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Synthesis of (؊)-Longithorone A: Using Organic Synthesis to Probe a Proposed Biosynthesis

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Synthesis of (؊)-Longithorone A: Using Organic Synthesis to Probe a Proposed Biosynthesis Synthesis of (؊)-longithorone A: Using organic synthesis to probe a proposed biosynthesis Carl A. Morales, Mark E. Layton, and Matthew D. Shair* Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 Edited by Kyriacos C. Nicolaou, The Scripps Research Institute, La Jolla, CA, and approved April 15, 2004 (received for review March 19, 2004) We present a full report of our enantioselective synthesis of The synthesis strategy for protected versions of 2 and 3 ,(؊)-longithorone A (1). The synthesis was designed to test the involved atropdiastereoselective ene–yne metathesis (14–16) feasibility of the biosynthetic proposal for 1 put forward by macrocyclization of 6 and 7, and simultaneous generation of the Schmitz involving intermolecular and transannular Diels–Alder 1,3-disubstituted dienes of both paracyclophanes (Fig. 3). reactions of two [12]-paracyclophane quinones. We have found The strategically positioned protected benzylic hydroxyl that if the biosynthesis does involve these two Diels–Alder reac- groups of 6 and 7 would be installed by enantioselective addition tions, the intermolecular Diels–Alder reaction likely occurs before of vinylzinc reagents to the corresponding electron-rich benzal- the transannular cycloaddition. The intermolecular Diels–Alder dehyde (17). These hydroxyl groups would then be used to gear precursors, [12]-paracyclophanes 38, 49, 59, and 60, were prepared the aromatic rings of 6 and 7 during the ene–yne metathesis atropselectively, providing examples of ene–yne metathesis mac- macrocyclizations to set the atropisomerism of 2 and 3. A(1,3) rocyclization. The 1,3-disubstituted dienes produced from the mac- strain (18) should disfavor rotamers 8 and 9 and enforce an rocyclizations represent a previously unreported substitution pat- atropdiastereoselective (19, 20) macrocyclization. After having tern for intramolecular ene–yne metathesis. Protected benzylic served their purpose as control elements in the macrocycliza- hydroxyl stereocenters were used as removable atropisomer con- tions, the protected benzylic hydroxyl groups would be removed trol elements and were installed by using a highly enantioselective reductively, yielding the paracyclophanes as single atropisomers. vinylzinc addition to electron-rich benzaldehydes 26 and 27. Our synthesis plan also relied upon ene–yne metathesis mac- rocyclization to generate 1,3-disubstituted dienes. It had been n intriguing question in natural product biosynthesis is demonstrated that with terminal alkynes intramolecular (21–27) Awhether nature uses Diels–Alder reactions. The answer to ene–yne metathesis generally affords 1,2-disubstituted dienes, this question appears to be yes, because there are many examples whereas intermolecular (28–30) ene–yne metathesis yields 1,3- of spontaneous Diels–Alder reactions in biosyntheses (1) as well disubstituted dienes (Fig. 4). as recently documented examples (2–4) of enzymatically influ- Because ene–yne metathesis had not been applied to the enced Diels–Alder reactions. Longithorone A (1) is a marine synthesis of macrocycles, we hoped to use our system to test the natural product that attracted our attention because of its preference for forming 1,2- vs. 1,3-disubstituted dienes in a unusual structure, but even more so because of the biosynthetic macrocyclization. proposal of Schmitz and co-workers (5, 6) that invoked two Diels–Alder reactions. Schmitz has proposed that 1 arises from Materials and Methods the combination of [12]-paracyclophane quinones 2 and 3 by an Details describing chemical synthesis, general procedures, in- intermolecular Diels–Alder reaction, affording ring E, and a strumentation, molecular modeling, optimization of ene–yne transannular (7) Diels–Alder reaction, generating rings A, C, metathesis macrocyclization conditions, and substrate tables for and D (Fig. 1). macrocyclizations and enantioselective vinylzinc additions can We viewed this interesting proposal as an opportunity to use be found in Supporting Materials and Methods, which is published organic synthesis to make protected versions of 2 and 3 and test, as supporting information on the PNAS web site. The procedures in the laboratory, the feasibility of the proposed Diels–Alder for the synthesis of tetracycles 4 and 46; macrocycles 14–20; reactions (8). In particular, we were hopeful that our experi- benzylic alcohols 25, 28, and 31; enynes 33, 37, and 39; paracy- ments might suggest whether the intermolecular Diels–Alder clophanes 35, 38, 41, 44, 45, and 49; truncated product 43; model reaction occurs preferentially between compound 4, which has compounds 48, and 50–53; and advanced intermediates 54–56 already undergone a transannular Diels–Alder, and paracyclo- and 58; along with corresponding spectral data can also be found phane 2 to generate 1 or between paracyclophanes 3 and 2 to in Supporting Materials and Methods. For details descriptions of generate 5, followed by a transannular Diels–Alder to afford 1. the synthesis of natural product 1; vinyl iodides 23 and 30; The isolation (5) of longithorones B (9) and C, [12]- benzaldehydes 26 and 27; benzylic alcohols 29 and 32; enynes 34 paracyclophane quinones that closely resemble the structures of and 40; paracyclophanes 36, 42, 59, and 60; and advanced 2 and 3, provided some support for the proposed biosynthesis of intermediates 61 and 52, see ref 13. longithorone A (Fig. 2). We found it intriguing that longithorones B and C exhibit Results and Discussion atropisomerism (10–12) and are single enantiomers. From these Development of Ene–Yne Metathesis Macrocyclization. Before our observations, we recognized that 2 and 3 must be constructed initial disclosure (13) of the synthesis of 1, macrocyclization atropselectively to test whether the absolute and relative stere- using ene–yne metathesis had not been reported (31), and it was ochemistry of 1 is derived solely from the planar chirality of 2 and unknown whether 1,2-disubstituted dienes or 1,3-disubstituted 3. Finally, the isolation of longithorone I suggested that the dienes would be generated. We prepared a series of acyclic biosynthesis of 1 may first involve an intermolecular Diels–Alder reaction between 2 and 3 followed by a transannular cycload- dition. In this paper we present a full description of our synthesis This paper was submitted directly (Track II) to the PNAS office. (13), findings that elucidate the timing of the Diels–Alder Abbreviations: TBS, tert-butyldimethylsilyl; ee, enantiomeric excess; TIPS, triisopropylsilyl; reactions proposed for the biosynthesis of 1, and additional TBAF, tetrabutylammonium fluoride; OTf, trifluoromethansulfonate. examples of ene–yne metathesis macrocyclization demonstrating *To whom correspondence should be addressed. E-mail: [email protected]. its usefulness in forming macrocyclic 1,3-disubstituted dienes. © 2004 by The National Academy of Sciences of the USA 12036–12041 ͉ PNAS ͉ August 17, 2004 ͉ vol. 101 ͉ no. 33 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0401952101 Downloaded by guest on September 23, 2021 SPECIAL FEATURE Fig. 1. Plan for a biomimetic synthesis of longithorone A (1). The order of the intermolecular and transannular Diels–Alder reactions is unknown. enynes and subjected them to conditions optimized for macro- unoptimized yields of 30% and 79%, respectively. The structure cyclization by using catalyst 10 (Scheme 1). Pronounced selec- of 22 was determined by x-ray analysis. Having demonstrated tivity for the formation of 1,3-disubstitued dienes over 1,2- that we could synthesize 1,3-disubstituted dienes from an ene– disubstituted dienes was observed in the reaction, especially for yne metathesis macrocyclization and use them in Diels–Alder ring sizes of 12 and greater. In a representative set of examples, reactions, we focused our efforts toward the synthesis of 1. enynes 11–15 were converted into 1,3-disubstituted diene mac- rocycles 16–20. Installation of the Atropisomer Control Element. Before the mac- An explanation for the preferred formation of 1,3- rocyclizations, it was necessary to enantioselectively install the disubstituted products in these reactions is that the low effective benzylic stereocenters in 6 and 7 that would gear the ring molarity of the reacting terminal olefin and terminal alkyne closure and produce the required atropisomers of the para- CHEMISTRY simulates an intermolecular ene–yne cross metathesis, which is cyclophanes. It had been disclosed that addition of a cis- or known to afford 1,3-disubstituted dienes. Furthermore, under an trans-vinylzinc to benzaldehyde affords secondary benzylic ethylene atmosphere (32, 33), intermolecular ene–yne metathe- alcohols in moderate enantioselectivities [86% and 73% en- ses have been shown to proceed by ethylene–yne cross metathe- antiomeric excess (ee), respectively] when an ephedrine-based sis followed by a terminal diene–olefin cross metathesis (28). We chiral ligand is used (34). However, addition of vinylzincs to believe that our system behaves similarly: ethylene–yne cross other arylaldehydes was not reported. We investigated the metathesis occurs first, affording a terminal 1,3-diene, followed enantioselective addition of the vinylzinc species derived from by terminal diene–olefin metathesis macrocyclization. The ex- vinyl iodide 23 to several benzaldehydes with differing elec- pected terminal 1,3-diene intermediates could be isolated from tronics and discovered that addition to electron-rich benzal- our ene–yne metathesis macrocyclizations when
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