ee and 93:7 d.r. at just 5 mol% loading and a more con-
venient concentration of 0.1m.
With an enantio- and diastereoselective process in hand, at-
tention turned to the question of substrate scope. It was
found that a,b-unsaturated imines bearing electron neutral,
electron-deficient, and electron-rich b-aromatic substituents
(i.e., leading to tetralones 23–29) reacted with 1 in the pres-
ence of 22 (5 mol%) with generally excellent levels of enantio-
and diastereocontrol (Table 2). The p-CF3 substituent is a minor
exception though 27 could still be formed in 86% ee and ca.
3:1 d.r. Tetralones incorporating heterocyclic substituents (i.e.,
30 and 31) could be readily prepared, and b-aliphatic substitu-
ents were also eminently compatible (i.e., 32–34).
The homophthalic anhydride component can also be al-
tered. Three substituted homophthalic anhydrides underwent
smooth cycloaddition with 12 catalysed by 22 to form 35–37
in good-excellent yields, good-excellent diastereocontrol and
excellent enantiomeric excess. The anion-stablising bromo-
and nitro-substituents facilitated faster, more selective chemis-
try (Scheme 1).
Scheme 1. Substrate scope: anhydride component.
was treated with NCS to produce the a-chloroimine 38[11a] in
excellent yield (Scheme 2). When stirred in a mixture of neutral
alumina and chloroform in air, this then underwent a hydroly-
The synthetic versatility of vinylogous amides is well docu-
mented.[15] In an attempt to demonstrate value beyond the
usual transformations associated with this functional group, 24
Scheme 2. Conversion of 24 to a-chloroketone 39.
Table 2. Substrate scope: the imine component.
sis-oxidation-b-ketodecarboxylation cascade in one pot to form
the a-chlorotetralone 39 in 96% ee as a single diastereomer.
To the best of our knowledge, this sequence to a-chloro-1-tet-
ralones is unprecedented and may be of some use given the
contemporary challenges associated with developing catalytic
asymmetric chlorination methodologies of non-activated ke-
tones.[19]
To provide mechanistic insight into the process, a DFT study
(M062X/6–311+G**// M062X/6-31G*, SMD (toluene), 233 K)
was carried out. Preliminary calculations involving the forma-
tion of 31 (see the Supporting Information (SI)) indicated that,
in the formation of the iminium-enolate ion pair in the pres-
ence of 22, the s-trans conformation of the imine is lower in
energy than the s-cis analogue. The energy profile for the for-
mation of both enantiomers of 31 (Figure 2) is interesting in
that, in the case of the generation of the major enantiomer
(R,S)-31, the cyclisation step is rate determining, whereas the
1,4-conjugate addition reaction is the slow step leading to the
formation of the (S,R)-antipode. The rate-determining step
(RDS) barrier height leading to the major enantiomer is calcu-
lated to be lower than the RDS associated with the minor.
Both pathways pass through a relatively stable 1,4-conjugate
addition adduct and the cyclisation step is essentially irreversi-
ble under the reaction conditions. Overall barriers are rather
low, which is consistent with smooth cycloaddition at À408C.
On examination of TSs associated with the key first stereo-
centre forming 1,4-conjugate addition reaction step for both
major and minor enantiomers, we observed a similar mode of
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stead, N-trityl imine derivatives of simple a,b-unsaturated alde-
hydes react with homophthalic anhydrides in the presence of
a novel catalyst to generate a-tetralones with excellent yield,
enantio- and diastereocontrol. Electron-rich, electron-deficient,
heterocyclic and aliphatic substituents at the b-position are all
well tolerated. The trityl group is of sufficient steric bulk to
divert the chemistry away from lactam formation and towards
conjugate addition, which also equips the product with a ver-
satile enaminone unit which can be efficiently unmasked as an
a-chloro ketone. DFT calculations indicate a bifunctional anion-
binding mode of catalyst action and illuminate the distinctive
role of the catalyst’s amide substituent and substrate trityl
group on stereocontrol.
Figure 2. Calculated (DFT) potential energy surface associated with the for-
mation of both enantiomers of 31.
Acknowledgements
This publication has emanated from research supported by the
Science Foundation Ireland (SFI -12-IA-1645). We are grateful
to the Irish Centre for High-End Computing (ICHEC) for the
provision of computational facilities.
action to that reported by Seidel and Vetticat during catalysis
of the Castagnoli reaction.[9] The catalyst stabilises and organis-
es the encounter between the enolate and iminium ion
through hydrogen-bonding interactions—namely between the
enolate and the thiourea unit and the iminium ion NÀH
proton and the catalyst’s amide group. In the TS associated
with the major enantiomer (R,S)-31 (Figure 3, left), the iminium
Conflict of interest
The authors declare no conflict of interest.
Keywords: computational study · cyclic anhydrides · density
functional calculations · electrophiles · Tamura cycloaddition
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3.6 kcalmolÀ1) consistent with the 99% ee observed.
In summary, the development of the first highly enantiose-
lective Tamura cycloaddition process of broad scope is report-
ed. The reaction does not require specialised alkenes incorpo-
rating electron-withdrawing groups at both olefin termini. In-
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116, 5623; b) K. Shibatomi, K. Kitahara, N. Sazaki, Y. Kawasaki, I. Fujisawa,
S. Iwasa, Nat. Commun. 2017, 8, 15600.
[20] For the seminal mechanistic work proposing iminium ion–enolate ion
pairs following proton transfer, see: O. Pattawong, D. Q. Tan, J. C. Fet-
tinger, J. T. Shaw, P. H.-Y. Cheong, Org. Lett. 2013, 15, 5130.
Manuscript received: January 8, 2019
Version of record online: && &&, 0000
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
5
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Asymmetric Catalysis
A. G. Collar, C. Trujillo, S. J. Connon*
&& – &&
Highly Enantio- and Diastereoselective
Catalytic Asymmetric Tamura
Cycloaddition Reactions
Tetralone and easy target: A highly
enantio- and diastereoselective Tamura
cycloaddition process involving simple
a,b-unsaturated imines to yield mallea-
ble a-tetralones is reported. In addition,
DFT calculations provided insight into
the catalyst mode of action and the ori-
gins of the observed enantiocontrol.
&
&
Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
6
ꢂ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!