Tuning of α-Silyl Carbocation Reactivity into Enone Transposition: Application to the Synthesis of Peribysin D, E-Volkendousin, and E-Guggulsterone

Article abstract of DOI:10.1021/acs.orglett.1c02173

A reliable method for enone transposition has been developed with the help of silyl group masking. Enantio-switching, substituent shuffling, and Z-selectivity are the highlights of the method. The developed method was applied for the first total synthesis of peribysin D along with its structural revision. Formal synthesis of E-guggulsterone and E-volkendousin was also claimed using a short sequence.

Full text of DOI:10.1021/acs.orglett.1c02173

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Letter
Tuning of α‑Silyl Carbocation Reactivity into Enone Transposition:
Application to the Synthesis of Peribysin D, E‑Volkendousin, and
E‑Guggulsterone
Paresh R. Athawale, Vishal M. Zade, Gamidi Rama Krishna, and D. Srinivasa Reddy*
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ABSTRACT: A reliable method for enone transposition has been developed with the help of silyl group masking. Enantio-
switching, substituent shuffling, and Z-selectivity are the highlights of the method. The developed method was applied for the first
total synthesis of peribysin D along with its structural revision. Formal synthesis of E-guggulsterone and E-volkendousin was also
claimed using a short sequence.
is present in conjugation, then it can undergo rearrangement
he multidirectional reactivity of the enone moiety makes
Tit an attractive functional group in organic synthesis. All because of the favored tertiary to secondary carbocation
rearrangement and silicon α-effect (Figure 1D).8
three carbon atoms and the oxygen present in the enone
system can be manipulated as per the requirement.1 Trans-
In addition, the silyl groups are reactive toward various
nucleophiles such as hydroxides, alkoxides, and fluorides,
which make them easy to detach from the substrate. A similar
kind of rearrangement of α-silyl alcohols was reported by
Honda and co-workers during the synthesis of allyl ethers.9 A
few more useful rearrangements of α-silyl alcohols were
reported by Sakaguchi et al., and a Cr(VI)-mediated oxidative
rearrangement was reported by Song et al.10 With this
background, we first prepared the PhMe2SiLi reagent as
described by Fleming et al. and added it to a model substrate
4,4-dimethyl-2-cyclohexen-1-one (3a).11 The reaction gave an
84% yield of the desired 1,2-addition product 3b (Scheme 1).
The next task was to perform the rearrangement of compound
3b to obtain compound 3c. Here, we used acetonitrile and
H2O as a mixture of solvents (in a 1:1 ratio), and a few drops
of TFA was added. The rearranged product was observed in
55% yield. Further tweaking the ratio of solvents (9:1
CH3CN/H2O) gave a 95% yield of the rearranged alcohol
(Scheme 1). In addition, for proto-desilylation of compound
position of both the carbonyl group and the olefinic bond
further enhances the synthetic utility of the enone synthons
and thereby offers a high degree of opportunity in organic
synthesis. On the contrary, dealing with these types of
compounds becomes difficult.2 Over the past few decades,
enones served as vital intermediates in natural product
synthesis.3 One such type of enone rearrangement was
attempted by our group during the synthesis of peribysin
family natural products.4 We wanted to achieve an enone
transposition reaction from compound 1 to compound 2
(Figure 1A). However, after screening a few conditions, we
settled for a six-step sequence with poor yields. The most
studied transformation of this kind is the oxidative rearrange-
ment of ter-alcohols to enones using CrVI-based reagents,5 but
the main drawback of this transformation is that the group
added to enone carbonyl is not detachable after rearrangement
(Figure 1B). Apart from this, there are a few known methods
in the literature; each has certain advantages and limitations.6
One such type of reaction is Wharton reaction, wherein α,β-
epoxy ketone is rearranged to the corresponding allylic alcohol
using hydrazine.7 With this background, we decided to develop
a transposition method using a silicon-based masking group
(Figure 1C) because a silyl lithium reagent can be easily
prepared and added to the carbonyl group, wherein an α-silyl
tertiary carbocation can be generated in situ. If a double bond
Received: June 29, 2021
https://doi.org/10.1021/acs.orglett.1c02173
© XXXX American Chemical Society
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Table 1. Optimization of Proto-desilylation
time
a
reagent
TFA
solvent
temp
reflux
(h)
observation
1
2
3
4
CH2Cl2
CH2Cl2
AcOH
THF/H2O rt to
70 °C
12
NR
NR
NR
decomposed
BF3·MeOH
BF3·AcOH
HI
0 °C to rt 10
rt
10
4
5
6
7
8
9
10
TBAF
KF
NaOMe
TBAF/HMPA
TBAF, KOH
TBAF, KOH
THF
reflux
5
2
6
2
16
NR
NR
NR
∼20%
64%
98%
DMF
MeOH
DMSO
THF
80 °C
reflux
80 °C
reflux
85 °C,
ΜW
b
b
THF
0.5
a
Reaction performed on a 100 mg scale. NR indicates no reaction,
b
and MW indicates microwave irradiation. Isolated yield.
reaction time was significantly decreased when the reaction
was carried out in a microwave at 85 °C with an excellent yield
of 98% (Table 1, entry 10). The mechanism of proto-
desilylation is the replacement of the phenyl ring on silicon
with the hydroxide to give silanol.15 In addition, the silanol
intermediate on reaction with fluoride ions gives the
desilylated alcohol 3d.
Finally, the allylic alcohol was oxidized using DMP to give
rearranged enone 3e in 85% yield. The whole sequence can be
performed with only two purification steps after rearrangement
and after a final oxidation step with an overall yield of 66%. It is
interesting to note that, when the reaction was started with 4,4-
dimethyl cyclohexenone, the end product is 6,6-dimethyl
cyclohexenone (an example of substituent shuffling). After
having the optimized reaction sequence in hand, we first
screened substituted cyclohexenones. The reaction of 2,6-
cyclohexenone of 2,4-dimethyl cyclohexenone. Similarly, 4-tert-
butyl cyclohexenone was transformed into 6-tert-butyl cyclo-
hexenone in 53% overall yield. Chiral substrate 5a gave
compound 5e in 28% overall yield. Here it is clear from these
four examples that when the substituent is present at positions
4 and 6 on cyclohexenones, in the end, the positions of these
substituents are exchanged. Next, we prepared two bicyclic
enones 7a and 8a. Enone 7a was derived from (+)-3-carene in
two steps that under the optimized conditions gave two
different enones, 7e and 7h. The structure of E-enone 7e was
confirmed by single-crystal X-ray diffraction during the alcohol
stage. These two enones and their intermediates can be utilized
as building blocks for natural product synthesis. Bicyclic enone
8a underwent smooth rearrangement to give enone 8e in 39%
overall yield. The structure of intermediate 8d of enone 8e was
confirmed via single-crystal X-ray diffraction, where the
equatorial hydroxyl group was observed after the rearrange-
ment reaction (Scheme 3). In addition, we tested the method
on our original target compound (conversion of compound 1
to 2) but it failed to give the desired product.
Figure 1. (A) Our previous work. (B) Traditional oxidative
transposition. (C) This work. (D) Silicon α and β effects.
Scheme 1. Optimization of Silyl Addition and Transposition
Reaction
3c to obtain compound 3d (Scheme 2), reaction with TFA,
BF3·MeOH, or BF3·AcOH did not give the desired product 3d.
Scheme 2. Optimization of Proto-desilylation
Instead, the starting material was recovered completely (Table
1, entries 1−3). Reaction with HI resulted in partial
decomposition of the starting material. In addition, fluoride-
and alkoxide-based reagents were unsuccessful in the
desilylation reaction (Table 1, conditions 5−7).12 The use of
HMPA along with TBAF as reported by Muraoka et al. gave an
∼20% yield of the desired product.13 Capperucci et al. have
reported a condition under which TBAF and KOH were used
in combination for the proto-desilylation of the triphenyl silyl
group.14 Under the same condition, we observed successful
removal of the phenyl dimethyl silyl group, which furnished
product 3d in 64% yield when refluxed in THF for 16 h. The
Next, we tested the commercially available enone 9a, which
gave a 56% overall yield of 9e. Here, interestingly, the Z-enone
was observed as the major product. The selectivity arose
during the rearrangement reaction where the bulky silyl group
prefers the less sterically crowded side to give alcohol 9c
having E-geometry. After deprotection, the geometry remained
unchanged to give the Z-enone. Hydrocinnamaldehyde-
derived enone 10a furnished the desired rearranged enone
10e with a 92:8 Z:E selectivity, whereas the corresponding
B
https://doi.org/10.1021/acs.orglett.1c02173
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Scheme 3. Substrate Scope of Enone Transposition
Scheme 4. Various Applications of the Developed Method
C
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isopropyl ketone 11a exclusively provided E-enone 11e. Here
the steric bulk of the isopropyl group was responsible for the
exclusive E-selectivity. Next, three more enones (12a−14a)
derived from R-citronellal, cyclohexane carboxaldehyde, and
hexanal were converted to their corresponding Z-enones
(12e−14e, respectively) in 46%, 44%, and 43% yields,
respectively. In the literature, few other metal-based methods
are available such as the Rh(I)-catalyzed reaction reported by
Zhuo et al. for Z-enone synthesis.16 Also, several other
methods of olefin isomerization are available, the majority of
which gives E-alkenes.17 Thus, we believe that the current
method will be more useful for accessing the Z-enones, which
are difficult to access by other methods.
protocol.4 To compound 24 was added PhMe2SiLi to give
addition product 25, which was then subjected to catalytic
TFA in CH3CN/H2O, which gave the desired product 26. In
addition to diol 26, a nonpolar compound observed in the
same reaction mixture after characterization was found to be
compound 27. In addition, the structure of compound 27 was
confirmed by conversion of 26 to 27 using TsCl and Et3N.
Mechanistically, the TBS group in compound 25 first is
deprotected to give free alcohol. Protonation of ter-alcohol
followed by elimination of a H2O molecule generates α-silyl
carbocation B, which rearranges to give intermediate C
(Scheme 4). Subsequent trapping of the carbocation by free
alcohol offers cyclized product D. Here, H2O and free alcohol
compete as nucleophiles to provide two different products, 26
and 27. Compound 27 after desilylation using TBAF and
KOH furnished diene 28 in 80% yield. Finally, diene 28 upon
reaction with molecular oxygen in the presence of Rose Bengal
in EtOH resulted in cyclic peroxide, which was reduced in situ
with NaBH4 to give peribysin D.21 All of the spectral data,
During the synthesis of substrates, we have generated a
library of functional building blocks having a silicon handle.
These vinyl silanes can be used for various purposes in organic
synthesis.12 Furthermore, the silicon-incorporated organic
compounds can be used in medicinal chemistry programs
because of the unique properties of the silicon-incorporated
compounds.18 Access to the enantiopure starting materials is
one of the key factors in the chiral pool synthesis of natural
products. Sometimes, it is difficult to access a particular
enantiomer for the synthesis because some compounds exist in
nature in only one enantiomeric form, or one of the isomers is
costly in most of the cases. Here we have demonstrated an
exciting application of the developed method for the
interconversion of R-carvone to S-carvone with an overall
yield of 65%. Similarly, the enantio-switching of (+)-apoverbe-
none to (−)-apoverbenone gave a 40% overall yield (Scheme
4). To further expand the scope of the method, we focused on
the synthesis of two bioactive steroidal natural products
guggulsterone (having mineralocorticoid, androgen, estrogen,
etc., receptor antagonist and activities) and volkendousin
(having anticancer activity).19 We treated 16-dehydropreg-
nenolone with PhMe2SiLi, which gave a 90% yield of silyl
addition product 18. Treatment of compound 18 with catalytic
TFA in a CH3CN/H2O mixture furnished 19 as a major
product. The structure of compound 19 was confirmed by
single-crystal X-ray diffraction, which helped us to fix the
double bond geometry and the newly generated chiral center.
Proto-desilylation of compound 19 furnished alcohol 20. All of
the data for compound 20 were in agreement with the reported
data. Compound 20 was previously transformed into E-
guggulsterone and E-volkedousin in one step each.19 Thus,
here, we have accomplished the formal synthesis of E-
guggulsterone and E-volkedousin using a short sequence.
Recently, we accomplished the synthesis and structural revision
of five peribysin family natural products isolated from Periconia
byssoides OUPS-N133 by Yamada and co-workers.4,20a The
most potent member from this series is peribysin D having an
IC50 value of 0.1 μM.
1
including H and 13C NMR data, were in agreement with the
literature report.17 It was clear from our previous work that the
structure of peribysin D may need to be stereochemically
revised (see ref 4). Thus, CD spectra were recorded, which
matched those reported by Yamada et al.20,22 On the basis of
all of these observations, spectral data, CD spectra, and our
previous work, the structure of peribysin D was revised.
In summary, we have developed a method for enone
transposition having potentially high synthetic utility. A silyl-
based masking group was chosen for in situ generation and
rearrangement of α-silyl carbocation species. The developed
method was successfully tested with a variety of substrates with
exciting outcomes such as substituent shuffling, enantio-
switching, and Z-selectivity. A library of vinyl silanes having
potentially high synthetic utility were generated during the
course of making the substrates. Using the developed method,
the first synthesis of peribysin D was achieved along with its
structural revision. Additionally, formal synthesis of two
bioactive natural products, E-guggulsterone and E-volkendou-
sin, was accomplished in a short sequence. Further applications
of the method are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02173.
General and experimental procedures, compound
characterization data, single-crystal X-ray data of
compounds 7d, 8d, and 19 and NMR spectra of
selected compounds (PDF)
Accession Codes
The originally proposed structure (tetracyclic) of peribysin
D was revised by Koshino et al. to a tricyclic structure on the
basis of the NMR studies.20b In addition to the impressive
biological activity, the structure of peribysin D was also
associated with some ambiguity, which necessitates the total
synthesis of the same. In our previous attempts to synthesize
peribysin D, we encountered challenges in installing the
oxygen functionality at the carbon next to the quaternary
methyl center. Here, we envisioned installing the oxygen
functionality at the desired position by using the method
presented here (Scheme 4, application III). Thus, we
synthesized compound 24 by our previously developed
CCDC 2089261−2089263 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
D. Srinivasa Reddy − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
D
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Academy of Scientific and Innovative Research (AcSIR),
pubs.acs.org/OrgLett
Letter
(e) Brenna, E.; Crotti, M.; De Pieri, M.; Gatti, F. G.; Manenti, G.;
Monti, D. Chemo-Enzymatic Oxidative Rearrangement of Tertiary
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Process. Adv. Synth. Catal. 2018, 360, 3677−3686.
Ghaziabad 201002, India; CSIR-Indian Institute of
Integrative Medicine, Jammu 180001, India; orcid.org/
0000-0003-3270-315X; Email: reddy.ds@iiim.res.in
(7) Wharton, P.; Bohlen, D. Communications-Hydrazine Reduction
of α, β-Epoxy Ketones to Allylic Alcohols. J. Org. Chem. 1961, 26,
3615−3616.
Authors
Paresh R. Athawale − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad 201002, India
Vishal M. Zade − Organic Chemistry Division, CSIR-National
Chemical Laboratory, Pune 411008, India; Academy of
Scientific and Innovative Research (AcSIR), Ghaziabad
201002, India
(8) Nguyen, K. A.; Gordon, M. S.; Wang, G. T.; Lambert, J. B.
Stabilization of beta positive charge by silicon, germanium, or tin.
Organometallics 1991, 10, 2798−2803.
(9) Honda, M.; Takatera, T.; Ui, R.; Kunimoto, Ko-Ki.; Segi, M.
Stereoselective synthesis of allyl ethers using α,β-unsaturated
acylsilanes. Tetrahedron Lett. 2017, 58, 864−869.
(10) (a) Sakaguchi, K.; Higashino, M.; Ohfune, Y. Acid-catalyzed
rearrangement of α-hydroxytrialkylsilanes. Tetrahedron 2003, 59,
6647−6658. (b) Sakaguchi, K.; Kubota, S.; Akagi, W.; Ikeda, N.;
Higashino, M.; Ariyoshi, S.; Shinada, T.; Ohfune, Y.; Nishimura, T.
Acid-catalyzed chirality-transferring intramolecular Friedel−Crafts
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Gamidi Rama Krishna − Organic Chemistry Division, CSIR-
National Chemical Laboratory, Pune 411008, India;
orcid.org/0000-0001-5313-7746
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02173
(11) Fleming, I.; Roberts, R. S.; Smith, S. C. The preparation and
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Notes
The authors declare no competing financial interest.
̀
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■
The authors acknowledge the Council of Scientific and
Industrial Research (CSIR), New Delhi, for financial support
through the CSIR-Sickle Cell Anemia Mission mode project
(HCP0008). P.R.A. and V.M.Z. thank CSIR, New Delhi, for
the award of senior research fellowships.
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confirm the stereochemistry.
F
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