Letter pubs.acs.org/OrgLett
Bioinspired Total Synthesis and Stereochemical Revision of the Fungal Metabolite Pestalospirane B Sandhya Badrinarayanan,† Christopher J. Squire,‡ Jonathan Sperry,† and Margaret A. Brimble*,†,‡,§ †
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand School of Biological Sciences, University of Auckland, 3A Symonds Street, Auckland, New Zealand § Maurice Wilkins Centre for Molecular Biodiscovery, 3 Symonds Street, Auckland, New Zealand ‡
S Supporting Information *
ABSTRACT: The total synthesis of both enantiomers of pestalospirane B, 2, has been achieved using a bioinspired tandem dimerization−spiroketalization reaction. Electronic circular dichroism (ECD) and X-ray analysis were used to revise the absolute stereochemistry of the natural product pestalospirane B from 3S, 3′S, 12R, 12′R to its enantiomer 3R, 3′R, 12S, 12′S.
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n 2011, Jaroszewski and co-workers1 isolated pestalospiranes A, 1, and B, 2, along with the benzo[c]oxepins 3−4 from the endophytic fungus, Pestalotiopsis virgatula, inhabiting the plant, Terminalia chebula (Figure 1).2,3 These benzo[c]oxepin
Scheme 1. Retrosynthetic Analysis for Pestalospiranes A 1 and B 2
Figure 1. Pestalospiranes A, 1, and B, 2, along with their likely biosynthetic precursors.
containing fungal metabolites are a small but growing group of natural products, and some exhibit anti-inflammatory and analgesic activity.4,5 Along with the characteristic benzo[c]oxepin motif, pestalospiranes A, 1, and B, 2, also contain an unprecedented 1,9,11,18-tetraoxadispiro[6.2.6.2]octadecane spiroketal skeleton and differ only in their absolute stereochemistry at one spirocenter. The overall structural elucidation of these natural products was achieved using a new HPLCPDA-MS-SPE-NMR (high-performance liquid chromatography−photodiode-array detection−mass spectrometry−solidphase extraction−nuclear magnetic resonance) hyphenated system, with the absolute stereochemistry determined using ECD spectroscopy supported by time-dependent density functional theory (TDDFT) calculations.1 No synthesis of this unique heterocyclic scaffold has been reported to date. The coisolation of benzo[c]oxepins 3 and 4 alongside the pestalospiranes suggests they are biosynthetically related, an observation that guided the design of our synthetic strategy (Scheme 1). It was proposed that both pestalospiranes A, 1, and B, 2, would be formed by a bioinspired tandem dimerization−spiroketalization6 of (R)-alcohol 6 (via the © 2017 American Chemical Society
oxonium ion 5) to forge the unique 1,9,11,18-tetraoxadispiro[6.2.6.2]octadecane scaffold. The key precursor 6 should be readily attainable from the cis-enone 7. The synthesis of cis-enone 7 began with the known alkynylsilane 8.7−10 Global deprotection, EOM protection, LiAlH4 reduction, and subsequent TBS protection furnished 9 in 65% yield over four steps (Scheme 2). LiHMDS-mediated coupling of 9 with Weinreb amide 1011,12 proceeded smoothly to give ynone 11, which underwent stereoselective semihydrogenation to cis-enone 7 in an H-cube flow reactor.13 With cis-enone 7 in hand, its cyclization to the benzo[c]oxepin was investigated. Upon treatment with CSA, cis-enone 7 underwent cyclization to afford a mixture of benzo[c]oxepins 12 and 13,14 the former resulting from EOM-cleavage (Scheme 2). Given that the reaction was run under an argon atmosphere in degassed solvent, a plausible explanation for the apparent change in oxidation state during this reaction is outlined in Received: May 7, 2017 Published: June 16, 2017 3414
DOI: 10.1021/acs.orglett.7b01371 Org. Lett. 2017, 19, 3414−3417
Letter
Organic Letters Scheme 2. Attempted Synthesis of Dimerization Precursor 6
Scheme 4. Bioinspired Tandem Dimerization− Spiroketalization
inseparable, the enantioselectivity of the reduction step could not be determined. Nevertheless, upon subjecting the crude mixture of 6 and 23 to trifluoroacetic acid, the bioinspired tandem spiroketalization−dimerization reaction proceeded in good yield to give an inseparable mixture of (+)-pestalospirane B, 2, (+)-pestalospirane A, 1, and the unnatural pestalospirane 24 in a 9:1:1 ratio.16 (+)-Pestalospirane B, 2, was clearly identified as the major component of the mixture by 1H NMR, 13 C NMR, and NOESY analyses, which were in full agreement with those in the isolation report, thus confirming the gross structure and relative stereochemistry of the natural product (Figure 2).1 As was the case in the isolation report,1 we were unable to separate pestalospiranes A, 1, and B, 2, despite extensive effort. Thus, in order to establish the enantiomeric excess of synthetic pestalospirane B, 2, the synthetic natural product had to be derivatized. The inseparable mixture of dimers 1, 2, and 24 was treated with EOM-Cl to give the protected dimer (+)-25 as the sole product, likely due to equilibration of the spiroketal mixture and/or loss of the minor components during purification. Chiral HPLC comparison of (+)-25 with a racemic sample prepared during exploratory studies16 showed (±)-25 had a poor ee of 20% (Table 1, entry 1). Further experimentation with the CBS reduction of 12 was therefore undertaken in an attempt to improve the ee of 6. The CBS catalyst and borane reagent were altered, and the reaction sequence was repeated. Unfortunately, use of (S)-butyl-CBS and (S)-tosyl-CBS22 catalysts also gave disappointing results (25% ee) (Table 1, entries 2 and 3). Substituting the reducing reagent for catecholborane resulted in a complex mixture, and none of the desired alcohol (+)-6 was detected by TLC or NMR analysis (Table 1, entry 4). Gratifyingly, the combination of (S)-Me-CBS and BH3·diethylaniline afforded 6 that was then converted to the pestalospirane B di-EOM derivative 25 possessing an excellent ee of 97% (Table 1, entry 5).16 With the enantiopurity of pestalospirane B, (+)-2, accurately determined from 25, attention turned to the absolute stereochemistry of the natural product. Jaroszewski and co-workers1 assigned the absolute stereochemistry of pestalospirane B, 2, by comparing TDDFT calculations (B3LYP/TZVVP level) with ECD spectroscopic data. The ECD spectrum of synthetic pestalospirane B, (+)-2,23 displayed a negative short-wavelength Cotton effect (λmax 250 nm), opposite to that reported for the natural product.1 The ECD spectrum of its enantiomer B, (−)-2,24 prepared using the (R)-Me-CBS catalyst in an analogous fashion to that described
Scheme 3. Addition of methanol to 7 gives the α-hydroxy dimethylacetal 17,15 which upon loss of methanol generates the Scheme 3. Proposed Mechanism for the Formation of 12
oxonium ion 18, a resonance form of the stabilized carbocation 19. Proton loss generates 20 that upon tautomerization affords α-methoxyketone 21, which itself undergoes thermodynamically favored oxonium ion formation resulting in increased conjugation. Subsequent attack of the benzylic alcohol on the oxonium center in 22 delivers benzo[c]oxepin 12. To the best of our knowledge this observation is unprecedented in the literature, and this rationale has not been validated further. Following the unsuccessful cyclization of 7 to 6, an alternative strategy was pursued. Complete hydrogenation of ynone 11 to the ketone 14 took place in the presence of 10% Pd/C in ethyl acetate. The acid-catalyzed cyclization of 14 could then be tuned to give either of the tetrahydrobenzo[c]oxepins 15 and 16 by using dry or aqueous methanol as the solvent (Scheme 2).16 Subjecting both 15 and 16 to a range of dehydrogenation conditions17−19 in an effort to secure the desired cyclization precursor 6 met with failure. Treating 15 and 16 with DDQ did effect dehydrogenation but also resulted in overoxidation of the secondary alcohol to a ketone affording 12 and 13 respectively, the same products isolated from our previous route. Attempts to prevent this overoxidation by reducing the amount of DDQ were unsuccessful. Since we could not access the desired dimerization precursor 6 using the routes outlined in Scheme 2, an enantioselective reduction of 12 was investigated in an attempt to reinstall the required stereochemistry in the cyclization precursor 6 (Scheme 4, Table 1). The enantioselective reduction of 12 using (S)-Me-CBS20,21 and BH3·DMS in THF at 0 °C resulted in an inseparable mixture of desired product 6 and 23 (4:1), the latter resulting from over-reduction. As 6 and 23 were 3415
DOI: 10.1021/acs.orglett.7b01371 Org. Lett. 2017, 19, 3414−3417
Letter
Organic Letters Table 1. Enantioselective Reduction of 12 and ee of Pestalospirane B Di-EOM Ether, 25 entry
catalyst (equiv)a
borane (equiv)
temp (°C)
time (h)
yield (%) 6:23b,c
ee (%)
1 2 3 4 5
S-Me-CBS (0.6) S-Ts-CBS (0.6) S-Bu-CBS (0.6) S-Me-CBS (0.6) S-Me-CBS (0.6)
BH3·SMe2 (1.0) BH3·SMe2 (1.0) BH3·SMe2 (1.0) Catecholborane (2.0) C6H5NEt2·BH3 (1.0)
0 0 0 −78 −20→0
0.5 0.5 0.5 1 0.5
75 (4:1) 75 (4:1) 75 (4:1) 0 75 (4:1)
20 25 25 − 97
CBS-catalyst and borane reagent in THF were premixed for 20 min before slow addition of 12. bYield (by mass) was calculated after quick filtration through silica gel. cRatio of 6:23 was determined after the dimerization based on recovered 23. a
Thus, the enantiomer that displays the same negative shortwavelength Cotton effect as natural pestalospirane B in the ECD spectrum is (−)-pestalospirane B, which is configured 3R,3′R,12S,12′S and not 3S,3′S,12R,12′R as originally proposed in the isolation report. In summary, we have accomplished a bioinspired total synthesis of the putative structure of pestalospirane B, (+)-2, the ECD data for which were opposite to those reported for the natural product. The ECD data of synthetic pestalospirane B, (−)-2, prepared through an analogous bioinspired route, matched those of the natural product. X-ray crystallographic analysis of its p-bromobenzoate derivative confirmed the four stereocenters in pestalospirane B to have the configuration 3R,3′R,12S,12′S and not 3S,3′S,12R,12′R as originally proposed.
Figure 2. Diagnostic NOE correlations for (+)-pestalospirane B, 2.
previously,16 matched that of the natural product (Figure 3). This result suggested the absolute stereochemistry of natural
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ASSOCIATED CONTENT
S Supporting Information *
Figure 3. ECD spectra of (+)-2 and (−)-2 (c 0.00036, acetonitrile).
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01371. Experimental procedure and full characterization data for all new compounds (PDF)
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pestalospirane B, 2, is actually opposite to that originally assigned. However, as no optical rotation of pestalospiranes A and B were reported,1 we could not unequivocally prove this with the ECD spectroscopic data alone. In order to unambiguously reassign the absolute stereochemistry of natural pestalospirane B, synthetic pestalospirane B, (−)-2, was converted into its p-bromobenzoyl derivative (−)-26, from which an X-ray crystal structure was obtained (Scheme 5).25 The C3 and C3′ atoms possess an Rconfiguration, and the C12 and C12′ atoms exhibit an Sconfiguration (Scheme 5). The refined Flack parameter26 for this structure is 0.035(11). The inverted structure when refined gives an R1 value of 0.0899 and Flack parameter of 0.976(17).
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jonathan Sperry: 0000-0001-7288-3939 Margaret A. Brimble: 0000-0002-7086-4096 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors thank Associate Professor Brent Copp (University of Auckland) for helpful discussions regarding the CD data analysis.
Scheme 5. Absolute Stereochemical Assignment of (−)-Pestalospirane B by X-ray Analysis
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REFERENCES
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Organic Letters Bouillant, M. L.; Bernilion, J.; Favre-Bonvin, J.; Salin, N. Naturforsch 1989, 44, 719−723. (6) For the formation of difructose dianhydrides (DFAs) via protic acid-catalysed dimerization of ketoses, see: García-Moreno, M. I.; Benito, J. M.; Mellet, C. O.; Fernández, J. M. G. Molecules 2008, 13, 1640−1670. (7) Bajwa, N.; Jennings, M. P. J. Org. Chem. 2006, 71, 3646−3649. (8) Yadav, J. S.; Mishra, A. K.; Dachavaram, S. S.; Ganesh Kumar, S.; Das, S. Tetrahedron Lett. 2014, 55, 2921−2923. (9) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084−5121. (10) Campos, K. R.; Cai, D.; Journet, M.; Kowal, J. J.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2001, 66, 3634−3635. (11) Paterson, I. Synthesis 1998, 1998, 639−652. (12) Paterson, I.; Wallace, D. J.; Velázquez, S. M. Tetrahedron Lett. 1994, 35, 9083−9086. (13) Wang, Z. In Lindlar Hydrogenation; Comprehensive Organic Name Reactions and Reagents; John Wiley & Sons, Inc.: 2010. (14) As the stereocenter was destroyed in this step, we attempted the same sequence with the alcohol masked with various protecting groups, all of which were unsuccessful. (15) For the acid-mediated rearrangement of α-hydroxy dimethylacetals to α-methoxyketones, see: (a) Creary, X.; Rollin, A. J. J. Org. Chem. 1977, 42, 4231−4238. (b) Moriarty, R. M.; Hou, K. C. J. Org. Chem. 1984, 49, 4581−4583. (16) See Supporting Information (SI) for full details. (17) Banerjee, A. K.; Vera, W.; Mora, H.; Laya, M. S.; Bedoya, L.; Cabrera, E. V. J. Sci. Ind. Res. 2006, 65, 299. (18) Burn, D.; Petrow, V.; Weston, G. Tetrahedron Lett. 1960, 1, 14− 15. (19) Iosub, A. V.; Stahl, S. S. J. Am. Chem. Soc. 2015, 137, 3454− 3457. (20) Corey, E.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861−2863. (21) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986− 2012. (22) Cho, B. T. Tetrahedron 2006, 62, 7621−7643. (23) Attempts to obtain a pure sample of (+)- or (−)-pestalospirane B by deprotection of their corresponding di-EOM ethers led to rapid degradation. As such, the ECD spectra were recorded on the 9:1:1 ratio of products obtained after the dimerization reactions. (24) The enantiomeric excess of (−)-pestalospirane B (−)-2 was calculated to be 98%; see SI for details. (25) Crystallographic data (reference number CCDC 1497364) can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; or
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