Letter pubs.acs.org/OrgLett
Biomimetic-Inspired Syntheses of Myrtucommuacetalone and Myrtucommulone J Hongxin Liu,†,‡ Luqiong Huo,‡ Bao Yang,‡ Yunfei Yuan,‡ Weimin Zhang,† Zhifang Xu,‡ Shengxiang Qiu,*,‡ and Haibo Tan*,‡ †
State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, P.R. China ‡ Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, P.R. China S Supporting Information *
ABSTRACT: Driven by bioinspiration and appreciation of their structures, the first biomimetic total syntheses with structural revision of the acylphloroglucinols myrtucommulone J and myrtucommuacetalone, two biologically meaningful natural products, were achieved through a biosynthetic hemiacetalization/dehydration/[3 + 3]-type cycloaddition domino sequence with high step efficiency. These syntheses result in a corrected structure for myrtucommulone J.
A
Scheme 1. Structures of 1 (Original and Revised) and 2
cylphloroglucinols, characterized by a tetramethylcyclohexenedione or acylphloroglucinol moiety, have fascinated many scientists in recent years due to their structural diversity, architectural complexity, and wide-ranging biological activity.1−3 Myrtucommulone J (1), isolated from Myrtus communis, was found to have a very specific antibacterial activity; it has an MIC of 0.38 μM against S. aureus, which is 35-fold more toxic against this species than it is to normal eukaryotic cells, and therefore, it is considered to be a promising antibiotic.4 Myrtucommuacetalone (2), also isolated from M. communis, was unambiguously elucidated through X-ray crystallographic analysis in 2013 as a novel acylphloroglucinol with an unprecedented complex tricyclic ketal skeleton.5 It exhibited highly significant inhibitory effects against nitric oxide (NO•) production and showed promising antiproliferative activity against T cells (IC50 < 0.5 μg/ mL). The remarkable biological activities and novel structural features of these two molecules make them appealing targets for the synthetic community. Serendipitously, when comparing the spectral data between 1 and 2, we were surprised at the similarities we found in their chemical formulas and NMR spectral data. The degree of similarity strongly implies that they should be closely related and share the same biogenetic pathway. On the basis of this similarity, we conducted a concerted effort to carefully interpret the NMR spectra of myrtucommulone J (1) and initially concluded that the major issue clouding its structure might be attributed to the likely misinterpretation of its spectral data due to its complexity. On the basis of the aforementioned information, a revision of the structure of 1 is suggested as depicted in Scheme 1. To further © 2017 American Chemical Society
determine the differences between the structural and physical characteristics of 1 and 2, we developed a biomimetic sequence for their total syntheses to confirm their structures. Our preliminarily proposed biogenesis of myrtucommulone J (1) and myrtucommuacetalone (2) focused on identifying key biosynthetic precursor 7 that could be transformed to 3,4dihydro-2H-furan-1-ium 58 and could then participate in the crucial biosynthetic [3 + 3]-type cycloaddition downstream due to its substantial electron deficiency (Scheme 2).6−8 Compound 5 was rationally deduced to be generated from 8 by a remarkable spontaneous carbonyl reduction/acidolysis/hemiacetalization/ dehydration cascade sequence. Moreover, the regioselectivity arising from the dihydropyran ring formation led to the skeletal differences between 1 and 2.9 Both key intermediates 4 and 8 are well-known natural products that are often discovered in myrtle plants.10 In particular, 8 is abundant in M. communis. In this regard, our initially proposed biogenetic pathway for these two Received: July 17, 2017 Published: August 25, 2017 4786
DOI: 10.1021/acs.orglett.7b02159 Org. Lett. 2017, 19, 4786−4789
Letter
Organic Letters
f were subsequently subjected to the optimized reaction conditions, and the results are compiled in Scheme 3. In each
Scheme 2. Our Proposed Biogenesis of 1 and 2
Scheme 3. Surveying the Substrate Scope of Phloroglucinolsa
natural products appears to be reasonable from a biosynthetic perspective. With this scenario in mind, we set out to optimize the reaction conditions with the readily accessible phloroglucinol 9 and ketone 1011 as the tentative substrates. Interestingly, when trifluoroacetic acid (TFA) was added to trigger the biomimetic domino hemiacetalization/dehydration/[3 + 3] cycloaddition sequence, tricyclic ketals 11 and 12 were obtained in 30% combined yield (entry 1) as shown in Table 1. In an attempt to
a
Conditions: 10 (0.2 mmol), 13 (0.2 mmol), TFA (50 uL), toluene (2.5 mL), THF (0.5 mL), rt, 3−6 h. [b] 9 (0.4 mmol), 13 (0.2 mmol), PTSA (0.02 mmol), toluene (3.0 mL), 60 °C, 0.5 h. bConditions: 9 (0.4 mmol), 13 (0.2 mmol), PTSA (0.02 mmol), toluene (3.0 mL), 60 °C, 0.5 h.
case, the corresponding desired tricyclic ketals 14a−f and 15a−f were delivered in excellent combined yields ranging from 82 to 90% within 3−6 h, and the isomeric ratios were usually approximately 1:2. The reactivity for this methodology appeared to be little influenced by steric constraints of acylphloroglucinol 13. Diacylphloroglucinols 13g−l, intriguing natural products or their analogues that are well-known in light of their antimicrobial properties,12 were investigated; their performance was inferior to 13a−f presumably due to their decreased nucleophilicity.13 However, switching to 0.1 equiv of PTSA as the acid catalyst was found to be critical in this transformation to deliver the corresponding products 14g−l in a highly efficient manner virtually irrespective of their aryl ring substitutions. Furthermore, the symmetry of 13g−l meant the products were not a mixture of inseparable regioisomers, making these substrates more practical than acylphloroglucinols 13a−f. For the scope of this methodology to be explored further, various α,β-unsaturated ketone analogues of 16 were examined (Scheme 4). When the C6-dimethyl (16c and d) and C4dimethyl (16e and f) substrates were subjected to the standard conditions, they provided the tricyclic ketal products 17c−f and 18c−f in lower yields but with better regioselectivities (usually
