Total Synthesis of Adunctin B

Article abstract of DOI:10.1021/acs.joc.8b00015

Total synthesis of (±)-adunctin B, a natural product isolated from Piper aduncum (Piperaceae), has been achieved using two different strategies, in seven and three steps. The efficient approach features highly atom economical and diastereoselective Friedel-Crafts acylation, alkylation reaction and palladium catalyzed Wacker type oxidative cyclization.

Full text of DOI:10.1021/acs.joc.8b00015

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Total Synthesis of Adunctin B
Dattatraya Hanumant Dethe, and Balu D. Dherange
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00015 • Publication Date (Web): 20 Feb 2018
Downloaded from http://pubs.acs.org on February 21, 2018
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The Journal of Organic Chemistry
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Total Synthesis of Adunctin B
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Dattatraya H. Dethe,* and Balu D. Dherange
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Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India.
Fax: (+91)-512-2596537; Phone: (+91)-512-2597436; email: ddethe@iitk.ac.in
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ABSTRACT: Total synthesis of (±)-adunctin B, a natural product isolated from Piper
aduncum (Piperaceae) has been achieved using two different strategies, in seven and three
steps. The efficient approach features highly atom economical and diastereoselective Friedel-
Crafts acylation, alkylation reaction and palladium catalyzed Wacker type oxidative
cyclization.
The Piperaceae (pepper family) is one of the largest family of flowering plants. The
family constitutes roughly 3,600 species. The distribution of Piperaceae family is pantropical
in nature and contains all variety of species from shrubs, herbs to trees. A monoecious shrub
Piper aduncum, L. (Piperaceae) distributed in Malesia, Papua New Guinea and large part of
tropical America, is used for the treating fresh wounds, diarrhoea,1 dysentery, and as a
haemostatic agent.2 Sticher and co-workers3 isolated adunctin A-E (1-5) along with known
methyllindaretin4 from the leaves of Piper adunctum. Spectral analysis (1D, 2D and single
crystal X-ray) established the structure of adunctin A (1) as monoterpene-substituted
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The Journal of Organic Chemistry
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Figure 1. Structures of adunctin B (2) and related natural products
dihydrochalcone, adunctin C (3), and D (4) as spirobenzofuran derivative, whereas adunctin
B (2) and E (5) as cinnamoyl-hexahydrodibenzofuran derivatives (Figure 1). Adunctin B (2)
has three stereocentres at 1”, 4” and 6” positions. It showed antibacterial effects toward
Micrococcus luteus at a concentration of 3.5 μg/mL.3
The first racemic synthesis of adunctin B (2) was reported by Arimitsu et al.5 in 2011
from commercially available 4,6-dimethoxysalicylaldehyde with 1.22% overall yield in 16
steps, using coumarin rearrangement strategy, previously developed in their lab. Encouraged
by our recent syntheses of methyllinderatin, linderol A and adunctin E,6 we became interested
in the total synthesis of adunctin B. Herein, we report concise total synthesis of (±)-adunctin
B (2) using highly atom economic and diastereoselective Friedel-Crafts reaction, followed by
palladium catalyzed Wacker-type oxidative cyclization.
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The Journal of Organic Chemistry
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Our retrosynthetic analysis of adunctin B (2) is depicted in Scheme 1. It was envisioned
that synthesis of adunctin B (2) could be achieved from alcohol 6 by dehydration to generate
the requisite double bond. The nucleophilic attack of phenolic OH group on epoxide 7, under
basic conditions would lead to the formation of tricyclic compound 6. Epoxidation on alkene
8 using m-CPBA would generate epoxide 7. The Friedel-Crafts alkylation of electron rich
dihydrochalcone 9 and dihydrocarveol 11 should furnish the key intermediate 8.
Dihydrochalcone 9 could be prepared from commercially available 5-methoxyresorcinol (10)
while, dihydrocarveol 11 could be obtained from carvone (12).
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Scheme 1. Retrosynthetic analysis for adunctin B (2)
The synthesis commenced with preparation of dihydrochalcone derivative 9, which
was previously synthesized in 4-5 steps, using protection-deprotection protocol.6,7 We
developed an alternate, protecting group free, one pot synthesis where, the commercially
available acid 13 was converted to corresponding acid chloride using oxalyl chloride,
followed by addition of 5-methoxyresorcinol (10) and AlCl3 afforded required
dihydrochalcone 9 as a single regioisomer in 69% yield (Scheme 2). The dihydrocarveol 11
was prepared from carvone (12) in one pot by regioselective double bond reduction using
Adam’s catalyst,8 followed by Luche reduction9 in 81% yield.
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