Enantiospecific Total Synthesis of (-)-Japonicol C

Article abstract of DOI:10.1021/acs.orglett.1c00560

An efficient and convergent first total syntheses of (±)-japonicol B and (-)-japonicol C have been completed. The notable points of the synthetic route are Lewis-acid-catalyzed Friedel-Crafts reaction for one pot C-C and C-O bond formations resulting in c

Full text of DOI:10.1021/acs.orglett.1c00560

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Enantiospecific Total Synthesis of (−)-Japonicol C
Dattatraya H. Dethe* and Appasaheb K. Nirpal
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ABSTRACT: An efficient and convergent first total syntheses of
( )-japonicol B and (−)-japonicol C have been completed. The
notable points of the synthetic route are Lewis-acid-catalyzed
Friedel−Crafts reaction for one pot C−C and C−O bond
formations resulting in construction of the tricyclic meroterpenoid
skeleton, one pot Pd(OH)2/C-catalyzed isomerization/hydro-
genation, and site selective sp3 C−H oxidation.
hallenging, complex architecture and potent biological
activities of naturally occurring phloroglucinol-based
biosynthetically derived from nonenzymatic reactions via series
of oxidation and cyclization reactions. The intermediate 8 was
supposed to be obtained from geranyl pyrophosphate (7) and
acylphloroglucinol moiety 6 via an alkylation reaction which in
turn upon cascade epoxide opening would lead to japonicol B
(2), japonicol C (4), and japonicol D (5) as shown in Scheme
1.2a
C
meroterpenoides have been attracting much attention from
the synthetic community.1a−d
Novel acylphloroglucinol meroterpenoid enantiomers
named (+)/(−)-japonicols A−D were isolated from Hypericum
japonicum by Zhang and co-workers in 2016 (Figure 1).2a,b H.
Scheme 1. Possible Biosynthetic Pathway for Japonicols B
(2), C (4), and D (5)
Figure 1. ( )-Japonicols A (1), B (2), C (4), and D (5) and ( ) 3-
epi-japonicol B (3).
japonicum harbors a group of structurally diverse secondary
metabolites which are a natural source of phloroglucinols,3a
xanthones,3b flavonoids,3c and other miscellaneous compound-
s.3a,d These metabolites belong to the Guttiferae family, which
is useful for the treatment of various infectious diseases,4a acute
and chronic hepatitis, gastrointestinal disorders, internal
hemorrhage, tumors,4b and viruses.4c Among all isolated
japonicol acylphloroglucinol derivatives, japonicols A (1), B
(2), and C (4) possess 2-oxabicyclo[3.3.1]nonane, pyrano[3,2-
b]pyran, and benzo[b]cyclopenta[e]oxepine ring systems,
respectively. Japonicols A−D exhibit inhibitor activity toward
KSHV infection.2 ( )-Japonicol B (2) shows moderate anti-
KSHV activity with an EC50 value of 8.75 μM with a selectivity
index of 16.06. The structure and relative stereochemistry of
japonicols A−D were fully elucidated by spectral analysis,
HRESIMS, and X-ray crystallography.2
Received: February 16, 2021
Published: March 17, 2021
Mimicking the biosynthesis of fused polycyclic ether natural
products to achieve endo selectivity is becoming a prevailing
subject in total synthesis.5a−d Zhang and co-workers have
postulated that japonicols A (1) and B (2) could be
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Based on the biosynthetic route as shown in Scheme 1, it
was envisioned that japonicol B (2) could be synthesized from
intermediate 9 via epoxide opening cascade cyclization,6a−c,7
which in turn could be obtained from alkene 8 on oxidation.
The compound 8 could be easily accessed by Friedel−Crafts
reaction of acylphloroglucinol 6 and commercially available
geraniol (7) (Scheme 2). On the other hand, it was
the starting material. This might be due to the presence of the
highly electron rich aromatic ring, which was prone to
oxidation.8c In order to overcome this problem, hydroxy
groups of compound 8 were protected as acetate using Ac2O,
Et3N, and a catalytic amount of DMAP in CH2Cl2, which
afforded triacetate 12 in 92% yield (Scheme 4). To our delight,
Scheme 4. Total Synthesis of Japonicol B (2) and epi-
Japonicol B (3)
Scheme 2. Retrosynthetic Analysis of Japonicol B (2)
hypothesized that japonicol C (4) could be obtained using
two different strategies: (i) metal selective hydrofunctionaliza-
tion of olefin 17 and (ii) reductive epoxide opening of
compound 19. Olefin 17 could be assembled by Friedel−
Crafts reaction of allyl alcohol 15 and acylphloroglucinol 6 by
one pot C−C and C−O bond formation (Scheme 3). It is
when olefin 12 was subjected to epoxidation in the presence of
m-CPBA in CH2Cl2, the reaction successfully afforded an
inseparable diastereomeric mixture of epoxides 13a,b in a 1:0.6
ratio which was unambiguously confirmed by NMR analysis.
Further, our task was to achieve the regio- and stereo-
selective epoxide opening cascade reaction. However, cascade
cyclization of the polyepoxide moiety for directly accessing the
fused polycyclic ether was efficient but challenging as
compared to that in a stepwise manner.9a−c Gratifyingly,
treatment of epoxide 13a,b with K2CO3 in MeOH/H2O (2:1)
endured acetyl deprotection followed by cascade cyclization
leading to the mixture of japonicol B (2) (2R*,4aS*,10aS* or
2S*,4aR*,10aR*) and 3-epi-japonicol B (3) (2R*,4aR*,10aS*
or 2S*,4aS*,10aR*) in a 1:2 diastereomeric ratio, which was
easily separated by using flash silica gel column chromatog-
raphy. The spectroscopic data of compound (2) was in
complete agreement with the naturally isolated japonicol B.2
These results were consistent with our expectation since the
diepoxy intermediate 13a,b favored endo selectivity to give
japonicol B (2) and 3-epi-japonicol B (3). The epoxide 13a,b
could follow the ring closing under acidic or basic conditions
via the 5-exo or 6-endo mode of cyclization which would lead
to the formation of either a tetrahydrofuran or tetrahydropyran
system, respectively. In the majority of methods, the acid
promoted cyclization (either Lewis or Brønsted)10a,b,11 was
explored, while the cyclizations in basic and neutral medium
were rare. The base induced ring closing was also expected to
follow the endo selectivity.12a−c Jamison and co-workers have
reported that water can promote highly regioselective 6-endo
cyclization.13a,b Basically, as expected by Baldwin’s rules,13c the
closure to the tetrahydrofuran (5-exo-tet) is favored under
both acid- and base-catalyzed conditions. However, six
membered ring formation is preferred under base-catalyzed
conditions, due to the increased steric hindrance of
nucleophilic attack at the more substituted epoxide terminus
as well as the more product-like transition structure with
shorter O−C bond length formation. The six-membered
Scheme 3. Retrosynthetic Analysis of Japonicol C (4)
worth mentioning that there are two possibilities for C−O
bond formation: (i) reaction with a tetrasubstituted cyclo-
pentene double bond would lead to the formation of six
membered pyran ring 16; (ii) reaction with a isopropylidene
double bond would lead to desired oxepane ring formation 17.
It was assumed that tetrasubstituted cyclopentene double bond
is thermodynamically more stable and comparatively less
reactive, which would lead to the desired outcome and
formation of an oxepane ring.
To check the feasibility of our hypothesis, acylphloroglucinol
6 was treated with commercially available geraniol (7) in the
presence of 10 mol % BF3·Et2O in CH2Cl2 as a solvent at 35
°C for 1 h to obtain the desired coupling product 8 in 90%
yield.8a−e Unfortunately, epoxidation of olefin 8 in the
presence of m-CPBA and DMDO led to decomposition of
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product is indeed thermodynamically favored.13d The structure
of unnatural synthetic analogue 3-epi-japonicol B (3) was
determined by 2D NMR, HMBC correlation from Me-d to C-
a, C-b, and C-c, and from Me-j and Me-i to C-g and C-h
together with the spin systems of H-a/H-b and H-e/H-f/H-g
in the H1−H1 COSY. The absence of the NOSY cross-peak of
H-b and Me-d implied trans fusion of the pyran ring, and also
the absence of NOSY cross-peak of H-b and H-g suggested
that they were trans to each other (see the Supporting
Information).
After successfully completing the total synthesis of japonicol
B (2) and 3-epi-japonicol B (3), we turned our attention
toward the synthesis of japonicol C (4). To begin, the required
allyl alcohol 15 was prepared in three steps starting from (R)-
(+)-limonene (14) by using literature reported procedures.14a,b
Alcohol 15 was subjected to Lewis-acid-catalyzed Friedel−
Crafts reaction15a−d with compound 6 in the presence of 30
mol % BF3·Et2O in CH2Cl2 at room temperature to generate
mixture of regioisomers 17 and 18 in 1:2 ratio in 87% yield,
which were separated by using silica gel column chromatog-
raphy (Scheme 5). According to our assumption, we did not
our disappointment, our initial attempts for Co-catalyzed
hydrofunctionalization of 21 to get 22 under different reaction
conditions such as Co(acac)2 in the presence of Et3SiH and
PhSiH3 using various solvents resulted in the decomposition of
the starting material or no reaction observed under Mn(dpm)3
conditions (Scheme 5). It might be due to the presence of the
free phenolic group, which quenched the radical reaction and
the chelation of Co(acac)2 with the free hydroxyl group. So,
both hydroxy groups were protected to their corresponding
acetates. Treatment of compound 17 with acetic anhydride
afforded acetate derivative 23 in 88% yield (Scheme 6); the
Scheme 6. Unsuccessful Attempts toward the Synthesis of
Japonicol C (4)
Scheme 5. Friedel−Crafts Reaction between 6, 20, and 15
structure of compound 23 was unambiguously established by
single crystal X-ray analysis (see the Supporting Information).
Next, we performed a hydration reaction on olefin 23 using
various metal catalysts to generate corresponding tertiary
alcohol (Table 1 in the Supporting Information). Initially, no
reaction was observed when manganese and iron based
catalysts were used for hydration reaction in the presence of
Et3SiH and PhSiH3 using various solvents like 1,2-Dichloro-
ethane, EtOH and i-PrOH (Table 1, entries 1−6). Mukaiyama
hydration using Co(acac)2 and phenylsilane in THF under O2
atmosphere at 35 °C afforded an undesired regioisomer of
japonicol C 24 in 68% yield (Table 1, entry 7; see the
Supporting Information).18a,b The structure and stereo-
chemistry of compound 24 were unambiguously established
by single crystal X-ray analysis of compound 25 (see the
Supporting Information), a deacetylated derivative of 24. The
stereochemical outcome of the Mukaiyama reaction could be
due to the Co−H hydride approaching from a less hindered
side, i.e., convex face (β-face), of the double bond and/or the
stability of the pyramidal (radical) intermediate providing the
hydroxyl group at ring junction.19a−c
observe the formation of compound 16. To overcome the
regioselectivity issue, the para-hydroxy group of compound 6
was protected as its MOM ether by using MOMCl and Et3N
to obtain compound 20, which was then subjected to Friedel−
Crafts reaction with allyl alcohol 15 under standard reaction
conditions to afford single regioisomer 21 in 80% yield. The
structure and relative stereochemistry of compound 21 were
unambiguously established by single crystal X-ray analysis (see
the Supporting Information). Usual methods for MOM
As discussed earlier in retrosynthetic analysis, next we
targeted reductive epoxide opening for completing the
synthesis of japonicol C (Scheme 7). Thus epoxidation of
compound 23 (Scheme 6) was performed using m-CPBA to
afford epoxide 26 in 69% yield. Attempts to obtain
regioselective reductive epoxide opening of 26, using various
conditions such as NaBH3CN and BF3·Et2O,15a CP2TiCl2 and
16
deprotection of 21 such as HCl, TFA, and BiCl3 failed to
generate the desired product. Finally, MOM deprotection of
21 was successfully achieved by refluxing with Sc(OTf)3 in i-
PrOH to afford required product 17.17
A straightforward and concise synthesis of japonicol C (4)
was envisioned by hydrofunctionalization of compound 21. To
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In conclusion, enantiospecific first total synthesis of
(−)-japonicol C was achieved in just five steps by evaluating
several challenging synthetic transformations, including (1) a
one pot protocol for the synthesis of the oxepane
meroterpenoid skeleton, (2) Pd(OH)2/C-catalyzed isomer-
ization/hydrogenation, and (3) stereo- and site-selective sp3
C−H oxidation. In addition, atom economical first total
synthesis of ( )-japonicol B was completed via Friedel−Crafts
alkylation and epoxide opening cascade cyclization. We also
developed a concise approach for the synthesis of the
unnatural analogue (+)-iso-japonicol C (25). The established
strategy could also be useful in the future for the synthesis of
additional natural products and related bioactive molecules.
Scheme 7. Regioselective Epoxide Opening
Zn,20a TBTH and AIBN, Pd/C and HCO2NH4
did not
20b−d
result in any outcome. We observed either no reaction or
decomposition of the starting material. Treatment of epoxide
26 with H2−Pd/C in MeOH/EtOAc at 35 °C afforded an
undesired regioisomer 24 again as a sole product in 61% yield.
1H and 13C of the compound obtained by epoxide opening
were identical to those of the Mukaiyama hydration product.
In epoxide 26, the bulky seven membered ring potentially
forced that catalyst adsorption to happen on the β-side,
sterically blocking the α-side and causing hydrogenation to
occur from the less crowded side, i.e., C3 carbon, which
resulted in the stereospecific product 24. Although our initial
approaches for japonicol C were unsuccessful, the Mukaiyama
hydration and reductive epoxide opening provided (+)-iso-
japonicol C (25).
After an extensive literature search, we came across site
selective oxidation developed by Fuch’s group which is a
powerful method for the oxidation of tertiary carbons and
oxygen activated C−H bonds to tertiary alcohols or ketones,
respectively.21 The Pd/C hydrogenation of 23 gave the
diastereomeric mixture (1:0.4). The desired trans stereo-
chemistry was obtained by using Pd(OH)2/C via isomerization
of tetrasubstituted olefin to the trisubstituted benzylic position
followed by hydrogenation22a,b in 98% yield as a single
diastereomer. The stereochemistry of 27 was confirmed by
single crystal X-ray analysis (see the Supporting Information).
To our delight, compound 27 was successfully oxidized by
using CrO3 and n-Bu4NIO4 in CH2Cl2/CH3CN afforded 28 in
44% yield with retention of stereochemistry (Scheme
8).21,23a−c Finally, hydrolysis of 28 furnished (−)-japonicol C
in 59% yield, and spectroscopic data (H1, C13 NMR spectra)
and optical rotation of (4) exactly correlated with reported
data of natural japonicol C. In addition, the stereochemistry of
japonicol C (4) was confirmed by single crystal X-ray analysis
(see the Supporting Information).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00560.
Experimental procedures and spectral data for all the
compounds (PDF)
Accession Codes
CCDC 2053098, 2054532−2054533, 2062516, and 2063961
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.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
■
Dattatraya H. Dethe − Department of Chemistry, Indian
Institute of Technology Kanpur, Kanpur 208016, India;
orcid.org/0000-0003-2734-210X; Email: ddethe@
iitk.ac.in
Author
Appasaheb K. Nirpal − Department of Chemistry, Indian
Institute of Technology Kanpur, Kanpur 208016, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00560
Notes
The authors declare no competing financial interest.
Scheme 8. Total Synthesis of (−)-Japonicol C
ACKNOWLEDGMENTS
■
A.K.N. thanks Mr. Sharad Sachan and Dr. Akhilkumar Shigh
for helping with the X-ray analysis. Department of Chemistry,
Indian Institute of Technology, Kanpur is greatly acknowl-
edged for providing fellowship, infrastructure, and facilities.
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