Oxidative prins-pinacol tandem process mediated by a hypervalent iodine reagent: Scope, limitations, and applications

Article abstract of DOI:10.1021/jo2019027

An oxidative Prins-pinacol tandem process mediated by a hypervalent iodine reagent has been developed. This oxidative version of the famous tandem process fits within the concept of "aromatic ring umpolung" and allows the stereoselective transformation of

Full text of DOI:10.1021/jo2019027

Article
pubs.acs.org/joc
Oxidative Prins-Pinacol Tandem Process Mediated by a Hypervalent
Iodine Reagent: Scope, Limitations, and Applications
Marc-Andre Beaulieu, Kimiaka C. Guerard, Gaetan Maertens, Cyrille Sabot, and Sylvain Canesi*
́
́
̈
Laboratoire de Met
́
hodologie et Synthes
̀ ́ ́ ̀ ́
e de Produits Naturels, Universite du Quebec a Montreal, C.P. 8888, Succ. Centre-Ville,
Montreal, H3C 3P8 Queb
́
́
ec, Canada
S
* Supporting Information
ABSTRACT: An oxidative Prins-pinacol tandem process
mediated by a hypervalent iodine reagent has been developed.
This oxidative version of the famous tandem process fits within
the concept of “aromatic ring umpolung” and allows the
stereoselective transformation of simple phenols into highly
elaborated spirocyclic dienone cores containing several
quaternary carbon centers. The scope and the limitations of
this process, including the study of its stereoselectivity, are
described in this article. As a direct application of this
stereoselective process, we describe the formal synthesis of
(−)-platensimycin, an important antibiotic agent.
mediated by a single-electron transfer (SET), the phenoxonium
ion 2 generated would be trapped via an oxidative Prins process
by the double bond, possibly through a cyclic chairlike transition
state. This would be followed by a stereocontrolled ring
contraction that should occur with retention of the configuration
of the emerging quaternary carbon center (Figure 1).
INTRODUCTION
■
Cationic molecular transpositions1 provide an esthetically
appealing route to complex molecular structures. A remarkable
transformation of this type is the elegant Prins-pinacol tandem
process; this method has been used as the key step in several
total syntheses of natural products, as demonstrated by
Overman and co-workers.2 An extension of this aliphatic
transformation to aromatic systems would open up several
opportunities in chemical synthesis. Our interest in oxidative
dearomatization of electron-rich aromatics3 mediated by
hypervalent iodine reagents4−6 led us to question whether an
analogous process could be initiated by oxidative activation.
While electron-rich aromatic systems normally react as
nucleophiles, oxidative activation converts them into highly
electrophilic species, which may then be intercepted with
appropriate nucleophiles. If one considers the behavior of
intermediate 2, this reversal of reactivity may be thought of as
involving “aromatic ring umpolung”.3 4d Phenol dearomatiza-
,
tion processes mediated by hypervalent iodine reagents such as
(diacetoxyiodo)benzene (DIB), an environmentally benign
reagent, are well-documented in the literature, and this has
elicited substantial interest in the synthetic arena.4−7 An
indication of how the formation of the corresponding
phenoxonium ion 2 can be efficiently achieved and sufficiently
stabilized to be trapped by a nucleophile is well apparent in the
work of Kita,7 who has shown that such processes are best
performed in solvents such as hexafluoroisopropanol (HFIP).8
Extending the aromatic ring umpolung concept9 to the famous
Prins-pinacol transformation would allow the rapid conversion
of simple and inexpensive cores, such as phenols, into more
complex spirodienone architectures,3i while controlling the
stereoselective formation of quaternary carbon centers, in a
single step.10 We assumed that during the umpolung activation,
Figure 1. Presumed course of the oxidative Prins-pinacol tandem
process.
Such spiro[4,5]decanyl scaffolds 4 are found in several
natural products having interesting biological properties such as
(+)-anhydro-β-rotunol 5,11 an antifungal agent, (+)-dehydro-
solanascone 6,12 an antibacterial product resulting from a
potential [2 + 2] cycloaddition process from 5, (−)-scopadulcic
acid A 7,13 an antiviral agent against herpes simplex virus type
1, and (+)-magellaninone 8,14 a compound belonging to the
lycopodium family15 (Figure 2).
Received: September 20, 2011
Published: October 11, 2011
© 2011 American Chemical Society
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be explained by considering that the first intermediate is a
highly delocalized carbonium ion, which can be represented by
2 (Figure 1, R1 = Br) as one of its resonance structures. We
believe that, because of the presence of the electron-
withdrawing bromine atoms, 2 would be the dominant
resonance form rather than the ortho-mesomer and thus
would be less susceptible to a bimolecular attack by external
nucleophiles at the ortho-position. As an additional advantage,
the bromine atoms provide a handle for the introduction of
other substituents, using transition metal chemistry. Compound
4g was obtained in a low 30% yield, about half of the yield
recorded earlier for substrates without substituents in position 2
(R3 = H). This result could shed light on the stereochemical
course of the reaction: a 1:1 epimeric mixture of the tertiary
alcohol moiety in 1g is oxidized, and it is possible that only one
diastereoisomer, having minimal A1,3 interactions, is a
competent substrate for the requisite oxidative Prins-pinacol
process. Indeed, the conformation of diastereomer 2g, which
presumably undergoes reaction, is such that the OTBS group is
subjected to minimal A1,3 interaction with the “inside” vinylic
hydrogen.16 This contrast with diastereomer 2g′, where the
allylic interaction is considerably more severe, due to the
presence of a more sterically demanding methyl group in
proximity to the same vinylic hydrogen. This interaction could
slow the Prins step of diastereoisomer 2g′ and divert the
reactive electrophilic species, created upon umpolung activation
of the phenol, toward other reaction pathways. In either case,
the major product of the reaction is cis-ketone 4g17 (Scheme 1).
To support this hypothesis, compound 1h, containing an
allyl substituent at position 2, was prepared. In this case, both
vinyl groups at position 3 (R4 = vinyl and R5 = H) were able to
trap the phenoxonium ion species, thus automatically placing
the OTBS group in an axial position in the transition state 2h,
to generate compound 4h in a 55% yield, comparable to that
obtained with similar substrates.
Figure 2. Natural products containing a spiro[4.5]decanyl core.
In this paper, we substantially extend the scope of the
oxidative Prins-pinacol process to phenol derivatives containing
allylic and propargylic alcohol moieties,3i and we present an
avenue for the stereoselective formation of tertiary and
quaternary carbon centers. Furthermore, as a first application
to this process, the synthesis of the known main cage of
(−)-platensimycin, a novel important class of antibiotic agent is
reported.
RESULTS AND DISCUSSION
■
We first investigated the scope and limitations of this process
on different phenols 1 containing a terminal alkene as an
internal nucleophile to trigger the oxidative Prins process
followed by a semipinacol-type rearrangement to produce the
main spirocyclic system 4. This reaction could be performed
either in HFIP at room temperature or at −15 °C in an equal
mixture of DCM/HFIP. To exemplify this transformation,
different phenols substituted at any position on the lateral chain
or at the ortho-positions were oxidized. A TBS moiety was first
used as an alcohol protecting group in order to avoid the
formation of the cyclic ether compound resulting from a direct
attack by the alcohol on the phenoxonium ion 2 generated
upon oxidation, as demonstrated by Kita and co-workers.7 A
summary of representative experiments appears in Table 1.
Table 1. Oxidative Prins-Pinacol Tandem Process of
Olefinic Substrates
This transformation is not restricted to the formation of
ketones but can be extended to the formation of aldehydes
from secondary allylic ethers. In this case, a protecting group
more hindered than a TBS group must be used. Indeed, in the
absence of a tertiary center, the phenoxonium ion, generated
during umpolung activation, is more accessible to the oxygen
atom and leads mainly to cycloether 10 via a five-membered
ring, and only a small amount of the desired compound 12 was
observed. In order to favor the 6-endo process, the secondary
alcohol moiety was protected with the bulky TIPS protecting
group. Moreover, the formation of aldehyde 12 required the
use of PIFA (phenyliodine(III)bis(trifluoroacetate) instead of
DIB, to prevent the formation of a mixed acetal, such as 15 in
43% yield. The formation of the latter resulted from the
nucleophilic attack of an acetate ion, released upon umpolung
activation, on intermediate 14. The presence of the less
nucleophilic trifluoroacetate ligands on the hypervalent iodine
complex (PIFA) allowed formation of the aldehyde 12 in 61%
yield. It should be noted, however, that the mixed acetal
function in 15 could be useful if a protected aldehyde is
required in the synthesis (Scheme 2).
entry
R1
R2
R3
R4
R5
yield (%)
a
b
c
d
e
f
H
H
H
H
Br
H
H
H
H
H
H
H
H
Me
H
H
H
Me
H
64
60
58
68
84
50
30
55
H
CHCH2
H
H
Ph
Me
Me
Me
H
H
Me
H
Me
H
Me
g
h
Me
allyl
Me
H
CHCH2
H
The anticipated ketones 4a−h emerged in good yields (up to
84%) and with very good diastereoselectivity, dictated by allylic
strain interactions in the chairlike transition state (entries f−h),
and only one other diastereoisomer was detectable by 1H NMR
(5−10%). This method produced compact polysubstituted
scaffolds containing substituents located at any of the positions
on the lateral chain. It should be noted that in the case of R5
being an alkyl group, the reaction simultaneously produces two
quaternary carbon atoms, one of which is also a spiro center.
The presence of bromines in ortho-positions appears to lead to
an increase of the global yield of this transformation. This may
In order to broaden the scope and test the limitations of this
transformation, we have also substituted the C-1 alkene
position with two methyl groups.9 This result suggests the
potential for constructing highly hindered cores containing two
contiguous quaternary carbon centers. Indeed, the elaboration
of such challenging systems is often prevented by the steric
hindrance of the first quaternary carbon center. During the
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Scheme 1. A1,3 Strain Interactions Involved during the Transition State of Compound 1g
Scheme 2. Formation of Aldehyde and Acetal Functionalities
oxidation of compound 16, the aldehyde 17 formed was not
stable and further transformed into the corresponding tricyclic
core 18 via a Michael addition on the dienone system mediated
by the aldehyde functionality to produce hemiacetal 18 in 40%
overall yield. It should be stressed that this is a one-pot
multistep, stereoselective transformation producing a function-
alized, highly congested tricyclic system 18 (Scheme 3).
(R)-1a (70% ee) was synthesized.18b During the umpolung
activation, the two conformers 21 and 21′ can equilibrate, but
the transition state originating from 21′ should be the most
stable (Scheme 1). Compound (R)-4a was obtained with the
same optical purity (70% ee)19 as the starting material used,
thus demonstrating the high reaction enantioselectivity in this
case (Scheme 4).
Our next stage was to develop an enantioselective pathway
enabling the formation of tertiary or quaternary carbon centers
from an enantiopure (or an enantioenriched) substrate
containing a stereogenic allylic alcohol functionality on the
acyclic lateral chain, such as (+)-13.18a For this to be successful,
the conformational equilibrium, involved during the chairlike
transition state, had to be easily shifted to one conformer,
considering all the possible A1,2, A1,3, and 1,3-diaxial steric
interactions, as well as the stereoelectronic effects involved.
Indeed, conformers 19 will lead stereoselectively, after a ring
contraction, to the two opposite stereocenters of 20. In this
case, the two conformers 19 and 19′ each have their own steric
interactions, resulting in overall low enantioselectivity. Con-
former 19′ has to accommodate A1,3 and 1,3-diaxial steric
interactions, whereas conformer 19 presents more severe A1,2
interactions. The balance of these effects results in the
formation of both enantiomers of compound 20 in 68% yield
with low enantiomeric excess19 (30%) (Scheme 4). Such a
result suggests that, in principle, and depending on the
protecting group used, the same enantiopure tertiary alcohol
13 could lead to an excess of either R or S compound 20.
Indeed, an O-TBS version of (R)-13 that would favor
conformer 19′ led to an excess of the opposite enantiomer
(R)-20 with a similar ee.19 To improve this enantioselectivity,
we removed the mismatched steric A1,2 interaction generated by
the allylic methyl group and the smaller TBS protecting group
was used. As a result, an enantioenriched form of compound
In order to develop an efficient stereoselective route to
compounds containing a quaternary carbon center, we resorted
to a diastereoselective reaction where one transition state would
be favored over the other. In the desired conformer 24, the set
stereochemistry of the quaternary methyl group dictates the
configuration of the emerging quaternary carbon center, such
that chirality transfer takes place with retention of configuration
(Scheme 5). Therefore, a trans-cycloether 23 was synthesized,
and in this case, only the formation the bicyclic transition state
24 was permitted. The required tetrahydrofuran core 23,
involving minimal A1,2 interaction between the equatorial
oxygen atom and the methyl group, and therefore presumably
thermodynamically favored, was obtained by acid treatment of
the mixture of triols 22 in 88% yield. The asymmetric version of
22 was assembled using Evans’ asymmetric alkylation
technology.20 Umpolung activation of cycloether 23 led to
the hemiketal 26 after the ring contraction, ring elongation
process in 70% yield. Further treatment of the crude mixture of
anomers 26 with Dess−Martin oxidation periodinate21 led to
keto-aldehyde 27 as a single diastereoisomer in 60% yield
overall from compound 23. As anticipated, on the basis of our
mechanistic hypothesis, compound 27 displayed a cis-relative
configuration between the two carbonyl branches. It should be
noted that, in this new process, we have efficiently created a
pair of contiguous stereocenters, one tertiary and the other
quaternary, with complete degree of stereocontrol, thus
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Scheme 3. Formation of Contiguous Quaternary Carbon Centers
Scheme 4. Stereoselectivity Issues Following the Conformational Equilibriums
Scheme 5. Efficient diastereoselective avenue for the formation of a quaternary carbon center
demonstrating the potential practical utility of this oxidative
process in a diastereoselective pathway (Scheme 5).
alkynes with yields similar to those of unhindered alkynes and
allows the generation of a contiguous quaternary carbon center
and a tetrasubstituted alkene moiety. In addition, the geometry
provided by the half-chair transition state 29 appears to tolerate
a wide range of bulky substituents on the lateral chain. Indeed,
the absence of 1,3-allylic strain interactions allows the presence
of substituents in position 2 and leads to good yields of the
desired system (up to 81%, 28f and 28h), by contrast with
compound 4h (Scheme 1). As already observed in Table 1, the
presence of bromines in the ortho-position increased consid-
erably the global yield of this transformation (30e versus 30f
and 30g versus 30h). This reaction can also generate a
conjugated aldehyde functionality (30m) in 47% yield from
compound 28m. The presence of a more hindered TIPS as an
oxygen protecting group was still required with a secondary
alcohol moiety to efficiently produce the aldehyde functionality.
As a demonstration of the potential of this new process,
We were also interested in extending this process to
acetylenic substrates 28 to readily produce interesting
polyfunctionalized and polysubstituted compact spiro[4,5]-
decanyl systems 30. In order to broaden the scope and
limitation of this new transformation, different phenols,
containing several substituents at any position on the lateral
chain, were investigated. The desired compound 30 was
obtained in 46−81% yield. A summary of representative
experiments appears in Table 2.
This novel tandem process allows the production, in useful
to good yield (up to 81%), of the scaffold 30, a compact
polysubstituted and functionalized subunit present in several
natural products. This key functionalized core was easily
obtained from simple and inexpensive phenols. It should be
stressed that this process occurs even in presence of hindered
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Table 2. Oxidative Prins-Pinacol Tandem Reaction with Alkynes
compound 31, containing a gem-dimethyl benzylic function-
ality, was prepared and the subsequent “umpolung activation”
of this polysubstituted phenol resulted in compound 32 in 51%
yield. In this case, the compact polyfunctionalized system
contains two contiguous quaternary carbon centers and a
trisubstituted alkene moiety. Such a hindered structure
represents a difficult scaffold to synthesize. This new process
represents an expeditious access to such challenging structures
(Scheme 6).
Scheme 7. 5-exo-dig Cyclization of Substrate with
Propargylic Ether at Position 7
Scheme 6. Formation of Contiguous Quaternary Carbon
Centers and a Trisubstituted Alkene Moiety
As an initial application of the oxidative Prins-pinacol tandem
sequence, we describe now a formal synthesis of (−)-platensi-
mycin 53.23 This substance is an exciting experimental
antibiotic that is believed to act as a FabF inhibitor.23a Its
unusual structure and potent bioactivity have elicited enormous
interest in the synthetic community.23 Our strategic approach
to (−)-platensimycin targeted compound 52, an advanced
intermediate in Nicolaou’s total synthesis24 (Figure 3).
The process was also extended to compounds containing a
propargylic ether in position 6 such as 33, producing the
aldehyde 34 in 51% yield via an exocyclic Prins-pinacol process.
In this case, a 5-exo-dig cyclization was observed instead of the
standard 6-endo-dig mode normally observed with substrates
such as 28 (Table 2), prompted by the sterically demanding
ether moiety generated in position 3. In the case of an
unsubstituted position 3, however, with an alkyne segment
substituted in position 5, the process now proceeds via a 5-exo-
dig mode cyclization, leading to the spiro[5.5]undecanyl
structure 34 with good selectivity (9/1) in favor of the E-
isomer, as observed by NMR. This new reaction course of
compounds containing an alkyne functionality, which hinges on
the position of the ether moiety during the oxidative Prins
transformation, opens the door to novel opportunities such as
the facilitated construction of the subunit present in the natural
product (−)-hispidospermidin 3522 (Scheme 7).
It should be noted that the oxidative Prins-pinacol reaction
proceeded sometimes with formation of byproducts such as 37
(Scheme 8; in 5−10% yield). The formation of such
spiro[5.5]undecanyl systems was rationalized by invoking an
alkyl migration from intermediate 36, occurring in competition
with ring contraction, albeit to a minor extent. While the ring
contraction was the major pathway, migration of the acyclic
moiety could occasionally be observed (Scheme 8).
The availability of a straightforward route to compounds
such as 4 or 30 presents new opportunities for the formation of
the main core of natural products such as (−)-platensimycin,
53. To that effect, the enantioenriched cycloether compound
23 was obtained using Evans’s asymmetric alkylation
technology from compound 38 (Scheme 5).3i At this stage,
we had assumed that a Baeyer−Villiger reaction or a similar
transformation on the hemiketal 26 would produce the
required tertiary alcohol functionality in a compound (43)
which contains the carbon framework of the desired target.
Unfortunately, direct treatment of compound 26 in presence of
mCPBA failed to produce 43, and instead, an epoxide was
recovered resulting from mCPBA over oxidation of alkene 42
(Scheme 9). Consequently, we proceeded to investigate
alternatives to the Baeyer−Villiger process, such as the useful
methodologies developed by Schreiber and co-workers.25,26
Indeed, during the phenolic activation of cycloether 23 with the
hypervalent iodine reagent, the resulting oxonium species 25
(Scheme 5) can be trapped in the same pot with hydrogen
peroxide, affording a 3:2 mixture of unassigned diastereo-
isomers of hydroperoxyketal 39 in 64% yield from 23
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Scheme 8. Formation of Spiro[5.5]undecanyl Byproducts
Figure 3. Structure of (−)-platensimycin and retrosynthetic logic.
Scheme 9. Schreiber Fragmentation Process on the Hydroperoxyketal 39
Scheme 10. Stereoselective Formation of the Tertiary
Alcohol Moiety
(Figure 3). Further treatment of this hydroperoxyketal in
presence of acetic anhydride25 furnished a mixture of the
desired alcohol 43 and the unwanted tetrasubstituted alkene 42
in 67% yield in a 3:2 ratio in favor of the alkene. This alkene
functionality presumably results from an elimination promoted
by the released acetate ion on the anti-periplanar hydrogen on
intermediate 41; the desired compound 43 would result from
the hydrolysis of the oxonium species 41 (Scheme 9).
To optimize the formation of alcohol 43, we decided to
perform this transformation in a biphasic medium using a
Schotten−Baumann-type procedure on hydroperoxides 39.
Indeed, in such conditions, the presence of water favored the
nucleophilic attack on the oxonium 41, leading almost
exclusively to the formation of the desired alcohol 43 with
the required configuration, thereby demonstrating the stereo-
selectivity of the oxidative process (Scheme 5). This trans-
formation could be performed with acetic anhydride; however,
2-nosyl chloride proved to be more convenient as a peroxide
activator, affording 43 in 72% yield. During this transformation,
the ketal function of 39 has been replaced by the desired
alcohol functionality (43) with retention of configuration in
good yield (Scheme 10).
treatment of 44 with thiophenol and TFA produced thio-acetal
45 in 70% yield. Unfortunately, all radical or anionic attempts
to produce the main cage core 52 from 45 failed, and only
traces of the desired compound 52 was observed during the
treatment of 45 with lithium naphthalenide (LN) (Scheme 11).
As first demonstrated by Nicolaou,24 it appears that the
formation of the main cage was not so straightforward, most
probably due to the presence of the quaternary carbon center.
Indeed, in the literature, few reactions allowing the formation of
such a system by a Michael addition have been reported;24 as
an example, the Stetter transformation did not proceed.24 To
be able to produce a formal synthesis of (−)-platensimycin, we
decided to sacrifice the second quaternary carbon center
generated with total stereocontrol during the “umpolung
activation” to obtain a flat and less hindered cyclopentene
moiety, in order to favor the Michael addition required. In the
Subsequently, the acetate group was removed and the
primary alcohol obtained was selectively oxidized to the
hemiketal 44 in presence of IBX in 80% yield. Further
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Scheme 11. First Unsuccessful Pathway to the Main Core
Scheme 12. Schreiber−Fenton Fragmentation Process
Scheme 13. Formal Synthesis of (−)-Platensimycin
event, hydroperoxide 39 was treated with a mixture of the
Fenton reagent (FeSO4) and Cu(OAc)2 in MeOH to produce
the intermediate 46, and a subsequent addition of K2CO3 to the
reaction mixture induced conversion to 47 in 44% overall yield
from 29. Compound 47 was obtained as a 3:1 mixture of
exocyclic (major) and endocyclic alkenes. The substitution of
Cu(OAc)2 by CuCl2 during the Schreiber fragmentation26 led
exclusively to the chloro compound 49 in good yield (74%)
with 4:1 selectivity in favor of the trans isomer but, as
presumed, subsequent treatment with DBU led mainly to the
undesired tetrasubstituted alkene 42. As demonstrated first by
Nicolaou et al.,24 both isomers of compound 48 converge to
the tetracyclic main core of platensimycin 52. Accordingly to
this hypothesis, no separation was required at this stage. The
alcohol mixture 47 was thus advanced to a mixture of the
corresponding aldehydes 48 in 74% yield by PCC oxidation
(Scheme 12).
Both compounds in the mixture 48 are known synthetic
precursors24 for (−)-platensimycin. Accordingly, they were
treated by Kagan’s reagent (SmI2),27 whereupon stereoselective
cyclization to alcohols 50 occurred via a regular aliphatic
umpolung transformation (Scheme 13).28 Finally, the alkene
mixture 50 was transformed to the known cage compound 52
upon treatment with TFA via the formation of a common
tertiary carbocation 51. The final elaboration of 52 to
(−)-platensimycin is well-known in the literature.24 Therefore,
the synthesis of 52 represents a formal synthesis of
(−)-platensimycin (Scheme 13).
CONCLUSION
■
In summary, an oxidative Prins-pinacol tandem process has
been developed. This version represents an extension to
aromatic systems of this important transformation and allows
the generation of compact polyfunctionalized and polysub-
stituted spiro[4.5]decanyl systems containing several quater-
nary carbon centers from inexpensive phenol derivatives. In
addition, we have devised an enantioselective and a
diastereoselective pathway to compounds containing tertiary
and quaternary carbon centers; these scaffolds are present in
numerous natural products that bear important biological
activities. As the first application of this novel process, a formal
synthesis of (−)-platensimycin has been achieved. This
demonstrates the synthetic potential of this novel oxidative
extension of the Prins-pinacol process, as well as the utility of
the “aromatic ring umpolung” concept.
EXPERIMENTAL SECTION
■
Unless otherwise indicated, 1H and 13C NMR spectra were recorded at
300 and 75 MHz, respectively, in CDCl3 solutions. Chemical shifts are
reported in parts per million on the δ scale. Multiplicities are described
as s (singlet), d (doublet), dd, ddd, etc. (doublet of doublets, doublet
of doublets of doublets, etc.), t (triplet), q (quartet), quin (quintuplet),
m (multiplet), and further qualified as app (apparent), br (broad).
Coupling constants, J, are reported in hertz. IR spectra (cm−1) were
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recorded from thin films. Mass spectra (m/e) were measured in the
electrospray (ESI) mode.
cis-2-Acetyl-3-methylspiro[4.5]deca-6,9-dien-8-one (4g): Pale
yellow oil, 0.030 mmol, 6.0 mg, 30% yield; IR ν (cm−1) 2958, 2930,
1707, 1661, 1620; H (300 MHz, CDCl3) δ 7.20 (dd, J = 9.9, 2.7 Hz,
1
General Procedure for the Oxidative Prins-Pinacol Process. A
solution of PhI(OAc)2 (“DIB”, 38 mg, 0.11 mmol, 1.1 equiv) in
(CF3)2CHOH (“HFIP”, 0.25 mL) was added over 5 s to a vigorously
stirred solution of phenol (0.1 mmol, 1 equiv) in 0.75 mL of a solution
of CH2Cl2/HFIP (2/1) cooled to −15 °C for a few seconds (to avoid
precipitation of HFIP) or in 0.75 mL of HFIP at room temperature.
After addition of DIB, the solution was stirred for 2 min, quenched
with 0.1 mL of acetone, filtered directly over silica gel (n-hexane/
EtOAc, 1:1), and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel chromatography with a mixture
of ethyl acetate/hexane to afford the corresponding dienone.
2-Acetylspiro[4.5]deca-6,9-dien-8-one (4a): Pale yellow oil, 0.064
1H), 6.93 (dd, J = 9.9, 2.7 Hz, 1H), 6.20 (d, J = 9.9 Hz, 1H), 6.16 (d,
J = 9.9 Hz, 1H), 3.39 (q, J = 8.1 Hz, 1H), 2.81−2.70 (m, 1H), 2.32
(dd, J = 14.4, 7.8 Hz, 1H), 2.22 (s, 3H), 1.92−1.72 (m, 3H), 1.30 (d,
J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 209.8, 186.0, 155.8,
153.6, 127.5, 126.5, 54.7, 46.9, 44.8, 38.3, 36.9, 31.8, 16.5; HRMS
(ESI) calcd for C13H17O2 (M + H)+ 205.1223, found 205.1226.
cis-2-Acryloyl-3-allylspiro[4.5]deca-6,9-dien-8-one (4h): Pale yel-
low oil, 0.055 mmol, 11.2 mg, 55% yield; IR ν (cm−1) 2928, 1701,
1662, 1623; 1H NMR (600 MHz, CDCl3) δ 6.82 (d, J = 10.0 Hz, 1H),
6.74 (d, J = 10.0 Hz, 1H), 6.38 (d, J = 10.0 Hz, 1H), 6.35 (d, J = 10.0
Hz, 1H), 5.68 (m, 2H), 5.09 (d, J = 17 Hz, 1H), 5.07 (d, J = 10 Hz,
1H), 4.94 (d, J = 16.4 Hz, 1H), 4.91 (d, J = 10 Hz, 1H), 2.57 (m, 2H),
2.45 (m, 1H), 2.39 (t, J = 7.6 Hz, 1H), 2.26 (m, 1H), 2.09 (dd, J =
13.5, 8.8 Hz, 1H), 1.91 (t, J = 11.7 Hz), 1.83 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 197.2, 185.8, 154.1, 148.2, 135.1, 134.3, 130.8, 130.4,
118.1, 117.3, 58.8, 48.2, 45.5, 38.4, 35.3, 30.6; HRMS (ESI) calcd for
C16H19O2 (M + H)+ 243.1380, found 243.1377.
1
mmol, 12.2 mg, 64% yield; IR ν (cm−1) 2957, 1707, 1660, 1623; H
NMR (600 MHz, CDCl3) δ 6.87 (dd, J = 10.2, 3.0 Hz, 1H), 6.86 (dd,
J = 10.2, 3.0 Hz, 1H), 6.21 (d, J = 10.8 Hz, 2H), 3.31 (quin, J = 7.8 Hz,
1H), 2.22 (s, 3H), 2.21−2.10 (m, 3H), 1.95−1.78 (m, 3H); 13C NMR
(150 MHz, CDCl3) δ 208.7, 185.9, 154.1, 152.9, 127.7, 127.6, 51.3,
48.5, 38.9, 37.5, 29.2, 28.0; HRMS (ESI) calcd for C12H15O2 (M + H)+
191.1067, found 191.1065.
2-Acryloylspiro[4.5]deca-6,9-dien-8-one (4b): Pale yellow oil,
0.060 mmol, 12.0 mg, 60% yield; IR ν (cm−1) 2935, 1661, 1615,
1404; 1H (600 MHz, CDCl3) δ 6.91 (d, J = 9.6 Hz, 2H), 6.43 (dd, J =
17.4, 9.6 Hz, 1H), 6.40 (d, J = 17.4 Hz, 1H), 6.23 (d, J = 9.6 Hz, 2H),
5.89 (d, J = 9.6 Hz, 1H), 3.58 (quin, J = 8.4 Hz, 1H), 2.21−2.17 (m,
3H), 1.99−1.82 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 200.6,
186.0, 154.2, 152.9, 135.4, 129.1, 127.7, 127.7, 48.7, 47.6, 39.1, 37.7,
28.5; HRMS (ESI) calcd for C13H15O2 (M + H)+ 203.1067, found
203.1063.
8-Oxospiro[4.5]deca-6,9-diene-2-carbaldehyde (12): Pale yellow
1
oil, 0.061 mmol, 10.7 mg, 61% yield; H NMR (300 MHz, CDCl3) δ
9.74 (s, 1H), 6.87 (d, J = 9.8 Hz, 1H), 6.77 (d, J = 9.8 Hz, 1H), 6.17
(d, J = 10.2 Hz, 1H), 6.22 (d, J = 9.8 Hz, 2H), 3.18 (m, 1H), 2.29−
2.14 (m, 3H), 1.99 (dd, J = 13.7, 9.4 Hz, 1H), 1.83 (t, J = 7.1 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 201.4, 185.8, 153.4, 152.5, 128.0, 127.8,
51.0, 48.3, 37.4, 36.7, 25.5; HRMS (ESI) calcd for C11H13O2 (M + H)+
177.0910, found 177.0908.
2-Hydroxy-10,10-dimethyl-4,5,9,9a-tetrahydro-2H-3,5a-metha-
nobenzo-oxepin-8(3H)-one (18): Pale yellow oil, 40% yield; 1H
NMR (600 MHz, CDCl3) δ 6.52 (dd, J = 10.2, 2.3 Hz, 2H), 6.17 (d,
J = 10.4 Hz, 1H), 5.35 (m, 1H), 4.09 (m, 1H), 2.77 (dd, J = 7.8, 3.4
Hz, 1H), 2.20 (dd, J = 7.8, 3.4 Hz, 1H), 1.94 (s, 1H), 1.94 (dd, J = 7.8,
3.4 Hz, 1H), 1.33 (s, 3H), 1.30 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 195.8, 152.3, 126.8, 82.8, 80.7, 68.5, 56.2, 38.3, 33.0, 31.4, 31.1, 29.6,
23.2; HRMS (ESI) calcd for C13H19O3 (M + H)+ 223.1329, found
223.1327.
2-Benzoyl-2-methylspiro[4.5]deca-6,9-dien-8-one (4c): Pale yel-
low oil, 0.058 mmol, 15.5 mg, 58% yield; IR ν (cm−1) 2935, 1667,
1
1622, 1445, 1260; H (300 MHz, CDCl3) δ 7.88 (d, J = 7.6 Hz, 2H),
7.54 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 6.93 (dd, J = 10.0,
2.9 Hz, 2H), 6.80 (dd, J = 10.0, 2.9 Hz, 1H), 6.23 (dd, J = 10.0, 1.7 Hz,
1H), 6.15 (dd, J = 10.0, 1.7 Hz, 1H), 2.81 (dt, J = 12.9, 7.0 Hz, 1H),
2.78 (d, J = 14.0 Hz, 1H), 2.06 (dt, J = 12.9, 7.0 Hz, 1H), 2.00 (dt, J =
12.9, 7.0 Hz, 1H), 1.93 (d, J = 14.0 Hz, 1H), 1.84 (dt, J = 12.9, 7.0 Hz,
1H), 1.64 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 204.1, 185.9,
154.5, 153.6, 135.1, 132.3, 129.2, 128.3, 127.6, 127.0, 55.5, 48.7, 47.8,
37.5, 37.3, 28.6; HRMS (ESI) calcd for C18H19O2 (M + H)+ 267.1380,
found 267.1381.
2-Acetyl-2-methylspiro[4.5]deca-6,9-dien-8-one (4d): Pale yellow
oil, 0.059 mmol, 12.1 mg, 59% yield; IR ν (cm−1) 2928, 1701, 1662,
1623; 1H NMR (600 MHz, CDCl3) δ 6.86 (d, J = 10.2 Hz, 2H), 6.17
(d, J = 10.2 Hz, 1H), 6.15 (d, J = 10.2 Hz, 1H), 2.48 (d, J = 14.4 Hz,
1H), 2.41−2.37 (m, 1H), 2.21 (s, 3H), 1.92−1.73 (m, 3H), 1.59
(d, J = 14.4 Hz), 1.41 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 211.1,
185.9, 154.4, 154.1, 127.2, 126.9, 56.7, 48.4, 45.3, 37.2, 36.1, 25.8, 25.2;
HRMS (ESI) calcd for C13H17O2 (M + H)+ 205.1223, found
205.1222.
2-Methyl-8-oxospiro[4.5]deca-6,9-diene-2-carbaldehyde (20): Pale
1
yellow oil, 68% yield; IR ν (cm−1) 2930, 1718, 1663, 1623; H NMR
(600 MHz, CDCl3) δ 9.57 (s, 1H), 6.92 (dd, J = 10.2, 3.2 Hz, 1H),
6.87 (dd, J = 10.2, 3.2 Hz, 1H), 6.21 (dd, J = 10.2, 3.2 Hz, 1H), 6.20
(dd, J = 10.2, 3.2 Hz, 1H), 2.40 (d, J = 14.4 Hz, 1H), 1.92−1.77 (m,
3H), 1.62 (d, J = 14.4 Hz, 1H), 1.92−1.73 (m, 3H), 1.35 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 202.9, 185.7, 153.8, 153.6, 127.3, 127.3,
54.8, 48.5, 43.3, 37.2, 34.2, 22.4; HRMS (ESI) calcd for C12H15O2 (M
+ H)+ 191.1067, found 191.1066.
2-Acetylspiro[4.5]deca-1,6,9-trien-8-one (30a): Pale yellow oil,
0.05 mmol, 9.7 mg, 51% yield; IR ν (cm−1) 2923, 1667, 1621,
1367; 1H (300 MHz, CDCl3) δ 6.80 (d, J = 9.6 Hz, 2H), 6.29 (d, J =
9.6 Hz, 2H), 6.11 (s, 1H), 2.82 (t, J = 7.5 Hz, 2H), 2.35 (s, 3H), 2.17
(t, J = 7.5 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 196.0, 185.2,
150.3, 148.7, 141.9, 128.7, 54.8, 34.6, 30.5, 26.9; HRMS (ESI) calcd
for C12H13O2 (M + H)+ 189.0910, found 189.0907.
2-Acetyl-1-butylspiro[4.5]deca-1,6,9-trien-8-one (30b): Pale yel-
low oil, 0.045 mmol, 10.9 mg, 45% yield; IR ν (cm−1) 2925, 1665,
1615, 1370; 1H (600 MHz, CDCl3) δ 6.74 (d, J = 9.9 Hz, 2H),
6.24 (d, J = 9.9 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.15 (t, J = 7.2 Hz,
2H), 2.11 (s, 3H), 2.10 (t, J = 7.2 Hz, 2H), 1.46−1.22 (m, 4H), 0.87
(t, J = 6.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 206.7, 185.0,
150.9, 149.9, 129.4, 128.3, 84.7, 76.1, 38.8, 38.2, 33.6, 30.5, 30.1, 21.8,
18.3, 13.5; HRMS (ESI) calcd for C16H21O2 (M + H)+ 245.1536,
found 245.1539.
2-Acetyl-7,9-dibromo-2-methylspiro[4.5]deca-6,9-dien-8-one
1
(4e): Pale yellow oil, 0.084 mmol, 30.2 mg, 84% yield; H NMR (600
MHz, CDCl3) δ 7.38 (d, J = 2.9 Hz, 1H), 7.33 (d, J = 2.9 Hz, 1H),
2.64 (d, J = 14.1 Hz, 1H), 2.37 (m, 1H), 2.24 (s, 3H), 2.41−2.37 (m,
1H), 2.21 (s, 3H), 1.97 (m, 1H), 1.91−1.82 (m, 2H), 1.65 (d, J = 14.1
Hz), 1.44 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 210.7, 172.5, 154.4,
120.4, 120.2, 56.8, 53.9, 44.2, 36.7, 36.3, 25.4, 25.1; HRMS (ESI) calcd
for C13H15Br2O2 (M + H)+ 362.9412, found 362.9416.
trans-3-Acetyl-1-methylspiro[4.5]deca-6,9-dien-8-one (4f): Pale
yellow oil, 0.050 mmol, 10.1 mg, 50% yield; IR ν (cm−1) 2924,
1
1711, 1663, 1624; H NMR (300 MHz, CDCl3) δ 6.86 (dd, J = 10.4,
2-Acetyl-1-decylspiro[4.5]deca-1,6,9-trien-8-one (30c): Pale yel-
low oil, 0.055 mmol, 18.0 mg, 55% yield; IR ν (cm−1) 2925, 2854,
2.2 Hz, 1H), 6.74 (dd, J = 10.4, 2.2 Hz, 1H), 6.36 (d, J = 10.4 Hz, 1H),
6.33 (d, J = 10.2 Hz, 1H), 3.34 (m, 1H), 2.40−2.10 (m, 3H), 2.23
(s, 3H), 1.94 (dd, J = 13.2, 8.2 Hz, 1H), 1.85 (d, J = 13.2, 8.2 Hz), 0.77
(d, J = 7.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 208.8, 186.4,
154.5, 149.4, 129.9, 129.8, 53.0, 49.0, 44.4, 39.3, 34.9, 29.1, 14.1;
HRMS (ESI) calcd for C13H17O2 (M + H)+ 205.1223, found
205.1218.
1
1720, 1673, 1628; H (600 MHz, CDCl3) δ 6.75 (d, J = 9.8 Hz, 2H),
6.25 (d, J = 9.8 Hz, 2H), 2.43 (t, J = 7.8 Hz, 2H), 2.15 (t, J = 7.8 Hz,
2H), 2.11 (s, 3H), 2.10 (t, J = 7.8 Hz, 2H), 1.46 (quin, J = 7.8 Hz,
1H), 1.47 (quin, J = 7.8 Hz, 2H), 1.36−1.21 (m, 16H), 0.87 (t, J = 7.8
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 206.7, 185.0, 150.9, 150.0,
129.4, 128.3, 84.8, 38.8, 38.2, 33.6, 31.8, 30.1, 29.5, 29.4, 29.2, 29.0,
9467
dx.doi.org/10.1021/jo2019027|J. Org. Chem. 2011, 76, 9460−9471

The Journal of Organic Chemistry
Article
28.7, 28.7, 28.5, 22.6, 18.6, 14.0; HRMS (ESI) calcd for C22H32NaO2
(M + Na)+ 351.2295, found 351.2297.
1.31 (m, 6H), 1.25 (d, J = 9.2 Hz, 1H), 0.93 (t, J = 7.8 Hz, 3H). 0.90
(t, J = 7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 189.3, 185.0,
150.1, 149.8, 133.9, 128.5, 128.2, 118.3, 96.6, 85.0, 80.4, 49.7, 39.5,
39.1, 37.2, 30.5, 29.6, 21.9, 18.7, 18.4, 13.5; HRMS (ESI) calcd for
C24H31O2 (M + H)+ 351.2319, found 351.2305.
2-Acetyl-3-methylspiro[4.5]deca-1,6,9-trien-8-one (30d): Pale
yellow oil, 0.046 mmol, 9.3 mg, 46% yield; IR ν (cm−1) 3482, 2959,
1663, 1622, 1666; 1H (600 MHz, CDCl3) δ 6.84 (dd, J = 10.0, 2.3 Hz,
1H), 6.72 (dd, J = 10.0, 2.3 Hz, 1H), 6.3 (d, J = 10.0 Hz, 1H), 6.28 (d,
J = 10.0 Hz, 1H), 6.07 (s, 1H), 3.34 (hex, J = 7.0 Hz, 1H), 2.40 (ddd,
J = 13.5, 8.2, 1.1 Hz, 1H), 2.34 (s, 3H), 1.79 (ddd, J = 13.5, 5.9, 1.1 Hz,
1H), 1.28 (d, J = 8.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 196.3,
185.1, 152.3, 151.6, 151.0, 141.5, 128.6, 128.5, 53.7, 42.8, 39.2, 27.5,
20.6; HRMS (ESI) calcd for C13H15O2 (M + H)+ 203.1067, found
203.1064.
1-Butyl-2-(hept-2-ynoyl)-4-methylspiro[4.5]deca-1,6,9-trien-8-
one (30k): Pale yellow oil, 56% yield; IR ν (cm−1) 2929, 2854, 2210,
1
1670; H (300 MHz, CDCl3) δ 6.80 (dd, J = 9.8, 2.7 Hz, 1H), 6.72
(dd, J = 9.8, 2.7 Hz, 1H), 6.32 (d, J = 9.8 Hz, 2H), 2.88 (dd, J = 16.4,
2.2 Hz, 1H), 2.61 (m, 1H), 2.59 (m, 2H), 2.45 (m, 1H), 2.38 (t, J =
7.0 Hz, 2H), 2.34 (dd, J = 16.4, 9.8 Hz, 1H), 2.20 (t, J = 7.0 Hz, 2H),
1.60−1.31 (m, 6H), 1.03 (d, J = 7.0 Hz, 3H), 0.98 (t, J = 7.8 Hz, 3H).
0.91 (t, J = 7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 186.0, 185.2,
167.1, 148.7, 148.6, 133.0, 129.4, 129.2, 115.2, 95.2, 85.7, 80.8, 75.7,
48.0, 43.2, 37.9, 30.5, 29.6, 21.9, 21.9, 18.6, 18.4, 15.3, 13.5, 13.4;
HRMS (ESI) calcd for C22H29O2 (M + H)+ 325.2162, found
325.2164.
3-Methyl-2-propioloylspiro[4.5]deca-1,6,9-trien-8-one (30e): Pale
yellow oil, 0.057 mmol, 12 mg, 57% yield; IR ν (cm−1) 2092, 1662,
1
1636, 857; H (300 MHz, CDCl3) δ 6.84 (dd, J = 10.4, 3.3 Hz, 1H),
6.73 (dd, J = 10.4, 3.3 Hz, 1H), 6.52 (d, J = 9.6 Hz, 1H), 6.34 (dd, J =
10.4, 3.3 Hz, 1H), 6.31 (dd, J = 10.4, 3.3 Hz, 1H), 3.37 (m, 1H), 3.25
(s, 1H), 2.47 (dd, J = 13.7, 8.8 Hz, 1H), 1.87 (dd, J = 13.7, 8.8 Hz,
1H), 1.33 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 185.0,
174.3, 152.3, 150.9, 150.1, 148.2, 129.0, 128.9, 80.1, 78.6, 53.5, 43.3,
38.5, 20.3; HRMS (ESI) calcd for C14H13O2 (M + H)+ 213.0910,
found 213.0905.
4-Methyl-2-propioloylspiro[4.5]deca-1,6,9-trien-8-one (30l): Pale
1
yellow oil, 54% yield; IR ν (cm−1) 2925, 2854, 1674, 1627; H (300
MHz, CDCl3) δ 6.79 (dd, J = 10.4, 3.3 Hz, 1H), 6.71 (dd, J = 10.4, 3.3
Hz, 1H), 6.61 (s, 1H), 6.41 (dd, J = 8.8, 3.3 Hz, 2H), 3.27 (s, 1H),
3.03 (dd, J = 16.5, 8.2 Hz, 1H), 3.03 (dd, J = 16.5, 8.2 Hz, 1H), 2.69
(m, 1H), 2.46 (ddd, J = 16.4, 10.4, 2.2 Hz, 1H), 0.99 (t, J = 7.1 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 185.4, 174.1, 167.1, 150.3,
148.6, 146.3, 130.8, 130.6, 79.7, 79.2, 57.6, 44.6, 36.8, 14.4; HRMS
(ESI) calcd for C14H13O2 (M + H)+ 213.0910, found 213.0907.
8-Oxospiro[4.5]deca-1,6,9-triene-2-carbaldehyde (30m): Pale
yellow oil, 45% yield; IR ν (cm−1) 2928, 1701, 1662, 1623; 1H
NMR (600 MHz, CDCl3) δ 9.86 (s, 1H), 6.79 (d, J = 10.0 Hz, 2H),
6.33 (d, J = 10.0 Hz, 2H), 6.30 (s, 1H), 2.83 (d, J = 7.6 Hz, 2H), 2.25
(d, J = 7.6 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ189.2, 185.3,
149.9, 149.8, 149.7, 129.3, 54.6, 35.1, 28.7; HRMS (ESI) calcd for
C11H11O2 (M + H)+ 175.0754, found 175.0751.
2-Acetyl-4,4-dimethylspiro[4.5]deca-1,6,9-trien-8-one (32): Pale
yellow oil, 51% yield; IR ν (cm−1) 1667, 1621; 1H NMR (600
MHz, CDCl3) δ 6.85 (d, J = 10.2 Hz, 2H), 6.37 (d, J = 10.2 Hz, 1H),
6.16 (t, J = 1.6 Hz, 1H), 2.64 (d, J = 1.6 Hz, 1H), 2.34 (s, 3H), 1.10
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 196.3, 184.9, 148.5, 148.0,
142.0, 130.4, 59.8, 49.7, 44.9, 26.4, 25.8; HRMS (ESI) calcd for
C14H17O2 (M + H)+ 217.1223, found 217.1232.
7,9-Dibromo-3-methyl-2-propioloylspiro[4.5]deca-1,6,9-trien-8-
one (30f): Pale yellow oil, 78% yield; IR ν (cm−1) 2092, 1733, 1677,
1
1641, 1072; H (300 MHz, CDCl3) δ 7.31 (d, J = 2.7 Hz, 1H), 7.20
(d, J = 2.7 Hz, 1H), 6.52 (d, J = 1.6 Hz, 1H), 3.37 (m, 1H), 3.30 (s,
1H), 2.56 (dd, J = 13.7, 8.8 Hz, 1H), 1.97 (dd, J = 13.7, 8.8 Hz, 1H),
1.33 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.7, 172.0,
153.0, 150.9, 150.2, 144.9, 129.3, 122.5, 122.3, 80.0, 79.2, 58.5, 42.7,
38.7, 25.5, 20.0; HRMS (ESI) calcd for C14H11Br2O2 (M + H)+
370.9100, found 370.9094.
1-Butyl-2-(hept-2-ynoyl)-3-methylspiro[4.5]deca-1,6,9-trien-8-
one (30g): Pale yellow oil, 60% yield; IR ν (cm−1) 2933, 2205, 1667,
1626; 1H (600 MHz, CDCl3) δ 6.78 (d, J = 9.9 Hz, 1H), 6.76 (d, J =
9.9 Hz, 1H), 6.28 (d, J = 9.9 Hz, 1H), 6.22 (d, J = 9.9 Hz, 1H), 2.67
(dd, J = 14.0, 8.2 Hz, 1H), 2.60 (qd, J = 8.2, 2.9 Hz, 1H), 2.37 (t, J =
7.0 Hz, 2H), 2.17 (t, J = 7.0 Hz, 2H), 1.70 (dd, J = 13.4, 2.9 Hz, 1H),
1.60−1.56 (m, 4H), 1.50−1.37 (m, 5H), 1.20 (d, J = 7.0 Hz, 3H), 0.94
(t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 190.3, 185.0, 150.1, 149.9, 128.4, 128.2, 96.4, 84.9, 80.0,
76.1, 44.8, 42.4, 39.2, 30.5, 29.6, 21.9, 21.8, 18.8, 18.6, 18.3, 13.5, 13.4;
HRMS (ESI) calcd for C22H29O2 (M + H)+ 325.2162, found
325.2156.
(E)-2-(8-Oxospiro[4.5]deca-6,9-dien-1-ylidene)acetaldehyde
(34): 9.6 mg, 0.051 mmol, 51%, as an oil; IR ν (cm−1) 2923, 2858,
1
1667, 1622, 1403, 1253, 1154, 863; H NMR (300 MHz, CDCl3) δ
7,9-Dibromo-1-butyl-2-(hept-2-ynoyl)-3-methylspiro[4.5]deca-
9.84 (d, 1H, J = 7.0 Hz), 6.76 (d, 2H, J = 10.1 Hz), 6.31 (d, 2H, J =
10.1 Hz), 5.77 (dt, 1H, J = 7.0, 2.5 Hz), 3.11 (td, 2H, J = 7.0, 2.5 Hz),
2.14 (m, 2H), 2.06 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 190.7,
185.5, 168.4, 149.7, 128.1, 125.1, 53.9, 37.2, 30.7, 24.0; HRMS (ESI)
calcd for C12H13O2 (M + H)+ 189.0910, found 189.0910.
1,6,9-trien-8-one (30h): Pale yellow oil, 81% yield; IR ν (cm−1) 2923,
1
2205, 1733, 1677; H (600 MHz, CDCl3) δ 7.21 (d, J = 2.7 Hz, 1H),
7.19 (d, J = 2.7 Hz, 1H), 2.67 (dd, J = 14.3, 9.3 Hz, 1H), 2.59 (m, 1H),
2.39 (t, J = 7.0 Hz, 2H), 2.18 (t, J = 7.0 Hz, 2H), 1.79 (dd, J = 13.7, 2.7
Hz, 1H), 1.63−1.27 (m, 8H), 1.20 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.0
Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
189.7, 171.9, 150.3, 149.8, 121.8, 97.2, 86.8, 80.0, 73.4, 44.7, 44.5, 42.8,
30.3, 29.6, 21.9, 21.9, 18.7, 18.4, 13.5, 13.4; HRMS (ESI) calcd for
C22H27Br2O2 (M + H)+ 483.0353, found 483.0343.
4-(((2S,3S)-2-methyl-2-(prop-1-en-2-yl)tetrahydrofuran-3-yl)-
methyl)phenol (23). To a solution of the triols 223i (50 mg, 0.2
mmol) in dry CH2Cl2 (2 mL) was added TFA (45 mg, 0.4 mmol, 2
equiv) and the solution was stirred for 90 min at 40 °C. The crude
mixture is purified directly on silica gel (n-hexane/EtOAc, 7:3) to
afford 23 compound 35 mg, 0.15 mmol) in 75% yield as an oil: IR ν
1-Decyl-2-(tridec-2-ynoyl)spiro[4.5]deca-1,6,9-trien-8-one (30i): Pale
yellow oil, 0.05 mmol, 23.9 mg, 50% yield; IR ν (cm−1) 2925, 2854,
(cm−1) 3312, 1610, 1221, 1164; H NMR (300 MHz, CDCl3) δ 7.04
1
1
1674, 1627; H (600 MHz, CDCl3) δ 6.76 (d, J = 9.8 Hz, 2H), 6.26
(d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.2 Hz, 2H), 4.99 (s, 1H), 4.85 (s,
1H), 3.74 (q, J = 8.2 Hz, 1H), 2.78 (d, J = 10.4 Hz, 1H), 2.31 (m,
2H), 1.89 (m, 1H), 1.82 (s, 3H), 1.71 (m, 1H), 1.30 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 153.9, 149.7, 133.1, 129.7, 115.2, 109.8,
86.1, 65.9, 47.4, 35.4, 31.4, 20.8, 18.8; HRMS (ESI) calcd for
C15H21O2 (M + H)+ 233.1536, found 233.1536.
3-Acetyl-3-methyl-8-oxospiro[4.5]deca-6,9-dien-2-yl)-
acetaldehyde (27). The crude mixture 26 resulting from the direct
oxidation of compound 23 (0.1 mmol, 25 mg) was quickly filtrated by
chromatography (EtOAc), concentrated under reduced pressure, and
dissolved in dry CH2Cl2 (0.75 mL). Dess−Martin periodinane (85 mg,
0.2 mmol) was added. The solution was stirred overnight (and verified
by TLC) at 40 °C. Then a solution of 2 mL of saturated aqueous
NaHCO3 and 2 mL of saturated aqueous sodium thiosulfate were
added. The mixture was diluted with 4 mL of ethyl acetate, the organic
(d, J = 9.6 Hz, 2H), 2.57 (t, J = 7.8 Hz, 2H), 2.16 (t, J = 7.2 Hz, 4H),
1.56 (quin, J = 7.8 Hz, 1H), 1.47 (quin, J = 7.8 Hz, 2H), 1.40−1.21
(m, 28H), 0.87 (t, J = 7.8 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ
185.9, 185.0, 149.7, 132.9, 128.4, 115.2, 95.5, 85.1, 80.5, 80.5, 75.8,
40.4, 38.7, 33.9, 31.8, 29.5, 29.5, 29.4, 29.2, 28.9, 29.2, 29.0, 28.9, 28.8,
28.8, 28.5, 27.6, 22.6, 18.9, 18.6, 14.0; HRMS (ESI) calcd for
C33H50NaO2 (M + Na)+ 501.3703, found 501.3700.
3-Allyl-1-butyl-2-(hept-2-ynoyl)spiro[4.5]deca-1,6,9-trien-8-one
(30j): Pale yellow oil, 53% yield; IR ν (cm−1) 2923, 2205, 1667, 1625,
1
1461; H (300 MHz, CDCl3) δ 6.75 (dd, J = 9.8, 2.7 Hz, 1H), 6.71
(dd, J = 9.8, 2.7 Hz, 1H), 6.28 (d, J = 9.8, 1.7 Hz, 1H), 6.21 (d, J = 9.8,
1.7 Hz, 1H), 5.65 (m, 1H), 5.11 (d, 17.0 Hz, 1H), 5.08 (d, J = 8.0,
1H), 2.59 (m, 2H), 2.45 (m, 1H), 2.37 (t, J = 7.0 Hz, 2H), 2.22 (m,
1H), 2.17 (t, J = 7.0 Hz, 2H), 1.80 (dt, J = 12.1, 7.1 Hz, 1H), 1.60−
9468
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The Journal of Organic Chemistry
Article
layer removed, and the aqueous phase extracted with EtOAc (2 × 4
mL), and the combined organic layers were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The crude
was purified by chromatography (n-hexane/EtOAc, 1:1) to afford
263 mg (60% over two steps) of compound 27 as a colorless oil: IR ν
the desired mixture of hemiketals: HRMS (ESI) calcd for C13H15O2
(M + H − H2O)+ 203.1067, found 203.1074.
(3a′S,6a′S)-6a′-Methyl-2′-(phenylthio)-2′,3′,3a′,4′,6′,6a′-
hexahydrospiro[cyclohexa[2,5]diene-1,5′-cyclopenta[b]furan]-4-
one (45). To a solution of the compound 44 (8.0 mg, 0.036 mmol) in
DCM (1.0 mL) were added PhSH (5 μL, 0.048 mmol, 1.4 equiv) and
TFA (5 μL, 0.068 mmol, 1.9 equiv). The reaction mixture was stirred
for 1 h. The crude product was directly purified by chromatography
(n-hexane/EtOAc, 80:20) to afford 7.0 mg (62%) of the desired
diastereomeric mixture as an oil: HRMS (ESI) for C19H20NaO2S (M +
Na)+ 335.1076, found 335.1073.
1
(cm−1) 2932, 1723, 1692, 1656; H NMR (300 MHz, CDCl3) δ 9.77
(s, 1H), 6.98 (d, J = 9.8 Hz, 2H), 6.16 (d, J = 9.8 Hz, 2H), 2.73−2.48
(m, 3H), 2.36 (d, J = 14.3 Hz, 1H), 2.19 (s, 3H), 1.99 (d, J = 9.8 Hz,
2H), 1.71 (d, J = 14.3 Hz, 1H), 1.44 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 200.2, 185.7, 155.0, 154.6, 127.0, 126.1, 57.9, 47.5, 45.7,
44.2, 43.9, 42.0, 28.2, 24.1; HRMS (ESI) calcd for C15H18O3Na
(M + Na)+ 269.1148, found 269.1147.
(S)-2-(2-Hydroxyethyl)-3-methylenespiro[4.5]deca-6,9-dien-8-
one (47). To a solution of compounds 39 (see formation of
compound 42, 18 mg, 0.068 mmol) in degassed MeOH at −15 °C
was dissolved Cu(OAc)2 (27 mg, 2 equiv), and the solution was stirred
5 min until the salt was soluble, then FeSO4 (12.5 mg, 1.2 equiv) was
added at −20 °C . The reaction was stirred until the starting material
disappeared by TLC (ethyl acetate/hexane 1:1), then the solution was
filtrated on silica gel chromatography and concentrated under vacuum.
The residue was dissolved in methanol (2 mL); K2CO3 solid (14 mg,
0.1 mmol) was added, and the solution was stirred until the starting
material disappeared by TLC, affording a mixture of alkenes 47 (6 mg,
44%) in a ratio ∼3/1 in favor of the exo isomer: colorless oil; 1H NMR
(exo isomer, 300 MHz, CDCl3) δ 6.98 (dd, J = 9.8, 3.3 Hz, 1H), 6.81
(dd, J = 9.8, 2.3 Hz, 1H), 6.16 (t, J = 9.8, 1.6 Hz, 2H), 5.08 (s, 1H),
5.02 (s, 1H), 3.74 (m, 2H), 2.92, (m,1H), 2.67 (dq, J = 15.9, 2.2 Hz,
1H), 2.43 (dd, J = 15.9, 1.6 Hz, 1H), 2.06 (m, 2H), 1.75 (m, 2H);
LRMS (ESI) for C13H16O2Na (M + Na)+ 227, identical to the
literature.24
2-(3-Methyl-8-oxospiro[4.5]deca-2,6,9-trien-2-yl)ethyl acetate
(42). A solution of PhI(OAc)2 (“DIB”, 80 mg, 0.25 mmol) in
(CF3)2CHOH (“HFIP”, 0.75 mL) was added over 10 s to a vigorously
stirred solution of phenol 233i (0.2 mmol, 1 equiv) in 2 mL of a
solution of CH2Cl2/HFIP (3/2) cooled to −17 °C for a few seconds
(to avoid precipitation of HFIP). After addition of DIB, the solution
was stirred for 1 min, and H2O2 (35%, 0.75 mL) was added to the
medium. The reaction was stirred for 5 min and filtered directly over
silica gel (n-hexane/EtOAc, 1:1), and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (ethyl acetate/hexane, 3:1) to afford a mixture
(37 mg, 64%) of two diastereoisomers 39 as an oil.3i The epimeric
mixture of compound 39 was rapidly used (17 mg, 0.064 mmol) in dry
DCM (0.6 mL); NEt3 (30 μL, 0.200 mmol, 3.1 equiv) was added
followed by Ac2O (20 μL, 0.200 mmol, 3.1), and the solution was
stirred for 1 h under argon and filtered directly over silica gel (n-
hexane/EtOAc, 1:1). The crude product was purified by chromatog-
raphy (n-hexane/EtOAc, 1:1) to afford 6.0 mg (38%) of compound 42
as well as 4.0 mg (24%) of compound 43 (oils): IR ν (cm−1) 1738,
1664, 1233; 1H NMR (300 MHz, CDCl3) δ 6.97 (d, J = 10.0 Hz, 2H),
6.21 (d, J = 10.0 Hz, 2H), 4.12 (t, J = 7.5 Hz, 2H), 2.53 (s, 2H), 2.50
(s, 2H), 2.43 (t, J = 7.5 Hz, 2H), 2.06 (s, 3H), 1.69 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 186.3, 170.9, 154.9, 132.5, 129.3, 127.1, 62.4,
47.8, 45.8, 27.5, 20.9, 13.6; HRMS (ESI) calcd for C15H19O3 (M + H)+
247.1329, found 247.1336.
(S)-2-(3-Methylene-8-oxospiro[4.5]deca-6,9-dien-2-yl)-
acetaldehyde (48). The alkene mixture 47 (11 mg, 0.054 mmol) was
dissolved in 2 mL of DCM, and PCC (24 mg, 0.11 mmol) was added;
the reaction was stirred until the starting material disappeared by
TLC (ethyl acetate/hexane 3:1) and filtered directly over silica gel
(n-hexane/EtOAc, 1:3). The filtrate was concentrated under reduced
pressure and purified by silica gel chromatography with a mixture of
ethyl acetate/hexane (3:1) to afford a mixture of aldehydes 48 (8.1
1
mg, 74%) as a colorless oil: H NMR (exo isomer, 300 MHz, CDCl3)
2-((2S,3S)-3-Hydroxy-3-methyl-8-oxospiro[4.5]deca-6,9-dien-2-
yl)ethyl acetate (43). To a solution of compound 39 (see formation
of compound 42, 63 mg, 0.239 mmol) in THF (2.5 mL) was added a
solution (2.5 mL) of saturated aqueous NaHCO3 followed by ortho-
NsCl (320 mg, 1.448 mmol, 6.0 equiv), then the solution was stirred
for 12 h and H2O (10.0 mL) was added. The aqueous phase was
extracted with EtOAc (3 × 5 mL), and the combined organic layers
were washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by chromatography
(n-hexane/EtOAc, 1:1) to afford 45.5 mg (72%) of the desired alcohol
δ 9.83 (s, 1H), 6.98−6.95 (m, 1H), 6.79−6.76 (m, 1H), 6.27−6.23 (m,
2H), 5.10 (s, 1H), 4.98 (s, 1H), 3.30 (m, 1H), 2.90 (dd, J = 18.1, 5.5
Hz, 1H), 2.66 (m, 2H), 2.47 (m, 1H), 2.15 (ddd, J = 13.0, 8.0, 1.6 Hz,
1 H), 1.69 (m, J = 13.0, 10.3 Hz, 1H); LRMS (ESI) C13H14O2Na
(M + Na)+ 225, identical to the literature.24
2-(3-Chloro-3-methyl-8-oxospiro[4.5]deca-6,9-dien-2-yl)ethyl ac-
etate (49). To a solution of compounds 39 (see formation of
compound 42, 26.5 mg, 0.1 mmol) in degassed MeOH (2 mL) at rt
was dissolved Cu(Cl)2 (27 mg, 0.2 mmol, 2 equiv), and the solution
was stirred 5 min until the salt was soluble. The mixture was cooled
at −30 °C, and FeSO4 (41 mg, 0.15 mmol, 1.5 equiv) was added. The
reaction was stirred 10 min at −30 °C, and the crude product was
directly purified by chromatography (n-hexane/EtOAc, 1:1), affording
a mixture of alkenes 47 (20.4 mg, 74%) in a ratio ∼4/1 in favor of the
1
as an oil: IR ν (cm−1) 2921, 1732, 1660, 1557; H NMR (300 MHz,
CDCl3) δ 7.16 (dd, J = 10.0, 2.7 Hz, 1H), 6.86 (dd, J = 10.0, 2.7 Hz,
1H), 6.16 (dd, J = 10.0, 2.7 Hz, 1H), 6.13 (dd, J = 10.0, 2.7 Hz, 1H),
4.12 (m, 2H), 2.06 (s, 3H), 2.01−1.89 (m, 7H), 1.68 (m, 2H), 1.38
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 186.1, 171.0, 157.0, 155.4,
126.1, 125.8, 81.1, 63.3, 51.4, 46.4, 44.8, 41.3, 27.2, 25.9, 20.9; HRMS
(ESI) calcd for C15H20NaO4 (M + Na)+ 287.1254, found 287.1267.
(3a′S,6a′S)-2′-Hydroxy-6a′-methyl-2′,3′,3a′,4′,6′,6a′-
hexahydrospiro[cyclohexa[2,5]diene-1,5′-cyclopenta[b]furan]-4-
one (44). To a solution of compound 43 (23 mg, 0.85 mmol) in
methanol (2.0 mL) was added finely powdered potassium carbonate
(12.0 mg, 0.9 mmol, 1.05 equiv). The reaction mixture was stirred for
25 min, and the methanol was partly removed by evaporation under
reduced pressure. The crude product was directly purified by
chromatography (DCM/MeOH, from 9:1 to 8:2) to afford 18.5 mg
(97%) of the desired compound. The corresponding diol (15.5 mg,
0.07 mmol) was disolved in a (1/1) DMSO/EtOAc mixture (2 mL),
and then was added IBX (30 mg, 0.11 mmol, 1.5 equiv). The reaction
mixture was stirred for 2 h, and H2O (5.0 mL) was added. The
aqueous phase was extracted with EtOAc (4 × 5 mL), and the
combined organic layers were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure to afford 24.0 mg (80%) of
1
trans isomer as a colorless oil: H NMR (300 MHz, CDCl3) δ 7.25
(dd, J = 9.8, 3.8 Hz, 1H), 6.86 (dd, J = 9.8, 3.8 Hz, 1H), 6.20 (dd, J =
9.8, 3.8 Hz, 1H), 6.17 (t, J = 9.8, 3.8 Hz, 1H), 4.14 (m, 2H), 2.50 (d,
J = 15.4 Hz, 1H), 2.20 (d, J = 15.4 Hz, 1H), 2.17−1.98 (m, 2H), 2.08
(s, 3H), 1.79 (m, 1H), 1.71 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
185.6, 171.1, 154.3, 154.3, 127.8, 126.6, 74.6, 63.1, 53.4, 49.9, 44.9,
41.3, 28.5, 27.2, 21.2; HRMS (ESI) calcd for C15H19ClNaO3
(M + Na)+ 305.0915, found 305.0919.
(4aS,5S,7R,8S,9aS)-8-Methyl-4a,5,6,7,8,9-hexahydro-5,8-epoxy-
7,9a-methanobenzo[7]annulen-3(4H)-one (Cage Compound 52). To
a vigorously stirred solution of compound 48 (8 mg, 0.04 mmol),
HMPA (73 mg, 0.4 mmol), and HFIP (10 mg, 0.06 mmol) in THF
(1.2 mL) at −78 °C was rapidly added SmI2 (0.09 mmol, 0.53 mL,
0.17 M in THF). The resulting mixture was stirred at that temperature
for 20 s before it was quenched with saturated aqueous NH4Cl
solution (4 mL). After extraction with EtOAc (3 × 5 mL), the
combined organic phase was dried over Na2SO4 and filtered. The
solvent was removed under vacuum, and the residue was dissolved in
9469
dx.doi.org/10.1021/jo2019027|J. Org. Chem. 2011, 76, 9460−9471

The Journal of Organic Chemistry
Article
CH2Cl2 (0.1 mL). To the resulting solution at 0 °C was added TFA
(0.25 mL), and the resulting mixture was stirred at that temperature
for 1.5 h. The solvent was then removed by a stream of argon, and the
residue was dissolved in EtOAc (5 mL). The resulting organic phase
was washed with saturated aqueous NaHCO3 solution (4 mL) and
brine (4 mL) and dried over Na2SO4. After filtration and removal of
the solvent under vacuum, the residue was purified by flash column
chromatography with EtOAc/hexanes (2/3) as eluent to give cage
compound 31 (2.8 mg, 36%): [α]D = −21 (c = 0.5 in CHCl3); H
NMR (600 MHz, CDCl3) δ 6.62 (d, J = 10.0 Hz, 1H), 5.94 (d, J =
10.0 Hz, 1H), 4.17 (t, J = 3.4 Hz, 1H), 2.43−2.29 (m, 4H), 1.97−1.94
(m, 2H), 1.90 (d, J = 11.6 Hz, 1H), 1.79−1.74 (m, 2H), 1.66 (d, J =
11.2 Hz, 1H), 1.45 (s, 3H); LRMS (ESI) C13H16O2Na (M + Na)+
found 227, identical to the literature.24
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20
1
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ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
́
39, 4667. (f) Quideau, S.; Looney, M. A.; Pouysegu, L. Org. Lett. 1999,
1, 1651. (g) Braun, N. A.; Bray, J.; Ousmer, M.; Peters, K.; Peters, E.
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(h) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: canesi.sylvain@uqam.ca.
■
́
Pouysegu, L.; Oxoby, M.; Looney, M. A. Tetrahedron 2001, 57, 319.
(k) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A.
Tetrahedron Lett. 2002, 43, 5193. (l) Canesi, S.; Bouchu, D.; Ciufolini,
M. A. Angew. Chem., Int. Ed. 2004, 43, 4336. (m) Quideau, S.;
ACKNOWLEDGMENTS
■
Acknowledgments is made to the Donors of the American
Chemical Society Petroleum Research Fund (ACS PRF) for
support of this research. We are also very grateful to the
Natural Sciences and Engineering Research Council of Canada
(NSERC), the Canada Foundation for Innovation (CFI), the
provincial government of Quebec (FQRNT and CCVC) and to
Boehringer Ingelheim (Canada) Ltd. for their precious financial
support. M.A.B. and K.C.G. thank, respectively, the NSERC
CGS-D and the NSERC Vanier CGS programs.
́
Pouysegu, L.; Deffieux, D. Curr. Org. Chem. 2004, 8, 113. (n) Canesi,
S.; Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175. (o) Honda, T.;
Shigehisa, H. Org. Lett. 2006, 8, 657. (p) Nicolaou, K. C.; Edmonds, D.
J.; Li, A.; Tria, G. S. Angew. Chem. 2007, 119, 4016. (q) Silva, L. F. Jr.;
Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.; Doriguetto, A. C. Org.
Lett. 2007, 9, 1433. (r) Quideau, S.; Pouyseg
2008, 467. (s) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299.
(t) Giroux, M. A.; Guerard, K. C.; Beaulieu, M. A.; Sabot, C.; Canesi,
S. Eur. J. Org. Chem. 2009, 3871. (u) Peuchmaur, M.; Saıdani, N.;
Botte, C.; Marechal, E.; Vial, H.; Wong, Y. S. J. Med. Chem. 2008, 51,
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This configuration has also been verified by a NOE differential
spectrum available in the Supporting Information.
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selectively reduced to the corresponding alcohol at 0 °C in THF, in
presence of 1.1 equiv of lithium tri-tert-butoxyaluminum hydride, and
this alcohol was coupled with the (R)-Mosher acid in presence of EDC
in CH2Cl2; see Supporting Information.
(20) The preparation of these materials is provided in ref 3i or as
Supporting Information.
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9471
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