Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Synthesis of Laingolide B Stereoisomers and Assignment of Absolute Configuration Chengsen Cui and Wei-Min Dai* Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. China S Supporting Information *
ABSTRACT: Total synthesis of (−)-(2R,9S)- and (+)-(2S,9S)stereoisomers of laingolide B has been accomplished by using sequential ring-closing metathesis (RCM) and alkene isomerization to construct the macrocyclic trans-N-methyl enamide moiety. The Myers alkylation was used to secure the C2 stereochemistry of the two RCM precursors from a common (9S)-C3−C9 alkyl iodide. The absolute configuration of laingolide B has been assigned as (2S,9R) by comparison of the optical rotation data.
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Island in Papua New Guinea),6 laingolide A and madangolide (collected in the vicinity of Madang, north coast of Papua New Guinea),7 and laingolide B (collected from shallow patch reefs in Apra Harbor, Guam).9 Structurally, palmyrolide A and laingolides share a 15-membered macrolactone core, while madangolide possesses a 17-membered macrolactone skeleton. The absolute configuration of palmyrolide A has been revised by total synthesis,4a consisting of a (5R,7R)-anti-Me/t-Bu relationship. The latter structural motif has been reported for apratoxin A albeit in (5S,7S)-configuration.11 The planar structures of laingolides and madangolide were proposed, but their absolute configuration has not been determined. Moreover, optical rotation data were not available for laingolide (2), laingolide A (3), and madangolide (5), rendering assignment of their absolute configuration difficult. In connection with our total synthesis studies on palmyrolide A and laingolides,12 we report here on the total synthesis of laingolide B stereoisomers and assignment of its absolute configuration as (2S,9R). Three unique structural elements are found in laingolide B (4), including the rare tert-butyl carbinol moiety, the trans-N-methyl enamide subunit, and the chlorinated exo-methylene group. It is quite challenging to deal with these structural motifs in a viable synthetic strategy for assembling the macrocycle. For the total synthesis of the related palmyrolide A, three types of intramolecular processes have been used to construct the trans-Nmethyl enamide subunit: (a) a CuI-catalyzed macroenamidation between a primary amide and a trans-alkenyl iodide followed by N-methylation4a,b,d,f,h,5b or directly using an N-methyl amide instead of a primary amide;4g (b) a ring-closing metathesis (RCM) reaction between an N-allyl-N-methyl amide and an alkene followed by alkene isomerization;4c,f and (c) a TFA-
arine cyanobacteria have been known to produce a variety of structurally novel and biologically active secondary metabolites, which are attractive sources of molecular probes for chemical biology studies and of lead compounds for drug discovery.1 In addition to the predominant compound types such as modified peptides, depsipeptides, polyketides, and peptide− polyketide hybrids, there is a small group of trans-N-methyl enamide-containing macrolides possessing a tert-butyl carbinol moiety.2 These unique macrolides include palmyrolide A (1),3−5 laingolide (2),6 laingolide A (3),7,8 laingolide B (4),9,10 and madangolide (5)7 as depicted in Figure 1. Palmyrolide A was isolated from a marine cyanobacterial assemblage composed of Leptolyngbya cf. and Oscillatoria spp. collected from Palmyra Atoll,3 whereas different collections of the marine cyanobacterium Lyngbya bouillonii produced laingolide (collected at Laing
Figure 1. Revised structure of palmyrolide A and the proposed planar structures of laingolides and madangolide. © XXXX American Chemical Society
Received: April 21, 2018
A
DOI: 10.1021/acs.orglett.8b01269 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters mediated dehydrative cyclization of an N-methyl amide and an aldehyde.4e As illustrated in Scheme 1, we envisioned assembly of
iodide (S)-10 via two key steps, i.e., the Negishi cross-coupling reaction13 of the organozinc 9 with (S)-10 and the Myers asymmetric alkylation using (1S,2S)-8 and (1R,2R)-8 to secure the configuration at C2.14 Alternatively, a B-alkyl Suzuki− Miyaura cross-coupling reaction between 11 and (S)-10 using our Pd(OAc)2−Aphos-Y catalyst system might provide 7a in a short linear sequence.15,16 Two (Z)-trisubstituted silylated alkenyl iodides rac-10 and 15 were prepared from rac-1217 and homopropargylic alcohol, respectively, via Pd-catalyzed silylstannylation13,18 using nBu3Sn−TMS to form the silylated alkenylstannanes rac-13 and 14 followed by selective tin−iodine exchange (Scheme 2).13 The alkyl borane 11 was readily prepared from the chiral 4acyloxazolidinone 1619a via methylation to give 1719b (92%) followed by hydroboration of 17 with dimeric 9-BBN.
Scheme 1. Retrosynthetic Analysis
Scheme 2. Attempted Suzuki Coupling Reactionsa
the laingolide B core via the RCM−alkene isomerization approach, which was reported for the total synthesis of palmyrolide A and (2S)-sanctolide A.4f Isomerization of a conjugated double bond within the 15-membered lactone into the trans-enamide is a critically important operation of the total synthesis, and its viability was confirmed in our total synthesis of laingolide A stereoisomers.12 The RCM−alkene isomerization approach is also advantageous over both the CuI-catalyzed macroenamidation, which is not compatible with the alkenyl chloride moiety, and the less efficient dehydrative cyclization. Moreover, it was noted that a cis-enamide-containing macrocyclic product could be formed via the CuI-catalyzed macroenamidation dependent on the reaction conditions.4d,5b The dehydrative cyclization in the presence of a protic acid did not give a high conversion nor a high product yield4e since the enamide moiety was liable toward ring-opening hydration.4b The dehydrative cyclization was also used in the synthesis of laingolide A diastereomers.8 However, a cis-enamidecontaining macrocyclic product was formed from a primary amide substrate, or a mixture of cis- and trans-N-methyl enamides was furnished if an N-methyl amide substrate was used. We decided to synthesize two laingolide B stereoisomers (2R,9S)-6a and (2S,9S)-6b from the corresponding acyclic hydroxy acids 7a and 7b,10 respectively, according to a sequence of amidation with N-allylmethylamine, esterification with acryloyl chloride, RCM, and alkene isomerization.4f,12 Both 7a and 7b could be derived from a common trisubstituted alkenyl
Conditions: (a) Pd(OAc)2 (5 mol %), Aphos-Y (7.5 mol %), K3PO4· 3H2O (3 equiv), THF, 70 °C, 7 h. a
The cross-coupling of the alkyl borane 11 was first examined with a bulky alkenyl bromide 18 using Pd(OAc)2−Aphos-Y as the catalyst, and the reaction proceeded smoothly at 70 °C to furnish the product 19 in 76% overall yield from 17. Unfortunately, the Pd-catalyzed cross-coupling reaction of 11 with both rac-10 and 15 failed under the same conditions used for 18. Only the dehydroiodination products 20 and 21 were isolated in 57% and 51% yields from rac-10 and 15, respectively, suggesting that the steric bias of the TMS group in rac-10 and 15 renders the transmetalation of the alkyl borane difficult.20 Next, we examined the Negishi coupling using 4-ethoxy-4oxobutylzinc bromide (9),21 (S)-(−)-3-methoxy-2-methyl-3oxopropylzinc bromide (22a), and 6-ethoxy-6-oxohexylzinc bromide (22b)21 with the (Z)-silylated alkenyl iodides (Scheme 3). It was pleasing to find that 22a reacted with the alkenyl iodide 15 in the presence of 10 mol % Pd(PPh3)4 at room temperature. B
DOI: 10.1021/acs.orglett.8b01269 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Negishi Coupling of (Z)-Silylated Vinyl Iodides
Scheme 4. Total Synthesis of (2R,9S)-Laingolide B (6a)
Although no coupling product 24a was formed in DMA for 24 h, the yields of 24a increased, after reacting for 7 h, from 18, 31, to 57%, respectively, in PhMe, Et2O, and THF. Similarly, 9 was coupled with rac-10 and 15 in THF to afford the products 24b and 24c, respectively, in 77% and 79% yields. The chiral (Z)silylated alkenyl iodide (S)-10 was prepared from (S)-1217 in 74% overall yield as described for rac-10 in Scheme 2. Silylation of (S)-10 gave the TBS ether (S)-23a (97%); the latter was coupled with 9 to give 24d in 77% yield. Moreover, coupling of 22b with 15 and 23b afforded 24e and 24f, respectively, in 67% and 83% yields. Finally, the acrylate rac-23c, prepared from rac10 (89%), underwent the coupling reaction with 22b to furnish the product 24g in 74% yield. In a similar manner, the acrylate (S)-23c was coupled with 9, leading to the formation of 24h in 82% yield. Synthesis of the laingolide B stereoisomer (2R,9S)-6a is shown in Scheme 4. Upon treating with NCS, the alkenyl TMS group in 24d was converted into the alkenyl chloride; it was followed by ester reduction and conversion of the primary alcohol into the alkyl iodide 25 in 60% overall yield from 24d. The Myers alkylation14 of (1S,2S)-8 with 25 produced 2610 quantitatively. Removal of the chiral auxiliary in 26 together with TBS ether cleavage gave the hydroxy acid, which was subjected to sequential amidation with N-allylmethylamine and acylation with acryloyl chloride to furnish 27 in 66% overall yield (three steps). The key RCM reaction within 27 proceeded smoothly using 10 mol % Grubbs II catalyst at room temperature for 24 h, followed by adding another portion of 10 mol % Grubbs II catalyst (rt, 24 h) to give ca. 90% yield of the macrolactone 28 with an unidentified minor component as an inseparable mixture. However, the dechlorinated byproduct 29 was not detected.22 Treatment of 28 with 10 mol % of RuH(PPh3)3(CO)Cl in refluxing PhMe (24 h at 0.013 M) gave the isomerized product (2R,9S)-6a and the byproduct 30 in 7:1 ratio and in 49% isolated yield for (2R,9S)-6a
{[α]D21 −237 (c 0.07, MeOH}. The E-geometry of the endocyclic double bond in 28 (J = 16.0 Hz) and 6a (J = 13.8 Hz) was assigned according to the coupling constants of the vinyl protons. Starting from (1R,2R)-8 and the same alkyl iodide 25, (2S,9S)-6b {[α]D23 +133 (c 0.07, MeOH} was synthesized (see Scheme S1 in the Supporting Information). Comparison of the 13 C NMR data (Figure 2) suggested that (2R,9S)-6a is the enantiomer of the natural laingolide B {[α]D20 +170 (c 0.07, MeOH}.9 It should be mentioned that the optical rotation of the synthetic sample 6a (which contains an inseparable dechlorination byproduct 30) was of magnitude comparable to the reported value of the natural laingolide B.
Figure 2. Comparison of 13C NMR data of (−)-(2R,9S)-6a (a) and (+)-(2S,9S)-(6b) (b) with the naturally occurring laingolide B. Δδ = δ(natural) − δ(synthetic). C
DOI: 10.1021/acs.orglett.8b01269 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters In conclusion, we have completed the first total synthesis of two stereoisomers of laingolide B, (−)-(2R,9S)-6a and (+)-(2S,9S)-6b, in a 12-step longest linear sequence from the known (S)-1217 in 9−10% overall yields. The RCM−alkene isomerization strategy has been demonstrated as a powerful tool in the construction of this unique 15-membered N-Me-enamidecontaining macrolide. With the two synthesized stereoisomers, it has been confirmed by comparison of the 13C NMR data that the naturally occurring laingolide B possesses a 2,9-anti-Me/t-Bu relationship, while comparison of the optical rotation data determines the (2S,9R) absolute configuration for the natural laingolide B. Assignment of the stereochemistry of laingolide B should facilitate determination of the absolute configuration of the related laingolide congeners. Our results on the total synthesis of laingolide A (2)12 and laingolide (3) will be disclosed in due course.
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Reddy, D. S. Chem. Commun. 2013, 49, 3342−3344. (e) Sudhakar, G.; Reddy, K. J.; Nanubolu, J. B. Tetrahedron 2013, 69, 2419−2429. (f) Wadsworth, A. D.; Furkert, D. P.; Brimble, M. A. J. Org. Chem. 2014, 79, 11179−11193. (g) Borra, S.; Amrutapu, S. K.; Pabbaraja, S.; Singh, Y. J. Tetrahedron Lett. 2016, 57, 4456−4459. (h) Yadav, J. S.; Suresh, B.; Srihari, P. Eur. J. Org. Chem. 2016, 2016, 2509−2513. (5) For the bioactivity of palmyrolide A and the synthetic analogues, see (a) Mehrotra, S.; Duggan, B. M.; Tello-Aburto, R.; Newar, T. D.; Gerwick, W. H.; Murray, T. F.; Maio, W. A. J. Nat. Prod. 2014, 77, 2553− 2560. (b) Philkhana, S. C.; Mehrotra, S.; Murray, T. F.; Reddy, S. Org. Biomol. Chem. 2016, 14, 8457−8473. (6) For the isolation and the proposed planar structure of laingolide, see Klein, D.; Braekman, J. C.; Daloze, D.; Hoffmann, L.; Demoulin, V. Tetrahedron Lett. 1996, 37, 7519−7520. (7) For the isolation and the proposed planar structures of laingolide A and madangolide, see Klein, D.; Braekman, J. C.; Daloze, D.; Hoffmann, L.; Castillo, G.; Demoulin, V. J. J. Nat. Prod. 1999, 62, 934−936. (8) For the total synthesis of laingolide A diastereomers, see Pomey, G.; Phansavath, P. Synthesis 2015, 47, 1016−1023. (9) For the isolation and the proposed planar structure of laingolide B, see Matthew, S.; Salvador, L. A.; Schupp, P. J.; Paul, V. J.; Luesch, H. J. Nat. Prod. 2010, 73, 1544−1552. (10) For a synthesis of the C1−C9 fragment of laingolide B, see Nitelet, A.; Jouvin, K.; Evano, G. Tetrahedron 2016, 72, 5972−5987. (11) For the isolation and the structure of apratoxin A, see Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.; Corbett, T. H. J. Am. Chem. Soc. 2001, 123, 5418−5423. (12) Lai, Y. Ph.D. Thesis, The Hong Kong University of Science and Technology, 2015. (13) Graf, K. M.; Tabor, M. G.; Brown, M. L.; Paige, M. Org. Lett. 2009, 11, 5382−5385. (14) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361−9362. (b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496−6511. (15) For reviews on B-alkyl Suzuki−Miyaura cross-coupling reaction, see (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544−4568. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442−4489. (c) Kotha, S.; Mandal, K. Chem. - Asian J. 2009, 4, 354−362. (d) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722−6737. (e) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417−1492. (f) Seidel, G.; Fürstner, A. Chem. Commun. 2012, 48, 2055−2070. (g) Heravi, M. M.; Hashemi, E. Tetrahedron 2012, 68, 9145−9178. (16) (a) Dai, W.-M.; Li, Y.; Zhang, Y.; Lai, K. W.; Wu, J. Tetrahedron Lett. 2004, 45, 1999−2001. (b) Dai, W.-M.; Zhang, Y. Tetrahedron Lett. 2005, 46, 1377−1381. (c) Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M. Org. Lett. 2007, 9, 2585−2588. (d) Dai, W.-M.; Li, Y.; Zhang, Y.; Yue, C.; Wu, J. Chem. - Eur. J. 2008, 14, 5538−5554. (e) Sun, L.; Dai, W.-M. Tetrahedron 2011, 67, 9072−9079. (f) Ye, N.; Dai, W.-M. Eur. J. Org. Chem. 2013, 2013, 831−835. (g) Wang, Y.; Dai, W.-M. Eur. J. Org. Chem. 2014, 2014, 323−330. (17) The alcohol rac-12 was prepared according to the asymmetric propargylation without using a chiral ligand, see: (a) Haddad, T. D.; Hirayama, L. C.; Buckley, J. J.; Singaram, B. J. Org. Chem. 2012, 77, 889− 898. (b) Hirayama, L. C.; Haddad, T. D.; Oliver, A. G.; Singaram, B. J. Org. Chem. 2012, 77, 4342−4353. (18) (a) Mitchell, T. N.; Killing, H.; Dicke, R.; Wickenkamp, R. J. Chem. Soc., Chem. Commun. 1985, 354−355. (b) Mitchell, T. N.; Wickenkamp, R.; Amamria, A.; Dicke, R.; Schneider, U. J. Org. Chem. 1987, 52, 4868−4874. (c) Ritter, K. Synthesis 1989, 1989, 218−221. (19) (a) Kaliappan, K. P.; Ravikumar, V. J. Org. Chem. 2007, 72, 6116− 6126. (b) Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085−1093. (20) For formation of alkyne byproducts in the cross-coupling of vicinyl alkenyl dihalides, see Organ, M. G.; Ghasemi, H.; Valente, C. Tetrahedron 2004, 60, 9453−9461. (21) Blumke, T. D.; Piller, F. M.; Knochel, P. Chem. Commun. 2010, 46, 4082−4084. (22) See Supporting Information for details.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01269. Detailed experimental procedures, compound characterization data, and copies of original 1H and 13C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chengsen Cui: 0000-0002-6867-1826 Wei-Min Dai: 0000-0001-5688-7606 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is supported in part by a General Research Fund grant (601211) from the Research Grant Council, The Hong Kong Special Administrative Region, P. R. China, and the Department of Chemistry, HKUST.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b01269 Org. Lett. XXXX, XXX, XXX−XXX
