Total syntheses of (±)-musellarins A-C

Article abstract of DOI:10.1039/c4cc05248j

The first, diastereoselective total syntheses of musellarins A-C were achieved concisely with 7.8-9.8% yields in 15-16 steps. The key synthetic features include (i) an Achmatowicz rearrangement, Kishi reduction, and Friedel-Crafts cyclization to construct

Full text of DOI:10.1039/c4cc05248j

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Total syntheses of (Æ)-musellarins A–C†
Zhilong Li, Tsz-Fai Leung and Rongbiao Tong*
Cite this: Chem. Commun., 2014,
50, 10990
Received 8th July 2014,
Accepted 23rd July 2014
DOI: 10.1039/c4cc05248j
www.rsc.org/chemcomm
The first, diastereoselective total syntheses of musellarins A–C were
achieved concisely with 7.8–9.8% yields in 15–16 steps. The key
synthetic features include (i) an Achmatowicz rearrangement, Kishi
reduction, and Friedel–Crafts cyclization to construct the tricyclic
framework and (ii) Heck coupling of aryldiazonium salts to introduce
the aryl group into the dihydropyran in a 2,6-trans fashion in the final
stage of synthesis.
Diarylheptanoid natural products are a family of secondary plant
metabolites isolated from various sources, featuring the structural
motif of a seven-carbon linkage of two aromatic rings.1 Many
diarylheptanoids displayed potent biological activities such as
Fig. 1 Musellarins and other types of diarylheptanoids.
antioxidant, anticancer, antibacterial, antifungal, antiosteoporosis, (IC50 26.7 mM) and A-549 (IC50 25.1 mM).3 The potential bioactivity
antihepatotoxicity, and melanogenesis inhibition, and therefore and unusual structures of musellarins within the family of diaryl-
have been increasingly recognized as potential therapeutic heptanoids prompted us to undertake their synthetic studies.
agents.1 Among over 400 known diarylheptanoid natural pro- Herein, we report the first total syntheses of musellarins A–C
ducts, musellarins A–E (Fig. 1) represent an unusual structural featuring a late stage stereoselective installation of the second aryl
class for the presence of the rare bicyclic tetrahydropyran motif. group via Heck coupling of aryl diazonium salts.
Musellarin A was reported in 2002 by Kinghorn2 and co-workers
Retrosynthetically (Scheme 1), we planned to introduce the
from hybrid plant fruits of musa  paradisiaca in Peru as the aryl group with different substituents via Heck coupling of enol
first example of diarylheptanoids containing such a bicyclic ether 2 and aryl diazonium salts,4 which was expected to
functionality, which had been established by extensive NMR simultaneously deliver the desired stereochemistry at C2 and an
studies and confirmed by single crystal X-ray diffraction analysis. In appropriate double bond at C3–C4. It was noted that the similar
2011, musellarin A was isolated again by Zhao3 and coworkers from Heck couplings yielding the 2,6-trans disubstituted tetrahydro-
monotypic plant Musella lasiocarpa in Yunan, China, in 0.0006% yield pyran with excellent diastereoselectivity has been elegantly
(18 mg from 3 kg of dry plant materials). Zhao et al. also obtained exploited by Schmidt in the total synthesis of centrolobine and
several new congeners of musellarin A: musellarins B–E containing various diarylheptanoid analogues (Type IV, Fig. 1).5 The enol
this rare bicyclic skeleton. Although the biological activities of ether 2 could be prepared from ketone 3 via Pd-catalyzed
musellarins C–E have not been reported, musellarin A significantly reduction of its corresponding enol triflate. The ketone 3 was
induced quinone reductase activity against Hepa1c1c7 cells,2 and envisioned to be derived from intramolecular Friedel–Crafts
musellarin B has shown moderate cytotoxicity against several cyclization6 of g-aryl enone 4, which could be readily synthesized
cancer cell lines including HL-60 (IC50 21.3 mM), SMMC-7721 from furfuryl alcohol 6 through Achmatowicz rearrangement7 and
Kishi reduction.8 Wittig olefination of 7 and 8 would deliver the
Department of Chemistry, The Hong Kong University of Science and Technology,
requisite alcohol 6 after hydrogenation.
Clearwater Bay, Kowloon, Hong Kong, China. E-mail: rtong@ust.hk
Our synthesis (Scheme 2) began with preparation of alcohol 10,
† Electronic supplementary information (ESI) available: Detailed experimental
which was obtained in an excellent yield from commercially available
isovanillin 9 by protection of the alcohol as triisopropylsilyl ether and
reduction of the resulting aldehyde with NaBH4. The alcohol 10 was
procedures, characterizations and copies of 1H- and 13C-NMR spectra of new
compounds, and X-ray crystallographic data. CCDC 1012651. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4cc05248j
10990 | Chem. Commun., 2014, 50, 10990--10993
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Fig. 2 ORTEP diagram of compound 3.
Table 1 Attempted conditions for one-pot Kishi reduction and intra-
molecular Friedel–Crafts cyclizationa
R3SiH
(equiv.) time (h)
Temp. (1C)/
Yieldc
Ratiob (4 : 3) (%)
Entry Acid (equiv.)
Scheme 1 Retrosynthetic analysis of musellarins A–C.
1
2
3
4
5
6
7
8
TFA (10)
TFA (10)
TFA (10)
BF3–Et2O (2)
BF3–Et2O (5)
Et3SiH À40/1
2 : 1
1 : 1
Complex
14 : 1
Complex
78
41
N/A
74
N/A
45
N/A
N/A
N/A
30
i-Pr3SiH À40/1
Et3SiH
Et3SiH
Et3SiH
À40/12
À78/1
À78/5
BF3–Et2O (0.5) Et3SiH
À78 - rt/24 5 : 1
TMSOTf (1)
TESOTf (0.3)
TBSOTf (0.3)
TiCl4 (1.2)
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
À78/1
À78/3
À78/3
À78/1
À78/1
Complex
Complex
Complex
0 : 1
9
10
11
SnCl4 (1)
Complex
N/A
a
b
The reaction was run with 20 mg of compound 5. Ratio was deter-
c
mined by NMR analysis of the crude reaction mixture. Combined yield
after flash column chromatography on silica gel. Notes: TFA: trifluoro-
acetic acid. TMSOTf: trimethylsilyl trifluoromethanesulfonate. TESOTf:
triethylsilyl trifluoromethanesulfonate. TBSOTf: tert-butyldimethylsilyl
trifluoromethanesulfonate.
attempted to improve the yield of 3 in the one-pot process
(Table 1). Under the classical Kishi reduction conditions reported
previously (entries 1 and 4), TFA (or BF3–Et2O) and triethylsilane
Scheme 2 Synthesis of the tricyclic compound 3.
then converted into the phosphonium salt 7 in two straightforward gave the dihydropyranone 4 as the major product in a good yield if
steps. Wittig olefination of aldehyde 8 and phosphorus ylide the reaction was quenched within 1 h. Extending the reaction
generated in situ from 7 produced a 2 : 3 E/Z mixture of alkene time (entry 3) or excess equivalent of BF3–Et2O (entry 5) did not
11 in 71% yield. The subsequent hydrogenation of 11 with Pd/C lead to any further conversion of 4 to 3. Instead, significant
in methanol (or ethyl acetate), however, resulted in a rather decomposition was observed. When the bulkier triisopropylsilane
complex mixture, partially due to over-reduction. Gratifyingly, (entry 2) was used as the hydride donor, intramolecular Friedel–
we found that magnesium9 (turnings) in methanol at room Crafts cyclization produced a 1 : 1 mixture of 4 and 3 in a low
temperature could effectively saturate the double bond with combined yield. Since other conditions employing triisopropyl-
concomitant deacetylation10 to provide the furfuryl alcohol 6 in silane and phenyldimethylsilane did not give a better yield of 3,
68% yield. Achmatowicz rearrangement of 6 was smoothly triethylsilane was used in further attempts. Reducing the equiva-
promoted by m-CPBA at 0 1C to provide the dihydropyranone lent of BF3–Et2O (entry 6) slowed the reduction and cyclization
hemiacetal 5 in 85% yield. Kishi reduction of 5 using a classical considerably, which required an elevated temperature and a longer
combination of trifluoroacetic acid and triethylsilane generated a reaction time for complete consumption of 5 but gave a lower yield
2 : 1 mixture of dihydropyranone 4 and a surprising Friedel–Crafts as compared to entry 4. Other strong Lewis acids (entries 7–9,
cyclization adduct 3 in 78% combined yield.
and 11) resulted in decomposition with a trace amount of desired
As we had planned in our design stage, the intramolecular compounds 3 or 4. Interestingly, TiCl4–Et3SiH gave the tricyclic
Friedel–Crafts cyclization of dihydropyranone 4 occurred in the compound 3 exclusively in 30% yield. Unfortunately, the overall
presence of BF3–Et2O at À78 1C to provide the tricyclic compound 3 yield was synthetically too low and could not be improved under
quantitatively, the structure of which was unambiguously con- various conditions. It appeared to us that two-step operations would
firmed using X-ray diffraction analysis (Fig. 2).
be the choice: Kishi reduction with TFA/Et3SiH or BF3–Et2O/Et3SiH
Encouraged by the unexpected result that Kishi reduction/ (entries 1 and 4) and independent Friedel–Crafts cyclization
Friedel–Crafts cyclization could occur in a one-pot manner, we with BF3–Et2O as shown in Scheme 2.
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Scheme 3 Synthesis of the key intermediate enol ether 2.
Next, we directed our attention to synthesize the tricyclic enol ether
2 via a two-step deoxygenation11 of ketone 3 (Scheme 3). To this end,
ketone 3 needed to be regioselectively deprotonated with a base to
generate an enol anion, which would be triflated with PhNTf2.
However, treatment of ketone 3 with PhNTf2 and a bulky base such
as KHMDS or LDA at À78 1C led to exclusive formation of vinyl triflate
12a in good yield.12 When the more sterically demanding base LiTMP
was used, a regiomeric mixture of 12a and 12b could be obtained in a
lower yield (40–50%) with a 1 : 1 ratio of diastereomers, which could
not be easily separated by column chromatography. In view of the
difficulty in efficient preparation of the enol triflate 12b using this
straightforward method, we set out to explore the possibility of olefin
isomerization13 for the synthesis of enol ether 2 from 12a. First, vinyl
triflate 12a was transformed into alkene 13 in an excellent yield by
palladium-catalyzed reduction.11 To our delight, the isomerization of
13 with the Wilkinson catalyst14 in the presence of DBU proceeded
smoothly upon refluxing to provide enol ether 2 in 63% yield,
which served as the common key intermediate for the synthesis of
musellarins A–C via Heck coupling with aryl diazonium salts.
Three aryl diazonium salts (15a–c), corresponding to musellarins
A–C, were prepared (Scheme 4) by using similar protocols in the
literature.5 Specifically, acetaminophen (14), a widely used over-the-
counter analgesic, could be successfully transformed into the aryl
diazonium salt 15a5e with 58% yield in two steps. The preparation of
aryl diazonium salts 15b and 15c could be achieved in excellent
yields from 16 and 18, respectively, via a three-step sequence:
acetylation, palladium-catalyzed reduction of nitro group to amine,
and diazotization. It was noteworthy that acetyl protection of the
Scheme 5 Completion of total syntheses of musellarins A–C.
phenol was essential to the success since 4-amino-phenols derived
from direct reduction of nitrophenols (16 and 18) were unstable and
could not be converted to the corresponding diazonium salts.
With both coupling partners in hand, we then explored the Heck
coupling using the conditions developed by Schmidt5 (Scheme 5).
Gratifyingly, the Heck reaction of the enol ether 2 with aryl diazonium
salts 15a–c using Pd(OAc)2 as a precatalyst occurred smoothly
to provide the corresponding coupling products, which were
immediately subjected to desilylation with TBAF and/or deacetyla-
tion with K2CO3/MeOH to furnish musellarins A–C, respectively, in
excellent yields with good diastereoselectivity (dr 7 : 1–9 : 1). Separa-
tion of the musellarins A–C from their minor diastereomers by
preparative TLC (silica gel) led to analytically pure musellarins A–C.
All spectroscopic data of our synthetic samples were identical to
those reported for natural musellarins A–C.15
In summary, we have accomplished the first concise total
syntheses of musellarins A–C in the longest linear sequence of
15–16 steps from commercially available materials. The synthetic
strategy was enabled by (i) exploitation of the Achmatowicz
rearrangement, Kishi reduction and Friedel–Crafts alkylation to
construct the tricyclic framework 3 with a cis ring conjunction
and (ii) high-yielding Heck coupling of aryl diazonium salts in
good trans-diastereoselectivity in the final stage of synthesis.
Importantly, the flexibility and convergence of the synthetic route
developed here would permit an expedient entry into musellarins
and their analogues for further biological studies.
This research was financially supported by HKUST and the
Research Grant Council of Hong Kong (ECS 605912, GRF 605113,
and GRF 16305314). The authors are also grateful to Prof. Dr Ian
Williams and Dr Herman Sung (HKUST) for the single crystal
X-ray diffraction analysis.
Notes and references
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Scheme 4 Synthesis of the aryl diazonium salts.
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