Letter Cite This: Org. Lett. 2018, 20, 4606−4609
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Total Synthesis of Pestalotioprolide E and Structural Revision of Pestalotioprolide F Debobrata Paul, Sanu Saha, and Rajib Kumar Goswami* Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, India
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S Supporting Information *
ABSTRACT: A short and convergent strategy for the first asymmetric total synthesis of cytotoxic macrolides pestalotioprolides E and F has been developed. The key features of this synthesis include Takai olefination, Sonogashira coupling, Niassisted partial hydrogenation of alkyne, modified Steglich reaction to generate the ester moiety, and intramolecular Horner−Wadsworth−Emmons (HWE) olefination to complete the macrocycle. This synthetic study revised the proposed structure of pesralotioprolide F.
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pestalotioprolides E and F consist of three stereogenic centers among which two are hydroxylated, a conjugated diene with E,Zgeometry and an E-olefin conjugated with the lactone carbonyl. The installation of a conjugated diene (C5−C8) and an olefin (C2−C3) separated by a hydroxylated center in a 14-membered macrocycle is unprecedented and hence provides a formidable challenge. We report herein a convergent and flexible common route for the first total synthesis of the target molecules that revised the putative structure of pestalotioprolide F. The retrosynthetic analysis of pestalotioprolides E (4) and F (5) is depicted in Scheme 1. The use of intramolecular HWE reaction in 14-membered ring formation is rare.5 We adopted this strategy as the key step for macrocyclization to make our synthesis more convergent. Pestalotioprolide E (4) would be realized therefore from the suitable HWE precursor 8a, whereas pestalotioprolide F (5) would be accessed from another HWE precursor, 8b. Both precursors 8a and 8b could be constructed
aturally evolved 14-membered macrolides drew substantial attention of the scientific community due to their broad structural variations and diverse range of biological activities.1 Liu and Proksch et al., in 2016, had discovered a new series of 14-membered macrolides, pestalotioprolides B−H (1− 7, Figure 1), from an endophytic fungi Pestalotiopsis microspora
Scheme 1. Retrosynthetic Analysis of Pestalotioprolides E (4) and F (5) Figure 1. Chemical structures of pestalotioprolides (B−H) (1−7).
isolated from fresh fruits of the mangrove plant Drepanocarpus lunatus.2 Many of these members are reported to exhibit good to moderate in vitro anticancer activities.2 Attractive architectural features, good bioactivities, and natural scarcity made them promising targets for chemical synthesis.3 In continuation of our ongoing program4 on the synthesis of bioactive natural products, especially on the pestalotioprolide family of macrolides,4a we envisaged the total synthesis of pestalotioprolides E and F to get these materials in sufficient quantities to allow further biological studies. Pestalotioprolides E and F exhibited cytotoxicities to murine lymphoma cell line (L5178Y) with IC50 values of 3.4, and 3.9 μM, respectively, while pestalotioprolide E showed promising activity against human ovarian cancer cell line (A2780) with an IC50 value of 1.2 μM.2 Structurally, © 2018 American Chemical Society
Received: June 18, 2018 Published: July 17, 2018 4606
DOI: 10.1021/acs.orglett.8b01894 Org. Lett. 2018, 20, 4606−4609
Letter
Organic Letters Scheme 2. Synthesis of Key Segments (9, 10, ent-10) of Pestalotioprolides E and F
separately from the common intermediate 9 and alcohol 10 or alcohol ent-10, respectively, using Sonogashira coupling4b,6 as one of the pivotal steps. The synthesis of key segments 9, 10, and ent-10 of pestalotioprolides E and F is delineated in Scheme 2. The known compound 11,7 prepared from commercially available (S)-(−) propylene oxide,7 was treated with TBAF to deprotect the TBS ether and then subjected to react with TESCl/Et3N/ DMAP to get the corresponding TES ether, which subsequently was treated with Me3SI/nBuLi4c,8 to obtain compound 12. Next, compound 12 was transmuted to compound 13 using TBSOTf/ 2,6-lutidine. Compound 13 was then dihydroxylated using OsO4/NMO and subsequently treated with NaIO4/NaHCO3 to produce the corresponding aldehyde, which was finally subjected to Takai olefination4c,9 to produce alcohol 14 in complete E-selectivity with in situ deprotection of TES ether. Alcohol 14 was then esterified with the known phophonate 1510 using the modified Steglich condition4d,11 to achieve compound 9 in 86% yield. However, the known compound 17,12 prepared from commercially available epoxide 16 following a literature procedure,12 was subjected to oxidative cleavage using OsO4/ NMO followed by NaIO4/NaHCO3. The resultant aldehyde was then exposed to Corey−Fuch reaction13 using CBr4/Ph3P/ Et3N followed by nBuLi treatment to yield the corresponding alkyne intermediate, which finally was reacted with Linaphthalenide to achieve compound 10 in 57% overall yield (over four steps). Following similar chemistry, commercially available epoxide ent-16 was transformed to the required compound ent-10 via the known intermediate ent-17 with good overall yield. The completion of total synthesis of the reported structure of pestalotioprolides E and F is described in Scheme 3. Compound 9 was separately subjected to Sonogashira coupling4b,6 with compounds 10 and ent-10 to obtain compounds 18a and 18b, respectively. Both compounds 18a and 18b were subjected separately to partial hydrogenation14 using Ni(OAc)2·4H2O/ NaBH4/EDA to produce compounds 8a and 8b, respectively. Compound 8a was then oxidized to the corresponding aldehyde and concomitantly was subjected to crucial intramolecular HWE olefination5 to complete the macrocycle. A number of conditions (Table 1) have been tested at this stage to optimize the HWE reaction for macrocyclization. Ba(OH)2·8H2O (entry 3) was found to be best compared to others to obtain compound 19a in 30% yield. No dimerized product was detected, but an
Scheme 3. Completion of Total Synthesis of Pestalotioprolide E (4) and Putative Structure of Pestalotioprolide F (5)
Table 1. Optimization of Intramolecular HWE Cyclization entry
conditions
time (h)
yield (%)
1 2 3 4
NaH, THF, 0 °C−rt KHMDS, THF, 0 °C−rt Ba(OH)2·8H2O, THF/H2O (40:1), 0 °C−rt DIPEA, LiCl, CH3CN, 0 °C−rt
1 12 2 3
10−15 no reaction 30 26
unidentified product in small amount was also found. Both the silyl ethers of compound 19a were then deprotected using CSA to achieve compound 4. In a similar way, compound 5 was synthesized from compound 8b via the intermediate 19b in good overall yield. The 1H and 13C NMR data (NMR comparisons in Table S1, Supporting Information) and optical rotation [reported [α]D20 = +222.0 (c 1.8, MeOH); observed 4607
DOI: 10.1021/acs.orglett.8b01894 Org. Lett. 2018, 20, 4606−4609
Letter
Organic Letters [α]D20 = +218.0 (c 0.1, MeOH)] of the synthesized compound 4 were in good agreement with the data reported for the isolated pestalotioprolide E2, which unambiguously confirmed its total synthesis. However, discrepancies in chemical shifts of 1H and 13 C NMR resonances between the synthesized compound 5 and isolated pestalotioprolide F were observed. The 1H NMR signals of H-3, H-7, and H-9 protons of the synthesized compound 5 recorded at δ 7.11, 6.40, and 4.04 ppm, respectively, whereas these resonances for the isolated compound were reported to be at δ 7.03, 6.26, and 3.98 ppm. Moreover, the 1H NMR splitting pattern at δ 1.75−0.8 ppm region was quite different from the reported spectra. The ROESY correlations of synthesized compound 5 were also differed. The ROESY correlations between H-2 and H-4 were observed in our case, whereas those were absent in the reported data of the isolated natural product (Figure S1, Supporting Information). Moreover, noticeable mismatches in the 13C NMR of C-2, C-3, C-11, and C-12 (NMR comparisons in Table S2, Supporting Information) were also observed. The optical rotation value of compound 5 deviated considerably from the reported value [reported [α]D20 = +9.0 (c 0.5, MeOH); observed [α]D20 = +64.6 (c 0.34, MeOH)]. This clearly indicated that isolated pestalotioprolide F might be a different diastereomer of the proposed structure (5). This led us to explore the actual structure of pestalotioprolide F. There are three stereocenters in the molecule that would give rise to a total of eight isomers. We have initially excluded four structures 4, ent-4 (enantiomer of compound 4), 5, and ent-5. Thus, it might be assumed that the actual structure of pestalotioprolide F would be one among the possible structures of 20, ent-20, 21, and ent-21 (Figure 2). As the major
Scheme 4. Completion of Total Synthesis of the Actual Structure of Pestalotioprolide F and Its Diastereomer
hydrogenated to obtain alcohol 24, which was subjected to IBX oxidation4a followed by Takai olefination to yield olefin 25 with complete E-selectivity. Olefin 25 was converted to compounds 20 and 21 in good overall yield via the intermediates 26a/26b and 27a/27b (Scheme 4) following the similar sequence of reactions as adopted in the synthesis of compounds 4 and 5 (Schemes 2 and 3). The 1H and 13C NMR data of both the compounds 20 and 21 were recorded. We were delighted to see that both the 1H and 13C NMR data of compound 20 matched perfectly with the reported data of isolated pestalotioprolide F (NMR comparisons in Table S3, Supporting Information). The optical rotation was also in good agreement [reported [α]D20 = +9.0 (c 0.5, MeOH); observed [α]D20 = +13.3 (c 0.17, MeOH)]. This result confirmed the total synthesis of the actual structure of isolated pestalotioprolide F. On the contrary, noticeable mismatches were observed in 1H and 13C NMR data (NMR comparisons in Table S4, Supporting Information) as well as in optical rotation value [observed [α]D20 = −64.4 (c 0.47, MeOH)] between the synthesized compound 21 and the isolated natural pestalotioprolide F. In summary, we report the first total synthesis of pestalotioprolides E and F using efficient synthetic routes comprising 21 and 20 linear steps from commercially available (S)-(−) propylene oxide and L-aspartic acid with 2.5% and 3.3% overall yield, respectively. We successfully installed a conjugated diene and a carbonyl conjugated olefin with definite geometry within 14-membeded macrocycles for the first time. Furthermore, our synthetic journey revealed that the reported structure (5) of pestalotioprolide F is not accurate. We hereby revise the structure (20) of pestalotioprolides F where the configurations of C4 and C9 hydroxylated centers are opposite to the currently accepted structure (5) of the molecule.
Figure 2. Possible structures of isolated pestalotioprolide F.
mismatches in 1H NMR were observed for the protons adjacent to C-4 and C-9 centers in the synthesized compound 5, we planned to change the configurations of C-4 and C-9 hydroxy centers by keeping the configuration of remote C-2 methyl center unchanged with respect to the proposed structure (5). Therefore, compounds 20 and 21 were considered as our new synthetic targets. We started our synthesis from the known compound 22,15a prepared from commercially available Laspartic acid15b (Scheme 4), which was converted to its corresponding sulfone using DIAD/Ph3P/PTSH followed by (NH4)6Mo7O24·4H2O/H2O2.4b The sulfone was treated with CSA/MeOH to get the corresponding TBS deprotected product, which was protected as TES ether using TESOTf/ 2,6-lutidine. The TES ether was then subjected to JuliaKocienski olefination4b,16 with the known aldehyde 2312a to get the corresponding E-olefin exclusively. The olefin was 4608
DOI: 10.1021/acs.orglett.8b01894 Org. Lett. 2018, 20, 4606−4609
Letter
Organic Letters
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(11) (a) Revu, O.; Prasad, K. R. J. Org. Chem. 2017, 82, 438−460. (b) Gu, Z.; Zakarian. Angew. Chem., Int. Ed. 2010, 49, 9702−9705. (12) (a) Kusakabe, M.; Kato, H.; Sato, F. Chem. Lett. 1987, 16, 2163− 2166. (b) Whitehead, A.; McParland, J. P.; Hanson, P. R. Org. Lett. 2006, 8, 5025−5028. (13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769. (14) Brown, C. A.; Ahuja, V. J. K. J. Org. Chem. 1973, 38, 2226−2230. (15) (a) Dachavaram, S. S.; Kalyankar, K. B.; Das, S. Tetrahedron Lett. 2014, 55, 5629−5631. (b) Yadav, J. S.; Shankar, K. S.; Reddy, A. S.; Reddy, B. V. S. Tetrahedron Lett. 2012, 53, 6380−6382. (16) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 1998, 26−28. (b) Ghosh, A. K.; Gong, G. Org. Lett. 2007, 9, 1437−1440.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01894. Experimental section, spectroscopic data, comparison Tables S1−S4, Figure S1, copies of NMR (1H and 13C) and HRMS of representative compounds, and 2D-NMR data (COSY, HSQC, HMBC, ROESY) of compounds 4, 5, 20, and 21 (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Rajib Kumar Goswami: 0000-0001-7486-0618 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS D.P. and S.S. thank the Council of Scientific and Industrial Research, New Delhi for the research fellowship. The financial support from Science and Engineering Research Board (Project no. EMR/2016/000988), DST, India, to carry out this work is gratefully acknowledged.
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DOI: 10.1021/acs.orglett.8b01894 Org. Lett. 2018, 20, 4606−4609
