Catalytic Enantioselective α,β,γ-Trioxygenation

Article abstract of DOI:10.1021/acs.orglett.5b03050

Applying a catalytic enantioselective aldehyde α-oxygenation condition to an enal substrate led to the discovery of the first α,β,γ-trifunctionalization cascade of enals. Under optimal conditions, a tryptophan-derived imidazolidinone catalyst in fluorinated aromatic solvents provided α,β,γ-trioxyaldehydes in up to 51% isolated yield (average of 80% yield per oxygenation step) and 85:15 er. Substitution at the δ position was tolerated, but not at the α, β, or γ positions. The reaction proceeded through initial TEMPO incorporation at the γ position, and rapid racemization of this intermediate, reversible conjugate addition of water, followed by TEMPO incorporation at the α position to set all three stereocenters with double dynamic kinetic resolution.

Full text of DOI:10.1021/acs.orglett.5b03050

Letter
pubs.acs.org/OrgLett
Catalytic Enantioselective α,β,γ-Trioxygenation
Jason S. Chen* and Gayan A. Abeykoon
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: Applying a catalytic enantioselective aldehyde
α-oxygenation condition to an enal substrate led to the
discovery of the first α,β,γ-trifunctionalization cascade of enals.
Under optimal conditions, a tryptophan-derived imidazolidi-
none catalyst in fluorinated aromatic solvents provided α,β,γ-
trioxyaldehydes in up to 51% isolated yield (average of 80%
yield per oxygenation step) and 85:15 er. Substitution at the δ
position was tolerated, but not at the α, β, or γ positions. The
reaction proceeded through initial TEMPO incorporation at
the γ position, and rapid racemization of this intermediate, reversible conjugate addition of water, followed by TEMPO
incorporation at the α position to set all three stereocenters with double dynamic kinetic resolution.
Scheme 1. Summary of Related Cascade Reactions
nantioselective transformations of aldehydes and enals
Epromoted by chiral amine catalysts have been heavily
studied since 2000.1 The most common variants of these
reactions are aldehyde α-functionalizations2 and enal β-
functionalizations,3 but reactions at more remote sites are
also known.4 α-Oxygenations have been developed using
nitrosobenzene,5 TEMPO radical,6 or singlet oxygen7 as the
oxygen source. β-Oxygenations through conjugate addition of
substituted hydroxylamines,8 alcohols,9 or hydrogen peroxide10
have been described, but have found limited application due to
their reversible nature.11 A nonenantioselective γ-oxygenation
using a TEMPO radical has been reported.12
Organocatalytic cascade reactions13 have also been popular.
Conjugate addition to an α,β-unsaturated iminium ion
(generated by condensation of an enal with an amine catalyst)
forms an enamine whose further reaction with an electrophile
leads to α,β-difunctionalization (1 → 2, Scheme 1). The α and
β positions may form new bonds to the same atom, generating
a three-membered ring.14 More often, the enal is coupled to
two different reaction partners. Organocatalytic α,β-difunction-
alizations involving oxygenation at the α15 or β16,9c position
have been developed, but organocatalytic α,β-dioxygenation is
unknown. Some examples of enal β,γ-difunctionalization (1 →
3) have been reported,17 but there is no precedent for enal
α,β,γ-trifunctionalization (organocatalytic or otherwise). How-
ever, ipso,α,β-trifunctionalizations of activated carboxylic acid
derivatives (4 → 5) have been described.18
We became interested in organocatalytic aldehyde α-
oxygenation using stoichiometric TEMPO6 as part of a strategy
for preparing anti-1,2-diols from simple aldehydes.19 The α-
oxygenation proceeds through an enamine mechanism,6c but
the optimal catalysts are imidazolidinone salts originally
designed to promote enal reactions through the intermediacy
of α,β-unsaturated iminium ions.1b This apparent mismatch led
us to wonder what would happen if an enal were subjected to
the α-oxygenation conditions. Would α-oxygenation proceed
with transposition of the alkene? Would conjugate addition of a
nucleophile occur? Or would γ-oxygenation be observed?
To distinguish these possibilities, we subjected enal 6
(Scheme 2) to the aldehyde α-oxygenation conditions. Enal 6
and TEMPO reacted under the influence of imidazolidinone
salt 7·HCl to give γ-oxyenal 8 and α,β,γ-trioxyaldehyde 9, both
in racemic form. Using an excess of enal 6 favored formation of
γ-oxyenal 8, and using an excess of TEMPO favored
trioxyaldehyde 9. Resubjecting γ-oxyenal 8 to the reaction
conditions effected its conversion into trioxyaldehyde 9,
demonstrating that γ-oxyenal 8 likely is an intermediate in
the cascade. The relative stereochemistry of trioxyaldehyde 9
was ascertained by comparing the NMR spectra of tetraacetate
Received: October 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03050
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
mmol reaction) in order to increase the reaction rate. At this
concentration, TEMPO became a significant contributor to
reaction volume; to further enhance the initial rate, TEMPO
was added in two portions. Under these conditions,
imidazolidinone salt 7·AcOH delivered trioxyaldehyde 12 in
higher yield and with superior stereoselectivity as compared
with the hydrochloride salt (Table 1, entries 1 and 2). A solvent
screen revealed improved enantioselectivity in toluene, but at
the expense of yield (Table 1, entries 3−6). Copper(II)
chloride was poorly dissolved in toluene, and so we speculated
that more polar fluorinated aromatic solvents may better
dissolve the copper salt and, thus, rescue the reaction yield
while retaining the improved stereoselectivity (Table 1, entries
7−10). This proved to be the case; use of pentafluorobenzene
delivered a higher yield of the major diastereomer than that
obtained in acetone (albeit with a lower yield of the combined
diastereomers) and an enantiomeric ratio comparable to that
achieved in toluene. The anion of the amine salt was then
varied, but no improvements were forthcoming (Table 1,
entries 11 and 12).
Scheme 2. Discovery of a Trioxygenation Cascade
a
TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy radical. TMP =
2,2,6,6-tetramethylpiperidinyl.
Believing that use of a sterically more demanding catalyst
would improve enantioselectivity, we switched to tryptophan-
derived catalyst 13·AcOH (Figure 1 and Table 1, entries 13−
derivative 10 against the published spectra of all diastereomers
of this compound.20 Shortly after we commenced these
experiments, Jang and co-workers reported the conversion of
enal 6 into γ-oxyenal ( )-8 under similar reaction conditions;12
however, they apparently did not observe trioxyaldehyde 9
since they used TEMPO as the limiting reagent.
C5 enal 6 is difficult to observe by TLC analysis due to its
moderate volatility, so reaction optimization was conducted on
C8 enal 11 (Table 1). Aldol and Michael reaction products
were observed, so enal 11 was added portionwise in order to
suppress its self-dimerization. The reaction was sluggish, and
thus it was run at high concentration (500 μL of solvent for a 1
Figure 1. Other secondary amine catalysts screened.
15).21 The desired trioxygenation did not proceed in acetone
using the bulkier catalyst; only aldol and Michael addition
products were observed. However, use of the bulkier catalyst
improved the enantiomeric ratio to 85:15 when the reaction
was conducted in pentafluorobenzene. Unfortunately, this
change also slowed the conversion of the intermediate γ-
oxyenal into trioxyaldehyde 12. The γ-oxyenal was present in
21% yield after 24 h, but the yield of trioxyaldehyde 12 peaked
at this time since the product slowly decomposed under the
reaction conditions. Nonetheless, a 59% combined yield of two
diastereomers of 12 was obtained. After aldehyde reduction to
facilitate chromatographic separation, the major diastereomer
was isolated in 51% overall yield (i.e., average of 80% yield per
oxygenation).
Amine salts of α,α-diarylprolinols 14 and related silyl ethers
15 also catalyzed the formation of trioxyaldehyde 12. However,
the reactions became even more sluggish when using these
catalysts, and neither yield nor stereoselectivity was improved.
Proline 16, proline methyl ester 17, and their salts did not
catalyze the trioxygenation cascade. However, proline hydro-
chloride (16·HCl) proved to be a good catalyst for γ-
oxygenation. The 71% isolated yield of γ-oxyenal 18 (Scheme
3) using enal 11 as the limiting reagent is comparable to the
best γ-oxygenation yields reported by Jang and co-workers
using TEMPO as the limiting reagent.12
Table 1. Trioxygenation Cascade Optimization
a
b
c
entry
amine salt
solvent
yield (%)
dr
er
1
7·HCl
acetone
acetone
THF
47
2.7:1
4.1:1
9.0:1
ND
43:57
61:39
66:34
ND
2
7·AcOH
7·AcOH
7·AcOH
7·AcOH
7·AcOH
7·AcOH
7·AcOH
7·AcOH
7·AcOH
7·TFA
78 (57)
3
39
4
DMSO
CHCl3
PhMe
0
5
0
ND
ND
6
42
5.5:1
5.0:1
6.8:1
>20:1
3.5:1
6.2:1
5.7:1
ND
73:27
71:29
72:28
70:30
75:25
68:32
71:29
ND
7
PhCF3
69 (52)
54
d
8
C6H3F3
C6HF5
C6F6
9
66 (59)
48
10
11
12
13
14
15
C6HF5
C6HF5
acetone
PhCF3
C6HF5
67
7·HCl
58
13·AcOH
13·AcOH
13·AcOH
0
45 (36)
59 (51)
6.4:1
8.9:1
84:16
85:15
a
Combined yield of two major diastereomers, determined by crude
As shown in Scheme 4, the optimized reaction of C5 enal 6
gave chiral trioxyaldehyde 9, but with an inferior enantiomeric
ratio than that achieved in the reaction of C8 enal 11. The
absolute configuration of trioxyaldehyde 9 (and, by extension,
the other trioxyaldehydes) was determined by comparing the
NMR in the presence of an internal standard. Yields in parentheses
refer to the isolated yield of the major diastereomer after NaBH4-
b
c
mediated reduction. Determined by crude NMR. Determined by
d
chiral HPLC for the major diastereomer. 1,3,5-Trifluorobenzene. ND
= not determined.
B
DOI: 10.1021/acs.orglett.5b03050
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Scheme 3. Proline-Catalyzed γ-Oxygenation
Scheme 6. Proposed Trioxygenation Mechanism
Scheme 4. Trioxygenation of Other Substrates
optical rotation of optically active tetraacetate 10 (Scheme 2)
against that of the known carbohydrate-derived tetraacetate.22
Since the functional group tolerance of the reaction conditions
has already been demonstrated in the context of α-oxygen-
ation,6 we investigated whether the cascade reaction tolerated
branching on or near the enal. Substrates with branching at the
α, β, or γ position did not undergo α,β,γ-trioxygenation or even
γ-oxygenation. Cinnamaldehyde was similarly unreactive. δ-
Branching was tolerated (see 19 → 20), but with poor kinetics.
Use of the less bulky catalyst 7·AcOH delivered a 38% yield of
the combined diastereomers, but the enantiomeric ratio
suffered.
NMR yields refer to the combined yield of two
diastereomers, determined by crude NMR in the presence of
an internal standard. Isolated yields refer to the yield of the
major diastereomer after NaBH4-mediated reduction.
We probed the reaction mechanism of the transformation
since such knowledge might assist in the design of improved
enal α,β,γ-trifunctionalizations. As shown in Scheme 5, racemic
substrate. The reaction proceeds through initial formation of γ-
oxyenal 18, a compound that undergoes rapid racemization
through the intermediacy of dienamine 21. β,γ-Dioxyaldehyde
22 is not detected, suggesting that consistent with the
nonaqueous reaction conditions, conjugate addition of water
is thermodynamically unfavorable.11 Our recent computational
study on 2,2,6,6-piperidinyl-masked vicinal diols23 reveals a
thermodynamic preference for the syn diastereomer of 22,
which adopts a six-membered ring hydrogen bond between the
β-hydroxyl proton and the piperidinyl nitrogen of the masked
γ-hydroxyl group (see 23). The stability conferred by this
hydrogen bond may play a role in achieving a sufficiently high
concentration of β,γ-dioxyaldehyde 22 for the subsequent α-
oxygenation to proceed at a viable rate; recall that
cinnamaldehyde is unreactive. Since water addition is reversible
and the enantiomers of γ-oxyenal 18 equilibrate, α-oxygenation
sets all three stereocenters with double dynamic kinetic
resolution. The configuration of the masked α-hydroxyl group
is consistent with that observed in the α-oxygenation of simple
aldehydes.6
Scheme 5. Evidence for Dynamic Kinetic Resolution
In conclusion, we discovered the first enal α,β,γ-trifunction-
alization cascade. The reported trioxygenation is of limited
synthetic utility due to moderate enantioselectivity, but the
mechanistic insight gained is expected to be useful for the
design of improved polyfunctionalization cascades. For
example, using a tethered nucleophile or a nucleophile that
adds irreversibly should enhance the overall reaction rate by
improving the thermodynamic driving force for the β-
functionalization step. The latter change might also enhance
enantioselectivity since the catalyst would be able to exert its
influence at two steps (α- and β-functionalization). Efforts to
translate these ideas into improved cascades are underway.
γ-oxyenal 18 reacted under the optimized trioxygenation
conditions to afford trioxyaldehyde 12 in 63% isolated yield
(single diastereomer after aldehyde reduction) with 82:18 er
and racemic recovered starting material ( )-18 in 25% isolated
yield. The 64% combined yield of compounds with the (R)
configuration at the γ position (12% (R)-18 + 52% major
enantiomer of 12) proves that the enantiomers of γ-oxyenal 18
interconvert under the reaction conditions to afford dynamic
kinetic resolution.16f,h
The above data lead to a clear mechanistic overview of the
cascade, outlined in Scheme 6 using enal 11 as a model
C
DOI: 10.1021/acs.orglett.5b03050
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Letter
1210. (e) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cor
Angew. Chem., Int. Ed. 2007, 46, 778.
́
dova, A.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03050.
■
S
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AUTHOR INFORMATION
Corresponding Author
■
́
*E-mail: jschen@iastate.edu.
Notes
Q.; Leijonmarck, H.; Cor
(g) Quintard, A.; Alexakis, A. Chem. Commun. 2011, 47, 7212.
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The authors declare no competing financial interest.
(h) McGarraugh, P. G.; Johnston, R. C.; Martínez-Munoz, A.; Cheong,
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P. H.-Y.; Brenner-Moyer, S. E. Chem. - Eur. J. 2012, 18, 10742.
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Escrich, C.; Davis, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134,
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Chem., Int. Ed. 2012, 51, 4104. (c) Appayee, C.; Fraboni, A. J.;
Brenner-Moyer, S. E. J. Org. Chem. 2012, 77, 8828.
ACKNOWLEDGMENTS
■
We thank J. L. Przybylski (Iowa State University) for technical
assistance. This research was supported by the National Science
Foundation (JSC: CHE-1453896; NMR spectrometers: CHE-
0946687 and MRI-1040098).
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