Letter pubs.acs.org/OrgLett
Stereoselective Total Synthesis of Carolacton Tapan Kumar Kuilya and Rajib Kumar Goswami* Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India S Supporting Information *
ABSTRACT: A short and convergent strategy for the stereoselective total synthesis of biologically active natural product carolacton has been accomplished. Our synthesis highlights the Urpi acetal aldol, Crimmins aldol, Ireland−Claisen rearrangement, TiCl4-assisted aldol followed by βhydroxy elimination to construct C7−C8 olefin, and ring-closing metathesis as the key steps for achieving the target molecule with an overall yield of 18.8%.
C
Kirschning and co-workers were the first to report an attractive total synthesis of carolacton (22 linear steps, 4.3% overall yield) using a series of metal-mediated reactions followed by the Yamaguchi macrocyclization to construct the macrocycle.5a Later, Phillips and co-workers developed a shorter and elegant synthetic route (14 linear steps, 7.9% overall yield) for carolacton, where the C11−C12 bond was installed using Grubbs ring-closing metathesis (RCM) followed by selective reduction of the resultant olefin in the presence of other olefins using Pd/C-mediated hydrogenation.5b However, the development of an alternative route toward the total synthesis of carolacton would be highly valued if the RCM could be performed to install the C15−C16 olefin rather than in the construction of the C11−C12 bond. The advantage in the former strategy is that the possibility of oversaturation of the others olefinic groups, which often is the case in selective hydrogenation of compounds having multiple olefinic groups, can be rescinded completely. We initially envisaged its synthesis as part of our continuing interest8 in the total synthesis of bioactive natural products together with an urge to develop an operationally simple and high-yielding synthetic route for carolacton and its analogues. In this report, we disclose a highly convergent and flexible synthetic route for the total synthesis of carolacton. Retrosynthetic analysis of carolacton (1) is illustrated in Scheme 1. The targeted molecule 1 could be synthesized from the advanced intermediate 2 by RCM followed by a number of functional groups transformations. The RCM precursor 2 could be conveniently assembled from alcohol 3 and acid 4 by intermolecular esterification reaction. The alcohol subunit 3 could be constructed from compound 5 and aldehyde 6 by TiCl4-assisted substrate-controlled syn-aldol reaction followed by elimination of the resultant hydroxy group.
arolacton (1, Figure 1) was discovered by the Kirschning and Müller groups from the extracts of Sorangium
Figure 1. Structure of carolacton (1).
cellulosum strain So ce960.1 It is a potential secondary metabolite that combats Streptococcus mutans and Streptococcus pneumonia, the major bacterial pathogens responsible for human dental caries and pneumococcal infections, respectively.2 The formation of biofilms (dental plaque) through the colonization of S. mutans is a serious issue in dental medicine and eradication of such biofilms is quite strenuous.3 Carolacton, in this regard, seemed to be an attractive agent as it reduced the cell viability of bioflims in very low concentration (0.005 μg/ mL).4 It has been established that carolacton inhibits the growth of Streptococcus mutans by interfering with serine/ threonine protein kinase PknB-mediated signaling in growing cells.2d Recent results indicate that while it does not damage the structure of the plasma membrane, it leads to gradual reduction of the membrane potential in S. mutans and S. pneumonia.2d Architecturally, carolacton is a 12-membered polyketide macrocyclic lactone embedded with eight stereogenic centers, two trans-olefin moieties, and an infrequently found side chain with terminal acid functionality.1 The promising bioactivity of carolacton (1) together with its natural scarcity as well as its structural uniqueness has drawn considerable attention of the scientific community. Synthetic efforts have resulted in two complete5 and a few fragment6 and analogue7 syntheses of carolacton. © 2017 American Chemical Society
Received: March 27, 2017 Published: April 24, 2017 2366
DOI: 10.1021/acs.orglett.7b00903 Org. Lett. 2017, 19, 2366−2369
Letter
Organic Letters
isomer by transforming it into a known compound 911 in four steps. First, compound 8 was treated with LAH to obtain the corresponding alcohol, which was then protected as TBDPS ether and subjected subsequently to oxidative cleavage followed by Wittig olefination using Ph3PCH3Br/n-BuLi to obtain the known compound 9 having a stereogenic center in the Sconfiguration. Next, compound 8 was reacted with NH(Me)OMe/Et3N/DMAP to obtain the corresponding Weinreb amide and subjected subsequently to EtMgBr addition followed by hydrogenation to access alcohol 10 in good overall yield (67%). Alcohol 10 was then oxidized to its corresponding aldehyde using DMP and reacted further with PPh3CH3Br/nBuLi following Wittig olefination to achieve the required compound 5 efficiently (73%). The synthesis of the requisite aldehyde 6 is described in Scheme 3. The known acetal 11, prepared from 1,3-
Scheme 1. Retrosynthetic Analysis of Carolacton (1)
Scheme 3. Synthesis of Aldehyde 6
The synthesis of compound 5 is described in Scheme 2. We started our synthesis from the known alcohol 79 which was Scheme 2. Synthesis of Intermediate 5
propanediol following a reported procedure,12 was subjected to a reaction with the titanium enolate generated in situ from (S)-phenylalanine-derived N-propionyl thiazolidinethione 1213 in the presence of TiCl4, Hunig’s base, and SnCl4 following the Urpi diastereoselective anti acetal aldol reaction14 to provide compound 13 as a major isomer (dr >15.1:1.0) in 87% yield. Reduction of the thaizolidinethione moiety of compound 13 with DIBAL-H afforded the corresponding aldehyde, which was further subjected to Crimmins aldol13 reaction in the presence of the known chiral auxiliary 14,13 TiCl4, and Hunig’s base to produce compound 15 as a major isomer with excellent overall yield (76%) and diastereoselectivity (dr >12.5:1.0). Compound 15 was then silylated by TBSOTf/2,6-lutidine and subsequently treated with DIBAL-H to obtain the required aldehydes 6 in 88% overall yield. The synthesis of C1−C15 fragments (3 and 3a) of carolacton (1) is described in Scheme 4. The two key fragments 5 and 6 (in our hand) were subjected to TiCl4-assisted syn-aldol reaction15 to provide the corresponding aldol adducts with very good yield (79%) and diastereoselectivity (dr >6:1). The mixture of isomers was treated with MsCl/pyridine followed by DBU16 to transmute them into α,β-unsaturated ketone 16 exclusively. The observed NOESY correlations of H3-19 methyl protons with both of the H3-18 and H3-20 methyl protons further confirmed the trans-geometry of C7−C8 olefin of compound 16. The keto functionality of compound 16 was
transformed to the corresponding ester using propionic anhydride/Et3N and was subsequently subjected to Ireland− Claisen rearrangement8f,10 in the presence of LiHMDS/TBSCl in THF/DMPU (4:1) to obtain the major isomer 8 in good yield (73%) and diastereoselectvivity (dr >4.7:1). The major isomer was separated from its minor counterpart using silica gel column chromatography and was confirmed as the desired 2367
DOI: 10.1021/acs.orglett.7b00903 Org. Lett. 2017, 19, 2366−2369
Letter
Organic Letters
oxidation. Next, the major isomer 3 was subjected to intermolecular esterification with acid 4 following the Yamaguchi protocol18 to access ester 2. Note that the minor isomer 3a was also transformed to the required ester 2 by coupling with the same acid 4 following the Mitsunobu esterification protocol.19 Thus, both of the isomers obtained during DIBAL-H reduction could be converted to the desired ester by choosing different esterification protocols. Next, the precursor compound 2 was subjected to a ring-closing metathesis reaction. 8e,20 Both the Grubbs (G-II) and Hoveyda−Grubbs (HG-II) catalysts have been tested under different conditions. It was observed that G-II catalyst did not function even after several attempts, but the HG-II catalyst provided the required macrocycle 19 in good yield (74%). The large coupling constant (J = 15.6 Hz) between the H-15 and H16 clearly indicated the trans-geometry of the newly formed olefin. Next, compound 19 was treated with TBAF to obtain the corresponding desilylated product5b and was subjected subsequently to DMP followed by Pinnick oxidation to obtain compound 20, which was finally treated with HF-Py to remove the acetonide protecting group to yield compound 1. The 1H and 13C NMR data (see the comparison Table 1 in the Supporting Information) and optical rotation {observed [α]23D = −197.0 (c 0.2, MeOH); reported [α]22D = −205 (c 1.07, MeOH)} of the synthesized compound 1 were in good agreement with the literature value of carolacton,1 which unambiguously confirmed its total synthesis. In summary, we have developed a highly convergent and flexible route for the total synthesis of bioactive natural product carolacton (1) from known compound 11 via a longest linear sequence of 13 steps with 18.8% overall yield. The strategy include implementation of diastereotopic Urpi acetal aldol for installation of C-3 and C-4 centers and Crimmins aldol for C-6 center, TiCl4-mediated aldol, and subsequent β-hydroxy elimination of both of the aldol products for construction of the C7−C8 olefin, the Yamaguchi and Mitsunobu esterifications for the utilization of both isomers 3 and 3a, and finally, the construction of C15−C16 olefin using a Hoveyda−Grubbs ringclosing metathesis protocol. It is noteworthy that a complex diene substrate such as 2, which bears α and α,β-stereocenters adjacent to the reaction site, participated in macrocyclization following RCM to form the 12-membered lactone proficiently. The above-mentioned attributes result in a highly efficient synthetic route compared to the existing strategies in terms of the number of steps involved, atom economy, and overall yield.
Scheme 4. Synthesis of Compounds 3 and 3a
then reduced by DIBAL-H following the Felkin−Ahn model to obtain the alcohols 3 and 3a in excellent yield (93%) and moderate diastereoselectivity (dr >2.5:1). Both of the isomers were then separated by silica gel column chromatography, and the stereochemistry of newly generated hydroxy center of the major isomer 3 was determined by converting it to the corresponding R- and S-Mosher’s esters 17 and 17a, respectively.8a,g All of the protons of Mosher’s esters 17 and 17a were assigned by 1H NMR (Scheme 4). The positive Δδ values [Δδ = δS − δR] obtained for C-3, C-5, C-6, C-7, C-9, and C-19 protons (easily detectable) from the set of esters 17 and 17a revealed that the C-9 center is in the S-configuration. The final step in our synthetic endeavor of carolacton (1) is shown in Scheme 5. The known alcohol 18, synthesized from Larabinose following a literature procedure,8c,17 was transformed to acid 4 in 81% yield using TEMPO/BAIB-mediated Scheme 5. Completion of Synthesis of Carolacton (1)
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00903. Experimental procedures, spectroscopic data, comparison Table 1, NMR (1H, 13C), and HRMS of representative compounds; 2D NMR data for compound 16 (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Rajib Kumar Goswami: 0000-0001-7486-0618 2368
DOI: 10.1021/acs.orglett.7b00903 Org. Lett. 2017, 19, 2366−2369
Letter
Organic Letters Notes
(15) (a) Roush, W. R.; Newcom, J. S. Org. Lett. 2002, 4, 4739. (b) Julian, L. D.; Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 6186. (16) Dinh, M.-T.; Bouzbouz, S.; Péglion, J.-L.; Cossy, J. Tetrahedron 2008, 64, 5703. (17) Thompson, D. K.; Hubert, C. H.; Wightman, R. H. Tetrahedron 1993, 49, 3827. (18) (a) Chou, C.; Hou, D. J. Org. Chem. 2006, 71, 9887. (b) Pulukuri, K. K.; Chakraborty, T. K. Org. Lett. 2014, 16, 2284. (19) (a) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551. (20) For ring-closing metathesis of complex diene having stereocenters near the reaction site, see: (a) Kita, M.; Watanabe, H.; Ishitsuka, T.; Mogi, Y.; Kigoshi, H. Tetrahedron Lett. 2010, 51, 4882. (b) Ghosh, A. K.; Cheng, X.; Bai, R.; Hamel, E. Eur. J. Org. Chem. 2012, 2012, 4130. (c) Ramírez-Fernández, J.; Collado, I. G.; Hernández-Galán, R. Synlett 2008, 2008, 339. (d) Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841. (e) Kusuma, B. R.; Brandt, G. E. L.; Blagg, B. S. J. Org. Lett. 2012, 14, 6242.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS T.K.K. thanks the Council of Scientific and Industrial Research, New Delhi, for research fellowships. Financial support from the Department of Science and Technology (Project No. EMR/ 2016/000988), India, to carry out this work is gratefully acknowledged.
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DOI: 10.1021/acs.orglett.7b00903 Org. Lett. 2017, 19, 2366−2369
