Asymmetric synthesis of tri- and tetrasubstituted trifluoromethyl dihydropyranones from α-aroyloxyaldehydes via NHC redox catalysis

Article abstract of DOI:10.1021/cs500667g

The asymmetric synthesis of tri- and tetrasubstituted trifluoromethyl dihydropyranones via an NHC-catalyzed redox process, introducing methyl, benzyl, and aryl substituents to the C(5) position, is presented. Their substrate-controlled derivatization into

Full text of DOI:10.1021/cs500667g

Research Article
pubs.acs.org/acscatalysis
Asymmetric Synthesis of Tri- and Tetrasubstituted Trifluoromethyl
Dihydropyranones from α‑Aroyloxyaldehydes via NHC Redox
Catalysis
Alyn T. Davies, Philip M. Pickett, Alexandra M. Z. Slawin, and Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, United Kingdom
S
* Supporting Information
ABSTRACT: The asymmetric synthesis of tri- and tetrasubstituted trifluoromethyl dihydropyranones via an NHC-catalyzed
redox process, introducing methyl, benzyl, and aryl substituents to the C(5) position, is presented. Their substrate-controlled
derivatization into δ-lactones and cyclic hemiacetals containing stereogenic trifluoromethyl groups is also described.
KEYWORDS: asymmetric organocatalysis, N-heterocyclic carbenes, cycloaddition, trifluoromethyl, dihydropyranones, δ-lactones
processes utilize [4 + 2] cycloadditions almost exclusively, with
β-substituted α,β-unsaturated ketones, ketimines, and aldimines
the most common substrates for such reactions.5,6 To date,
little work has examined α,β-disubstituted α,β-unsaturated
ketones in these processes, which would introduce substituents
at the C(5) position of the dihydropyranone. The state of the
art in this area is represented by work from Kobayashi and Chi,
which has been limited to activated biscarbonyl functionalities
when preparing C(5)-substituted dihydropyranones (Scheme
2).7−9
We have previously shown that α-aroyloxyaldehydes can act
as acyl azolium precursors, allowing the synthesis of both esters
and amides in good yield.10a Alternatively, these α-aroyloxy-
aldehydes can be used as azolium enolate precursors, able to
undergo formal [4 + 2] cycloaddition processes with α,β-
unsaturated β-trifluoroketones and N-aryl-N′-aroyldiazines.10
These aldehydes offer bench-stable alternatives to α-halo-
aldehydes5 or α-aryloxyaldehydes11 and can be synthesized in a
single step from the corresponding aldehyde using the protocol
of Ishihara et al.12
INTRODUCTION
■
The asymmetric synthesis of complex molecules containing
contiguous stereocenters has been the focus of extensive
research owing to the prevalence of such motifs in Nature and
the significant challenges in their formation.1 Organocatalysis
has become a highly efficient method for the synthesis of these
systems,2 with N-heterocyclic carbenes (NHCs) established as
effective organocatalysts for asymmetric transformations.3
Within this field, NHC-catalyzed redox chemistry allows access
to three distinct reactivity modes through which bonds can be
constructed. Acyl azoliums and azolium enolates can be
accessed from α-functionalized aldehydes, while homoenolates,
as well as acyl azoliums and azolium enolates, can be utilized
from enals (Scheme 1).4
[4 + 2] Cycloadditions are a key reaction class within NHC-
catalyzed redox azolium enolate chemistry. Currently reported
Scheme 1. NHC Redox Catalysis Mode of Reactivity
In this article, the asymmetric NHC-catalyzed redox [4 + 2]
cycloaddition of α-aroyloxyaldehydes with a range of trifluoro-
methylenones is reported. This process accommodates
variation at both the α- and β-positions within the trifluoro-
methylenone acceptor, as well as incorporation of the
pharmaceutically relevant trifluoromethyl unit (Scheme
3).13,14 This protocol allows methyl, benzyl, and aryl
substituents to be introduced at the C(5) position of the
Received: May 15, 2014
Revised: June 20, 2014
Published: June 24, 2014
© 2014 American Chemical Society
2696
dx.doi.org/10.1021/cs500667g | ACS Catal. 2014, 4, 2696−2700

ACS Catalysis
Research Article
Scheme 2. Previous Work of Kobayashi and Chi
Incorporating C(5) Substituents within Dihydropyranones
Scheme 4. Typical δ-Lactone Synthesis via Evans Aldol
Chemistry20
synthesized by an enamine−aldol reaction between a trifluoro-
ketone and a substituted benzaldehyde. Treatment of amino-
indanol-derived NHC precatalyst 1 (10 mol %) with cesium
carbonate in dichloromethane with 1.5 equiv of α-aroyloxy-
aldehyde and 1 equiv of α,β-unsaturated trifluoromethylketone
gave the syn-dihydropyranone in 65% yield, >95:5 dr, and 99%
ee (Table 1).
Further investigations varied the α-substituent on the α,β-
unsaturated trifluoromethylketone, giving differing substitution
at the C(5) position of the dihydropyranone. Applying the
same conditions to an α-methyl α,β-unsaturated trifluoro-
Scheme 3. Expansion of C(5) Scope and Derivatization to
Highly Functionalized δ-Lactones
Table 1. [4 + 2] Cycloadditions: α-Substituent Variation of
Trifluoromethylenone
dihydropyranone products through NHC redox catalysis. The
synthetic utility of the dihydropyranones formed has also been
shown through their conversion into δ-lactones through
substrate-controlled stereoselective hydrogenation.
The δ-lactone motif is a privileged structural class within
Nature, appearing within numerous natural products that
exhibit a wide range of biological activity.15 Many of these δ-
lactones contain multiple, contiguous stereocenters, and as
such, there is great interest in the preparation of such
synthetically challenging molecules.16 The majority of currently
reported processes for δ-lactone synthesis rely on the
prevalence of C(4) hydroxy substituents in δ-lactone-
containing natural products. Usual approaches to δ-lactone
synthesis tackle the problem in the same way as Nature,17
namely, through an aldol condensation and subsequent
lactonization. A common method of approaching this aldol
reaction stereoselectively is through the chiral auxiliary
chemistry developed by Evans (Scheme 4).18,19 The method
described within this article therefore offers an alternative,
catalytic, two-step route toward tetrasubstituted δ-lactones,
allowing access to unusual substitution patterns that have not
been previously accessed.
RESULTS AND DISCUSSION
■
Initial studies probed the effect of the α-substituent on the α,β-
unsaturated trifluoromethylketone in a model cycloaddition
using α-aroyloxyaldehyde 2. Synthesis of the α,β-unsaturated
trifluoromethylketone was achieved by the protocol of Yuan et
al.21 using N-phenyltrifluoroacetimidoyl chloride. The α,β-
disubstituted α,β-unsaturated trifluoromethylketones were
a
b
Isolated yield of major diastereoisomer. Diastereomeric ratio
c
1
determined by analysis of the crude H NMR spectra. Enantiomeric
excess determined by chiral HPLC or chiral GC analysis. Using
CH2Cl2. Using THF.
d
e
2697
dx.doi.org/10.1021/cs500667g | ACS Catal. 2014, 4, 2696−2700

ACS Catalysis
Research Article
methylketone gave 44% conversion into the tetrasubstituted
syn-dihydropyranone 4 in >95:5 dr. Changing the solvent to
THF gave the product in 59% yield, >95:5 dr, and >99% ee.22
With an optimized process for the synthesis of C(5)-substituted
dihydropyranones, investigation of the scope of the α-
substituent on the α,β-unsaturated trifluoromethylketone was
undertaken. Incorporation of C(5) benzyl and phenyl
substituents (5 and 6), as well as electron-donating and
electron-withdrawing aryl substituents (7 and 8), proceeded in
good to excellent yield, with excellent diastereo- and enantio-
selectivity throughout (Table 1).
Further work probed variation at the C(3) position of the
dihydropyranone arising from modification of the α-aroyloxy-
aldehyde component. A methyl group is readily incorporated (3
and 11) as well as an extended alkyl chain (Bu, 9 and 12) and
an alkyl group containing a protected pendant heteroatom (R =
CH2CH2OBn, 10 and 13) (Table 2). However, α-aroyloxy-
aldehydes containing β-branching (e.g., R = i-Pr) are
completely unreactive in this system.23
ortho-substituted aryl groups, and the 2-naphthyl group (15−
18). Exploration of the scope continued using α-methyl α,β-
unsaturated trifluoromethylketone, with the introduction of a
para-bromo substituent (19) being well-tolerated.22 The
electron-withdrawing para-nitro group again required reduced
reaction times (20), and other electron-withdrawing aryl
groups (R = p-FC6H4, 21) could also be incorporated.
Electron-donating aryl groups (R = p-OMeC6H4, 22; R = p-
MeC6H4, 11) and heteroaromatic groups (R = 2-furyl, 23) were
tolerated (Table 3); however, no conversion into the desired
product was observed when attempting to introduce an ortho-
bromo group.
Further Functionalization: Synthesis of δ-Lactols and
δ-Lactones. Having successfully synthesized a variety of
dihydropyranones, we examined their further transformation
Table 3. [4 + 2] Cycloadditions: β-Substituent Variation of
the Trifluoromethylenone
Table 2. [4 + 2] Cycloadditions: α-Aroyloxyaldehyde
Variation
a
b
Isolated yield of major diastereoisomer. Diastereomeric ratio
c
1
determined by analysis of the crude H NMR spectra. Enantiomeric
excess determined by chiral HPLC or chiral GC analysis. Using
CH2Cl2. Using THF.
d
e
Further variation of the β-position of the α,β-unsaturated
trifluoromethylketone was investigated. Introducing a para-
bromophenyl substituent to the C(4) position of the
dihydropyranone (14) allowed for the absolute configuration
to be assigned by X-ray crystallography as (3S,4S).24
Interestingly this example required a reduced reaction time
compared to other substrates, suggesting the electronic nature
of the α,β-unsaturated trifluoromethylketone is important in
controlling reactivity within this system. Electron-donating aryl
groups were also tolerated, as well as heteroaromatic groups,
a
b
Isolated yield of major diastereoisomer. Diastereomeric ratio
c
1
determined by analysis of the crude H NMR spectra. Enantiomeric
excess determined by chiral HPLC or chiral GC analysis. Using
CH2Cl2. Using THF.
d
e
2698
dx.doi.org/10.1021/cs500667g | ACS Catal. 2014, 4, 2696−2700

ACS Catalysis
Research Article
into synthetically useful chiral building blocks containing a
stereogenic trifluoromethyl group. Treatment of dihydro-
pyranone 3 with lithium aluminum hydride gave the quaternary
trifluoromethyl lactol 24 in 81% yield as a single diastereo-
isomer.14a The generality of this process was examined, with
Proposed Mechanism. The mechanism and stereo-
selectivity of this NHC redox process is believed to proceed
in a similar manner to that proposed by the groups of Bode and
Kozlowski, through a concerted, but highly asynchronous,
hetero-Diels−Alder reaction (Scheme 6).25 After deprotonation
incorporation of a variety of C(3) substituents (R1
=
CH2CH2OBn, 25; R1 = Bu, 26), as well as a C(4) electron-
rich (R2 = p-OMeC6H4, 27) and halogenated (R2 = p-BrC6H4,
28) aryl substituent, with products formed in good yield,
excellent diastereomeric ratio, and enantiomeric excess24
(Table 4).
Scheme 6. Proposed Catalytic Cycle
Table 4. Reduction of Dihydropyranones with LiAlH4
of triazolium salt precatalyst 1, reversible addition of the free
NHC I to the aldehyde gives adduct II.26 A deprotonation/
reprotonation step allows access to Breslow intermediate III,
which can eliminate para-nitrobenzoate to leave azolium enol
IV. Deprotonation allows access to the azolium enolate
intermediate V, which undergoes a concerted, but highly
asynchronous, hetero-Diels−Alder [4 + 2] cycloaddition to
leave VI.25 Elimination of the free carbene catalyst completes
the catalytic cycle and provides the product.
a
b
Isolated yield of major diastereoisomer. Diastereomeric ratio
c
1
determined by analysis of the crude H NMR spectra. Enantiomeric
excess determined by chiral HPLC or chiral GC analysis. Reaction
performed at −78 °C.
d
CONCLUSION
■
In summary, the synthesis of a number of tri- and tetra-
substituted trifluoromethyl dihydropyranones from α,β-unsatu-
rated trifluoromethylketones and α-aroyloxyaldehydes using an
NHC-catalyzed redox process has been demonstrated,
producing synthetically useful products in good yield, diastereo-
selectivity, and enantioselectivity. Stereoselective derivatization
of the products under substrate control has also been shown.
Current research within this laboratory is focused on
developing alternative novel asymmetric processes using α-
aroyloxyaldehydes in NHC redox catalysis.
To access a δ-lactone containing four contiguous stereo-
centers, hydrogenation of dihydropyranone 11 gave δ-lactone
29 in good yield22 and as a single diastereoisomer. The relative
configuration within 29 was confirmed by NOESY analysis.22
Ring opening of δ-lactone 29 through treatment with catalytic
DMAP in methanol provided 30 in good yield, >95:5 dr, and
>99% ee (Scheme 5).
Scheme 5. Hydrogenation of Dihydropyranone 11 and Ring
Opening to Hydroxyester 30
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental procedures and characterization, as well as 1H
and 13C NMR spectra for novel compounds and crystallo-
graphic data where relevant can be found in the Supporting
Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
a
b
Isolated yield of major diastereoisomer. Diastereomeric ratio
c
1
Corresponding Author
determined by analysis of the crude H NMR spectra. Enantiomeric
excess determined by chiral HPLC or chiral GC analysis.
*E-mail: ads10@st-andrews.ac.uk.
2699
dx.doi.org/10.1021/cs500667g | ACS Catal. 2014, 4, 2696−2700

ACS Catalysis
Research Article
16, 964−967. (d) Morrill, L. C.; Smith, S. M.; Slawin, A. M. Z.; Smith,
A. D. J. Org. Chem. 2014, 79, 1640−1655.
Notes
The authors declare no competing financial interest.
(15) (a) Chiu, P.; Leung, L. T.; Ko, B. C. B. Nat. Prod. Rep. 2010, 27,
1066−1083. (b) Florence, G. J.; Gardner, N. M.; Paterson, I. Nat.
Prod. Rep. 2008, 25, 342−375.
ACKNOWLEDGMENTS
■
(16) (a) Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.;
Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 2000, 122, 8654−8664. (b) Girotra, N. N.; Wendler,
N. L. Tetrahedron Lett. 1982, 23, 5501−5504. (c) White, J. D.;
Blakemore, P. R.; Green, N. J.; Hauser, E. B.; Holoboski, M. A.;
Keown, L. E.; Nylund Kolz, C. S.; Phillips, B. W. J. Org. Chem. 2002,
67, 7750−7760.
We thank the Royal Society for a University Research
Fellowship (A.D.S.), and the European Research Council
under the European Union’s Seventh Framework Programme
(FP7/2007-2013) ERC Grant Agreement No. 279850
(A.T.D.). We also thank the EPSRC UK National Mass
Spectrometry Facility at Swansea University.
(17) Gokhale, R. S.; Tsuji, S. Y.; Cane, D. E.; Khosla, C. Science 1999,
284, 482−485.
REFERENCES
■
(18) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23−32. (b) Davies,
S. G.; Nicholson, R. L.; Smith, A. D. Org. Biomol. Chem. 2004, 2,
3385−3400.
(1) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134−7186.
(2) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 9202−9205.
(3) For reviews on NHC catalysis, see: (a) Marion, N.; Díez-
(19) Catalytic methods of δ-lactone synthesis are uncommon,
although not unheard of: (a) Casas, J.; Engqvist, M.; Ibrahem, I.;
́
Kaynak, B.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 1343−1345.
́
Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988−3000.
(b) Albrecht, L.; Richter, B.; Krawczyk, H.; Jørgensen, K. A. J. Org.
Chem. 2008, 73, 8337−8343.
(b) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606−5655. (c) Moore, J. L.; Rovis, T. Top. Curr. Chem. 2010, 291,
77−144. (d) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev.
2013, 42, 4906−4917.
(20) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720−
14721.
(21) Zhang, D.; Yuan, C. Eur. J. Org. Chem. 2007, 3916−3924.
(22) See Supporting Information for further details on optimization
and stereochemical assignment.
(23) α-Aryl α-aroyloxyaldehydes rearrange under redox NHC
catalysis conditions to give the corresponding α-aroyl acetophenone;
see ref 10a.
(24) Crystallographic data for 14, 19, and 28 have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 984035, CCDC 984036, and CCDC
984037, respectively.
(25) Allen, S. E.; Mahatthananchai, J.; Bode, J. W.; Kozlowski, M. C.
J. Am. Chem. Soc. 2012, 134, 12098−12103.
(26) Collett, C. J.; Massey, R. S.; Maguire, O. R.; Batsanov, A. S.;
O’Donoghue, A. C.; Smith, A. D. Chem. Sci. 2013, 4, 1514−1522.
(4) For reviews on NHC redox catalysis, see: (a) Vora, H. U.;
Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617−1639.
(b) Douglas, J.; Churchill, G.; Smith, A. D. Synthesis 2012, 44, 2295−
2309.
(5) (a) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 9518−9519. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am.
Chem. Soc. 2006, 128, 15088−15089.
(6) Azolium enolates can be accessed from unfunctionalized
aldehydes and NHCs with an external oxidant: (a) Zhao, X.; Ruhl,
K. E.; Rovis, T. Angew. Chem., Int. Ed. 2012, 51, 12330−12333.
(b) Mo, J.; Yang, R.; Chen, X.; Tiwari, B.; Chi, Y. R. Org. Lett. 2013,
15, 50−53.
(7) (a) Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I.
Org. Lett. 2009, 11, 3934−3937. (b) Fang, X.; Chen, X.; Chi, Y. R. Org.
Lett. 2011, 13, 4708−4711.
(8) Substitution at the α-position of the acceptor is possible by using
an imidazolidinone ring system: O’Bryan McCusker, E.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2013, 52, 13616−13620.
(9) Azolium enolates accessed via ketenes have also been shown to
react with α-substituted enones: (a) Lv, H.; You, L.; Ye, S. Adv. Synth.
Catal. 2009, 351, 2822−2826. (b) Lv, H.; Chen, X.-Y.; Sun, L.-H.; Ye,
S. J. Org. Chem. 2010, 75, 6973−6976. (c) Jian, T.-Y.; Chen, X.-Y.;
Sun, L.-H.; Ye, S. Org. Biomol. Chem. 2013, 11, 158−163.
(10) (a) Ling, K. B.; Smith, A. D. Chem. Commun. 2011, 47, 373−
375. (b) Davies, A. T.; Taylor, J. E.; Douglas, J.; Collett, C. J.; Morrill,
L. C.; Fallan, C.; Slawin, A. M. Z.; Churchill, G.; Smith, A. D. J. Org.
Chem. 2013, 78, 9243−9257. (c) Taylor, J. E.; Daniels, D. S. B.; Smith,
A. D. Org. Lett. 2013, 15, 6058−6061.
(11) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc.
2009, 131, 18028−18029.
(12) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K. Angew. Chem., Int.
Ed. 2011, 50, 5331−5334.
(13) The trifluoromethyl group is highly desired due to the unique
physicochemical properties it can impart onto molecules: (a) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320−330. (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369.
(c) Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and
Applications; Petrov, V. A.; John Wiley & Sons: Hoboken, NJ, 2009; pp
397−506.
(14) Previous work on incorporating trifluoromethyl groups from the
Smith group: (a) Morrill, L. C.; Douglas, J.; Lebl, T.; Slawin, A. M. Z.;
Fox, D. J.; Smith, A. D. Chem. Sci. 2013, 4, 4146−4155. (b) Stark, D.
G.; Morrill, L. C.; Yeh, P.-P.; Slawin, A. M. Z.; O’Riordan, T. J. C.;
Smith, A. D. Angew. Chem., Int. Ed. 2013, 52, 11642−11646. (c) Yeh,
P.-P.; Daniels, D. S. B.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2014,
2700
dx.doi.org/10.1021/cs500667g | ACS Catal. 2014, 4, 2696−2700