Tandem sequence of phenol oxidation and intramolecular addition as a method in building heterocycles

Article abstract of DOI:10.1021/jo302002j

A tandem phenol oxidation-Michael addition furnishing oxo- and -aza-heterocycles has been developed. Dirhodium caprolactamate [Rh ₂(cap)₄] catalyzed oxidation by T-HYDRO of phenols with alcohols, ketones, amides, carboxylic acids, and N-Boc protected amines tethered to their 4-position afforded 4-(tert-butylperoxy)cyclohexa-2,5-dienones that undergo Bronsted acid catalyzed intramolecular Michael addition in one-pot to produce oxo- and -aza-heterocycles in moderate to good yields. The scope of the developed methodology includes dipeptides Boc-Tyr-Gly-OEt and Boc-Tyr-Phe-Me and provides a pathway for understanding the possible transformations arising from oxidative stress of tyrosine residues. A novel method of selective cleavage of O-O bond in hindered internal peroxide using TiCl₄ has been discovered in efforts directed to the construction of cleroindicin F, whose synthesis was completed in 50% yield over just 3 steps from tyrosol using the developed methodology.

Full text of DOI:10.1021/jo302002j

Article
pubs.acs.org/joc
Tandem Sequence of Phenol Oxidation and Intramolecular Addition
as a Method in Building Heterocycles
Maxim O. Ratnikov, Linda E. Farkas, and Michael P. Doyle*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S
* Supporting Information
ABSTRACT: A tandem phenol oxidation−Michael addition furnishing oxo- and -aza-heterocycles has been developed.
Dirhodium caprolactamate [Rh2(cap)4] catalyzed oxidation by T-HYDRO of phenols with alcohols, ketones, amides, carboxylic
acids, and N-Boc protected amines tethered to their 4-position afforded 4-(tert-butylperoxy)cyclohexa-2,5-dienones that undergo
Brønsted acid catalyzed intramolecular Michael addition in one-pot to produce oxo- and -aza-heterocycles in moderate to good
yields. The scope of the developed methodology includes dipeptides Boc-Tyr-Gly-OEt and Boc-Tyr-Phe-Me and provides a
pathway for understanding the possible transformations arising from oxidative stress of tyrosine residues. A novel method of
selective cleavage of O−O bond in hindered internal peroxide using TiCl4 has been discovered in efforts directed to the
construction of cleroindicin F, whose synthesis was completed in 50% yield over just 3 steps from tyrosol using the developed
methodology.
nones upon treatment with TiCl4 (eq 2),4b with 4-substituents
that include alkyl, cycloalkyls, and allyl. This protocol was
INTRODUCTION
Recently, we reported dirhodium caprolactamate [Rh2(cap)4]
catalyzed oxidation of 4-subtituted phenols by 70% aqueous
solution of tert-butyl hydroperoxide (T-HYDRO).1 This
protocol furnishes 4-(tert-butyldioxy)cyclohexa-2,5-dienones
in yields generally above 70% (eq 1). The radical nature of
■
recently applied to the syntheses from p-cresol of vitamin K1
(36% yield, 5 steps) and vitamin K3 (79% yield, 4 steps).6 In a
more recent study, Rovis employed 4-hydroperoxy-2,5-
dienones in an enantioselective cascade acetylation−oxo-
Michael addition tandem sequence for the synthesis of
anticancer agents bearing the peroxide functionality (Scheme
the oxidation tolerates a variety of alkyl, aryl, and carboxylate
groups and is insensitive to nucleophiles or dioxygen. 4-
Substituted 2,5-dienone scaffolds are prepared by Rh2(cap)4
catalyzed oxidation by T-HYDRO with yields higher than those
1).4a
We envisioned that the 4-substituent of 2,5-dienone could
serve as a functional handle for syntheses of bicyclic products
achieved with Oxone2 and with fewer byproducts than are
bearing the peroxide functionality. Furthermore, the versatility
of the Rh2(cap)4 oxidative system1,7 indicated a potential for
conducting oxidation and intramolecular cyclization steps in
one-pot. Although several protocols were reported for
desymmetrization of 4-subtituted 2,5-dienones,3b,8 the
Brønsted acid catalyzed intramolecular oxo-Michael addition
generated with hypervalent iodine reagents.2,3 The versatility
and stated advantages of phenol oxidation by T-HYDRO and
commercial availability of 4-substituted phenols prompted us to
explore applications of phenol oxidation in synthesis.
4-(Alkylperoxy)cyclohexa-2,5-dienones are synthetically use-
ful fragments4 and are known to form under oxidative stress in
lipid cell membranes.5 Murahashi has shown that 4-(tert-
butyldioxy)cyclohexa-2,5-dienones afford 2-substituted p-qui-
Received: September 13, 2012
© XXXX American Chemical Society
A
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Scheme 1. Asymmetric Synthesis of 1,2,4-Trioxanes from 4-(Hydroperoxy)cyclohexa-2,5-dienones
is the most attractive.2,9 Carreno prepared a series of cis-furan
Table 1. Catalyst Optimization for Phenol Oxidation by T-
HYDRO
and cis-pyran-fused cyclohexenones in 47−91% yield from
correspoding 4-substituted 2,5-dienones using p-toluenesul-
fonic acid (TsOH) to promote the intramolecular oxo-Michael
addition.9 A chiral version of the intramolecular oxo-Michael
addition of 4-substituted 2,5-dieones was developed by You.2
The method forms cis-fused 1-oxo- and 1,4-dioxo-heterocycles
in 71−92% yield and 61−95% ee in the presence of BINOL-
derived chiral phosphoric acids (Scheme 2). Moreover,
activation of the 2,5-dienone fragment by a Brønsted acid
was expected to be general not only for alcohols but also for
carboxylates and aza-nucleophiles.
a
entry
catalyst
RuCl3
catalyst loading, mole %
yield, %
1
2
3
4
1
1
1
2
23
48
66
48
RuCl2(PPh3)3
Rh2(cap)4
Rh2(cap)4
Scheme 2. The Asymmetric Intramolecular Oxo-Michael
Addition Catalyzed by BINOL-Derived Chiral Phosphoric
Acid
a
Determined by 1H NMR spectroscopy from the ratio of the
absorption (6.32 ppm, d, J = 10.2 Hz, 2H) corresponding to 2 and that
for the biphenyl internal standard (7.60 ppm, d, J = 7.2 Hz, 4H).
1
Although H NMR spectroscopic and TLC analyses showed
that the sample contained only 2,5-dienone 2 after 1.5 h in the
reaction mixture from Rh2(cap)4 catalyzed phenol oxidation by
T-HYDRO, the isolated yield was not quantitative. The
reaction temperature was lowered to room temperature in an
1
attempt to improve product yield, and H NMR spectroscopy
revealed the formation of transient o-quinone 3 along with a
53% yield of 2,5-dienone 2 (eq 3). However, o-quinone 3 was
RESULTS AND DISCUSSION
■
Development of the phenol oxidation−Michael addition
tandem transformation was begun with tyrosol 1, the precursor
to cleroindicin F2 which is a component of Clerodendrum
indicum plant extracts used to treat malaria and rheumatism.10
Initial phenol oxidation experiments were conducted under
conditions previously developed for the Rh2(cap)4 oxidation of
4-substituted phenols [4 equiv of T-HYDRO in 1,2-dichloro-
ethane (DCE) at 40 °C].1 The evaluation of the most active
catalysts for 4-substituted phenol oxidation with T-HYDRO
[RuCl3, RuCl2(PPh3)3, and Rh2(cap)4]1 at 1.0 mol % loading
revealed that dirhodium caprolactamate provided the best yield
in the conversion of 1 to 2 (Table 1, entries 1−3). The use of
2.0 mol % of Rh2(cap)4 eroded the yield of 2,5-dienone 2
(entry 4) while 0.5 mol % of Rh2(cap)4 gave incomplete
conversion. Thus, 4 equiv of T-HYDRO in 1,2-dichloroethane
(DCE) at 40 °C using 1.0 mol % of Rh2(cap)4 was selected as
the first approximation of optimal conditions.
unstable under the reaction conditions, and its decomposition
products were insoluble in the reaction mixture after 1.5 h at 40
°C. The evaluation of solvents, concentrations, anhydrous
TBHP, and different modes of reactant addition gave no
improvement of 2,5-dienone 2 yield (Supporting Information).
The versatility of Rh2(cap)4 catalyzed phenol oxidation by T-
HYDRO was examined for 4-substituted phenols bearing
alcohol groups, carboxylic acids, methyl ketone, and the Boc-
protected amine. The corresponding 2,5-dienones were isolated
B
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Table 2. Dirhodium Caprolactamate Oxidation of Phenols Bearing Tethered Nucleophiles by T-HYDRO
a
b
c
Yield after the silica gel plug. A total of 2.0 mol % of [Rh2(cap)4] were used. The yield of volatile p-quinone (6.70 ppm, s, 4H) was determined by
1H NMR spectroscopy from the ratio of the absorption for 15 to that for the biphenyl internal standard (7.60 ppm, d, J = 7.2 Hz, 4H).
in 45−65% yields (Table 2). Similar to the oxidation of 1,
phenol oxidations presented in Table 2 contained only 2,5-
dienone products in their reaction mixtures. Pure 2,5-dienone
products can be rapidly isolated by filtration of the reaction
mixture through a silica gel plug. Although product yields vary,
phenol oxidation by T-HYDRO, catalyzed by Rh2(cap)4, is not
restricted by carboxylic acid, alcohol, and ketone substituents
that could serve as potential nucleophiles in subsequent
reactions. Likewise, the presence of the N-Boc group in
tyramine 12 did not alter the oxidation pathway and furnished
2,5-dienone 13 in 59% yield (entry 5). The oxidation of p-
hydroxybenzyl alcohol 14, however, produced p-quinone
presumably due to fragmentation of the initially formed
mixed peroxide to the observed p-benzoquinone (entry 6).1
All prepared 2,5-dienones were rapidly isolated by filtration of
the reaction mixture through a silica gel plug.
The development of a phenol oxidation−Michael addition
tandem transformation was initiated with the combination of
catalysts for phenolic oxidation by Rh2(cap)4 and oxo-Michael
addition by BINOL-based phosphoric acid 17. However,
addition of 17 inhibited the oxidation step (Table 3, entries 1
and 2), but introduction of 17 after completion of the phenol
oxidation furnished 16 with >20:1 diastereoselectivity after 16 h
at room temperature (entry 3). The stereochemistry of the
bicyclic ring junction was extrapolated by analogy with the
Brønsted acid catalyzed intramolecular oxo-Michael addition of
4-hydroperoxy-2,5-dienones reported by Carreno.9 Further-
more, the addition of drying reagents improves percent
conversion in the oxo-Michael reaction (entries 4−6). Addition
C
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Table 3. Optimization of Conditions for Tandem Phenolic Oxidation−Michael Addition
a,
b
c,d
entry
loading of acid 17, %
mode of addition
additive
conversion of phenol oxidation, %
conversion of Michael addition, %
e
1
2
3
4
5
6
10
2
simultaneous
simultaneous
stepwise
―
―
―
4 Å sieves
4 Å sieves
Na2SO4
45
70
nd
nd
78
85
17
91
10
10
2
100
100
100
stepwise
stepwise
10
stepwise
100
a
b
Conversion of phenol oxidation step was determined from relative concentrations of 1 and 2. Relative concentrations of 1 and 2 were determined
by 1H NMR spectroscopy from the ratio of the absorptions (6.70 ppm, dd, J = 8.0, 2.1 Hz, 2H) corresponding to 1 and (6.32 ppm, d, J = 10.2 Hz,
c
2H) corresponding to 2, and that for the biphenyl internal standard (7.60 ppm, d, J = 7.2 Hz, 4H). Conversion of the Michael addition step was
d
determined from relative concentrations of 2 and 16. Relative concentrations of 2 and 16 were determined by 1H NMR spectroscopy from the ratio
of the absorptions (6.32 ppm, d, J = 10.2 Hz, 2H) corresponding to 2, (6.09 ppm, d, J = 10.3 Hz, 1H) corresponding to 16, and that for the biphenyl
e
internal standard (7.60 ppm, d, J = 7.2 Hz, 4H). nd: not determined.
of anhydrous Na2SO4 was found to give optimal results for the
stepwise Rh2(cap)4 phenol oxidation by T-HYDRO followed
by Brønsted acid catalyzed oxo-Michael addition.
products were improved if L-tyrosine derivatives lacked the
carboxylic acid group (entry 4) or contained an ester
functionality (entries 5 and 6). The lower product yield
obtained in the absence of carboxylic acid is presumably caused
by the lower yield in the phenol oxidation step (compare Table
5, entries 1 and 5 with Table 2, entries 1 and 2). Diastereomers
formed from 31 and 32 were separable on silica gel and isolated
as individual isomers. The diastereochemistry of the ester group
was determined by NOE experiments for diastereomers 31 and
32 (Figure 2). The phenol oxidation−aza-Michael addition
occurred in the presence of the amide group but required 1.5
equiv of Brønsted acid (entry 7). Furthermore, although the
oxidation of dipeptide 37 could occur at the benzylic position
of a phenylalanine residue as well as at the phenol group of a
tyrosine residue, only the latter process was observed (entry 8).
The enantioselective version of the Brønsted acid catalyzed
intramolecular Michael addition was also investigated. Accord-
ing to the mechanistic proposal by You, phosphoric acid 39
binds to the carbonyl and alcohol groups with the hydroperoxy
group positioned away from the phosphoric acid (Figure 3).2
Substitution of a tert-butyl group for a hydrogen atom of the
hydroperoxide was expected to have no effect on the course of
the reaction. However, the cyclization of 5 catalyzed by 39
afforded only moderate enantioselectivity (up to 59% ee) and
took a considerably longer time (eq 4) than cyclization of 4-
hydroperoxy-2,5-dienone (Figure 3).2 A shorter alcohol linker
gave a greater degree of enantiocontrol, reaching 70% ee for
cyclization of 2 (eq 5). Unfortunately, phosphoric acid 39
showed no catalytic activity with 2,5-dienone 12. The less
sterically phosphoric acid 40 catalyzed the cyclization of 12,
albeit at the expense enantiomeric excess (eq 6).
The isolated yields of cyclic products of the tandem
Rh2(cap)4 catalyzed phenol oxidation and Brønsted acid
catalyzed oxo-Michael addition were identical within exper-
imental error to the yields for the two-pot tandem sequence.
Hydrobenzofuran 16 and hydrobenzopyran 18 were prepared
in 62% and 52% isolated yields, respectively, as single
diastereomers (Table 4, entries 1 and 3). The oxo-Michael
addition could also be catalyzed by TsOH with similar results
(entry 2). Secondary alcohol 19 formed a mixture of only two
out of four possible diastereomers (7.4:1) that were separated
by column chromatography in 59% isolated yield (entry 4).
The major diastereomer (20) was determined by a NOESY
experiment that showed a cross-peak of two axial protons in the
α-positions to the ether oxygen of 20 (Figure 1). The
formation of lactone 22 showed that the developed tandem
protocol could be applied to phenols with carboxylic acids
tethered to the 4-position (entry 5). Factoring in the isolated
yields of 2, 5 and 7 for phenol oxidation (Table 1, entry 3, and
Table 2, entries 1 and 2) into the isolated yields of 16, 18, and
22 for the tandem phenol oxidation−Michael addition (Table
4, entries 1, 2, 3, and 5) suggests that oxo-Michael addition
occurs in yields above 80%.
To further elaborate the potential for generality of the
tandem phenol oxidation−Michael addition, L-tyrosine deriva-
tives were chosen as substrates due to their role in oxidative
stress11 and associated transformations.5,11b In agreement with
the results from the phenol oxidations reported in Tables 2 and
4, L-tyrosine derivatives furnished single 2,5-dienone products
along with polar unidentified materials that did not interfere
with the subsequent Brønsted acid catalyzed cyclization.
Carbamates 23 and 25 afforded dihydroindole derivatives 24
and 26 in 42% and 31% isolated yield, respectively (Table 5,
entries 1 and 2). No cyclization was observed with acetyl-
protected amine 27 (entry 3). The highest yield in the tandem
reaction of L-tyrosine derivatives 23, 25, and 27 was achieved
with 24 suggesting that the Boc-group is preferred for
protection of the amine group in the phenol oxidation−aza-
Michael addition process. The isolated yields of bicyclic
Finally, the developed tandem phenol oxidation−oxo-
Michael addition was employed for synthesis of cleroindicin
F. To achieve this goal, selective reduction of the internal
peroxide group was necessary. Several reagents and procedures
applicable for reduction of internal peroxide 41 (eq 7)12 were
employed for the reduction of the tert-butylperoxy group of 16.
However, no desired product was isolated with any of these
methods (Supporting Information). Surprisingly, dropwise
addition of TiCl4 solution in DCM to an anhydrous solution
of pure peroxide 16 in DCM afforded 42 in 81% yield as a
D
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Table 4. Tandem Phenol Oxidation−Oxo-Michael Addition
a
b
c
Major diastereomer is shown. After flash chromatography through silica gel. Phenolic oxidation forms 21% o-quinone that undergoes
d
e
decomposition under reaction conditions. The ratio of 20/21 is 7.4:1. Each diastereomer is isolated as an individual compound.
CONCLUSION
■
In conclusion, the scope of Rh2(cap)4 catalyzed phenol
oxidations was expanded to phenols bearing carboxylic acids,
alcohols, methyl ketone, and Boc-protected amine functional
groups tethered to the 4-position. The one-pot stepwise
tandem sequence of the phenol oxidation followed by the
Brønsted acid catalyzed Michael addition was developed. This
Figure 1. Determination of stereochemistry of hydrobenzopyrane 20.
protocol improves the overall yield of cleroindicin F from
phenol 1 from 22%2 to 50%. The scope of Brønsted acid
catalyzed intramolecular Michael addition to 2,5-dienones was
expanded to include carboxylates and Boc-protected amine
nucleophiles. The developed tandem protocol also includes
multifunctional dipeptides. Finally, the selective cleavage of a
hindered internal peroxide bond of 16 upon the treatment with
TiCl4 was discovered.
single product (eq 8). Thus, cleroindicin F was synthesized
from tyrosol 1 in 50% overall yield over 3 steps, a process that
is superior for cleroindicin F syntheses to those of You (3 steps,
22% overall yield),2 of Pettus (10 steps, 18% overall yield),10c
and of Hoveyda (9 steps, 17% overall yield).13 Interestingly, the
use of other Lewis acids in this protocol showed either no
reactivity or led either to decomposition of 16 or reverse
Michael reaction (Supporting Information). Treatment of
peroxide 29 with TiCl4 formed a complex mixture of products.
EXPERIMENTAL SECTION
General Information. All reactions were performed under
atmospheric conditions unless the conditions are specified. H NMR
■
1
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Table 5. Tandem Phenol Oxidation−Aza-Michael Addition
a
b
c
Major diastereomer is shown. cis-Diastereomer of the bicyclic scaffold is formed in >20:1 ratio. Each diastereomer is isolated as an individual
d
compound. Determined by 1H NMR spectroscopy from the ratio of the absorption (6.09 ppm, d, J = 10.4 Hz, 1H) corresponding to 26 and that
for the biphenyl internal standard (7.60 ppm, d, J = 7.2 Hz, 4H). N.R.: no intramolecular aza-Michael addition. Cyclization was achieved with
e
f
TsOH (1.5 equiv).
Figure 2. NOE analysis of dihydroindols 31 and 32.
F
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chromatography was performed on silica gel coated glass plates (250
μm, F-254), and spots were visualized with either 254 nm ultraviolet
light or a KMnO4 stain. Flash chromatography used silica gel (32−63
μm). High-resolution mass spectra (HRMS) were acquired on a ESI-
TOF spectrometer using CsI as a standard. Rh2(cap)4 was prepared
according to the literature procedure.14 Enantiomeric exesses were
determined using a HPLC AD-H column and i-PrOH−hexane mixture
as the eluting solvent. The concentration of TBHP in the commercial
T-HYDRO reagent was determined by iodometric titration to be 70%
by weight.
Spectra of peroxide 11 are in agreement with published
information.4b Phosphoric acids 17, 39, 40 were prepared according
to the published procedure.15 Compounds 30,16 33,16 35,17 and 3717
were prepared according to published procedures. Compounds 24, 29,
31, 32, 34, 36, 38, 43, and 44 containing N-Boc group appeared as a
1
pair of rotamers in H and 13C NMR spectra.
Figure 3. Mechanistic model of You for enantioselective desymmet-
rization of 2,5-dienones catalyzed by chiral phosphoric acid.2.
General Procedure for Transition Metal Complex Catalyzed
Phenolic Oxidation. The phenol derivative (2.0 mmol), Rh2(cap)4
(0.02 mmol, 1 mol %), and DCE (4.0 mL) were placed in a 4-dram
screw-cap vial containing a magnetic stirring bar. The suspension
containing a small amount of undissolved phenol derivative and
Rh2(cap)4 was heated to 40 °C at 250 rpm, and T-HYDRO (8.0
mmol, 4 equiv, 110 μL) was added all at once via syringe. The vial
containing the suspension was loosely capped to allow release of
pressure built-up, and its contents were stirred using a magnetic
stirring bar at 40 °C. All solid materials dissolved within 10 min after
T-HYDRO addition. After 1.5 h, the reaction mixture was transferred
to a 100-mL round-bottom flask, concentrated under reduced
pressure, and the residue was purified by column chromatography
(silica gel, DCM/AcOEt/hexane). Fractions containing the product
were combined, and the solvent was evaporated under reduced
pressure. The peroxide product was dried under high vacuum for 20
min (0.09 Torr, room temperature).
4-(tert-Butylperoxy)-4-(2-hydroxyethyl)cyclohexa-2,5-dien-1-one
(2): 298 mg; 66%, Rf 0.30 (EtOAc/DCM/hexane (1:1:1)); colorless
oil; 1H NMR (500 MHz, CDCl3) δ 7.03 (d, J = 10.2 Hz, 2H), 6.32 (d,
J = 10.2 Hz, 2H), 3.77 (t, J = 6.2 Hz, 2H), 2.03 (t, J = 6.2 Hz, 2H),
1.22 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 186.0, 150.3, 129.5,
80.6, 78.2, 58.0, 39.3, 26.2; IR (neat, cm−1): 3432, 3048, 2979, 2930,
1669, 1627, 1363, 1193, 1079, 1045, 984, 927, 857; EI-HRMS:
calculated for C12H18O4 (M + H), 227.12834; found, 227.12667.
4-(tert-Butylperoxy)-4-(3-hydroxypropyl)cyclohexa-2,5-dien-1-
one (5): 312 mg, 65%, Rf 0.24 (EtOAc/DCM/hexane (1:1:1));
1
colorless oil; H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 10.2 Hz,
2H), 6.28 (d, J = 10.2 Hz, 2H), 3.63 (t, J = 6.3 Hz, 2H), 1.89−1.71
(comp, 2H), 1.66−1.44 (comp, 3H), 1.20 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 185.8, 150.4, 129.9, 80.2, 78.9, 62.4, 32.9, 26.6, 26.4;
EI-HRMS: calculated for C13H20O4 (M + H), 241.14399; found,
241.14334.
[1-(tert-Butylperoxy)-4-oxocyclohexa-2,5-dien-1-yl]acetic acid
(7): 216 mg, 45%, Rf 0.20 (EtOAc/DCM/hexane (1:1:1)); colorless
oil; 1H NMR (500 MHz, CDCl3) δ 7.05 (d, J = 10.0 Hz, 2H), 6.31 (d,
J = 10.0 Hz, 2H), 2.79 (s, 2H), 1.21 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 195.0, 185.3, 147.5, 130.2, 80.9, 75.9, 31.2, 26.3; EI-HRMS:
calculated for C12H16O5 (M + H), 241.10760; found, 241.10911.
3-[1-(tert-Butylperoxy)-4-oxocyclohexa-2,5-dien-1-yl]propanoic
acid (9): 234 mg, 46%, Rf 0.26 (EtOAc/DCM/hexane (1:1:1));
1
colorless oil; H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 10.2 Hz,
2H), 6.32 (d, J = 10.2 Hz, 2H), 2.39 (t, J = 7.9 Hz, 2H), 2.10 (t, J = 7.9
Hz, 2H), 1.22 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 185.5, 177.4,
149.3, 130.4, 80.4, 78.1, 31.0, 28.1, 26.3; EI-HRMS: calculated for
C13H18O5 (M + H), 255.12325; found, 255.12305.
4-(tert-Butylperoxy)-4-(3-oxobutyl)cyclohexa-2,5-dien-1-one
(11): 312 mg, 62%, Rf 0.50 (EtOAc/DCM/hexane (1:1:1)); colorless
oil; 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 10.2 Hz, 2H), 6.28 (d,
J = 10.2 Hz, 2H), 2.39 (t, J = 7.7 Hz, 2H), 2.12 (s, 3H), 2.01 (t, J = 7.7
Hz, 2H), 1.20 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 206.9, 186.1,
150.3, 130.6, 80.7, 78.9, 37.7, 30.5, 29.8, 26.8; EI-HRMS: calculated for
C14H20O4 (M + H), 253.14399; found, 253.14494.
spectra were recorded on 400 and 600 MHz spectrometers.
Tetramethylsilane (TMS) was used as a reference (0.00 ppm) for all
spectra. Data are reported as follows: chemical shift (in ppm, δ),
integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, sept = septet, br = broad, m = multiplet, comp = composite)
and coupling constants (in Hz). 13C NMR spectra were recorded on a
125 MHz spectrometer operated with complete proton decoupling.
Chemical shifts are reported in ppm utilizing the central resonance of
the CDCl3 absorption as a reference (77.0 ppm). Thin layer
G
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1
tert-Butyl [2-[1-(tert-Butylperoxy)-4-oxocyclohexa-2,5-dien-1-yl]-
hexane (1:1:16)); colorless oil; H NMR (500 MHz, CDCl3) δ 6.91
(d, J = 10.3 Hz, 1H), 5.99 (d, J = 10.3 Hz, 1H), 4.60 (dd, J = 12.2, 5.1
Hz, 1H), 3.90−3.72 (m, 1H), 2.94 (dd, J = 16.1, 12.2 Hz, 1H), 2.70
(dd, J = 16.2, 5.1 Hz, 1H), 2.14−1.99 (m, 1H), 1.83−1.70 (m, 1H),
1.67−1.53 (m, 1H), 1.49 (dd, J = 13.2, 3.3 Hz, 1H), 1.23 (s, 9H), 1.21
(t, J = 6.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 198.3, 153.5,
129.2, 80.0, 77.3, 70.1, 65.3, 40.1, 27.9, 27.2, 26.5, 21.1; EI-HRMS:
calculated for C14H22O4 (M + H), 255.15972; found 255.15974.
(3aR,7aR)-3a-(tert-Butylperoxy)-3,3a,7,7a-tetrahydro-1-benzo-
furan-2,6-dione (22): 192 mg, 40%, Rf 0.30 (EtOAc/DCM/hexane
ethyl]carbamate (13): 384 mg, 59%, Rf 0.30 (EtOAc/DCM/hexane
1
(1:1:1)); colorless oil; H NMR (500 MHz, CDCl3) δ 6.91 (d, J =
10.1 Hz, 2H), 6.28 (d, J = 10.1 Hz, 2H), 4.68 (s, 1H), 3.18 (br d, J =
6.3 Hz, 2H), 1.93 (t, J = 7.1 Hz, 2H), 1.43 (br s, 9H), 1.20 (s, 9H);
13C NMR (126 MHz, CDCl3) δ 185.5, 149.5, 130.0, 80.8, 80.4, 79.5,
78.0, 36.9, 35.9, 28.4, 26.3; EI-HRMS: calculated for C17H27O5N (M +
H), 326.19675; found, 326.19541.
General Procedure for Tandem Phenol Oxidation−Michael
Addition Sequence. 4-(tert-Butyldioxy)cyclohexa-2,5-dienone (2.0
mmol), [Rh2(cap)4] (0.02 mmol, 0.01 equiv), and DCE (4.0 mL)
were placed in a 4-dram screw-cap vial containing a magnetic stirring
bar. The suspension containing a small amount of undissolved phenol
derivative and Rh2(cap)4 was heated to 40 °C in an oil bath at 250
rpm, and T-HYDRO was added all at once via syringe. The vial
containing the reaction mixture was loosely capped to allow release of
pressure built-up, and its contents were stirred using a magnetic
stirring bar at 40 °C. All solid materials dissolved within 10 min of T-
HYDRO addition. After 90 min, the reaction mixture was allowed to
cool to room temperature, and anhydrous Na2SO4 (600 mg), followed
by TsOH or (rac)-BINOL-PO2H (0.20 mmol, 0.1 equiv), was added
to the mixture. The suspension was stirred overnight at room
temperature, then transferred to a 100-mL round-bottom flask and
concentrated under reduced pressure, and the residue was purified by
column chromatography (silica gel, DCM/AcOEt/hexane). Fractions
containing the product were combined, and the solvent was
evaporated under reduced pressure. The peroxide product was dried
under high vacuum for 20 min (0.09 Torr, room temperature).
(3aR,7aR)-3a-(tert-Butylperoxy)-3,3a,7,7a-tetrahydro-1-benzo-
furan-6(2H)-one (16): 280 mg, 62%, Rf 0.14 (EtOAc/DCM/hexane
1
(1:1:4)); colorless oil; H NMR (500 MHz, CDCl3) δ 6.75 (dd, J =
10.3, 1.2 Hz, 1H), 6.24 (d, J = 10.3 Hz, 1H), 5.11 (dd, J = 8.2, 1.2 Hz,
1H), 3.24−2.97 (comp, 2H), 2.89−2.65 (comp, 2H), 1.24 (s, 9H);
13C NMR (126 MHz, CDCl3) δ 193.5, 171.4, 144.0, 131.5, 81.4, 80.4,
78.7, 40.4, 38.7, 26.3; EI-HRMS: calculated for C12H16O5 (M + H),
241.10760; found, 241.10701.
(2S,3aR,7aR)-1-(tert-Butoxycarbonyl)-3a-(tert-butylperoxy)-6-
oxo-2,3,3a,6,7,7a-hexahydro-1H-indole-2-carboxylic acid (24): 310
mg, 42%, Rf 0.36 (DCM/MeOH (9:1)); colorless oil; H NMR (500
MHz, CDCl3) δ 10.14 (br s, 1H), 6.98−6.81 (m, 1H), 6.09 (d, J = 10.4
Hz, 1H), 4.82−4.63 (m, 1H), 4.63−4.43 (m, 1H), 3.43−3.14 (m, 1H),
2.85−2.56 (m, 1H), 2.55−2.26 (comp, 2H), 1.54−1.40 (comp, 9H),
1.23−1.18 (comp, 9H); 13C NMR (126 MHz, CDCl3) δ 196.0, 195.8,
175.8, 172.9, 155.6, 153.0, 148.2, 146.7, 130.5, 130.3, 85.2, 84.4, 82.6,
81.0, 80.8, 80.7, 59.6, 59.2, 58.5, 58.1, 42.2, 41.5, 37.5, 35.8, 28.4, 28.1,
26.7, 26.3; EI-HRMS: calculated for C18H27NO7 (M + H), 370.18668;
found, 370.18606.
1
tert-Butyl (3aR,7aR)-3a-(tert-Butylperoxy)-6-oxo-2,3,3a,6,7,7a-
hexahydro-1H-indole-1-carboxylate (29): 358 mg, 55%, Rf 0.34
(EtOAc/DCM/hexane (1:1:4)); colorless oil; H NMR (500 MHz,
1
1
(1:1:8)); colorless oil; H NMR (500 MHz, CDCl3) δ 6.77 (dd, J =
CDCl3) δ 7.08−6.79 (m, 1H), 6.06 (d, J = 10.4 Hz, 1H), 4.77−4.50
(m, 1H), 3.70−3.41 (m, 2H), 3.24−2.96 (m, 1H), 2.51−2.31 (m, 1H),
2.31−2.19 (m, 1H), 2.19−2.02 (m, 1H), 1.46 (s, 9H), 1.21 (s, 9H);
13C NMR (126 MHz, CDCl3) δ 197.0, 154.1, 148.9, 130.1, 86.1, 80.4,
80.1, 77.2, 58.7, 44.7, 42.7, 32.6, 28.4, 26.4; EI-HRMS: calculated for
C17H27NO5 (M + H), 326.19685; found, 326.19641. The enantio-
meric excess was determined by HPLC on an AD-H column (97:3
hexanes/i-PrOH, 1.0 mL/min): tR (major) = 7.04 min; tR (minor) =
8.84 min.
10.3, 1.6 Hz, 1H), 6.09 (d, J = 10.3 Hz, 1H), 4.46 (td, J = 5.0, 1.6 Hz,
1H), 3.96 (dd, J = 7.8, 6.7 Hz, 2H), 2.87 (dd, J = 16.9, 5.0 Hz, 1H),
2.68 (dd, J = 16.9, 4.4 Hz, 1H), 2.32 (dt, J = 13.5, 6.7 Hz, 1H), 2.08
(dt, J = 13.5, 7.8 Hz, 1H), 1.23 (s, 9H); 13C NMR (126 MHz, CDCl3)
δ 196.7 (C), 147.4 (CH), 129.7 (CH), 84.2 (C), 80.2 (C), 79.2 (CH),
66.0 (CH2), 41.3 (CH2), 36.9 (CH2), 26.4 (CH3); IR (neat, cm−1):
3034, 2877, 2932, 2881, 1688, 1386, 1363, 1190, 1067, 1017, 877; ESI-
HRMS: calculated for C12H18O4 (M + H), 227.12841; found,
227.12817. The enantiomeric excess was determined by HPLC on
an AD-H column (80:20 hexanes/i-PrOH, 1.0 mL/min): tR (major) =
4.13 min; tR (minor) = 4.75 min.
1-tert-Butyl 2-Methyl (2S,3aR,7aR)-3a-(tert-Butylperoxy)-6-oxo-
2,3,3a,6,7,7a-hexahydro-1H-indole-1,2-dicarboxylate (31): 132 mg,
35%, Rf 0.23 (EtOAc/DCM/hexane (1:1:4)); colorless oil; H NMR
1
(4aR,8aR)-4a-(tert-Butylperoxy)-2,3,4,4a,8,8a-hexahydro-7H-
(600 MHz, CDCl3) δ 6.94−6.85 (m, 1H), 6.09−6.03 (m, 1H), 4.85−
4.61 (m, 1H), 4.55−4.39 (m, 1H), 3.81−3.71 (comp, 3H), 3.28−3.03
(m, 1H), 2.81−2.56 (comp, 2H), 2.27−2.11 (m, 1H), 1.47−1.39
(comp, 9H), 1.24−1.19 (comp, 9H); 13C NMR (126 MHz, CDCl3) δ
196.3, 196.1, 171.4, 170.5, 153.5, 153.0, 147.7, 146.9, 130.4, 130.1,
129.5, 125.7, 85.5, 84.3, 80.9, 80.8, 80.6, 80.5, 59.2, 58.2, 57.8, 52.1,
52.0, 42.7, 41.5, 37.6, 36.7, 28.4, 28.2, 26.3; EI-HRMS: calculated for
C19H29NO7 (M + H), 384.20222; found, 384.20319.
chromen-7-one (18): 250 mg, 52%, Rf 0.08 (EtOAc/DCM/hexane
1
(1:1:4)); colorless oil; H NMR (500 MHz, CDCl3) δ 6.53 (dd, J =
10.2, 2.0 Hz, 1H), 6.15 (d, J = 10.2 Hz, 1H), 4.06 (td, J = 3.9, 2.0 Hz,
1H), 3.92 − 3.80 (m, 1H), 3.44 (td, J = 11.1, 2.7 Hz, 1H), 3.00 (dd, J
= 16.8, 3.5 Hz, 1H), 2.57 (dd, J = 16.8, 4.2 Hz, 1H), 2.10 − 1.93
(comp, 2H), 1.79−1.67 (m, 1H), 1.68−1.54 (m, 1H), 1.21 (s, 9H);
13C NMR (126 MHz, CDCl3) δ 197.6 (C), 147.1 (CH), 132.5 (CH),
79.9 (C), 75.7 (C), 75.3 (CH), 66.3 (CH2), 41.1 (CH2), 31.9 (CH2),
26.5 (CH3), 22.9 (CH2); EI-HRMS: calculated for C13H20O4 (M +
H), 241.14394; found, 241.14362. The enantiomeric excess was
determined by separation on a HPLC on an AD-H column (90:10
hexanes/i-PrOH, 1.0 mL/min): tR (major) = 4.51 min; tR (minor) =
5.35 min.
(2S,4aR,8aR)-4a-(tert-Butylperoxy)-2-methyl-2,3,4,4a,8,8a-hexa-
hydro-7H-chromen-7-one (20): 254 mg, 52%, Rf 0.26 (EtOAc/
DCM/hexane (1:1:16)); colorless oil; 1H NMR (500 MHz, CDCl3) δ
6.46 (dd, J = 10.1, 2.4 Hz, 1H), 6.16 (d, J = 10.1 Hz, 1H), 4.01 (dd, J =
5.5, 2.4 Hz, 1H), 3.50 (dtd, J = 12.1, 6.1, 4.2 Hz, 1H), 3.03 (dd, J =
16.9, 3.3 Hz, 1H), 2.50 (dd, J = 16.9, 2.5 Hz, 1H), 2.13−1.92 (comp,
2H), 1.69 (dt, J = 13.6, 4.6 Hz, 1H), 1.38−1.24 (m, 1H), 1.20 (s, 9H),
1.12 (d, J = 6.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 197.7 (C),
146.1 (CH), 133.0 (CH), 79.9 (C), 75.8 (CH), 75.1 (C), 73.2 (CH),
41.5 (CH2), 32.8 (CH2), 30.6 (CH2), 26.5 (CH3), 21.3 (CH); EI-
HRMS: calculated for C14H22O4 (M + H), 255.15972; found,
255.15941.
1-tert-Butyl 2-Methyl (2S,3aS,7aS)-3a-(tert-Butylperoxy)-6-oxo-
2,3,3a,6,7,7a-hexahydro-1H-indole-1,2-dicarboxylate (32): 83 mg,
1
21%, Rf 0.31 (EtOAc/DCM/hexane (1:1:4)); colorless oil; H NMR
(600 MHz, CDCl3) δ 6.92−6.82 (m, 1H), 6.12−6.05 (m, 1H), 4.79−
4.61 (m, 1H), 4.61−4.41 (m, 1H), 3.82−3.72 (comp, 3H), 3.40−3.14
(m, 1H), 2.67−2.51 (m, 1H), 2.51−2.42 (m, 1H), 2.41−2.27 (m, 1H),
1.53−1.40 (comp, 9H), 1.25−1.18 (comp, 9H); 13C NMR (126 MHz,
CDCl3) δ 196.6, 196.2, 172.9, 172.8, 153.6, 153.0, 147.6, 146.9, 130.6,
130.4, 129.6, 125.8, 85.8, 85.0, 80.9, 80.6, 59.7, 59.6, 59.5, 59.0, 52.5,
52.3, 42.6, 42.2, 38.0, 37.3, 28.4, 28.2, 26.4, 26.3; EI-HRMS: calculated
for C19H29NO7 (M + H), 384.20222; found, 384.20352.
Di-tert-butyl (2S,3aR,7aR)-3a-(tert-Butylperoxy)-6-oxo-
2,3,3a,6,7,7a-hexahydro-1H-indole-1,2-dicarboxylate (34): 176 mg,
41%, Rf 0.27 (EtOAc/hexane (1:5)); colorless oil; 1H NMR (500
MHz, CDCl3) δ 6.90−6.80 (m, 1H), 6.11−6.02 (m, 1H), 4.83−4.63
(m, 1H), 4.45−4.26 (m, 1H), 3.39−3.11 (m, 1H), 2.65−2.38 (comp,
2H), 2.39−2.28 (m, 1H), 1.52−1.40 (comp, 18H), 1.27−1.19 (comp,
9H); 13C NMR (126 MHz, CDCl3) δ 196.6, 196.4, 169.1, 168.8,
153.3, 153.3, 148.3, 147.7, 130.2, 130.0, 85.5, 84.4, 81.3, 81.0, 80.8,
80.7, 80.5, 80.3, 59.4, 59.3, 58.5, 58.4, 42.6, 41.7, 37.9, 37.0, 28.4, 28.2,
(2R,4aR,8aR)-4a-(tert-Butylperoxy)-2-methyl-2,3,4,4a,8,8a-hexa-
hydro-7H-chromen-7-one (21): 36 mg, 7%, Rf 0.09 (EtOAc/DCM/
H
dx.doi.org/10.1021/jo302002j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
28.1, 26.4, 26.4; EI-HRMS: calculated for C22H35NO7 (M + H),
426.24896; found, 426.24793.
combined, dried over Na2SO4, and the solvent was evaporated on
rotary evaporator to yield cleroindicin F 42 as a colorless liquid (38
mg, 81%) that matched the previously reported 1H NMR spectrum.10c
Di-tert-butyl (2S,3aS,7aS)-3a-(tert-Butylperoxy)-6-oxo-
2,3,3a,6,7,7a-hexahydro-1H-indole-1,2-dicarboxylate (43): 88 mg,
21%, Rf 0.37 (EtOAc/hexane (1:5)); colorless oil; 1H NMR (500
MHz, CDCl3) δ 6.96−6.83 (m, 1H), 6.14−5.99 (m, 1H), 4.91−4.59
(m, 1H), 4.43−4.26 (m, 1H), 3.27−3.01 (m, 1H), 2.83−2.53 (comp,
2H), 2.25−2.07 (m, 1H), 1.53−1.40 (comp, 18H), 1.25−1.18 (comp,
9H); 13C NMR (126 MHz, CDCl3) δ 196.9, 196.5, 171.3, 171.2,
153.3, 153.2, 147.8, 147.3, 130.7, 130.4, 85.8, 84.9, 81.8, 81.7, 80.6,
80.5, 60.2, 60.1, 59.6, 42.5, 42.1, 38.2, 37.2, 28.3, 28.2, 27.9, 27.9, 26.3,
26.2; EI-HRMS: calculated for C22H35NO7 (M + H), 426.24896;
found, 426.24793.
ASSOCIATED CONTENT
■
S
* Supporting Information
Optimization procedures and NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
tert-Butyl (2S,3aR,7aR)-3a-(tert-Butylperoxy)-2-[(2-ethoxy-2-
oxoethyl)amino]carbonyl-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-in-
dole-1-carboxylate (36): 68 mg, 30%, Rf 0.16 (EtOAc/DCM/hexane
Corresponding Author
*mdoyle3@umd.edu
1
Notes
(1:1:1)); colorless oil; H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H),
7.01−6.82 (m, 1H), 6.76 (s, 1H), 6.07 (d, J = 10.4 Hz, 1H), 4.95−4.62
(m, 1H), 4.59−4.36 (m, 1H), 4.30−3.79 (comp, 4H), 3.53−3.16 (m,
1H), 2.88−2.13 (comp, 3H), 1.49 (comp, 9H), 1.28 (t, J = 7.1 Hz,
3H), 1.19 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 195.9, 195.5,
171.9, 170.8, 169.4, 168.4, 154.7, 153.2, 148.7, 147.5, 130.5, 130.0,
85.7, 85.2, 81.9, 81.5, 80.5, 61.4, 60.4, 59.9, 42.0, 41.7, 41.4, 40.7, 37.6,
35.9, 29.7, 28.3, 27.9, 26.4, 26.3, 14.1; EI-HRMS: calculated for
C22H34N2O8 (M + H), 455.23947; found, 455.24020.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The support of the National Science Foundation (CHE-
0748121) for this research is gratefully acknowledged. Maxim
O. Ratnikov is grateful for a Graduate Assistance in Areas of
National Need (GAANN) Fellowship during 2010-2011 and
2011-2012 academic years.
(2S,3aR,7aR)-tert-Butyl 3a-(tert-Butylperoxy)-2-(((S)-1-methoxy-
1-oxo-3-phenylpropan-2-yl)carbamoyl)-6-oxo-2,3,3a,6,7,7a-hexa-
hydro-1H-indole-1-carboxylate (38): 30 mg, 13%, Rf 0.35 (EtOAc/
1
REFERENCES
DCM/hexane (1:1:1)); colorless oil; H NMR (500 MHz, CDCl3) δ
■
7.69−6.64 (comp, 7H), 6.14−5.97 (m, 1H), 5.02−4.26 (comp, 3H),
3.76−3.59 (comp, 3H), 3.49−2.74 (comp, 4H), 2.59−2.13 (comp,
2H), 1.55−1.32 (comp, 9H), 1.30−1.06 (comp, 9H); 13C NMR (126
MHz, CDCl3) δ 195.9, 195.7, 171.7, 171.5, 170.9, 170.3, 155.0, 154.9,
148.9, 148.8, 147.8, 147.5, 136.3, 136.0, 85.7, 85.2, 81.8, 80.6, 80.5,
60.1, 60.0, 59.8, 56.1, 54.0, 53.8, 52.0, 51.8, 42.4, 41.9, 38.4, 38.3, 37.8,
37.7, 35.6, 35.3, 28.4, 28.3, 28.0, 26.7, 26.4, 26.3; EI-HRMS: calculated
for C28H38N2O8 (M + H), 531.27079; found, 531.26927.
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Choi, H.; El-Khalafy, S. H.; Doyle, M. P. J. Org. Chem. 2011, 76, 2585.
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(2S,3aS,7aS)-tert-Butyl 3a-(tert-Butylperoxy)-2-(((S)-1-methoxy-
1-oxo-3-phenylpropan-2-yl)carbamoyl)-6-oxo-2,3,3a,6,7,7a-hexa-
hydro-1H-indole-1-carboxylate (44): 103 mg, 39%, Rf 0.46 (EtOAc/
1
DCM/hexane (1:1:1)); colorless oil; H NMR (500 MHz, CDCl3) δ
7.65−6.65 (comp, 5H), 6.17−6.03 (m, 1H), 4.94−4.29 (comp, 3H),
3.77−3.58 (comp, 3H), 3.48−3.25 (comp, 2H), 3.19−2.86 (comp,
2H), 2.62−2.25 (comp, 2H), 1.59−1.53 (m, 1H), 1.51−1.37 (comp,
9H), 1.29−1.20 (comp, 9H); 13C NMR (126 MHz, CDCl3) δ 197.0,
196.8, 168.6, 167.5, 153.7, 153.4, 147.4, 146.5, 130.6, 130.1, 129.3,
128.4, 84.8, 83.3, 80.9, 80.7, 80.6, 80.1, 60.1, 59.6, 58.9, 56.2, 52.0,
46.2, 43.5, 42.0, 40.0, 38.6, 38.2, 37.2, 28.4, 28.3, 26.4, 25.6, 24.6; EI-
HRMS: calculated for C28H38N2O8 (M + H), 531.27079; found,
531.26875.
General Procedure for Asymmetric Intramolecular Michael
Addition. 4-(tert-Butylperoxy)cyclohexa-2,5-dienones (0.10 mmol),
chiral phosphoric acid (0.010 mmol, 0.1 equiv), and dry DCM (0.25
mL) were added under nitrogen to an oven-dried 1-dram screw-cap
vial containing a magnetic stirring bar, and the reaction was stirred for
20 h at room temperature. The suspension was stirred overnight at
room temperature and then transferred to a 100-mL round-bottom
flask, concentrated under reduced pressure, and the residue was
purified by column chromatography (silica gel, DCM/AcOEt/hexane).
Fractions containing the product were combined, and the solvent was
evaporated under reduced pressure. The peroxide product was dried
under high vacuum for 20 min (0.09 Torr, room temperature).
General Procedure for Dialkylperoxide 16 Cleavage by
Lewis Acids. Peroxide 16 (0.30 mmol, 68 mg) and dry DCM (1.5
mL) were placed under nitrogen in an oven-dried 5-mL round-bottom
flask capped with a septum. The Lewis acid (0.60 mmol) was slowly
added to the solution at room temperature, and the reaction was
stirred for 4 h at room temperature. A light brown precipitate formed
after 30 s. The suspension was poured into an aqueous 5% solution of
Na2CO3 (9 mL), the organic layer was separated, and the aqueous
layer was washed with AcOEt (3 × 15 mL). The organic layers were
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