Synthesis of elaiolide and halichoblelide aglycone

Article abstract of DOI:10.1016/j.tetlet.2019.04.032

A synthesis of two structurally related macrodiolides representing the aglycone of natural products elaiophylin and halichoblelide is described. The key transformation for both is a Ti(II)-mediated (silyloxy)enyne cyclization, generating a new methyl ster

Full text of DOI:10.1016/j.tetlet.2019.04.032

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Synthesis of elaiolide and halichoblelide aglycone
Gregory W. O'Neil, Andrew J. Phillips
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S0040-4039(19)30381-8
https://doi.org/10.1016/j.tetlet.2019.04.032
TETL 50747
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Tetrahedron Letters
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18 April 2019
22 April 2019
Please cite this article as: O'Neil, G.W., Phillips, A.J., Synthesis of elaiolide and halichoblelide aglycone,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.032
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Synthesis of elaiolide and halichoblelide aglycone
Gregory W. O’Neil1, and Andrew J. Phillips2
1Department of Chemistry, Western Washington University, Bellingham, WA, 98225, USA
2C4 Therapeutics, Watertown MA, 02472, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A synthesis of two structurally related macrodiolides representing the aglycone of
natural products elaiophylin and halichoblelide is described. The key transformation
for both is a Ti(II)-mediated (silyloxy)enyne cyclization, generating a new methyl
stereocenter and providing a diene that can be selectively cross metathesized with
crotonic acid.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
macrodiolide
reductive cyclization
(silyloxy)enyne
total synthesis
In January 2002, as part of a program targeting antitumor materials, Numata and
coworkers reported the isolation and structure of the cytotoxic macrolide halichoblelide from
Streptomyces hygroscopicus OUPS-N92, which was originally obtained from the marine fish
Halichoeres bleekeri.1 Bioassay-directed fractionation (cyctotoxicities against P388 cell line) and
purification employing a combination of Sephadex and silica gel column chromatography
followed by reverse-phase HPLC led to the isolation of halichoblelide (1, 7.2 mg from 80 L
culture medium) as a colorless powder (Figure 1). In addition to the P388 cell line (ED50 = 0.63
ng mL-1), halichoblelide A was screened against a number of other cancer cell lines including
breast (BSY-1), lung (NCI-H522), and gastric (MKN74).1 The tested mean value of log GI50
over all cell lines was 5.25 ng mL-1.
Since then, the halichoblelide family of natural products has expanded to include
halichoblelides B-D (Figure 1).2 Structurally these compounds are very closely related to the
symmetric macrodiolide elaiophylin (2, Figure 1), which was first isolated in 1959 by Arcamone
and coworkers from cultures of Streptomyces melanosporus.3 Elaiophylin has shown cytotoxicity
against several human and murine tumor cell lines, as well as potent antimicrobial activities
 Corresponding author. Tel.: +01-360-650-6283; fax: +01-360-650-2826; e-mail: gregory.o’neil@.wwu.edu

against gram-positive bacteria. The first synthesis of elaiophylin was reported by Kinoshita and
coworkers in 1986.4 In the previous year Seebach reported the synthesis of an aglycone
derivative originally obtained from the acidic methanolysis of elaiophylin and later identified as
11,11',13,13'-tetra-O-methylelaiolide.5 Evans and Paterson reported syntheses of the non-
methylated aglycone derivative (i.e. “elaiolide”, 3, Figure 1),6,7 which was isolated after
deglycosylation of elaiophylin with p-TsOH in MeCN/H2O by Zeeck and Bindseil.8 More
recently, Mulzer has described a formal synthesis of elaiolide and another related macrodiolide
natural product efomycine M.9
Figure 1. Structures of natural products halichoblelide A (1), B and D, along with structurally
related elaiophylin (2) and its aglycone derivative elaiolide (3).
Common to all of these compounds is a macrodiolide core containing an anti-propionate
subunit adjacent to a trans-disubstituted alkene. We have developed a (silyloxy)enyne reductive
cyclization method to access subunits of this type,10 and demonstrated its utility in the total
synthesis of natural products dictyostatin-111 and 7-demethylpiericidin A1.12 In this paper, we
describe the synthesis of elaiolide and halichoblelide aglycone from a common intermediate 4
that was prepared by Ti(II)-mediated cyclization of (silyloxy)enyne 5 (Figure 2).

Figure 2. Synthesis plan for elaiolide and halichoblelide aglycone based on a (silyloxy)enyne
reductive cyclization of 5.
Our synthesis began by silylation of allyl alcohol 613 with bromosilane 7 giving 5 in high
yield (Scheme 1). Treatment of 5 with Ti(II), prepared in situ from Ti(OPri)4 and n-BuLi,14 in
THF at -40 C provided cyclic siloxane 8 as a single diastereomer in 80% yield. Cross
metathesis with crotonic acid and 10 mol % Grubbs' second generation catalyst (Ru-II) in
toluene at 80 C produced exclusively the (E,E)-siloxane acid 9 in 60% isolated yield and 82%
yield based on recovered starting material (BRSM). It is worth noting the ability of silicon in this
reaction to overcome the chemoselectivity issues reported by Morita and Kuwahara when
attempting to prepare this subunit of elaiolide by cross-metathesis.15 Desilylation with TBAF in
MeCN at 85 C gave the corresponding seco-acid 10 that was then dimerized under modified
Yamaguchi conditions16 to give macrodiolide 4 in 52% yield for the two steps.
Scheme 1. Synthesis of macrodioloide 4 by Ti(II)-mediated (silyloxy)enyne cyclization.

Deprotection of both PMB-groups in 4 produced diol 11 in 92% yield and bisected the
route to elaiolide (3) reported by Evans (Scheme 2).6 The synthesis of 3 from 11 was then
completed as previously described featuring a highly stereoselective aldol reaction with ethyl
ketone 12. In this way, elaiolide was obtained in three steps and 53% yield from 11. Spectral data
for our sample matched that previously reported.6
The synthesis of halichoblelide was made more challenging due to its lack of symmetry.
Desymmetrization of 4 was accomplished by mono PMB-deprotection using a slow addition of 1
equivalent of DDQ to give a statistical mixture of 4, mono-PMB-ether 13, and diol 11 (Scheme
3). The desired compound, 13 could be isolated from this mixture in 48% yield. Oxidation of 13
with Dess-Martin periodinane gave an intermediate aldehyde that was immediately treated with
the chlorophenylboryl enolate of 12 providing aldol adduct 14 as a single diastereomer in 74%
yield for the two steps.
Scheme 2. Synthesis of elaiolide (3) from compound 4.
Scheme 3. Desymmetrization of 4 and subsequent aldol reaction.

Introduction of the other halichoblelide side chain began with removal of the remaining
PMB ether to give diol 15 in 92% yield (Scheme 4). Selective oxidation of the primary hydroxyl
with TEMPO/CaOCl generated an intermediate aldehyde that was treated with the titanium
enolate of thiazolidinethione 16.17 The thiozolidinethione auxiliary was chosen for its ease of
removal, however this inherent lability also made purification of the direct aldol adduct difficult.
Because of this, the crude product was treated with methanol/imidazole, resulting in the
formation of methyl ester 17 that was isolated in 48% yield from 15. Deprotection of the di-tert-
butylsilylene acetal with HF•pyr in pyridine then completed our synthesis halichoblelide
aglycone (18).
The NMR chemical shifts for compound 18 were generally in good agreement with those
reported for halichoblelide (1),1 with the greatest differences appearing on the more drastically
truncated side (i.e. loss of a disaccharide, R2, Figure 3). While glycosidic groups are known to be
important for biological activity,18,19 elaiolide was reported to retain some of the biological
activity of elaiophylin.4 Based on the NMR similarity of 18 to halichoblelide and elaiolide as it
correlates to structure,20 we assume that compound 18 is biologically active, however the nature
and extent of that actvity remains to be investigated.
Scheme 4. Synthesis of halichoblelide aglycone (18)

1
Figure 3. Differences in H NMR chemical shifts between 18 and those reported for the natural
product halichoblelide1 (calculated as δ18 – δhalichoblelide).
Acknowledgments
Financial support from University of Colorado is gratefully acknowledged.
References and notes
1. Yamada, T.; Katsuhiko, M.; Numata, A. Tetrahedron Lett. 2002, 43, 1721.
2. (a) Yamada, T.; Kikuchi, T.; Tanaka, R.; Numata, A. Tetrahedron Lett. 2012, 53, 2842.
(b) Han, Y.; Tian, E.; Xu, D.; Ma, M.; Deng, Z.; Hong, K. Molecules 2016, 21, 970.
3. Arcamone, F. M.; Bertazzoli, C.; Ghione, M.; Scotti, T. G. Microbiol. 1959, 7, 207.
4. Toshima, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett. 1986, 27, 4741.
5. Seebach, D.; Chow, H-F.; Jackson, R. F.; Lawson, K.; Sutter, M. A.; Thaisrivongs, S.;
Zimmerman, J. J. Am. Chem. Soc. 1985, 107, 5292.
6. Evans, D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454.
7. Paterson, I.; Lombart, H-G.; Allerton, C. Org. Lett. 1999, 1, 19.
8. Bindseil, K. U.; Zeeck, A. J. Org. Chem. 1993, 58, 5487.
9. Barth, R.; Mulzer, J. Tetrahedron 2008, 64, 4718.
10. O’Neil, G. W.; Phillips, A. J. Tetrahedron Lett. 2004, 45, 4253.
11.O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340.
12. Keaton, K. A.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 408.
13. Available in 3-steps and 60% yield from crotonaldehyde. See: Koide, K.; Finkelstein, J.
M.; Ball, Z.; Verdine, G. L. J. Am. Chem. Soc. 2001, 123, 398.
14. (a) Eisch, J. J.; Gitua, J. N.; Otieno, P. O.; Shi, X. J. J. Organomet. Chem. 2001, 624,
229. See also: (b) Rassadin, V. A.; Six, Y. Tetrahedron 2014, 28, 787. For examples of
other reactions employing Ti(OiPr)4/n-BuLi see: (c) Tarselli, M. A.; Micalizio, G. C.
Org. Lett. 2009, 11, 4596. (d) Jeso, V.; Aquino, C.; Cheng, X.; Mizoguchi, H.;
Nakashige, M.; Micalizio, G. C. J. Am. Chem. Soc. 2014, 136, 8209
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16. Hikota, M.; Sakurai, Y.; Horita, K.; Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.

17. Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894.
18. Weymouth-Wilson, A. C.; Nat. Prod. Rep. 1997, 14, 99-110.
19. Kren, V.; Martinková, L. Curr. Med. Chem. 2001, 8, 1303.
20. For a complete comparison of NMR data for 18, our synthesized elaiolide, and
halichoblelide see the Supplementary Material.
Supplementary Material
Analytical data and experimental procedures for compounds 4, 5, 8-11, 13-15, 17 and 18.

Highlights for: Iodine-mediated rearrangements of diallylsilanes
 Natural product aglycones elaiolide and halichoblelide A were synthesized.
 The syntheses featured a diastereoselective (silyloxy)enyne reductive cyclization.
 A chemoselective cross-metathesis led to completion of the macrodiolide core.