Total synthesis of the proposed structure of astakolactin

Article abstract of DOI:10.3762/bjoc.10.252

The first total synthesis of the proposed structure of astakolactin, a sesterterpene metabolite isolated from the marine sponge Cacospongia scalaris, has been achieved, mainly featuring Johnson-Claisen rearrangement, asymmetric Mukaiyama aldol reaction an

Full text of DOI:10.3762/bjoc.10.252

Total synthesis of the proposed structure of astakolactin
Takayuki Tonoi*, Keisuke Mameda, Moe Fujishiro, Yutaka Yoshinaga and Isamu Shiina*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2421–2427.
Department of Applied Chemistry, Tokyo University of Science,1-3
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
doi:10.3762/bjoc.10.252
Received: 29 June 2014
Accepted: 01 October 2014
Published: 17 October 2014
Email:
Takayuki Tonoi* - tonoi@rs.tus.ac.jp; Isamu Shiina* -
shiina@rs.kagu.tus.ac.jp
Associate Editor: D. Dixon
* Corresponding author
© 2014 Tonoi et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aldol reaction; astakolactin; lactonization; MNBA; terpenoids
Abstract
The first total synthesis of the proposed structure of astakolactin, a sesterterpene metabolite isolated from the marine sponge
Cacospongia scalaris, has been achieved, mainly featuring Johnson–Claisen rearrangement, asymmetric Mukaiyama aldol reaction
and MNBA-mediated lactonization.
Introduction
Astakolactin (1) is a novel sesterterpene metabolite [1-5] first
reported in 2003 by Roussis et al [6]. It was isolated from the
marine sponge Cacospongia scalaris, which was collected from
the gulf of Astakos in the Ionian Sea near Greece. The structure
proposed for compound 1 is a bicyclic linear sesterterpenoid
bearing a furan unit and an eight-membered lactone tethered by
Figure 1: Proposed structure of astakolactin (1).
a non-conjugated triene chain (Figure 1). Although the
proposed structure of compound 1 is unusual, given that a
number of compounds isolated from sponges of the same natural products possessing useful biological activities [14-19].
species have a steroid-like structure [7-9], the structure does Among them, the 8-membered (and 9-membered) lactone
resemble that of marine furanosesterterpene natural products, framework is rather unusual in nature [20-24]. We have already
such as variabilin [10,11], which exhibit a large spectrum of developed the synthetic method of lactones with various ring
intriguing biological activities [12,13]. Therefore, compound 1 sizes using 2-methyl-6-nitrobenzoic anhydride (MNBA) under
is also expected to possess biological activities similar to those mild reaction conditions in the presence of a nucleophilic cata-
of other furanosesterterpenes.
lyst such as 4-(dimethylamino)pyridine (DMAP) [25,26]. By
using this method, we have demonstrated that unusual saturated
In addition, medium-sized lactones (8–11 membered rings) are medium-sized lactones, which are generally difficult to
significant structural motifs because they are found in many construct because of the ring strain and transannular interac-
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tions [27,28], can be effectively prepared [29,30]. Therefore, in from compound 5. The construction of the α-methylene-β-
order to determine the chemical structure and the expected bio- hydroxy ester moiety in 5, which is commonly known as a
logical activity of compound 1, we executed the total synthesis Morita–Baylis–Hillman adduct, would be achieved via an aldol
of compound 1 by exploitng the MNBA-mediated lactonization reaction between aldehyde 6 and ester 7, followed by oxidative
for the formation of its 8-membered lactone moiety.
deselenization [37]. The linear precursor 8 would be prepared
from (E,E)-farnesol using the previously reported method based
on the Julia–Kocienski-type transformation [11].
Results and Discussion
The rationalized synthesis of 1 primarily involved the linear
synthesis of the prenyl chain precursor from commercially The synthetic route to 1 is depicted in Scheme 2. It commenced
available (E,E)-farnesol to form the corresponding seco-acid from the readily accessible furanylated alcohol 13 [11], which
and the subsequent construction of the 8-membered lactone was prepared from (E,E)-farnesol via a 10-step sequence. First,
moiety. The retrosynthetic analysis of 1 is depicted in Scheme 1 oxidation of 13 provided aldehyde 6. The aldol reaction of 6
[31].
with ester 7 in the presence of base and the subsequent oxida-
tive deselenization of the resulting adduct 14 yielded a
Morita–Baylis–Hillman-type product 5 [37] in two steps.
Reduction of 5 and the regioselective protection of the less-
hindered primary hydroxy group in the resulting diol 15 gave
the monoprotected alcohol 16. This alcohol was then subjected
to the Johnson orthoester–Claisen rearrangement, yielding only
the (Z)-isomer 17 [36] in satisfactory yield. After the reduction
of 17, the resulting aldehyde 18 was subjected to the aldol reac-
tion with ethyl acetate to afford the adduct 19. Diastereoselec-
tive methylation of the ester enolate moiety of 19 with MeI
afforded only the anti-product 20 [32,33], which was then
subjected to the deprotection of the TBDPS group with HF·pyri-
dine, followed by cleavage of the ethyl ester group in 21 to give
the desired seco-acid 2 in high yield.
Eventually, the lactonization of 2 was performed under several
sets of reaction conditions (Scheme 3 and Table 1). We prelimi-
narily attempted the Yamaguchi mixed-anhydride method [38]
with 2,4,6-trichlorobenzoyl chloride (TCBC) as an activating
agent, which is one of the best-known lactonization methods so
far. However, the desired lactone 1 was obtained in a lower
yield (33%, Table 1, entry 1) accompanied by unidentified com-
plex products. Moreover, the S-pyridyl ester lactonization
method [39] afforded no desired product at all as shown in
Table 1, entry 2. Next, the MNBA-mediated lactonization
[25,26,29,30] was then carried out; in sharp contrast to the first
two methods, only the targeted 8-membered lactone 1 was
selectively obtained in moderate yield (60%, Table 1, entry 3),
and formation of the undesired β-lactone was avoided. Further-
more, the lactonization yield was improved from 60 to 71% by
decreasing the substrate concentration from 2.0 to 1.0 mM
Scheme 1: Retrosynthetic analysis.
First, the 8-membered ring in 1 could be efficiently constructed (Table 1, entry 4). During the MNBA-mediated lactonization,
via lactonization using MNBA with DMAP. The chain pre- no epimerization occurred at the α position of lactone carbonyl
cursor 2 would be constructed via an aldol reaction with ethyl group. Thus, the total synthesis of the proposed structure of 1
acetate, followed by anti-selective methylation [32,33]. The was achieved.
trisubstituted alkene moiety of the prenyl chain of 3 could be
stereoselectively constructed via a Johnson orthoester–Claisen We next focused on the synthesis of the diastereomer of 1, 2,3-
rearrangement of 4 [34-36], which would be generated trans-astakolactin (1’), to thoroughly uncover its molecular
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Beilstein J. Org. Chem. 2014, 10, 2421–2427.
Scheme 2: Synthesis of 2,3-cis-astakolactin.
Scheme 3: MNBA-mediated lactonization.
structure and stereochemistry, starting from the aldehyde 18, The asymmetric Mukaiyama aldol reaction of aldehyde 18 with
which was prepared according to the procedure [11] described enol silyl ether 22 (derived from S-ethyl propanethioate) in the
in Scheme 2. It was postulated that the precursor 26 (Scheme 4) presence of (S)-diamine-Sn(II) complex (S)-23 as the catalyst
of the ring-closed product (1’) possessing a syn-α-methyl-β- and n-Bu2Sn(OAc)2 proceeded smoothly to afford the corres-
hydroxy carboxylic acid moiety could be accessed via an asym- ponding aldol 24 as the desired (2,3)-syn adduct in good yield
metric Mukaiyama aldol reaction [40-42] and our universal and excellent enantio- and diastereoselectivities (90% yield,
lactonization strategy. The synthetic route to 1’ is shown in 83% ee for syn, and 93/7 syn/anti ratio). Next, the transforma-
Scheme 4.
tion to the seco-acid 26 was achieved via successive deprotec-
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Beilstein J. Org. Chem. 2014, 10, 2421–2427.
Table 1: Yields of astakolactin (1) using several lactonizations.
Entry
Reagents (equiv)
Conditions
Yield/%a
THF/CH2Cl2 (2 mM)
slow add. (12 h)
1
2
3
TCBC (1.0)/Et3N (1.1)/DMAP (6.0)
(PyS)2 (1.5)/PPh3 (1.6)/Ag(OTf) (2.0)
MNBA (1.3)/DMAP (6.0)
33
N.D.
60
CHCl3/MeCN (2 mM)
slow add. (12 h)
CH2Cl2 (2 mM)
slow add. (12 h)
CH2Cl2 (1 mM)
slow add. (12 h)
4
MNBA (1.3)/DMAP (6.0)
71
aIsolated yield.
Scheme 4: Synthesis of 2,3-trans-astakolactin.
tion of the TBDPS group and the thioester moiety in 25. The Finally, determination of the exact structure of astakolactin was
lactonization of 26 was then performed in the presence of attempted by comparing the 1H and 13C NMR spectra of the
MNBA and DMAP to afford 1’ with the desired stereochem- synthetic compounds 1 and 1’ with those reported for astako-
istry in 62% yield.
lactin (Figure 2 and Figure 3).
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Beilstein J. Org. Chem. 2014, 10, 2421–2427.
Figure 2: Δδ (ppm) of 1H NMR chemical shifts in 1. Δδ corresponds to the difference in chemical shift for natural and synthetic products (Δδ = δ(syn-
thetic) – δ(natural)).
Figure 3: Δδ (ppm) of 1H NMR chemical shifts in 1’. Δδ corresponds to the difference in chemical shift for natural and synthetic products (Δδ = δ(syn-
thetic) – δ(natural)).
The chemical shifts for the terpene chain of the synthetic com- Mukaiyama aldol reaction, and our MNBA-mediated lactoniza-
pound 1 in the 1H and 13C NMR spectra were quite similar to tion as key steps. It was found that the 1H and 13C NMR data of
those in the spectra of the natural product (Figure 2; see also synthesized 1 and 1’ are not identical with those of the natural
Supporting Information File 1). However, the chemical shifts compound. Further studies to elucidate the complete structure
corresponding to the lactone ring moiety (from C-1 to C-7) in of astakolactin are now in progress.
the 1H and 13C NMR spectra were somewhat different from
those in the corresponding spectra of the natural product. Experimental
Similar discrepancies in the spectral data were also found for General procedure for the synthesis of 1 using the MNBA-
the diastereomer 1’ (Figure 3; see also Supporting Information mediated lactonization. To a solution of MNBA (14 mg,
File 1). These facts indicate that the proposed eight-membered 0.04 mol) and DMAP (23 mg, 0.19 mmol) in dichloromethane
lactone moiety is not comprised in the naturally occurring (25 mL) at room temperature was slowly added a solution of the
astakolactin. On the basis of these results, it was concluded that seco-acid 2 (13 mg, 0.03 mol) in dichloromethane (6.2 mL)
the structures of synthetic compounds 1 and 1’ and the natural with a mechanically driven syringe over a 12 h period. After
product are very similar, but not completely identical.
cooling to 0 °C, saturated aqueous sodium hydrogen carbonate
was added. The mixture was extracted with dichloromethane,
and the organic layer was washed with brine and water and
Conclusion
In conclusion, we have achieved the total synthesis of the dried over sodium sulfate. After evaporation of the solvent, the
proposed structures of astakolactin (1) and its stereoisomer (1’), crude product was purified by thin-layer chromatography on
with a Johnson–Claisen rearrangement, an asymmetric silica gel (hexane/ethyl acetate 2:1) to afford 1 (9 mg, 71%). IR
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Beilstein J. Org. Chem. 2014, 10, 2421–2427.
9. Cimino, G.; Cafieri, F.; De Napoli, L.; Fattorusso, E. Tetrahedron Lett.
1978, 19, 2041–2044. doi:10.1016/S0040-4039(01)94744-6
10.Faulkner, D. J. Tetrahedron Lett. 1973, 14, 3821–3822.
doi:10.1016/S0040-4039(01)87045-3
(neat): 3455, 2931, 1735 cm−1; 1H NMR (CDCl3) δ 7.33 (s, 1H,
5’’-H), 7.21 (s, 1H, 2’’-H), 6.27 (s, 1H, 4’’-H), 5.33 (t, J = 7.5
Hz, 1H, 1’-H), 5.17 (t, J = 7.5 Hz, 1H, 9’-H), 5.10 (t, J = 7.5
Hz, 1H, 5’-H), 5.08 (d, J = 12.0 Hz, 1H, 7-H), 4.60 (d, J = 12.0
Hz, 1H, 7-H), 4.09–4.02 (m, 1H, 3-H), 2.96 (dq, J = 5.0, 7.0 Hz,
1H, 2-H), 2.45 (t, J = 7.0 Hz, 2H, 11’-H), 2.30 (ddd, J = 2.5,
8.5, 14.5 Hz, 1H, 5-H), 2.24 (dt, J = 7.0, 7.5 Hz, 2H, 10’-H),
2.12 (dt, J = 7.5, 7.5 Hz, 2H, 2’-H), 2.08 (dt, J = 7.5, 7.5 Hz,
2H, 6’-H), 2.01 (dd, J = 7.5, 14.5 Hz, 1H, 5-H), 2.01 (t, J = 7.5
Hz, 2H, 3’-H), 1.99 (t, J = 7.5 Hz, 2H, 7’-H), 1.94–1.85 (m, 1H,
11.Takabe, K.; Hashimoto, H.; Sugimoto, H.; Nomoto, M.; Yoda, H.
Tetrahedron: Asymmetry 2004, 15, 909–912.
doi:10.1016/j.tetasy.2004.01.031
12.Barrow, C. J.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod. 1989, 52,
346–359. doi:10.1021/np50062a022
13.Liu, Y.; Mansoor, T. A.; Hong, J.; Lee, C.-O.; Sim, C. J.; Im, K. S.;
Kim, N. D.; Jung, J. H. J. Nat. Prod. 2003, 66, 1451–1456.
doi:10.1021/np030268e
4-H), 1.83 (d, J = 7.0 Hz, 1H, OH), 1.83–1.76 (m, 1H, 4-H), 14.Nicolaou, K. C. Tetrahedron 1977, 33, 683–710.
doi:10.1016/0040-4020(77)80180-4
1.59 (s, 6H, 4’-Me, 8’-Me), 1.22 (d, J = 7.0 Hz, 3H, 2-Me);
15.Masamune, S.; Bates, G. S.; Corcoran, J. W.
13C NMR (CDCl3) δ 176.6 (1), 142.5 (5’’), 138.8 (2’’), 136.2
Angew. Chem., Int. Ed. Engl. 1977, 16, 585–607.
(6), 135.7 (8’), 134.1 (4’), 130.5 (1’), 125.0 (3’’), 124.9 (5’),
doi:10.1002/anie.197705851
123.8 (9’), 111.1 (4’’), 74.1 (3), 65.7 (7), 42.5 (2), 39.6 (7’),
16.Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569–3624.
39.4 (3’), 35.1 (4), 29.9 (5), 28.4 (10’), 26.6 (6’), 26.2 (2’), 25.0
(11’), 16.0 (4’-Me, 8’-Me), 11.6 (2-Me); HRMS: [M + Na]+
calcd for C25H36O4Na, 423.2506; found, 423.2488.
doi:10.1016/S0040-4020(01)91380-8
17.Rousseau, G. Tetrahedron 1995, 51, 2777–2849.
doi:10.1016/0040-4020(94)01064-7
18.Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041–2114.
doi:10.1021/cr00038a012
19.Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106,
911–939. doi:10.1021/cr0301402
Supporting Information
20.Tapiolas, D. M.; Roman, M.; Fenical, W.; Stout, T. J.; Clardy, J.
J. Am. Chem. Soc. 1991, 113, 4682–4683. doi:10.1021/ja00012a048
21.Buszek, K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc. 1994, 116,
5511–5512. doi:10.1021/ja00091a082
Supporting Information File 1
Experimental procedures, analyitical data, and copies of 1H
and 13C NMR spectra of all new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-252-S1.pdf]
22.McWilliams, J. C.; Clardy, J. J. Am. Chem. Soc. 1994, 116,
8378–8379. doi:10.1021/ja00097a060
23.Buszek, K. R.; Sato, N.; Jeong, Y. Tetrahedron Lett. 2002, 43,
181–184. doi:10.1016/S0040-4039(01)02078-0
24.O’Sullivan, P. T.; Buhr, W.; Fuhry, M. A. M.; Harrison, J. R.;
Davies, J. E.; Feeder, N.; Marshall, D. R.; Burton, J. W.; Holmes, A. B.
J. Am. Chem. Soc. 2004, 126, 2194–2207. doi:10.1021/ja038353w
25.Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004,
69, 1822–1830. doi:10.1021/jo030367x
Acknowledgements
The authors are grateful to Professor Vassilios Roussis (Univer-
sity of Athens) for giving the spectral data of astakolactin. This
study was partly supported by a Research Grant from the Center
for Chirality and Grants-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture, Japan.
26.Shiina, I. Bull. Chem. Soc. Jpn. 2014, 87, 196–233.
doi:10.1246/bcsj.20130216
27.Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95–102.
doi:10.1021/ar00064a001
References
1. Hanson, J. R. Nat. Prod. Rep. 1986, 3, 123–132.
28.Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117–3125.
doi:10.1002/1099-0690(200009)2000:18<3117::AID-EJOC3117>3.0.C
O;2-5
doi:10.1039/np9860300123
2. Hanson, J. R. Nat. Prod. Rep. 1992, 9, 481–489.
doi:10.1039/np9920900481
29.Shiina, I.; Hashizume, M.; Yamai, Y.; Oshiumi, H.; Shimazaki, T.;
Takasuna, Y.; Ibuka, R. Chem. – Eur. J. 2005, 11, 6601–6608.
doi:10.1002/chem.200500417
3. Hanson, J. R. Nat. Prod. Rep. 1996, 13, 529–535.
doi:10.1039/np9961300529
30.Shiina, I. Chem. Rev. 2007, 107, 239–273. doi:10.1021/cr050045o
31.Shibamoto, K.; Fukui, H.; Shiina, I. Abstracts of Papers, 49th
Symposium on the Chemistry of Natural Products, Sapporo, 2007, 49,
569–574.
4. Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–49. doi:10.1039/b009029h
5. Liu, Y.; Wang, L.; Jung, J. H.; Zhang, S. Nat. Prod. Rep. 2007, 24,
1401–1429. doi:10.1039/b617259h
6. Tsoukatou, M.; Siapi, H.; Vagias, C.; Roussis, V. J. Nat. Prod. 2003,
66, 444–446. doi:10.1021/np020471u
http://ci.nii.ac.jp/lognavi?name=nels&lang=en&type=pdf&id=ART00087
07858
7. Cimino, G.; De Rosa, S.; De Stefano, S.; Sodano, G.
Comp. Biochem. Physiol., Part B: Comp. Biochem. 1982, 73b,
471–474. doi:10.1016/0305-0491(82)90061-x
8. Cafieri, F.; De Napoli, L.; Fattorusso, E.; Santacroce, C.; Sica, D.
Tetrahedron Lett. 1977, 18, 477–480.
32.Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1980, 63, 197–200.
doi:10.1002/hlca.19800630118
33.Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1985, 63, 109.
34.Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.;
Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92,
741–743. doi:10.1021/ja00706a074
doi:10.1016/S0040-4039(01)92670-x
2426

Beilstein J. Org. Chem. 2014, 10, 2421–2427.
35.Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002.
doi:10.1021/cr020703u
36.Trost, B. M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005,
127, 7014–7024. doi:10.1021/ja050340q
37.Shiina, I.; Yamai, Y.; Shimazaki, T. J. Org. Chem. 2005, 70,
8103–8106. doi:10.1021/jo051276y
38.Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993. doi:10.1246/bcsj.52.1989
39.Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614–5616.
doi:10.1021/ja00824a073
40.Mukaiyama, T.; Kobayashi, S.; Uchiro, H.; Shiina, I. Chem. Lett. 1990,
19, 129–132. doi:10.1246/cl.1990.129
41.Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T.
J. Am. Chem. Soc. 1991, 113, 4247–4252. doi:10.1021/ja00011a030
42.Shiina, I. Chem. Rec. 2014, 14, 144–183. doi:10.1002/tcr.201300022
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