Logo Beilstein Institut

A carbohydrate approach for the formal total synthesis of (−)-aspergillide C

  1. 1 ,
  2. 1,2,3 ,
  3. 1 and
  4. 2,3
1Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
2Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Hyderabad, 500037, India
3Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
  1. Corresponding author email
Associate Editor: D. Dixon
Beilstein J. Org. Chem. 2014, 10, 3122–3126. https://doi.org/10.3762/bjoc.10.329
Received 09 Sep 2014, Accepted 09 Dec 2014, Published 23 Dec 2014

Abstract

An enantioselective formal total synthesis of aspergillide C is accomplished using commercially available tri-O-acetyl-D-galactal employing a Ferrier-type C-glycosylation, utilizing a Trost hydrosilylation and protodesilylation as key reactions.

Keywords: alkynylation; chiron approach; Ferrier-type C-glycosylation; macrolide

Introduction

Aspergillides A, B and C (Figure 1) (three, novel, bicyclic, 14-membered macrolides with 2,6-cis or trans-fused di- or tetrahydropyan rings) are unexpected, novel, secondary metabolites, isolated from the marine-derived fungus Aspergillus ostianus strain 01F313 in bromine-modified 1/2PD culture medium [1-4]. Interestingly, these compounds show cytotoxicity against mouse lymphocytic leukemia cells (L1210) with LD50 values of 2.1, 71.0, and 2.0 μg/mL, respectively [5,6]. The striking structural architecture and interesting biological properties have attracted significant attention from synthetic chemists with respect to their total synthesis [7-26] and have inspired medicinal chemists to synthesize diverse analogues in search for better potential molecules [27]. We have recently developed the total synthesis of these 14-membered macrolides and have accomplished the total syntheses of aspergillide B [15] and both enantiomers of aspergillide C [21]. The chiron approach has been a conventional strategy to achieve the total synthesis of complex, natural products with known handedness. Herein we disclose our strategy for the formal total synthesis of (−)-aspergillide C in a concise manner following the chiron approach.

[1860-5397-10-329-1]

Figure 1: Structures of aspergillides.

Retrosynthetic Analysis

Through a retrosynthetic analysis, we envisaged that the macrolide 3 could be prepared from the seco acid 4 which can be easily accessed from 5 in five steps (Scheme 1). Compound 5, in turn, can be synthesized from commercially available tri-O-acetyl-D-galactal (6) and alkyne 7 through a Ferrier-type C-glycosylation reaction followed by the reduction of the triple bond to the trans double bond. Alkyne 7 can be synthesized from alkyne 8 involving an isomerization reaction. Alkyne 8 was easily accessible from (R)-propylene oxide (9) through an epoxide opening reaction with 1-butyne.

[1860-5397-10-329-i1]

Scheme 1: Retrosynthetic analysis for (−)-aspergillide C.

Results and Discussion

In recent work on aspergillides, Achmatowicz adducts were utilized as the key source for the construction of the dihydropyran moiety and the side arm was synthesized using a Zipper rearrangement as a key reaction after an epoxide ring opening reaction of (R)-propylene oxide/(S)-propylene oxide with n-BuLi. In the present context, we have focused on a chiron approach for the synthesis of aspergillide C and thus chose commercially available tri-O-acetyl-D-galactal as the raw material, which can be directly utilized for the synthesis of the dihydropyran motif. The side arm fragment 10 was readily available in large amounts starting from (R)-propylene oxide (9) as shown in Scheme 2. We proceeded further by utilizing it for masking the functionalities. Compound 10 was disilylated using TMSCl in the presence of n-BuLi and later treated with 1 N HCl to get the free secondary alcohol which was further treated with benzoyl chloride in the presence of pyridine to produce the corresponding benzoyl ester 7 as a side chain fragment to be utilized for a Ferrier-type C-glycosylation reaction with the sugar tri-O-acetyl-D-galactal (6). Compound 6 was treated with silylated alkyne 7 in the presence of SnCl4 to afford alkynylated dihydropyran 11 as the only isomer, resulting in an 85% yield. The resulting dihydropyran ring was found to have a 2,6-trans configuration, owing to the attack of the alkyne from the opposite face of the acetyl-protected carbinol present in C6 position [28-31]. The geometry of the compound was also characterized by 2D NMR studies wherein significant NOESY correlations were observed for the C2 proton and the methylene protons of the carbinol moiety present on C6. Also, the NOESY correlation was absent between the C2 proton and the C6 proton (Figure 2).

[1860-5397-10-329-i2]

Scheme 2: Synthesis of 11. Reaction conditions: (a) n-BuLi, THF/HMPA (5:1), −78 °C to rt, 12 h, 95%; (b) Li, t-BuOK, H2N(CH2)3NH2, rt, 4 h, 92%; (c) i. n-BuLi, TMSCl, THF, −78 °C, 92%. ii. pyridine, C6H5COCl, CH2Cl2, 0 °C to rt, 1 h, 98%; (d) SnCl4, CH2Cl2, 0 °C to rt, 1 h, 85%.

[1860-5397-10-329-2]

Figure 2: Key NOESY correlations observed in compound 11.

After the alkynylation reaction, the stage was set to proceed further for the partial reduction of the alkyne moiety to obtain the trans-configured olefin. Based on our previous experience with this transformation, we proceeded directly with Trost’s hydrosilylation–protodesilylation protocol [32], where alkyne 11 was treated with excess triethoxysilane in the presence of a catalytic amount of [Cp*Ru(MeCN)3]PF6 to afford vinyl triethoxysilane 12 (Scheme 3). Compound 12 was then protodesilylated upon exposure to HF/pyridine to yield the desired trans-olefin 5. Compound 5 possessed the required stereochemical configuration including the desired trans-olefin geometry, but required a one-carbon homologation to access the matched seco acid 4. To achieve the one-carbon homologation with appropriate functionality, it was necessary to perform sequential chemoselective transformations. In this regard, we proceeded by selectively deprotecting the acetyl groups (without affecting the benzoate functionality) by employing acetyl chloride in anhydrous methanol to afford diol 13 [33]. A two-fold silylation and selective mono desilylation afforded primary alcohol 14 which was converted to its corresponding nitrile via the triflate. The nitrile functionality was hydrolysed with 8 N NaOH in ethanol to yield the seco acid 4. The seco acid 4 was already utilized for the total synthesis of (−)-aspergillide C through macrolactonization and TBS deprotection as reported earlier by Kuwahara (Table 1) [23]. Thus, by synthesizing 4, we have achieved the formal total synthesis of (−)-aspergillide C.

[1860-5397-10-329-i3]

Scheme 3: Synthesis of 4 and formal total synthesis of (−)-aspergillide C (3). Reaction conditions: (a) [Cp*(MeCN)3Ru]PF6, (EtO)3SiH, CH2Cl2, 0 °C to rt, 1 h, 95%; (b) HF/pyridine, pyridine, THF, 0 °C, 5 min, 90%; (c) cat. AcCl, MeOH, rt, 12 h, 90%; (d) (i) TBSCl, imidazole, DMAP, CH2Cl2, rt, 12 h, 95%; (ii) 70% HF in pyridine, THF, 0 °C, 12 h, 90%; (e) (i) Tf2O, 2,6-lutidine, −78 °C, 10 min; (ii) NaCN, DMF/DMSO, 18-crown-6, 90 °C, 30 min 88% overall for two steps; (f) 8 N NaOH, EtOH, 90 °C, 3 h, 75%.

Table 1: Comparision of 1H and 13C NMR data of seco acid 4 with earlier data.

Position Kuwahara data [23] Our data
δ mult [J (Hz)]
CDCl3, 500 MHz 		13C NMR CDCl3,125 MHz δ mult [J (Hz)]
CDCl3, 300 MHz 		13C NMR
CDCl3, 75 MHz
1   174.9 (COOH)   175.0
2 2.72 (dd, J = 16.1, 8.8, 1H)
2.53 (dd, J = 16.1, 3.9, 1H) 		37.7 (CH2) 2.71 (dd, J = 15.9, 9.1)
2.53 dd (15.9, 3.8) 		37.8
3 3.93–3.96 (m, 1H) 68.1 (CH) 3.93–3.98 (m) 68.1
4 4.18 (dt, J = 8.8, 3.2, 1H) 69.5 (CH) 4.18 (dt J = 9.0, 3.2) 69.6
5 5.85–5.91 (m, 2H) 126.7 (CH) 5.84–5.91 (m) 126.7
6 127.5 (CH)   127.5
7 4.69 (d, J = 5.9, 1H) 72.5 (CH) 4.68 (d, J = 5.3) 72.4
8 5.51 (dd, J = 15.6, 5.9, 1H) 130.7 (CH) 5.51 (dd, J = 15.8, 6.0) 130.7
9 5.66 (dt, J = 15.6, 6.6, 1H) 134.8 (CH) 5.77–5.60 (m) 134.6
10 2.00–2.08 (m, 1H)
2.08–2.16 (m, 1H) 		36.0 (CH2) 1.96–2.20 (m) 35.9
11 1.34–1.52 (m, 3H)
1.55–1.63 (m, 1H) 		24.4 (CH2) 1.34–1.52 (m) 24.5
12 31.7 (CH2) 31.7
13 3.82 (sex, J = 6.3, 1H) 64.4 (CH) 3.82 (sex, J = 6.0) 64.4
14 1.18 (d, J = 6.3, 3H) 22.8 (CH3) 1.18 (d J = 6.0) 22.9
15 0.093 (s, 3H) −4.6 (Si-CH3) 0.09 (s) −4.6
16 0.086 (s, 3H) −4.1 (Si-CH3) 0.08–0.10 (m) −4.1
17 – 18.2 (C) – 18.2
18 0.90 (s, 9H) 25.9 (C(CH3)3) 0.90 (s) 25.9
OH 1.25 (s, 1H) – 1.25 (s) –

Conclusion

In conclusion, a formal total synthesis of (−)-aspergillide C has been achieved through a concise, stereocontrolled synthesis of the known key intermediate 4 in 8 steps with an overall yield of 36.9% starting from commercially available tri-O-acetyl-D-galactal. A C-glycosidation, Trost’s hydrosilylation and protodesilylation protocol have been used as the key steps for achieving the formal total synthesis.

Supporting Information

Supporting Information File 1: Experimental details and analytical data.
Format: PDF Size: 1.2 MB Download

Acknowledgements

N.H.K. thanks NIPER-Hyderabad for financial assistance in the form of a fellowship. P.S. acknowledges partial funding from CSIR, New Delhi as part of the XII Five Year Plan Programme under title ORIGIN (CSC-108) and partial funding from a research grant (GAP-390) from the Ministry of Earth Science Programme, Drugs from the Sea. Y.S. acknowledges CSIR, New Delhi for financial assistance.

References

  1. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2011, 28, 196–268. doi:10.1039/c005001f
    Return to citation in text: [1]
  2. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2010, 27, 165–237. doi:10.1039/b906091j
    And references cited therein.
    Return to citation in text: [1]
  3. Thomas, T. R. A.; Kavlekar, D. P.; LokaBharathi, P. A. Mar. Drugs 2010, 8, 1417–1468. doi:10.3390/md8041417
    Return to citation in text: [1]
  4. Haefner, B. Drug Discovery Today 2003, 8, 536–544. doi:10.1016/S1359-6446(03)02713-2
    Return to citation in text: [1]
  5. Kito, K.; Ookura, R.; Yoshida, S.; Namikoshi, M.; Ooi, T.; Kusumi, T. Org. Lett. 2008, 10, 225–228. doi:10.1021/ol702598q
    Return to citation in text: [1]
  6. Ookura, R.; Kito, K.; Saito, Y.; Kusumi, T.; Ooi, T. Chem. Lett. 2009, 38, 384. doi:10.1246/cl.2009.384
    Return to citation in text: [1]
  7. Nagasawa, T.; Kuwahara, S. Tetrahedron Lett. 2010, 51, 875–877. doi:10.1016/j.tetlet.2009.12.032
    Return to citation in text: [1]
  8. Díaz-Oltra, S.; Angulo-Pachón, C. A.; Murga, J.; Carda, M.; Marco, J. A. J. Org. Chem. 2010, 75, 1775–1778. doi:10.1021/jo9027038
    Return to citation in text: [1]
  9. Díaz-Olta, S.; Angulo-Pachón, C. A.; Murga, J.; Falomir, E.; Carda, M.; Marco, J. A. Chem. – Eur. J. 2011, 17, 675–688. doi:10.1002/chem.201001682
    Return to citation in text: [1]
  10. Fuwa, H.; Yamaguchi, H.; Sasaki, M. Org. Lett. 2010, 12, 1848–1851. doi:10.1021/ol100463a
    Return to citation in text: [1]
  11. Fuwa, H.; Yamaguchi, H.; Sasaki, M. Tetrahedron 2010, 66, 7492–7503. doi:10.1016/j.tet.2010.07.062
    Return to citation in text: [1]
  12. Sabitha, G.; Reddy, D. V.; Rao, A. S.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 4195–4198. doi:10.1016/j.tetlet.2010.06.013
    Return to citation in text: [1]
  13. Kanematsu, M.; Yoshida, M.; Shishido, K. Angew. Chem. 2011, 123, 2666–2668. doi:10.1002/ange.201007327
    Return to citation in text: [1]
  14. Izuchi, Y.; Kanomata, N.; Koshino, H.; Hongo, Y.; Nakata, T.; Takahashi, S. Tetrahedron: Asymmetry 2011, 22, 246–251. doi:10.1016/j.tetasy.2011.01.016
    Return to citation in text: [1]
  15. Sridhar, Y.; Srihari, P. Eur. J. Org. Chem. 2013, 578–587. doi:10.1002/ejoc.201201155
    Return to citation in text: [1] [2]
  16. Liu, J.; Xu, K.; He, J.; Zhang, L.; Pan, X.; She, X. J. Org. Chem. 2009, 74, 5063–5066. doi:10.1021/jo900820f
    Return to citation in text: [1]
  17. Diaz-Oltra, S.; Angulo-Pachón, C. A.; Kneeteman, M. N.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2009, 50, 3783–3785. doi:10.1016/j.tetlet.2009.04.026
    Return to citation in text: [1]
  18. Nagasawa, T.; Kuwahara, S. Biosci., Biotechnol., Biochem. 2009, 73, 1893–1894. doi:10.1271/bbb.90221
    Return to citation in text: [1]
  19. Hande, S. M.; Uenishi, J. Tetrahedron Lett. 2009, 50, 189–192. doi:10.1016/j.tetlet.2008.10.115
    Return to citation in text: [1]
  20. Mueller Hendrix, A. J.; Jennings, M. P. Tetrahedron Lett. 2010, 51, 4260–4262. doi:10.1016/j.tetlet.2010.06.025
    And also reference [9] and [13].
    Return to citation in text: [1]
  21. Srihari, P.; Sridhar, Y. Eur. J. Org. Chem. 2011, 6690–6697. doi:10.1002/ejoc.201100917
    Return to citation in text: [1] [2]
  22. Kanematsu, M.; Yoshida, M.; Shishido, K. Tetrahedron Lett. 2011, 52, 1372–1374. doi:10.1016/j.tetlet.2011.01.078
    Return to citation in text: [1]
  23. Nagasawa, T.; Kuwahara, S. Org. Lett. 2009, 11, 761–764. doi:10.1021/ol802803x
    Return to citation in text: [1] [2] [3]
  24. Panarese, J. D.; Waters, S. P. Org. Lett. 2009, 11, 5086–5088. doi:10.1021/ol902154p
    Return to citation in text: [1]
  25. Sharma, G. V. M.; Manohar, V. Tetrahedron: Asymmetry 2012, 23, 252–263. doi:10.1016/j.tetasy.2012.02.009
    Return to citation in text: [1]
  26. Nagasawa, T.; Kuwahara, S. Heterocycles 2012, 85, 587–613. doi:10.3987/REV-12-727
    Return to citation in text: [1]
  27. Lambu, M. R.; Kumar, S.; Yousuf, S. K.; Sharma, D. K.; Hussain, A.; Kumar, A.; Malik, F.; Mukherjee, D. J. Med. Chem. 2013, 56, 6122–6135. doi:10.1021/jm400515c
    Return to citation in text: [1]
  28. Yadav, J. S.; Raju, A. K.; Sunitha, V. Tetrahedron Lett. 2006, 47, 5269–5272. doi:10.1016/j.tetlet.2006.05.159
    Return to citation in text: [1]
  29. Isobe, M.; Poosaha, W.; Saeeng, R.; Kira, K.; Yenjai, C. Org. Lett. 2003, 5, 4883–4885. doi:10.1021/ol035957w
    Return to citation in text: [1]
  30. Saeeng, R.; Sirion, U.; Sahakitpichan, P.; Isobe, M. Tetrahedron Lett. 2003, 44, 6211–6215. doi:10.1016/S0040-4039(03)01540-5
    Return to citation in text: [1]
  31. Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa, T. Chem. Commun. 1998, 2665–2676. doi:10.1039/a804940h
    Return to citation in text: [1]
  32. Trost, B. M.; Ball, Z. T.; Jöge, T. J. Am. Chem. Soc. 2002, 124, 7922–7923. doi:10.1021/ja026457l
    Return to citation in text: [1]
  33. Yeom, C.-E.; Lee, S. Y.; Kim, Y. J.; Kim, B. M. Synlett 2005, 1527–1530. doi:10.1055/s-2005-869838
    Return to citation in text: [1]

© 2014 Srihari et al; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

Other Beilstein-Institut Open Science Activities
Journal Logo
Institut Logo
Preprint Logo
Symposia Logo