New Strategy for Forging Contiguous Quaternary Carbon Centers via H 2 O 2 -Mediated Ring Contraction

Article abstract of DOI:10.1055/s-0036-1590979

Stereospecific construction of contiguous quaternary carbon centers constitutes a major challenge in natural product synthesis. A general protocol that enables stereospecific construction of all stereoisomers of such a moiety remains elusive. In this article, we will discuss the oxidative ring contraction of all-substituted cyclic α-formyl ketones mediated by H ₂ O ₂, which provides a facile access to the stereospecific construction of contiguous quaternary carbon centers.

Full text of DOI:10.1055/s-0036-1590979

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–H
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A
en
J. Hu et al.
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New Strategy for Forging Contiguous Quaternary Carbon Centers
via H2O2-Mediated Ring Contraction
Jiadong Hua
Xin Yub
Ar
O
Weiqing Xie*a,c
0
0
0
0
0-
0
0
2
8-
3
4
3
2-
3
6
4
H2O2
R1 R3
R1
R2
R3
R2
CO2H
(+)-cuparene
Ar
H
a Shaanxi Key Laboratory of Natural Products & Chemical Biology,
College of Chemistry & Pharmacy, Northwest A&F University,
22 Xinong Road, Yangling 712100, Shaanxi, P. R. of China
xiewq@nwafu.edu.cn
b Instrumental Analysis and Research Center, Shanghai University,
Shanghai 200444, P. R. of China
c Key Laboratory of Botanical Pesticide R&D in Shaanxi Province,
Yangling, Shaanxi 712100, P. R. of China
OAc
HCOOH
O
n
n
· mild reaction conditions
· stereospecific ring contraction
· access to all stereoisomers
tochuinyl acetate
Ar = 4-MeC6H4
Received: 25.07.2017
Accepted after revision: 24.08.2017
Published online: 12.09.2017
DOI: 10.1055/s-0036-1590979; Art ID: st-2017-p0581-sp
Abstract Stereospecific construction of contiguous quaternary carbon
centers constitutes a major challenge in natural product synthesis. A
general protocol that enables stereospecific construction of all stereo-
isomers of such a moiety remains elusive. In this article, we will discuss
the oxidative ring contraction of all-substituted cyclic α-formyl ketones
mediated by H2O2, which provides a facile access to the stereospecific
construction of contiguous quaternary carbon centers.
Weiqing Xie (Right) pursued his PhD degree at Shanghai Institute of
Organic Chemistry (SIOC) under the supervision of Professor Dawei Ma
after obtaining his BSc degree in chemistry from Lanzhou University in
2002. In 2007, he was appointed as assistant professor at SIOC upon
receiving his PhD degree. From 2009 to 2011, he worked as postdoc in
the John R. Falck group at UT Southwestern of Medical Center at Dallas.
Then he returned to SIOC and begun his academic career as associate
professor in Professor Ma’s group. In 2015, he moved to Northwest A&F
University and set up his research group. His research interests include
total synthesis of complex natural products and related synthetic meth-
odologies.
Jiadong Hu (Left) received both his BSc degree in pharmacy (2013) and
MSc degree in medicinal chemistry (2016) from China Pharmaceutical
University, Nanjing, under the supervision of Professor Yisheng Lai. Af-
ter that, he began his PhD studies in chemical biology at Northwest A&F
University, Yangling, in the laboratory of Professor Weiqing Xie.
Key words interrupted Baeyer–Villiger reaction, malondialdehyde, cy-
clic α-formyl ketones, ring contraction, contiguous quaternary carbon
centers
Quaternary carbon centers are widely distributed in
natural products (Figure 1, e.g., jiadifenolide,1a minfien-
sine1b), which often determine the unique three-dimension
structure of those natural products. More frequently, con-
tiguous quaternary carbon centers can be found in struc-
turally complex natural products (Figure 1, e.g., maoecrys-
tal V,2a acutumine2b). In some particular families of natural
products, the contiguous quaternary carbon centers are a
pair of diastereoisomers.3 For example, the contiguous qua-
ternary carbon centers of communesin F and perophorami-
dine are diastereoisomers (Figure 1).3a–e The same phenom-
ena can also be observed in cuparene sesquiterpenoids
such as tochuinyl acetate and herbertenolide.3f–h Due to the
steric repulsion between substituents of contiguous quater-
nary carbon centers, stereoselective construction of such
moieties constitutes the major challenge in the total syn-
thesis of those natural products. To this end, elegant strate-
gies have been designed toward the stereospecific building-
up of such frameworks simultaneously for shortening syn-
thetic steps.4 For example, Ma and co-workers developed an
intramolecular oxidative coupling strategy to establish con-
tiguous quaternary carbon centers in the total synthesis of
vincorine and aspidophylline.5 Diels–Alder cycloaddition is
also a common strategy for forging such moieties as
demonstrated in Qin’s synthesis of perophoramidine.6 Oth-
er reactions such as rearrangements and transition-metal-
catalyzed reactions could also provide facile access to such
framework in one step for natural product synthesis.7 De-
spite those tremendous progresses, the limitation of these
strategies is also obvious: usually only one specific dia-
stereoisomer is accessible. In this regard, a general protocol
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

B
J. Hu et al.
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that enables stereospecific construction of all stereoisomers
of contiguous quaternary carbon centers is scarce and re-
mains elusive.
tones.9 However, this protocol has not been fully explored
as sluggish reaction mixtures are obtained when the reac-
tion is performed in solution. As shown by Barton and col-
leagues,8 UV irradiation of tetraphenyl-substituted cyclo-
hexanone 1 in THF delivered cyclopentane 4 only in 20%
yield via a process of homolytic C–C bond cleavage, de-
carbonylation and recombination of biradical intermediate
3 (Scheme 1). The low yield resulted from side reaction
pathways such as abstracting a proton from the solvent and
fragmentation of the active biradical intermediate. Most
importantly, the stereochemistry of the two stereogenic
carbon centers could not be retained due to the fast stereo-
chemical interconversion of the biradical intermediate be-
fore the C–C bond was reformed.
O
OH
N
Me
O
N
OH
O
OH
O
O
jiadifenolide
minfiensine
O
O
O
O
OMe
OH
MeO
MeO
O
Cl
N
O
O
Me
maoecrystal V
acutumine
To this end, Garcia-Garibay discovered that the irradia-
tion of the crystalline cyclohexanone 5 in solid state pro-
duced cyclopentane 8 in quantitative yield with retention
of the stereoconfiguration of the two tetrasubstituted car-
bon centers.10 The authors proposed that as the biradical
intermediate was constrained in the crystalline lattice, the
subsequent decarbonylation and recombination process of
the biradical species 6 proceeded much faster than the in-
terconversion of the stereochemistry of the radical centers,
which led to the preservation of the stereoconfiguration.
This breakthrough in photo-decarbonylation of cycloketone
paved a general way toward stereospecific construction of
contiguous quaternary carbon centers. However, the dis-
advantages of this protocol include: (1) working only for
crystalline ketones; (2) needing conjugated substituents
(e.g., phenyl, ester) adjacent to the carbonyl to stabilize the
putative biradical intermediate; (3) using UV irradiation to
initiate the homolytic cleavage of the C–C bond. Therefore,
synthetic applications in total synthesis of complex natural
products by taking advantage of this method are scarce.
As our continuing interests in total synthesis of natural
products, we have long been concentrated on exploring
more effective and general protocols for stereospecific
building-up contiguous quaternary carbon centers.11 To this
end, we recently disclosed that a H2O2-mediated ring con-
natural products with both stereoisomers of
continous quaternary carbon centers:
Me
Ac
N
N
N
N
Cl
Cl
Br
N
N
N
N
H
H
Me
communesin F
perophoramidine
O
OAc
O
Me
tochuinyl acetate
herbertenolide
Figure 1 Natural products embodied contiguous quaternary carbon
centers
In this respect, photo-induced decarbonylation8 of all-
substituted cyclic ketones is an appealing method for forg-
ing contiguous quaternary carbon centers as the stereocen-
ter adjacent to carbonyl could be stereospecifically estab-
lished relying on the enriched enolate chemistry of ke-
in solution:
O
O
Ph Ph
Ph
Ph
Ph
Ph
slow
Ph
Ph
hv, THF
– CO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20%
1
2
3
4
in solid:
O
O
Ph Ph
fast
– CO
Ph
Ph
OH
Ph
Ph
OH
hv
OH
HO
Ph
Ph
HO
HO
HO
OH
5
6
7
8
crystalline
· crystalline ketone;
stereospecific
· conjugated substituents for stabilizing bisradical;
· UV irradiation
Scheme 1 Photo-induced decarbonylation of cyclic ketones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

C
J. Hu et al.
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traction of all-substituted cyclic α-formyl ketones provided
an unparalleled tool for forging contiguous quaternary car-
bon centers.12 Herein, we would like to detail the story on
the discovery of this protocol.
O
O
O
H
H2O2, EtOAc, 5 h, 85%
HO
H
H
or CSA, H2O2, EtOAc
1 h, 93%
OTBDPS
OTBDPS
9a
10a
O
O
O
X
R
HO
HO
HO
OR
H
Ph
H
H
10e: R = Me; 1 h, 89%
10f: R = allyl; 1 h, 87%
10g: R = n-hexyl; 1 h, 86%
10h: R = Bn; 4 h, 83%
10a: R = TBDPS; 1 h, 93%
(gram scale; 88%)
10b: R = propargyl; 1 h, 79%
10c: R = Bn; 1.5 h, 84%
10d: R = Tr; 1 h, 86%
10m: X = 4-Me, 1 h, 84%
10n: X = 4-Br, 1 h, 94%
10o: X = 3-Cl, 1 h, 89%
10p: X = 2-F, 1 h, 95%
Scheme 2 H2O2-promoted oxidative rearrangement of malondialde-
hyde
The well-studied Baeyer–Villiger oxidation of aldehydes
and ketones mediated by peroxy acid or H2O2 predominant-
ly leads to esters via the rearrangement of the Griegee in-
termediate.13 However, the interrupted Baeyer–Villiger re-
action occurs when the Griegee intermediate is captured by
a tethered electrophile, which leads to new transforma-
tions.14–16 During the investigation of the chemistry of
malondialdehyde, we unexpectedly observed that the treat-
ment of malondialdehyde 9a with 30% aqueous H2O2 pro-
duced carboxylic acid 10a in high yield, instead of the de-
sired Baeyer–Villiger oxidation product.14 Further optimiza-
tion of the reaction conditions showed that the reaction
was accelerated by adding a catalytic amount of camphor-
sulfonic acid. The substrate scope of this reaction was quite
general, and a variety of malondialdehyde with different
functional groups underwent smoothly oxidative rear-
rangement to yield corresponding carboxylic acids in good
to excellent yields (Scheme 2). Moreover, the reaction was
operationally simple and usually completed in short time
and gave a very clean reaction mixture.
Scheme 3 Mechanistic studies
aldehyde was shifted to the α-position of the resulting car-
boxylic acid. Subsequently, the relative energies in the gas
phase of different intermediates and transition states were
calculated by density functional theory (DFT) with the
B3LYP/6-31g(d) set the in Gaussian 09 program. The results
clearly indicated that the first step of this reaction was the
formation of Griegee intermediate I via nucleophilic attack
of the aldehyde by H2O2, which has been extensively stud-
ied (Figure 2).13 This step was also the rate-determining
step of this reaction with a ΔG of 19.5 kcal/mol. The follow-
ing stage was the cyclization of the hydroperoxide with the
other carbonyl to give 1,2-dioxolane II instead of the migra-
tion of the α-carbon to the oxygen of peroxide, as the calcu-
lation showed that the former has a much lower reaction
barrier (15.4 kcal/mol for cis isomer and 14.6 kcal/mol for
trans isomer) than that (27.8 kcal/mol) of the latter. Eventu-
ally, a concerted hydride migration, C–C bond and O–O
bonds cleavage of 1,2-dioxolane II afforded the carboxylic
acid and formic acid. Notably, this process was highly ener-
getically favored by a large ΔG of –104.0 kcal/mol.
Upon establishing the reaction mechanism of oxidative
rearrangement of malondialdehyde, we posited that if cyclic
α-formyl ketone 11 was subjected to the action of H2O2,
ring contraction product 14 and dicarboxylic acid 15 might
be generated by following two different reaction pathways.
As shown in Scheme 4, initial nucleophilic attack of hydro-
gen peroxide to α-formyl ketones 11 would produce hy-
droxyl peroxide 12, which was trapped by the appendage
ketone leading to bicycle intermediate 13. Subsequent de-
To gain insights into the reaction mechanism, the con-
versation of malondialdehyde 9a over time was monitored
by NMR spectroscopy using d3-chlorform as solvent
(Scheme 3). The conversion-vs-time curve showed that
there was an induced period for the reaction, which was as-
cribed to the self-catalyzed effect of the resulted carboxylic
acids. Upon completion of the reaction, formic acid was de-
1
tected by H NMR and 13C NMR analysis. Furthermore, α-
deuterated malondialdehyde d-9e was synthesized using a
LiAlD4 reduction and oxidation procedure. The oxidative re-
arrangement of d-9e by H2O2 delivered carboxylic acid d-
10e with the α-proton being totally deuterated. Those ex-
periments indicated that both aldehydes were converted
into carboxylic acids and one of the α-protons of malondi-
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J. Hu et al.
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H
O
H
H
OHC
O
O
H
O
H
DG
O
O
O
(kcal/mol)
H
H
H
O
T-BV
H
27.8 (13.7)
O
Baeyer-Villiger oxidation
O
H
OHC
O
H
H
O
O
O
O
H
H
H
H
H
O
O
O
O
O
O
O
O
O
H
H
H
O
H
O
O
T1
19.5 (4.9)
H
O
O
H
H
H
O
T2
cis
H
15.4 (-1.6)
T3
trans
13.9 (-0.8)
trans
14.6 (-2.4)
cis
11.5 (-4.2)
cis
-1.1 (-15.9)
8.3 (-5.2)
0 (0)
H
trans
-1.9 (-16.8)
O
H
Dial + H2O2+2HCOOH
O
O
H
O
O
H
H
H
O
OHC
H
H
O
O
O
O
H
H
O
H
H
O
O
O
O
O
O
O
H
H
H
O
I
Griegee Intermediate
H
-104.0 (-105.2)
II
Figure 2 Free-energy profile of the oxidative rearrangement of malondialdehyde
O
OH
OH
O
O
R1 R3
O
O
H2O2
R2
CO2H
R1
R2
R3
O
CO2H
H
R3
CO2H
+
H2O2
H
OH
OH
H
+
t-BuOH
50 o
R1
R2
C
n
n
14
15
11a
14a
15a
11
26%
41%
H2O2
C–C bond
cleavage
alkyl migration
– HCO2H
path b
path a
H
H
O
H
H
H
OH
O
O
H2O2
HO
O
O
OH
H
O
O
CO2H
+
O
O
OH
HO
HO
OH
OH
b H
R1
R2
R1
R2
R1
R2
H
OH
R3
a
R3
R3
16
17
36%
18
24%
n
n
12
13
13
Scheme 5 Precedents of H2O2-mediated oxidative rearrangement of
cyclic α-formyl ketones
Scheme 4 Plausible reaction pathways of all-substituted cyclic α-
formyl ketones with H2O2
composition of 1,2-dioxolane 13 might yield the ring-trac-
tion product 14 via concerted alkyl migration, C–C and O–O
bond cleavage (path a). Another competitive reaction path-
way was also feasible, which was the concerted shift of hy-
dride and C–C and O–O bond cleavage, leading to dicarbox-
ylic acid 15 (path b). If the former pathway was favored, this
reaction would serve as a general platform for the construc-
tion of all stereoisomers of contiguous quaternary carbon
centers from all-substituted cyclic α-formyl ketones.
with H2O2favorably delivered the ring-contraction product
17.16 The switch of the reaction pathway may be ascribed to
the rigid scaffold of trans-decalin of 16, which retarded the
antiperiplanar requirement for the migration of hydride.16
Therefore, we postulated that introducing substituents on
the α-carbons of the cyclic α-formyl ketone might favor the
ring-contraction pathway by changing the conformation of
the 1,2-dioxolane intermediate and augmenting the migra-
tory ability of the α-carbon as well.
However, our hypothesis was plagued by the fact that
the hydride-shift pathway (path b) may be the major reac-
tion pathway owing to the greater migratory aptitude of
hydride and the release of ring strain of the cyclic ketone.
As shown by Payne, explosion of 2-formylcyclohexanone
11a to H2O2 gave pimelic acid as the major product (41%
yield),15 which was formed via the hydride-shift pathway
(Scheme 5). However, Middleton and Stock later discovered
that when oxidative rearrangement of α-formyl ketones 16
To verify our hypothesis, we prepared a series of α-
formyl cyclohexanones (Scheme 6, 11b–d) with an increas-
ing number of substituents on the α-carbons. Although no
reaction was observed for 11a under our previous reaction
conditions,14 putting one methyl on C-1 was beneficial for
the reaction, favorably producing ring-contraction product
14b with 1.8:1 regioselectivity. This outcome could be as-
cribed that the positive charge built on C-1 in the rear-
rangement process was stabilized by methyl. To our delight,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

E
J. Hu et al.
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hopefully to improve the regioselectivity. As displayed in
Table 1, addition of Brønsted acids was detrimental to the
reaction in respect to yields and regioselectivity (Table 1,
entries 2–6). Lewis acids such as Cu(OTf)2 and AgOTf were
ineffective for improving the outcome of this reaction (Ta-
ble 1, entries 7 and 8). The failure of optimizing reaction
conditions indicated that it might be the substrate structure
that dictates the regioselectivity of this reaction.
O
O
R3
H2O2
EtOAc
R1
R2
CO2H
CO2H
R3
R1
R2
H
3
1
R1
+
R3
CO2H
R2
rt
open flask
11
substrate
14
15
product
substrate
product
HO2C
Me
O
OH
O
O
NR
Me
To gain more insights to the influence of substituents on
this reaction and explore the substrate scope, a library of
cyclic α-formyl ketones was prepared and evaluated under
the standard reaction conditions. It is outstanding that
spiro-cycloketones with different substituents on C-1 only
produced ring-contraction products in excellent yields
(Scheme 7, 81–97% yield for 14e–l). All-substituted cyclic
α-formyl ketones with acyclic substituents on C-3 could
also be transferred to ring-contraction products in synthet-
ically acceptable yields (Scheme 7, 81–84% for 14d,m–o)
with 4–5:1 regioselectivity. Removal of one substituent on
C-3 of the ketone slightly diminished the isolated yield and
regioselectivities (Scheme 7, 14c and 14q). Interestingly,
when phenyl was present on C-1, the ring-contraction
product was the sole product (Scheme 7, 14r). Moreover, α-
phenyl-substituted cycloketones with six-to-eight-mem-
bered rings exclusively gave ring-contraction products in
high yields (Scheme 7, 14s–u). However, a significant
amount of dicarboxylic acid was isolated for the substrate
with a twelve-membered ring (Scheme 7, 14v). It was note-
worthy that fused carboxylic acid 14p was predominantly
produced when bridged an α-formyl ketone was employed.
With the influence of substituents on the reaction path-
way being established, we turned our attention to explore
whether the reaction was stereospecific by using enantio-
pure substrates. We prepared a parallel of enantioenriched
cyclic α-formyl ketones via enantioselective palladium-cat-
alyzed decarboxylative allylation17a,b or ion-pair organocat-
alyzed iodo-cycloetherification.17c A selected example was
illustrated in Scheme 8. The palladium-catalyzed decarbox-
ylative allylation of enol carbonate 16 using (R,R)-ANDEN-
phenyl as ligand gave cyclohexanone 17 in 84% ee by fol-
lowing Trost’s protocol.17b Attachment of formyl to cyclo-
hexanone 17 followed by benzylation mediated by t-BuOK
provided two separable stereoisomers 19a and 19b in 26%
and 30% yields, respectively. To our delight, the attachment
of a phenyl group on C-3 also favored the ring-contraction
pathway. H2O2-mediated rearrangement of 19a and 19b
only afforded corresponding carboxylic acid 20a and 20b in
high yields. To our satisfaction, the stereochemistry of car-
boxylic acid 20a and 20b was completely preserved based
on HPLC analysis and 2D NMR spectra experiments. Those
results firmly established that the oxidative ring-contrac-
tion process was highly stereospecific.
81%
14d/15d 4.2:1
11a
11d
HO2C
Me
O
O
O
O
HO2C
Me
Me
Me
95%
14e/15e >99:1
64%
14b/15b 1.8:1
11e
11b
HO2C
Me
O
O
Me
79%
14c/15c 3.8:1
11c
Scheme 6 The effect of substituents
introduction of methyl on C-3 could also improve regiose-
lectivity (ca. 4:1 for 14c and 14d), probably due to the in-
creasing migratory aptitude of C-3. It is outstanding that
spiro-cyclohexenone 11e only goes through the ring-con-
traction pathway, delivering carboxylic acid 14e in 95%
yield.
Table 1 Optimization of Reaction Conditionsa
O
O
Me
HO2C
Me
conditions
+
HO2C
CO2H
Me
11b
14b
15b
Entry
Catalyst (0.1 equiv)
Time (h)
43b/44bb
43b (%)c
1
2
3
4
5
6
7
8
–
4
1.8:1
1:1.2
1.6:1
1:1.1
1:1
64
40
43
44
44
34
47
35
(C6H5O)2PO2H
CF3COOH
TsOH
2.5
3
2.5
3
TfOH
NHTf2
3
1:1
Cu(OTf)2
AgOTf
3
1:1
3
1:1
a Reaction conditions: To a solution of cyclic ketone 11b (0.1 mmol) in eth-
yl acetate (1 mL), additive (0.01 mmol), H2O2 (30% aqueous solution, 0.3
mmol) was added.
b Determined by 1H NMR analysis.
c Isolated yield.
As a Brønsted acid was beneficial for the oxidative rear-
rangement of malondialdehyde, we also investigated vari-
ous additives for the oxidative ring contraction of 11b,
To display the synthetic utility of this oxidative ring-
contraction reaction, synthesis of cuparene-type sesquiter-
penoids (+)-cuparene and tochuinyl acetate were subse-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

F
J. Hu et al.
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O
O
CO2H
R3
H2O2
EtOAc
R1
R2
CO2H
R3
R1
R2
3
1
R1
+
R3
CO2H
R2
rt
open flask
11
14
15
from acyclic hexa-substituted ketones:
from spiro hexa-substituted ketones:
14e: R3 = Me
14f:
95% >99:1
84% >99:1
81% >99:1
93% >99:1
92% >99:1
96% >99:1
HO2C
R3
R3
R
3 = Bn
3 = Me
3 = Allyl
3 = Bn
4.2:1
4.9:1
5.2:1
HO2C
R
R
R
84%
83%
84%
14d:
14m:
14n:
gram scale
R
R
R
3 = Ph
14g:
14h:
14i:
3 = allyl
3 = 3-oxobutyl
HO2C
Allyl
HO2C
Allyl
R3
14j:
R
3 = Bn
97% >99:1
91% >99:1
94% >99:1
90% >99:1
gram scale
14o
82% 4.6:1
4.3:1
14k
14l:
R
R
3 = Ph
gram scale
3 = allyl
81%
from penta-substituted ketones:
from tetra-substituted ketones:
92%
>99:1
14s: n = 1
14t: n = 2
14u: n = 3
14v: n = 7
Ph
HO2C
R3
14c: R3 = Me
3.8:1
3.5:1
>99:1
HO2C
91%
92%
66%
79%
78%
93%
>99:1
>99:1
1.9:1
14q: R3 = Bn
H
14r:
R
3 = Ph
from bridged hexa-substituted ketone:
CO2H
14p
95% >99:1
Me
Scheme 7 Substrate scope
quently executed (Scheme 9). Initially, gram-scale synthesis
of chiral ketone 22 (92% ee) was smoothly realized via a
one-pot 3-exo iodo-cycloetherification/Wagner–Meerwein
rearrangement process by using 1 mol% chiral-pair catalyst
C1.17c However, direct removal of iodide of ketone 22 with
AIBN/Bu3SnH18a or Zn/HOAc18b only led to a messy reaction
mixture due to participation of the carbonyl. Eventually, a
two-step procedure via reduction (LiAlH4) followed by oxi-
dation (PCC) of ketone 22 successively provided ketone 23
in 80% yield and 89% ee. Introduction of formyl into ketone
23, followed by methylation delivered the all-substituted α-
formyl cyclohexanone 24a and 24b, which were separated
O
O
O
Ph
CO2H
Bn
Allyl
Ph
H2O2, EtOAc
rt
O
O
Allyl
Allyl
Bn
Ph
19a
26%, 83% ee
20a
97%, 84% ee
16
+
O
O
Ph2P
PPh2
Ph
Ph
CO2H
Bn
H2O2, EtOAc
rt
O
Allyl
Allyl
Bn
H
N
NH
O
19b
20b
30%, 84% ee
78%, 85% ee
(R,R)-ANDEN-Phenyl
Pd2dba3⋅CHCl3
t-BuOK, BnBr
t-BuOH
toluene
–78 °C to rt
O
O
O
HCO2Et,
NaH, MeOH
Ph
Ph
Allyl
Allyl
toluene
0 °C to rt
87%, 84% ee
18
17
94%
Scheme 8 Stereospecific construction of contiguous quaternary car-
Scheme 9 Asymmetric synthesis of sesquiterpene (+)-cuparene and
bon centers
tochuinyl acetate
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

G
J. Hu et al.
Synpacts
Synlett
by column chromatography. Oxidative ring contraction of
those two ketones mediated by H2O2 yielded corresponding
cyclopentane 25a and 25b in 97% and 87% yield. It should
be pointed out that no dicarboxylic acids were detected in
the 1H NMR spectra of the crude reaction mixtures. The ste-
reochemistry of the contiguous quaternary carbon centers
were preserved as shown by HPLC and 2D NMR analysis,
which was further confirmed by X-ray crystallography
analysis of 24a and 25b. Eventually, asymmetric synthesis
of (+)-cuparene was accomplished by a sequence of reduc-
tion, Swern oxidation followed by Wollfe–Kishner reduc-
tion of 25a. The other stereoisomer 25b was advanced to
tochuinyl acetate via reduction of the carboxylic acid fol-
lowed by acylation of the resulting primary alcohol.
In summary, the serendipitous discovery of oxidative
rearrangement of 2,2-disubstituted malondialdehyde re-
veals a new interrupted Baeyer–Villiger reaction. Mechanis-
tic studies suggested the process proceeds by the capture of
a Griegee intermediate by appendage carbonyl and frag-
mentation of the 1,2-dioxolane intermediate via concerted
hydride shift, and C–C and O–O bond cleavage. Inspired by
this novel reaction pathway, the H2O2-mediated oxidative
rearrangement of cyclic α-formyl ketones was subsequently
investigated. The oxidative ring contraction was deter-
mined to be the major reaction pathway for cyclic α-formyl
ketones, which depended on the α-substituents adjacent to
the cyclic ketone. This protocol provides a stereospecific ac-
cess to all stereoisomers of contiguous quaternary carbon
centers from corresponding stereodefined cyclic α-formyl
ketones. Asymmetric synthesis of (+)-cuparene and to-
chuinyl acetate was also successively implemented by em-
ploying this novel protocol. Unfortunately, cyclopentanones
and acyclic ketones are not suitable substrates for this reac-
tion and predominantly give C–C bond-cleavage products.
Further studies of the H2O2-mediated oxidative rearrange-
ment to expand its substrate scope and its applications on
natural product synthesis deserve to be extensively investi-
gated in the future.
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Funding Information
We are grateful for financial support from the National Natural Sci-
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the Scientific Research Foundation of Northwest A&F University
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