Total Synthesis of (+)-Lepadin F

The lepadin family [Figure 1], comprised of eight cis-decahydroquinoline members, was identified from 1991 to 2002 from different sources such as tunicate Clavelina lepadinformis,1 flatworm Prostheceraeus villatus,2 tropical marine tunicate Didemnum sp,3 and Australian great barrier reef ascidian, Aplidium tabascum.4 They possess biological activities ranging from cytotoxicity, inhibitions of tyrosine kinase, anti-plasmodial and anti-trypanosomal properties as well as anti-malarial properties,1-4 and have attracted attention from several synthetic groups.5-11 Figure 1 The Lepadin Family While all contain a cis-1-aza-decalinic motif, members of the lepadin family display a diversified array of relative stereochemical relationships at C2, C3, C4a, C5, and C8a [Scheme 1]. For the 1,2-stereochemical relationship, the C2,3 relative configuration consists of two types: Cis in A-C, F, and G, and trans in D, E, and H for which the absolute configuration was recently confirmed by Ma.9 The C4a,5 relative configuration also consists of two types: Trans in A-C and cis in D-H. For the 1,3-stereochemical relationship, the C2,8a relative configuration consists of syn in A-E, and H with a more challenging anti relative configuration in F and G. Consequently, the lepadin family can be divided into three major subfamilies based on their relative stereochemical relationships at C2, C3, C4a, C5, and C8a [Scheme 1]. Scheme 1 A General Approach to Lepadins We12 had envisioned that all three subfamilies could be accessed from the orthogonal protected common intermediate 1, which could be prepared from a stereoselective intermolecular aza-[3 + 3] annulation13-15 using chiral vinylogous amide 3. Given our recent success in the alkaloid synthesis employing this annulation,16 we elected to first pursue the most challenging member of the family, lepadin F,17 containing the 1,3-anti relative configuration for C2,8a. Despite numerous efforts in the synthesis of lepadins, an elegant total synthesis of lepadin F was only accomplished very recently by Blechert.10 We report here our total synthesis of (+)-lepadin F. Our total synthesis efforts commenced with the known diol 518 [Scheme 2], which was prepared from 3 in 2 steps consisting of aza-[3 + 3] annulation and OsO4-dihydroxylation19,20 of C3,4 olefin of the initial annulation product 2.21 We focused on identifying a useful reductive protocol to remove C4-OH group. While the use of “Super Hydride” [LiBEt3H], and Red-Al were not successful, an excess amount of Et3SiH in the presence of 10-12 equiv of TFA19 led to alcohol 6 in 95% yield. Removal of the chiral auxiliary in 6 was not eventful and could be achieved either directly by using 1.1 equiv of TFA and 60 psi H2 in the presence of Pearlman’s catalyst Pd(OH)2/C, or sequentially by first removing the TBS group. It is noteworthy that lowering the amount of TFA led to incomplete hydrogenation and a low yield of vinylogous amide 7. When using > 25 psi H2, over reduction of 6 at C5 as well as C4a,8a was observed. Stereochemical assignment of alcohol 6 was achieved unambiguously using its single-crystal X-ray structure [Figure 2]. Figure 2 X-Ray Structure of Alcohol 6 Scheme 2 Reductive Removal of C4-OH group With vinylogous amide 7 in hand, we encountered difficulties in distinguishing nucleophilicities of C3-OH group and the vinylogous amide. Silylation proved to be the only way to selectively protect the C3-OH group, and a subsequent trifluoroacetylation afforded the orthogonally protected vinylogous amide 9 [Scheme 3]. However, hydrogenations of C4a,8a olefin in 9 employing standard conditions such as Pt/C and P d/C were not successful with the reduction of C5 carbonyl being the major identifiable pathway when using Adam’s catalyst PtO2. Scheme 3 Difficulties in Hydrogenating the C4a,8a-Olefin This failure detours our original plan for setting up the C2,8a-anti relative stereochemistry based on our earlier work.16b We had anticipated that by analogy to that of 13 [Figure 3], the pseudo-axially oriented N-trifluoroacetyl group would dictate the stereochemical outcome during the hydrogenation of the C4a,8a olefin in 9. On one hand, the addition of C3-OTBS group in 9 should augment the desired stereochemical outcome by further shielding the top face of C4a,8a olefin. However, a close examination of its model reveals that to be mutually axial while minimizing the gauche interaction, C3-OTBS group also pushes C2-Me group closer to C8a, thereby shielding the bottom face of the olefin. Figure 3 Additional Steric Impact of the C3-OTBS Group Collective observations of over reduction of C5-carbonyl group22 provoked us to explore an alternative route. As shown in Scheme 4, a high yielding standard protection of alcohol 6 with Ac2O gave acetate ester 15. After failing with Wittig-type olefination,23 a 3-step sequence that features Eschenmoser’s episulfide contraction24,25 led to α,β-unsaturated ester 16 exclusively as an E-isomer [assigned via NOE experiments]21 in 64% overall yield from 15. A double hydrogenation of C4a,8a and C5,1′ olefins in 16 was achieved with surprising ease, leading to ester 17 in 91% yield as a separable 5:1 mixture of diastereomers with respect to the C5 stereochemistry. Scheme 4 Homologation of a Vinylogous Amide Motif The anti relative stereochemistry at C2,8a as well as the all cis relationship at C8a,4a,5 in 17 was confirmed using NOE experiments,21 and these stereochemical outcomes are very reasonable judging from the model of 16 [inside the box], which was drawn based on the conformation shown for the X-ray structure of alcohol 6. Success in executing this alternative plan allowed us to complete a total synthesis of (+)-lepadin F from ester 17 as summarized in Scheme 5. Key features are: (1) the reductive removal of the chiral auxiliary in 17 concomitant with Boc-protection; (2) inversion of C3-OH group in 18 through a sequence of Dess-Martin periodinane oxidation and NaBH4-reduction; (3) capping of the inverted C3-OH in 19 with TBDPSCl under more forcing conditions to give silyl ether 20; (4) C5-sidechain elongation in aldehyde 21 with sulfone 2226 via adopting Julia-Kocienski olefination conditions to afford alkene 23; and (5) esterification of alcohol 24 employing Yamaguchi conditions. This culminates a total synthesis of (+)-lepadin F in 20 steps with a 15.2% overall yield from chiral vinylogous amide 3, Scheme 5 Total Synthesis of (+)-Lepadin F It is noteworthy that Ma’s work with lepadin D, E, and H9 as well as Blechert’s recent synthesis of F10 prompted us to choose sulfone 22 with (S)-configuration at C5′. Spectroscopically, our synthetic sample matched those reported by Carroll4 using C6D6 as the NMR solvent.27,28 We have described here an enantioselective total synthesis of (+)-lepadin F that confirms its absolute configuration. The synthetic sequence features an intermolecular aza-[3 + 3] annulation, homologation of a vinylogous amide through Eschenmoser’s episulfide contraction, and a highly stereoselective hydrogenation essential for achieving the 1,3-anti relative stereochemistry at C2 and C8a. Efforts are underway in constructing other lepadin family members.