Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes

Article abstract of DOI:10.1002/anie.202104352

A direct and asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O-TIPS-protected anti-aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti-α-amino-β-hydroxy and α,β-dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol.

Full text of DOI:10.1002/anie.202104352

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A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Direct and Enantioselective Aldol Reactions Catalyzed by Chiral
Nickel(II) Complexes
Authors: Pedro Romea, Felix Urpi, Gabriel Aullón, Stuart C. D.
Kennington, Saul F. Teloxa, Miguel Mellado-Hidalgo, Oriol
Galeote, Sabrina Puddu, Marina Bellido, and Mercè Font-
Bardia
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10.1002/anie.202104352
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Direct and Enantioselective Aldol Reactions Catalyzed by Chiral
Nickel(II) Complexes
Stuart C. D. Kennington,[a] Saul F. Teloxa,[a] Miguel Mellado-Hidalgo,[a] Oriol Galeote,[a] Sabrina
Puddu,[a] Marina Bellido,[a] Pedro Romea,*[a] Fèlix Urpí,*[a], Gabriel Aullón,[b] and Mercè Font-Bardia[c]
Dedicated to Professor David A. Evans on the occasion of his 80th birthday
[a]
Dr. S. C. D. Kennington, Dr. S. F. Teloxa, M. Mellado-Hidalgo, O. Galeote, S. Puddu, M. Bellido, Prof. P. Romea, Prof. F. Urpí
Department of Inorganic and Organic Chemistry. Section of Organic Chemistry
Universitat de Barcelona
Carrer Martí i Franqués 1-11, 08028 Barcelona (Spain)
E-mail: pedro.romea@ub.edu; felix.urpi@ub.edu
Prof. G. Aullón
Department of Inorganic and Organic Chemistry. Section of Inorganic Chemistry
Universitat de Barcelona
[b]
[c]
Carrer Martí i Franqués 1-11, 08028 Barcelona (Spain)
Dr. M. Font-Bardia
X-ray Diffraction Unity, CCiTUB
Universitat de Barcelona
Carrer Solé i Sabarís 1-3, 08028 Barcelona (Spain)
Supporting information for this article is given via a link at the end of the document.
Abstract:
A direct and asymmetric aldol reaction of N-acyl
thiazinanethiones with aromatic aldehydes catalyzed by chiral
nickel(II) complexes is documented. The reaction gives the
corresponding O-TIPS protected anti aldol adducts in high yields and
with a remarkable stereocontrol and atom economy. Furthermore, the
straightforward removal of the achiral scaffold provides
enantiomerically pure intermediates of synthetic interest, which
involve precursors for anti α-amino-β-hydroxy and α,β-dihydroxy
carboxylic derivatives. Theoretical calculations account for the
observed high stereocontrol.
The enantioselective construction of the carbon backbone of
chiral molecules has been at the forefront of organic synthesis in
the last decades. It is therefore hardly surprising that classical
transformations such as aldol and Michael reactions or Diels-
Alder cycloadditions still hold a prominent position among the
most important synthetic methods.[1] In this context, the continuing
demand for increasingly more efficient procedures in accordance
with the premises dictated by selectivity and economy in
synthesis[2,3] has given rise to the development of a plethora of
catalytic methods for the enantioselective construction of carbon–
carbon bonds.[4] Unfortunately, the scope of most of them is rather
narrow, which hampers further development and prevents a
comprehensive exploitation of their possibilities. Thus,
considering the benefits arising from a general approach, we
envisaged that metal enolates from a single platform might
participate in a number of direct, enantioselective, and catalytic
transformations provided that the appropriate electrophiles were
generated in the reaction mixture and evolve through similar open
transition states (Scheme 1).
Scheme 1. Direct and Enantioselective Carbon–Carbon Bond Forming
Reactions from Carbonylic Compounds
chiral catalyst to undergo direct and stereocontrolled aldol
reactions.[5] With this aim, we have identified N-acyl
thiazinanethiones as worthy substrates for our purposes and we
now describe our findings on direct and highly enantioselective
aldol reactions with aromatic aldehydes catalyzed by chiral
nickel(II) complexes in which the resultant protected aldol
compounds are selectively obtained with remarkable atom
economy. Importantly, this reaction gives access in a single step
to protected anti aldol adducts and supplements syn methods
previously described by Evans,[6] and Kumagai and Shibasaki
(Scheme 2).[7,8] Furthermore, the reaction shows a wide scope for
the nucleophilic partner, which also permits the obtention of
enantiomerically pure protected α-azido-β-hydroxy and α,β-
dihydroxy derivatives in high yields under mild conditions
(Scheme 2).
In this context, activated aldehydes shown in Scheme 1 might
react with carbonylic species in the presence of a base and a
1
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Table 1. Influence of the chiral nickel(II) complex in the stereochemical outcome
of the aldol reaction.
Entry
L*
anti/syn[a]
ee 2a[b]
Yield 2a (%)[c]
1
2
3
4
(Me3P)2NiCl2
88:12
88:12
80:20
50:50
–
79
(+)-DIOPNiCl2
< 5
98
99
< 10
67
(R)-SEGPHOS
(R)-DTBM-SEGPHOS
43
5
6
7
(R)-BINAP
80:20
80:20
83:17
97
98
83
75
76
71
(R)-Tol-BINAP
(R)-Xyl-BINAP
Scheme 2. Direct and enantioselective aldol reactions catalyzed by chiral metal
complexes.
[a] Established by 1H NMR (400 MHz) analysis. [b] Established by chiral HPLC
analysis. [c] Isolated yield.
Exploratory experiments using N-propanoyl derivatives of several
achiral heterocycles, TESOTf, and (Me3P)2NiCl2 proved the
feasibility of our approach for a direct and stereocontrolled aldol
reaction as well as the advantage of thiazolidinethione and
thiazinanethione over other heterocyclic scaffolds. In this respect
and despite both scaffolds produce similar results, the slower
kinetics observed for the thiazolidinethione made the
thiazinanethione counterpart the best choice for further
developments (see Table SI-1).[9]
The impact of the bulk of ligands in the reaction led us to explore
the influence of the activating Lewis acid. We thus assessed the
commercially available TMS, TBS, TES, and TIPS triflates. In the
reaction with (Me3P)2NiCl2, all these silyl triflates except TMSOTf,
which produced similar diastereomeric ratios but larger amounts
of deprotection, can be used interchangeably (see Table SI-2).
On the contrary, we observed a significant change of selectivity
when [(R)-Tol-BINAP]NiCl2 was used instead. Indeed,
stereoselectivity depends upon the silyl triflate: less bulky
TMSOTf and TBSOTf gave lower diastereoselectivities than
TESOTf, whereas the bulkiest TIPSOTf increased the
diastereomeric ratio up to 85:15 (compare entry 1–4 in Table 2).
In turn, enantiocontrol was excellent for all these reagents.
Then, we examined the stereocontrol provided by different of
chiral nickel(II) complexes. It is important to highlight that these
complexes are robust, easy to handle and prepare from the
corresponding chiral ligands and NiCl2, and that are properly
activated in the reaction mixture at the same time as the aldehyde
by simple treatment with a silyl triflate.[10] Therefore, the role of the
silyl triflate is twofold since it activates the aldehyde as well as
converting the nickel(II) chloride complex into the true catalytic
species.[11] Results summarized in Table 1 show that N-propanoyl
thiazinanethione 1 reacts with 4-methoxybenzaldehyde (a) in the
presence of minute amounts of a large array of nickel(II)
complexes with the exception of DIOPNiCl2 (entry 2 in Table 1).
Indeed, achiral (Me3P)2NiCl2 provided a mixture of silyl aldol
adducts with a remarkable diastereomeric ratio (dr 88:12) from
which racemic anti adduct 2a was isolated with a 79% yield (entry
1 in Table 1), whereas other chiral complexes also catalyzed the
desired aldol reaction with full conversion. Interestingly, the steric
hindrance of the chiral ligands plays a key role in the
stereochemical outcome of the reaction. Indeed, the DTBM-
SEGPHOS diphosphine gave an equimolar mixture of anti and
syn diastereomers, whereas the less bulky SEGPHOS performed
much better and afforded an 80:20 anti/syn mixture (compare
entry 3 and 4 in Table 1); in addition, the absolute stereocontrol
was outstanding and enantiomerically pure (ee ≥ 98%) aldol
adduct 2a was isolated in both cases. Furthermore, the BINAP
family gave much more consistent results, although the
stereochemical outcome of the reaction slightly depended on the
bulk of the ligand, the Tol-BINAP ligand being the most
appropriate in terms of stereocontrol and yield (compare entries
5–7 in Table 1).
Table 2. Influence of the Lewis acid in the stereochemical outcome of the aldol
reaction.
Entry
R3SiOTf
anti Adduct
dr[a]
ee anti[b]
Yield anti (%)[c]
1
2
TESOTf
TMSOTf
2a
3a
80:20
73:27
98
nd
76
nd
3
4
TBSOTf
TIPSOTf
4a
5a
75:25
85:15
99
99
67
80
[a] anti/syn Ratio established by 1H NMR (400 MHz) analysis. [b] Established
by chiral HPLC analysis. [c] Isolated yield.
We also evaluated other variables. The temperature had a
modest positive effect on the diastereomeric ratio when cooled to
–40 °C but duly decreased the rate of reaction, so we maintained
–20 °C as the reaction temperature. Finally, a comprehensive
evaluation of the different variables considered together indicated
that the reaction of N-propanoyl thiazinanethione 1 with a in the
2
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presence of 2 mol% of [(R)-Tol-BINAP]NiCl2, 1.3 equivalents of
TIPSOTf, and 1.5 equivalents of 2,6-lutidine in only 1 h at –20 °C
afforded the protected anti aldol adduct 5a in 82% yield with an
excellent stereocontrol (dr 85:15, ee 99%).
afforded the anti aldol adducts 5j and 5k in high yields after 2 h
by using 5 mol% of the nickel(II) complex.
Once the feasibility of the enantioselective anti aldol reaction had
been demonstrated, we assessed the influence of the
substituents of the acyl group on the addition of N-acyl
thiazinanethiones 6–13 to a. The results shown in Table 4
highlight the key role of steric bulk in the stereochemical outcome
of the aldol reaction. Indeed, the enantioselectivity is consistently
excellent for the N-acyl thiazinanethiones 6–8, but the
diastereoselectivity and consequently the yield are eroded from
5a (R: Me, dr 85:15, 82%) to 17a (R: Et, dr 81:19, 78%) and 18a
(R: i-Bu, dr 75:25, 60%) as well as the catalyst loading requiring
With the reaction conditions optimized for a, we moved to
evaluate the scope of the reaction with other aromatic
aldehydes.[12] Results summarized in Table 3 prove that the
reaction is sensitive both to the electronic character and the steric
hindrance of the substituents of the aromatic aldehyde. Indeed,
electron donating groups at the para position enabled highly
stereocontrolled aldol reactions (dr 85:15 and ee up to 99%) and
permitted the isolation of enantiomerically pure anti adducts 5a
and 5b in 82% and 77% respectively. Benzaldehyde (c) required
an increase in catalyst loading to 10 mol% to attain similar results,
but the more deactivated 4-chlorobenzaldehyde (d) only provided
anti adduct 5d with a 61% yield after three days at –20 °C or a
modest 49% yield when the reaction was carried out at 0 °C for
15 h owing to the formation of a by–product arising from the attack
of the nucleophilic exo sulfur atom to the activated aldehyde. In
turn, more electron-rich 2-naphthaldehyde (e) gave adduct 5e in
a remarkable 62% yield and ee 97% by using 5 mol% of catalyst.
Other isomers of a were also assessed with satisfactory results.
As expected, the 3-methoxy (f) turned out to be less reactive but
gave the corresponding anti adduct 5f in 66% yield with 10 mol%
of the catalyst after three days. More surprisingly, 2-
methoxybenzaldehyde (g) led to 5g as a single stereoisomer (dr
97:3 and ee 97%) in a 56% yield using 5 mol% of the catalyst.
Parallel aldol reaction of meta-tolyl aldehyde h proceeded
efficiently, but the ortho counterpart i resulted to be completely
inactive and did not afford the desired adduct 5i. This indicates
that bulky groups close to the carbonyl group hinder the approach
to the enolate, whereas we speculate that the outstanding results
from g may be due to the formation of a chelated oxocarbenium
intermediate in which the ortho substituent remains far from the
carbonyl center. Finally, aromatic aldehydes containing π-
electron rich heterocycles, as the furan j and thiophene k,
an increase from
2 mol% to 5 mol%. Moreover, the
chemoselectivity is excellent and the presence of common
functional groups such as alkenes, alkynes, halides, or esters
does not have a noticeable influence, so enantiomerically pure
(ee 94–99%) protected anti adducts 19a–22a were isolated in
good to high yields (62–76%). Finally, the presence of a strong
electron withdrawing α-CF3 group inhibits the reaction, but the α-
benzyloxy derivative affords the anti adduct 24a in a highly
efficient manner, which provides straightforward access to
protected anti α,β-dihydroxy compounds. At this stage, we trialled
introducing an azido group at the α position. Unfortunately, all our
attempts failed and we were obliged to consider the use of the
thiazolidinethione scaffold. As previously mentioned, such a
heterocycle enables aldol reactions but with slower kinetics than
the
thiazinanethione
counterpart.
To
our
pleasure,
thiazolidinethione-based substrates 14–16 (m = 0 in Table 4) also
gave excellent results. Indeed, and in spite of requiring a longer
reaction time, N-propanoyl thiazolidinethione 14 (R: Me) and the
more bulky 15 (R: CH2CHMe2) also afforded the corresponding
aldol adducts 25a and 26a with high yields and ee (99 and 95%
respectively). Finally, the azido thiazolidinethione 16 (R: N3)
proved especially successful and afforded in just 2 h the α-azido-
β-silyloxy adduct 27a virtually as a single stereoisomer (dr 95:5,
ee 99%) with a 93% yield.[13]
Table 3. TIPSOTf-Mediated aldol reaction of 1 with aromatic aldehydes.
3
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