Asymmetric synthesis of Rauhut-Currier-type esters via Mukaiyama-Michael reaction to acylphosphonates under bifunctional catalysis

Article abstract of DOI:10.1039/c8cc07561a

A highly enantioselective organocatalytic Mukaiyama-Michael reaction of silyloxy dienes and α,β-unsaturated acyl phosphonates under bifunctional organocatalysis is presented. The new reactivity triggered by the catalyst conducted to Rauhut-Currier type es

Full text of DOI:10.1039/c8cc07561a

Showcasing research from Jose Aleman’s group at
Universidad Autonoma de Madrid, Spain.
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Asymmetric synthesis of Rauhut–Currier-type esters
via Mukaiyama–Michael reaction to acylphosphonates
under bifunctional catalysis
As well as the domino effect making the chips fall on the
domino token 1,3, the bifunctional organocatalyst triggers
the reaction through the less reactive 1,3 position of the silyl
dienol ether in a highly enantioselective Mukaiyama–Michael
reaction to acylphosphonates.
See Jose A. Fernández-Salas,
José Alemán et al.,
Chem. Commun., 2018, 54, 13941.
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Asymmetric synthesis of Rauhut–Currier-type
esters via Mukaiyama–Michael reaction to
acylphosphonates under bifunctional catalysis†
Cite this: Chem. Commun., 2018,
54, 13941
Received 18th September 2018,
Accepted 22nd October 2018
a
bcd
Vıctor Laina-Martın,
Roberto del Rıo-Rodrıguez,a Sergio Dıaz-Tendero,
´
´
´ ´ ´
Jose A. Fernandez-Salas *a and Jose Aleman
*
ab
´
´
´
DOI: 10.1039/c8cc07561a
rsc.li/chemcomm
A
highly enantioselective organocatalytic Mukaiyama–Michael successfully in the presence of certain electrophiles. Indeed,
reaction of silyloxy dienes and a,b-unsaturated acyl phosphonates only very specific and reactive substrates such as terminal
under bifunctional organocatalysis is presented. The new reactivity vinylic carbonyl compounds have shown sufficient reactivity.
triggered by the catalyst conducted to Rauhut–Currier type esters, via However, mono- and gem-disubstituted double bonds are more
a formal conjugate addition to a,b-unsaturated esters. This protocol challenging electrophiles for this transformation.
proceeds under mild conditions with complete regioselectivity and
excellent enantiocontrol.
The catalytic Mukaiyama-aldol (MA) reaction has become
a powerful tool for the enantioselective construction of C–C
bonds.4 Despite the great efforts made in the development of
The development of efficient and practical strategies for the MA reactions, the conjugate addition to a,b-unsaturated esters,
stereoselective construction of C–C bonds is an ongoing objec- which are difficult substrates to activate,5 still stands as an
tive and still holds a preferred position in organic chemistry outstanding objective in asymmetric organocatalysis. Indeed,
research.1 In this field, the Rauhut–Currier reaction has been only one example has recently been reported by List and
widely developed over the years, becoming a powerful tool for coworkers in which a silylium imidodiphosphorimidate Lewis
the construction of valuable compounds from two structurally acid has been shown to be a very efficient catalyst in the
diverse olefins.2 In particular, asymmetric intramolecular asymmetric Mukaiyama–Michael reaction to a,b-unsaturated
Rauhut–Currier processes have been extensively explored and esters (Scheme 1, eqn (b)).6 Similarly, the organocatalysed
reported during the last few years.2a Different groups have vinylogous Mukaiyama-aldol (VMA) reaction has been widely
focused their attention on developing chiral catalysts based developed and has become the preferred method for the stereo-
on different nucleophilic species able to trigger the reaction.2,3 selective synthesis of vinylogous aldol type products.4e,7 The
However, the intermolecular cross-asymmetric version is still orbital coefficients provoke the observed 1,5-nucleophilic attack,8
underdeveloped and only a few groups have described efficient while the reactivity through the less reactive 3 position of the
methodologies (Scheme 1, eqn (a)).3 In pursuit of this challenging
objective, these research groups have described the use of well-
designed multifunctional chiral phosphine-based catalysts, which
have only allowed the efficient a-functionalization of 3-aroyl
acrylates and para-quinone methides mainly with vinyl ketones.3b,e–h
Despite these particular achievements, the enantioselective inter-
molecular cross Rauhut–Currier reaction has been applied
a
´
´
´
Departamento de Quımica Organica (Modulo 1), Facultad de Ciencias,
´
Universidad Autonoma de Madrid, 28049-Madrid, Spain.
E-mail: jose.aleman@uam.es; Web: www.uam.es/jose.aleman
b Institute for Advanced Research in Chemical Sciences (IAdChem),
´
Universidad Autonoma de Madrid, 28049 Madrid, Spain
c Condensed Matter Physics Center (IFIMAC), Facultad de Ciencias,
´
Universidad Autonoma de Madrid, 28049 Madrid, Spain
d
´
´
Departamento de Quımica (Modulo 13), Facultad de Ciencias,
´
Universidad Autonoma de Madrid, 28049-Madrid, Spain
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc07561a
Scheme 1 Previous works (A and B) and the present work (C).
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Table 1 Screening of reaction conditions for the addition of 2a to 1a in
the presence of different catalysts 3a
dienolate has been practically unexplored (Scheme 1, eqn (c)).
Taking into account the challenge of expanding the asymmetric
intermolecular Rauhut–Currier reaction,9 we envisioned that the
addition of silyl dienol ethers to acylphosphonates,10 followed by
an in situ acyl substitution, could potentially lead to Rauhut–
Currier type esters. In order to achieve this objective, the
nucleophilic addition to the conjugated system (1,4-addition)
would need to take place through the less reactive position (1,3)
of the silyl dienol ether. Herein, we describe a Mukaiyama–
Michael process of silyl dienol ethers to a,b-unsaturated acyl
phosphonates catalysed by a bifunctional organocatalyst.11 The
special and unusual reactivity shown by these dienolates when
activated by the bifunctional organocatalyst and the use of acyl-
phosphonates as ester surrogates have allowed us to develop
the formal synthesis of Rauhut–Currier-type esters, not easy to
access otherwise. In addition, very challenging b-mono and
b-disubstituted formal acrolein adducts have been addressed
using this methodology. Based on our experience in bifunc-
tional catalysis,9,12 we began our investigations by studying the
reaction of acylphosphonate 1a as a model substrate with a
trimethyl silyl dienolate derivative 2a and different thiourea
and squaramide bifunctional organocatalysts (Table 1). Firstly,
we examined catalysts 3a and 3b which led, after in situ treat-
ment with BnOH and DBU, to the desired Rauhut–Currier
type ester with moderate enantioselectivities (entries 1 and 2).
Taking into account these preliminary results, the squaramide-
quinine catalyst 3d was tested and it clearly enhanced the
selectivity of the process (90% ee) (entry 3). All four squar-
amides bearing a member of the quinine family (3c–f) led to
similar yields and enantioselectivities of the desired Rauhut–
Entry
3
Solvent
t (h)
Yield 5a (%)c
eed
59
66
90
91
89
À88
À82
94
96
90
93
90
93
97
1b
2b
3b
4
5
6
7
8
9
10
11
12e
13e
14e
3a
3b
3d
3d
3e
3f
3c
3d
3d
3d
3d
3d
3d
3d
THF
THF
THF
THF
THF
THF
THF
DCM
p-Xylene
MeCN
DME
THF
36
36
36
36
36
36
36
36
36
36
36
36
48
36
36
51
32
40
34
36
42
36
36
35
30
59
30
57
DCM
p-Xylene
a
All the reactions were performed on a 0.1 mmol scale in the presence
b
of 3 (10 mol%) in 0.3 mL of solvent. 3 equiv. of water was added.
c
d
e
Isolated yield. Determined by SFC chromatography. 3d (20 mol%)
and 0.6 mL of solvent (0.17 M).
Currier ester (entries 4–7). Different solvents were then studied While a silyl dienol ether bearing a longer aliphatic chain was
taking 3d as the optimised catalyst (entries 8–11). p-Xylene was well tolerated (5m), the presence of a phenyl group as a sub-
considered as the optimum solvent (entry 9) as it led to higher stituent did not conduct to the desired product. To our delight,
enantioselectivity. A lower concentration and a higher catalyst when a 4-substituted silyloxy diene (2b) was tested, challenging
loading boosted the efficiency of the reaction and yielded the b,b-disubstituted Rauhut–Currier adducts (5k–5l) were obtained
desired product 5a with a 57% yield and 97% enantiomeric with excellent enantioselectivities.
excess (entry 14).
Interestingly, when the in situ acyl substitution was not
Once the reaction conditions had been optimised (entry 14, performed under the optimised reaction conditions, the reac-
Table 1), we studied the scope of the reaction considering tion conducted to the formation of the dihydropyranone deri-
differently substituted a,b-unsaturated acyl phosphonates vative 4a after an in situ lactonization through intermediate I.
(Table 2). The Mukaiyama–Michael reaction embraced a variety Subsequent lactone opening in the presence of BnOH and
of aromatics with complete regioselectivity observed in all DBU led to the desired Rauhut–Currier type ester as a unique
cases. The reaction proceeded smoothly with the p-tolyl sub- product in quantitative yield (Scheme 2, eqn (a)). These control
stituted double bond (5b) with an excellent enantioselectivity experiments suggested that the moderate yields obtained might
(96% ee). Acyl phosphonates bearing a poor aromatic ring (5c) come from the intrinsic instability of 4a under the reaction
led to the desired Rauhut–Currier product with excellent enantio- conditions during the long reaction times.13 Considering the
selectivity, retaining the efficiency of the reaction. Differently whole process, which involves conjugate addition of the dienolate,
substituted halogenated phosphonates at either the ortho, meta cyclisation and lactone opening, the functionalised esters are
or the para position were very well tolerated, conducting to the obtained in synthetically useful yields. In order to explain the
b-substituted esters with excellent enantioselectivities (5d–h). observed configuration, a stereochemical proposal is shown in
The protocol enabled access to the corresponding ester in the Scheme 2. We propose that the nitrogen of the quinine moiety
presence of conjugated heterocyclic acylphosphonate with excel- directly triggers the Mukaiyama–Michael reaction from the si-face
lent enantioselectivities and moderate yield (5i). In the same of the acyl phosphonate and the silyloxy diene reacts through its
manner, silyl dienolate reacted with an aliphatic conjugated carbon 3 due to the close proximity.
system, affording 5j with complete enantiocontrol albeit with a
Lactone rings are structural motifs very often present in
slightly lower yield. Other silyl dienolates were also studied. natural products. Among naturally occurring lactones, the
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Table 2 Scope of reaction for the addition of 2 to 1 in the presence of 3da
products series was assigned by the correlation with a known
compound in the literature (6a) and by circular dichroism. It was
determined as R, assuming the same stereochemical outcome for
all the compounds 4, 5 and 6 (see the ESI†).
In conclusion, we have described an asymmetric Mukaiyama–
Michael reaction of silyl dienolates to a,b-unsaturated acyl
phosphonates as ester surrogates. The employed bifunctional
organocatalyst orchestrated the approach of the silyloxy diene to
the Michael acceptor, leading to the formation of Rauhut–
Currier type esters. The reaction proceeded under mild conditions
with complete regioselectivity, excellent enantiocontrol and a
reasonably high range of a,b-unsaturated phosphonates. In addi-
tion, the methodology led to tri- and tetra-substituted Rauhut–
Currier type esters.
We are grateful to the Spanish Government (CTQ2015-64561-R
and CTQ2016-76061-P) and the European Research Council (ERC-
CG-UNBICAT, contract number: 647550). J. A. F.-S. and V. L.-M.
thank the Spanish Government for a Juan de la Cierva Contract
´
and the Universidad Autonoma de Madrid for a predoctoral
fellowship (FPI-UAM), respectively. Financial support from the
Spanish Ministry of Economy and Competitiveness, through the
‘‘Maria de Maeztu’’ Program of Excellence in R&D (MDM-2014-
0377), is also acknowledged. We acknowledge the generous
allocation of computing time at the CCC (UAM).
a
Conflicts of interest
All the reactions were performed on a 0.1 mmol scale in 0.6 mL of
p-xylene. Enantiomeric excess was determined by SFC chromatography.
There are no conflicts to declare.
Notes and references
1 (a) V. Farina, J. T. Reeves, C. H. Senanayake and J. J. Song, Chem.
Rev., 2006, 106, 2734–2793; (b) M. Breuer, K. Ditrich, T. Habicher,
B. Hauer, M. Keßeler, R. Stu¨rmer and T. Zelinski, Angew. Chem.,
Int. Ed., 2004, 43, 788–824.
2 For selected general reviews on the R–C reaction, see:
(a) K. Chandra Bharadwaj, RSC Adv., 2015, 5, 75923–75946;
(b) P. Xie and Y. Huang, Eur. J. Org. Chem., 2013, 6213–6226;
(c) J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346,
1035–1050; (d) C. E. Aroyan, A. Dermenci and S. J. Miller, Tetrahedron,
2009, 65, 4069–4084; (e) D. K. Nair, T. Kumar and I. N. N. Namboothiri,
Synlett, 2016, 2425–2442; ( f ) A. M. Wensley, N. T. McDougal and
S. E. Schaus, in Lewis Base Catalysis in Organic Synthesis, ed. E. Vedejs
and S. E. Denmark, Wiley-VCH, 2016, pp. 655–714. For selected recent
examples on the R–C reaction, see; (g) X. Su, W. Zhou, Y. Li and
J. Zhang, Angew. Chem., Int. Ed., 2015, 54, 6874–6877; (h) S. Takizawa,
T. M.-N. Nguyen, A. Grossmann, D. Enders and H. Sasai, Angew. Chem.,
Int. Ed., 2012, 51, 5423–5426.
3 (a) Q. Zhao, C. Pei, X. Guan and M. Shi, Adv. Synth. Catal., 2011, 353,
1973–1979; (b) S. Li, Y. Liu, B. Huang, T. Zhou, H. Tao, Y. Xiao, L. Liu
and J. Zhang, ACS Catal., 2017, 7, 2805–2809; (c) W. Zhou, P. Chen,
M. Tao, X. Su, Q. Zhao and J. Zhang, Chem. Commun., 2016, 52,
7612–7615; (d) C. Qin, Y. Liu, Y. Yu, Y. Fu, H. Li and W. Wang, Org.
Lett., 2018, 20, 1304–1307; (e) H. Wang, K. Wang, Y. Man, X. Gao,
L. Yang, Y. Ren, N. Li, B. Tang and G. Zhao, Adv. Synth. Catal., 2017,
359, 3934–3939; ( f ) T.-C. Kang, L.-P. Wu, Q.-W. Yu and X.-Y. Wu,
Chem. – Eur. J., 2017, 23, 6509–6513; (g) X. Dong, L. Liang, E. Li and
Y. Huang, Angew. Chem., Int. Ed., 2015, 54, 1621–1624; (h) W. Zhou,
X. Su, M. Tao, C. Zhu, Q. Zhao and J. Zhang, Angew. Chem., Int. Ed.,
2015, 54, 14853–14857.
Scheme 2 (a) Control experiment and isolation of intermediate 4a. Proposed
coordination model. (b) Derivatization of dihydropyranone derivatives 4 to
compounds 6a and 6b.
5,6-dihydropyran-2-one moiety is of considerable interest from a
chemical and pharmacological perspectives.14 Taking advantage of
the enantioselective formation of lactone 4a, 4,5-disubstituted
dihydropyranones 6a and 6b were obtained with excellent enantio-
selectivities via simple alkene metathesis with styrene (Scheme 2,
eqn (b)). The absolute configuration of the Rauhut–Currier type
4 For selected reviews, see: (a) S. B. J. Kan, Kenneth K.-H. Ng and
I. Paterson, Angew. Chem., Int. Ed., 2013, 52, 9097–9108; (b) J.-i.
Matsuo and M. Murakami, Angew. Chem., Int. Ed., 2013, 52,
9109–9118; (c) S. Hosokawa, Tetrahedron Lett., 2018, 59, 77–88;
This journal is ©The Royal Society of Chemistry 2018
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´
´
´
(d) S. V. Pansare and E. K. Paul, Chem. – Eur. J., 2011, 17, 8770–8779;
9 M. Frıas, R. Mas-Balleste, S. Arias, C. Alvarado and J. Aleman, J. Am.
Chem. Soc., 2017, 139, 672–679.
´
´
´
(e) M. Frıas, W. Cieslik, A. Fraile, A. Rosado-Abon, A. F. Garrido-
´
Castro, F. Yuste and J. Aleman, Chem.
–
Eur. J., 2018, 24, 10 Acylphosphonates have been proven to be efficient ester surrogates.
10906–10933.
For a general review, see: (a) H. Jiang, M. W. Paixao, D. Monge and
5 For selected examples of conjugate addition of various nucleophiles
to a,b-unsaturated esters, see: (a) J. Y. Kang and R. G. Carter, Org.
Lett., 2012, 14, 3178–3181; (b) Y. Kobayashi, Y. Taniguchi,
N. Hayama, T. Inokuma and Y. Takemoto, Angew. Chem., Int. Ed.,
2013, 52, 11114–11118; (c) A. J. M. Farley, C. Sandford and D. J.
Dixon, J. Am. Chem. Soc., 2015, 137, 15992–15995; (d) J. Yang, A. J. M.
K. A. Jørgensen, J. Am. Chem. Soc., 2017, 132, 2775–2783. For
selected recent examples, see: (b) D. Kowalczyk and Ł. Albrecht,
J. Org. Chem., 2016, 81, 6800–6807; (c) A.-D. Steinkamp, M. Frings,
´
I. Thome, I. Schiffers and C. Bolm, Chem. – Eur. J., 2015, 21,
7705–7708; (d) H.-Li Ma, L. Xie, Z. Zhang, J.-Q. Li, Z.-H. Qin and
B. Fu, Adv. Synth. Catal., 2016, 358, 1011–1016.
Farley and D. J. Dixon, Chem. Sci., 2017, 8, 606–610; (e) E. Canales 11 For selected reviews on bifunctional organocatalysis and hydrogen bond
and E. J. Corey, J. Am. Chem. Soc., 2007, 129, 12686–12687.
6 T. Gatzenmeier, P. S. J. Kaib, J. B. Lingnau, R. Goddard and B. List,
Angew. Chem., Int. Ed., 2018, 57, 2464–2468.
activation, see: (a) W.-Y. Siau and J. Wang, Catal. Sci. Technol., 2011, 1,
1298–1310; (b) P. R. Schreiner, Chem. Soc. Rev., 2003, 32, 289–296;
(c) A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713–5743.
´
7 For a review, see: (a) S. V. Pansare and E. K. Paul, Chem. – Eur. J., 12 (a) A. Parra, R. Alfaro, L. Marzo, A. Moreno-Carrasco, J. L. Garcıa Ruano
´
and J. Aleman, Chem. Commun., 2012, 48, 9759–9761; (b) V. Marcos,
2011, 17, 8770–8779; (b) M. Kalesse, M. Cordes, G. Symkenberga and
H.-H. Lu, Nat. Prod. Rep., 2014, 31, 563–594; (c) S. Hosokawa,
Tetrahedron Lett., 2018, 59, 77–88. For selected examples, see:
(d) R. P. Singh, B. M. Foxman and L. Deng, J. Am. Chem. Soc.,
2010, 132, 9558–9560; (e) N. Zhu, B.-C. Ma, Y. Zhang and W. Wang,
Adv. Synth. Catal., 2010, 352, 1291–1295; ( f ) V. Bhasker, M. Gravel
and V. H. Rawal, Org. Lett., 2005, 7, 5657–5660; (g) S. E. Denmark
and G. L. Beutner, J. Am. Chem. Soc., 2003, 125, 7800–7801;
(h) M. Sickert and C. Schneider, Angew. Chem., Int. Ed., 2008, 47,
´
´
J. Aleman, J. L. Garcıa Ruano, F. Marini and M. Tiecco, Org. Lett., 2011,
´
13, 3052–3055; (c) F. Esteban, W. Cieslik, E. M. Arpa, A. Guerrero-
´
´
Corella, S. Dıaz-Tendero, J. Perles, J. A. Fernandez-Salas, A. Fraile and
´
´
J. Aleman, ACS Catal., 2018, 8, 1884–1890; (d) V. Laina-Martın,
´
´
´
´
J. Humbrıas-Martın, J. A. Fernandez-Salas and J. Aleman, Chem.
´
Commun., 2018, 54, 2781–2784; (e) T. Rigotti, A. Casado-Sanchez,
´
˜
S. Cabrera, R. Perez-Ruiz, M. Liras, V. de la Pena O’Shea and
´
J. Aleman, ACS Catal., 2018, 8, 5928.
´
´
3631–3634; (i) L. Ratjen, P. Garcıa-Garcıa, F. Lay, M. E. Beck and 13 The lower yield observed for cyclic product 4a might also be due to
B. List, Angew. Chem., Int. Ed., 2011, 50, 754–758. its instability during the isolation process.
8 S. E. Denmark, J. R. Heemstra and G. L. Beutner, Angew. Chem., 14 J. A. Marco, M. Carda, J. Murga and E. Falomir, Tetrahedron, 2007,
Int. Ed., 2005, 44, 4682–4698.
63, 2929–2958.
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