Synthesis and Properties of Allenic Natural Products and Pharmaceuticals

Hoffmann‐Röder, Anja; Krause, Norbert

doi:10.1002/anie.200300628

Cited by 844 publications

(391 citation statements)

References 272 publications

(157 reference statements)

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“…4 In 2001, Okamoto also reported the isolation of 1 from the sea hare aplysia kurodai and found it functions as a Na + /K + ATPase inhibitor with IC50 = 0.7 μM. 5 In this communication, we(1) Suzuki, M.; Kurosawa, E. Phytochemistry 1985, 24, 1999-2002 (2) For review on bromoallene natural products, see: HoffmannRöder, A.; Krause, N. Angew. Chem.…”

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confidence: 95%

First Total Synthesis and Structural Reassignment of (−)-Aplysiallene

Wang

Pagenkopf

2007

Org. Lett.

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The first total synthesis of (-)-aplysiallene has been completed in 16 steps, and features a key sequential Mukaiyama aerobic oxidative cyclization to prepare the fused bis-THF core. The original stereochemical assignment has been revised as shown.Aplysiallene 1 was first isolated in 1985 from the red alga Laurencia okamurai Yamada by Suzuki and Kurosawa. 1 Its intriguing structural features include 1) a unique cis-fused 2,6-dioxabicyclo[3,3,0]octane skeleton consisting of two trans-tetrahydrofuran rings, 2) an unusual (E,E)-bromodiene side chain, and 3) an Rbromoallene 2 appendage. The absolute stereochemistry of 1 was assigned according to its strong negative optical rotation (due to the allene 3 ) and the relative stereochemistry was assigned by NOE correlations and comparison with kumausallene. 4 In 2001, Okamoto also reported the isolation of 1 from the sea hare aplysia kurodai and found it functions as a Na + /K + ATPase inhibitor with IC50 = 0.7 μM. 5 In this communication, we(1) Suzuki, M.; Kurosawa, E. Phytochemistry 1985, 24, 1999-2002 (2) For review on bromoallene natural products, see: HoffmannRöder, A.; Krause, N. Angew. Chem. Int. Ed. 2004, 43, 1196-1216 (3) Lowe, G. report the first asymmetric total synthesis of aplysiallene and provide evidence for its structural revision. 6 It was envisaged that the R-bromoallene substituent could be prepared from the corresponding R-propargyl alcohol 2a, which in turn should be accessible by an antiselective alkynylation between aldehyde 3 and trimethylsilylacetylene. 7 Although we are unaware of precedence for the direct introduction of the bromodiene subunit, a plausible derivation could be from alcohol 4, which would be stereoselectively prepared by sequential oxidative cyclization 8 of the known (R,R)-diol 5.The synthesis began with reaction of (S,S)-diepoxybutane 6 with vinyl magnesium bromide in the presence of CuBr to give the (S,S)-diol ent-5 in 72% yield. Note the stereochemistry of ent-5 is opposite to that required for the reported natural product, so this should in principle lead to a synthesis of ent-1. While the isolated yield of 13b was only 35%, the dienes 13a and 13b were separable by flash chromatography on gram scale, and unwanted 13a can be recycled by ozonolysis followed by a NaBH4 work up to give alcohol ent-4 in 53% yield. In contrast, attempted conversion of 13a directly into 9 by ozonolysis with a PPh3 work up resulted in complete decomposition of 13a.With the bromodiene side chain at hand, deprotection of the silyl ether 13b by treatment with TBAF followed by Swern oxidation afforded the highly labile aldehyde ent-3 (81%, 2 steps), which was used immediately in the following addition step. As expected, alkynylation of ent-3 with the titanium acetylide of trimethylsilylacetylene (generated in situ with nBuLi and ClTi(OiPr)3) gave ent-2 (13) Initial efforts were undertaken to furnish the bromodiene side chain on a model system by a one-step olefination strategy, but such reactions under various conditions consistently gave ...

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confidence: 95%

First Total Synthesis and Structural Reassignment of (−)-Aplysiallene

Wang

Pagenkopf

2007

Org. Lett.

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“…Analysis of the 1 H, 13 C, and HMQC NMR data of 4 (Table 2) revealed the same p-substituted 4-(hydroxymethyl)phenyl unit as found in 1-3, but the resonances for the allenyl portion of 1-3 were significantly different from those for the subunit connected to C-8 in 4. The signals for H-11 (δ H 2.93) and C-10 (δ C 83.7) and C-11 (δ C 74.5) are indicative of an ethynyl moiety.…”

Section: Resultsmentioning

confidence: 86%

“…It was assigned the molecular formula C 17 H 22 O 7 (seven degrees of unsaturation) by HRESIMS (m/z 361.1262 [M + Na] + ; ∆ -0.4 mmu). Analysis of the 1 H, 13 C, and HMQC NMR data (Table 1) revealed four exchangeable protons, three oxygenated sp 3 methylenes, five oxygenated methines, six aromatic carbons (four of which are protonated), and three sp 2 carbons (δ C 76.6, 87.9, and 208.0) possibly due to the presence of an allenyl unit. 4 NMR resonances for the four aromatic protons were observed as two sets of doublets (8.5 Hz each) at δ H 6.91 and 7.32, respectively, suggesting the presence of a p-substituted phenyl ring.…”

Section: Resultsmentioning

confidence: 99%

Allenyl and Alkynyl Phenyl Ethers from the Endolichenic Fungus Neurospora terricola

Zhang¹,

Liu²,

Lu³

et al. 2009

J. Nat. Prod.

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Terricollenes A−C (1−3), new allenyl phenyl ethers, and terricolynes (4−6), new alkynyl phenyl ethers, have been isolated from the crude extract of the endolichenic fungus Neurospora terricola. The structures of these compounds were elucidated primarily by NMR experiments. The absolute configurations of 1 and 2 were determined by reversed-phase HPLC analysis on the o-tolylthiocarbamates of the liberated sugars upon acid hydrolysis, whereas that of 4 was assigned using the modified Mosher method. Compound 1 showed modest cytotoxicity against the human tumor cell lines HeLa and MCF-7.

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“…This would suggest that a common structural feature may be responsible for the toxicity. It is highly probable that the acetylenic propargyl group gives rise to allenes which are generally cytotoxic [23]. Preparation and testing of the partially reduced (allenic) and fully reduced (propylic) analogs of these compounds should give more insight into the mechanism of toxicity to macrophages.…”

Section: Resultsmentioning

confidence: 99%

Activity of Novel Tryptophan Analogs against Trypanosoma cruzi and Leishmania donovani

Mung’ong’o¹,

Mugoyela²,

Hooper³

et al. 2009

East and Central African Journal of Pharmaceutical Sciences

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Drugs available for the treatment of Chagas disease and Leishmaniasis are grossly inadequate and have many drawbacks. Most of them are ineffective for the chronic form of the disease. The drugs available are expensive and most need parenteral administration. In addition, most of them are extremely toxic and resistance develops fast. There is an urgent need for new, safe and more effective drugs. As part of the continued search for novel antitrypanosomal drugs, the present study was aimed at the design and synthesis of novel tryptophan analogs which have a potential to inhibit essential trypanosomal enzymes. Some of these compounds have shown significant activity against Trypanosoma brucei brucei in vitro. In the present study, 17 of the most promising compounds were selected and tested for possible activity against the biochemically closely related protozoans Trypanosoma cruzi and Leishmania donovani using in vitro models. Seven compounds showed significant activity against T. cruzi, producing more than 50 % inhibition of multiplication at or below 30 µM concentrations. Four compounds also had significant activity against L. donovani promastigotes in vitro. These findings support the common observation that antiprotozoal drugs tend to exhibit a broad spectrum of activity among various protozoans.

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Synthesis and Properties of Allenic Natural Products and Pharmaceuticals

Cited by 844 publications

References 272 publications

First Total Synthesis and Structural Reassignment of (−)-Aplysiallene

First Total Synthesis and Structural Reassignment of (−)-Aplysiallene

Allenyl and Alkynyl Phenyl Ethers from the Endolichenic Fungus Neurospora terricola

Activity of Novel Tryptophan Analogs against Trypanosoma cruzi and Leishmania donovani

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