Halenaquinol

Other examples of determination of absolute stereochemistry by theoretical calculation of the CD spectra include ( + )-l,8a-dihydro-3,8-dimethylazulene (2)93 and ( + )-halenaquinol (3) and its derivatives94. 

The yellow pigment halenaquinol sulfate (410) has been isolated from the Okinawan sponge Xestospongia sapra and is a pentacyclic hydroquinone [345]. The absolute stereochemistry was determined to be 6S by comparing the CD spectrum of a derivative with a theoretically calculated spectrum [346]. Theoretical calculation of CD spectra of halenaquinol sulfate (410) isolated from X. exigua and X. sapra determined that the absolute stereostructure was 12bS [347]. The pentacyclic compound, xestoquinol sulfate (411) has been isolated from an Okinawan collection of X. sapra and its structure was elucidated on the basis of spectroscopic data and a chemical conversion [348]. 

In a related study, the Shibasaki group examined cyclizadon of naphthyl triflate 10.1 (Scheme 8G.10) [23], Cyclization of 10.1 under standard cationic conditions gave Heck product 10.2 in 78% yield and 87% ee. Evidently, the reaction is fairly tolerant of the nature of the aryl group, because both 10.1 and 9.3 behaved similarly. An interesting variation of this reaction was also demonstrated in which Suzuki coupling and asymmetric Heck cyclization were performed in a one-pot operation. Thus, treatment of ditriflate 10.3 with borane 10.4 under standard Heck conditions provided 10.2 in similar enantioselectivity to the stepwise procedure, albeit in quite low yield. Heck product 10.2 was converted in several steps to the natural products, halenaqui-none (10.5) and halenaquinol (10.6). 

A simple procedure to prepare 5-aryl- and 5-pyridyl-2-furaldehydes from inexpensive, commercially available 2-furaldehyde diethyl acetal was reported. The reaction proceeded in a four-step, one-pot procedure and the yield of coupling step was usually between 58-91% <02OL375>. A facile route to 3,4-furandicarboxylic acids was developed. DDQ-oxidation of 2,5-dihydrofuran derivatives, which were produced from dimethyl maleic anhydride, furnished the desired esters of furan-3,4-dicarboxylic acid <02S1010>. The furan-fused tetracyclic core of halenaquinol and halenaquinone possessing antibiotic, cardiotonic, and protein tyrosine kinase inhibitory activities was synthesized. Intramolecular cycloaddition of an o-quinodimethane with furan gave the adduct as a single isomer via an enrfo-transition state, which was converted to trisubstituted furan by oxidation-elimination reactions <02T6097>. 

As depicted in Scheme 41, an intramolecular cycloaddition of the furan 2,3-double bond of a furan tethered to a cyano-substituted benzocyclobutene via an intermediate quinone dimethide was used for the synthesis of the tetracyclic core of halenaquinol and halenaquinone <2001SL1123, 2002T6097>. The reaction proceeded via an OT,7i9-transition state to produce the cycloadduct 72 exclusively. A related chemistry is shown in Equation (56), in... 

Halenaquinone and halenaquinol (75) Asymm. intermol. HR-Suzuki cascade [174]... 

Total Synthesis and Absolute Stereochemistry of Novel Biologically Active Marine Natural Products of Halenaquinol Family Theoretical Studies of CD Spectra... 

Halenaquinol 2 was methylated in refluxing acetone with iodomethane in the presence of potassium carbonate in the dark yielding dimethyl ether (+)-17 as yellow needles (Scheme 1) mp 235 °C [a]23 )+150.1° (CH2CI2). To differentiate the two carbonyl groups at the 3- and 6-positions, halenaquinol dimethyl ether (+)-17 was selectively reduced with NaBH4 in the presence of CeCl3-7H20, which... 

Figure 2. CD spectrum of halenaquinol dimethyl ether (12b5)-(+)-17 derived from the natural sample of halenaquinol solvent, EtOH.

The naphthalene-diene compounds (-)-22 and (+)-23 were also derived directly from halenaquinol dimethyl ether (+)-17 by the reduction and subsequent terr-butyldimethylsilylation (Scheme 3). Diketone (-i-)-17 was reduced and then treated with hydrochloric acid, as in the case of ketone (+)-19 of Scheme 2, giving rranj-methoxy alcohol (-)-24 and cj j-methoxy alcohol (-)-25, respectively. Each alcohol was then converted to its /ert-butyldimethylsilyl ether, which was identical with the authentic sample derived from compound (+)-19. 

It was quite interesting that naphthalene-diene compounds (-)-22, (-t-)-23, (-)-24, and (-)-25 exhibited much stronger CD Cotton effects than other halenaquinol derivatives. For example, the UV spectrum of rra j-methoxysilyl ether (-)-22 shows two intense n- K bands (Figure 4) the broad band at 324 nm (e 27 000) with complex vibrational structures and the sharp band at 218 nm (e 42 000). In... 

As discussed above, we succeeded in the theoretical determination of the absolute stereochemistry of novel marine natural products of halenaquinol family. It is quite natural that chemists, as the next step, want to prove their absolute configurations theoretically determined in an experimental way. So, we started to... 

As a synthetic strategy, we performed the retrosynthesis and adopted the synthetic route shown in Scheme 4, where halenaquinol (12b5)-(+)-2 can be prepared by the reduction of halenaquinone (12b5)-(+)-l. The naphthoquinone... 

We achieved the first total synthesis of (+)-halenaquinol 2 and (+)-halenaqui-none 1 as follows.l The carbonyl group at the 1-position of the optically pure (8a/ )-(-)-Wieland-Miescher ketone 33, -98.96° (c 1.039, benzene), was... 

In the case of the total synthesis of halenaquinol (12b5)-(+)-2 and halenaquinone (12b5)-(+)-l, we started from the Wieland-Miescher ketone (8a/ )-(-)-33, as discussed above. Therefore, it is evident that the synthetic sample of halenaquinol dimethyl ether (+)-17 has the (12b5) absolute configuration. 19 if the theoretical determination of the absolute stereochemistry of the halenaquinol family is correct, the chiroptical data of [ ]d and CD spectra of the synthetic sample should be identical with those of the authentic sample of (+)-17 derived from... 

Since the absolute configuration of the angular methyl group is retained throughout the reactions discussed above, these results lead to the experimental and unambiguous determination that the absolute stereochemistry of (+)-halenaquinol and (+)-halenaquinone is 12bS. In addition, these synthetic results also proved that the absolute configurations of halenaquinol compounds theoretically determined were actually correct. 

As discussed above, the absolute stereochemistry of halenaquinone (+)-l and halenaquinol (+)-2 has been theoretically determined by the calculation of the CD spectra of naphthalene-diene derivatives by means of the tt-electron SCF-CI-DV MO method. 18 To apply the same method to these xestoquinone compounds, xesto-quinol dimethyl ether (+)-74 was converted to naphthalene-diene derivative 75 by reduction with sodium borohydride in the presence of cerium(IIl) chloride23 and methanol, followed by treatment with pyridinium p-toluenesulfonate and methanol (Scheme 16).20 The product obtained was a mixture of two stereoisomers of the methoxyl group at the 4-position, from which a single isomer 75 was isolated as... 

The absolute stereostructures of halenaquinone (+)-l, halenaquinol (+)-2, halenaquinol sulfate (-i-)-3, xestoquinone (+)-4, and xestoquinol 62, novel pentacyclic marine natural products isolated from tropical marine sponges, were theoretically determined to be 12bS, respectively, on the basis of the calculation of the CD spectra of naphthalene-diene derivatives by the re-electron SCF-CI-DV MO method. These studies also clarified that the theoretical CD method was applicable to such complex natural products. 

The theoretical determination of the absolute stereochemistry of halenaquinol and halenaquinone has been done in collaboration with Prof. Isao Kitagawa and his coworkers of Osaka University, to whom the authors thank for their contribution. Our studies described here were supported in part by grants from the Ministry of Education, Science, and Culture, Japan, the Suntory Institute of Bioorganic Research, and the Japan Association of Chemistry. 

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