Total synthesis of (+)-tanikolide, a toxic and antifungal δ-lactone, utilizing bromoalkene intermediates conveniently synthesized from vicinal dibromoalkane by regioselective elimination

Article abstract of DOI:10.1016/j.tetlet.2004.09.085

Stereoselective total synthesis of (+)-tanikolide, a bioactive δ-lactone marine natural product, was successfully accomplished by using regioselective HBr elimination reaction of 3-acyloxy-1,2-dibromoalkanes, Pd-mediated coupling reaction, and the Sharpless asymmetric epoxidation as key steps.

Full text of DOI:10.1016/j.tetlet.2004.09.085

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8273–8275
Total synthesis of (+)-tanikolide, a toxic and antifungal
d-lactone, utilizing bromoalkene intermediates
conveniently synthesized from vicinal dibromoalkane
by regioselective elimination
Tadaaki Ohgiya and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 24 August 2004; revised 10 September 2004; accepted 13 September 2004
Abstract—Stereoselective total synthesis of (+)-tanikolide, a bioactive d-lactone marine natural product, was successfully accomp-
lished by using regioselective HBr elimination reaction of 3-acyloxy-1,2-dibromoalkanes, Pd-mediated coupling reaction, and the
Sharpless asymmetric epoxidation as key steps.
Ó 2004 Elsevier Ltd. All rights reserved.
(+)-Tanikolide (1)1 is a biologically active d-lactone nat-
ural product isolated from the lipid extract of the marine
cyanobacterium, Lyngbia majuscula, collected in Tanik-
eli Island, Madagascar. The structural character of 1 is a
chiral quaternary carbon center with a hydroxymethyl
group and a multicarbon chain, similar to that of (ꢀ)-
malyngolide 2.2 1 exhibited antifungal activity against
Candida albicans, along with LD50 3.6lg/mL against
brine shrimp and 9.0lg/mL against snail.1 To under-
stand the structure–activity relationship, synthetic stud-
ies of 1 have been reported as follows.3 The first total
synthesis of (+)-1 was achieved by using a catalytic
asymmetric hydrogen transfer reaction of a tricyclic
alcohol.3a Methodologies using the ring-closing meta-
thesis (RCM) for construction of the d-lactone moiety
as key steps were reported for the total synthesis of
(+)-1 by two groups.3c,d
mediated coupling reaction, the total synthesis of bio-
logically active natural products was reported: when 3-
O-substituted-1-alkyl-1,2-dibromoalkanes were submit-
ted to this elimination reaction, the syn- and anti-orient-
ated derivatives provided the same trans-eliminated
process.4 As an additional demonstration of the regio-
selective elimination reaction, we describe herein stereo-
selective total synthesis of 1 using our regioselective HBr
elimination reaction of 3-O-substituted-1-alkyl-1,2-di-
bromoalkane derivatives,4 Pd-mediated coupling reac-
tion,5 and the Sharpless asymmetric epoxidation as the
key steps (Fig. 1).6
Recently, we developed an efficient highly regioselective
HBr elimination reaction of 2-bromo-1-alkenes synthe-
sized from the corresponding 3-aryloxy- or 3-acyloxy-
1,2-dibromoalkanes under mild basic conditions. By
employing this methodology and the transition metal-
Keywords: Antifungal lactone; Bromoalkene; Tanikolide; Regioselec-
tive elimination; Lyngbia majuscula.
*
Corresponding author. Tel./fax: +81 45 566 1717; e-mail:
nisiyama@chem.keio.ac.jp
Figure 1. Structures of tanikolide 1 and malyngolide 2.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.085

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T. Ohgiya, S. Nishiyama / Tetrahedron Letters 45 (2004) 8273–8275
yield, which was submitted to bromination with Pyr.-
HBr3 to yield the racemic anti-dibromide 7 in 95% yield.
Regioselective trans-elimination of the vicinal dibromide
carrying the acyloxy group at the adjacent position with
DBU4 provided the bromoalkene derivatives 8, 9, and
10 in 94% yield (8:9:10 = 60:1:1), the stereochemistry
of which was determined by the NOE experiments.
The p-nitrobenzoyl group was converted into a BOM
ether, due to the fact that allyl acylates produce a p-allyl
complex under the Pd-mediated coupling conditions.7
Thus, hydrolysis under basic conditions, followed by
chromatographic separation, afforded 11 in 94% yield,
which was etherified with BOMCl–iPr2NEt to give 4 in
98% yield. The desired Pd-coupling reaction5 was
achieved by using Pd(dppf)Cl2 to give 12 in 73% yield.
In the next oxidation step, the Sharpless asymmetric
dihydroxylation8 did not proceed at low temperature.
Upon reacting at ambient temperature, the induced
enantioselectivity of the oxidation product 13 was less
than 50% ee.9
Scheme 1. Retrosynthesis of 1.
Retrosynthetic analysis indicated that 1 would be con-
structed from 3 by using the Sharpless asymmetric epoxi-
dation6 and lactonization (Scheme 1). The allyl alcohol 3
may be synthesized by the Pd-mediated coupling reac-
tion5 from bromoalkene 4, readily available by bromina-
tion of alkene 5, and the following regioselective HBr
elimination reaction.4
Accordingly, we employed the Sharpless asymmetric
epoxidation6 for construction of a chiral quaternary car-
bon center (Scheme 3). Cleavage of the BOM group of
12 under acidic conditions afforded the allyl alcohol 3
in 80% yield. The asymmetric epoxidation of 3 was
achieved by the general protocol of the Sharpless epoxi-
dation6 to give 14 in 99% yield as 92–94% ee,9 which
upon TBDPS etherification gave 15 in quantitative
yield. Reductive opening of the epoxy ring of 15 was
achieved with LiEt3BH at 60°C to give a 1:1 mixture
of diol 16 and the silyl-migrated isomer 17 in 94% yield,
Along this line, synthesis of 1 commenced with acylation
of 5 (Scheme 2). As the regioselectivity and yield of our
HBr elimination reaction were regulated by the electron-
withdrawing effect of the O-functional groups at the
adjacent position of the vicinal dibromoalkyl moiety,4
we selected a p-nitrobenzoyl group, carrying a strong
electron-withdrawing effect, as an acyl moiety. Acyla-
tion of 5 gave the corresponding ester 6 in quantitative
Scheme 2. Reagents and conditions: (a) p-NO2C6H4COCl, Pyr., CH2Cl2, rt (100%). (b) Pyr.-HBr3, AcOH, rt (95%). (c) DBU, DMF, 50°C (94%;
8:9:10 = 60:1:1). (d) LiOH, dioxane, 0°C (94%). (e) BOMCl, iPr2NEt, CH2Cl2, rt (98%). (f) 5mol% Pd(dppf)Cl2, BrZnCH2CH2CH2COOEt, THF–
t
PhMe, 90°C (73%). (g) AD-mix-a, aq BuOH, rt (85%).

T. Ohgiya, S. Nishiyama / Tetrahedron Letters 45 (2004) 8273–8275
8275
Scheme 3. Reagents and conditions: (a) concd HCl, EtOH, 50°C (80%). (b) (ꢀ)-DET, TBHP, Ti(OiPr)4, CH2Cl2, ꢀ30°C (99%). (c) TBDPSCl, Imd,
DMF, rt (100%). (d) LiEt3BH, THF, 60°C (94%; 16:17 = 1:1). (e) PCC, MS4A, CH2Cl2, 0°C (60%; 18:19 = 6:1). (f) TBAF, THF, rt (87%).
Watanabe, M.; Honda, T. Tetrahedron 2002, 58, 8929–
8936; (d) Carda, H.; Rodriguez, S.; Castillo, E.; Bellido, A.;
Diaz-Oltra, S.; Marco, J. A. Tetrahedron 2003, 59, 857–
864; (e) Koumbis, A. E.; Dieti, K. M.; Vikentiou, M. G.;
Gallos, J. K. Tetrahedron Lett. 2003, 44, 2513–2516; (f)
Schomaker, J. M.; Borhan, B. Org. Biomol. Chem. 2004, 2,
621–624.
which underwent lactonization with PCC to give a 6:1
mixture of the six-membered ring lactone 18 and the
seven-membered ring lactone 19 in 60% yield. Finally,
treatment of the mixture with TBAF afforded (+)-1 in
22
25
87% yield, ½aꢁ +1.9 (c 1.0, CHCl3) {lit.,1 ½aꢁ +2.3 (c
D
D
0.65, CHCl3)}. The synthetic (+)-1 was identical to the
natural product under the full range of spectroscopic
data.1
4. Ohgiya, T.; Nishiyama, S. Chem. Lett. 2004, 33, 1084–1085.
5. Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298–3299.
In conclusion, the total synthesis of (+)-1, a toxic and
antifungal metabolite, was accomplished by utilizing
our efficient and simple bromoalkene synthesis by the
regioselective HBr elimination reaction. As demon-
strated, our approach is applicable to other congeners.
Further investigation is in progress.
6. (a) Finn, M. G.; Sharpless, K. B. In On the Mechanism of
Asymmetric Epoxydation with Titanium-Tartrate Catalysts.
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic:
Tokyo, 1985; Vol. 5, pp 247–308; (b) Katsuki, T.; Sharpless,
K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.
7. (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980,
102, 4730–4743; (b) Trost, B. M.; Asakawa, N. Synthesis
1999, 1491–1494.
References and notes
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4585–4588; (b) Sharpless, K. B.; Amberg, W.; Bennani, Y.
L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-
L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J.
Org. Chem. 1992, 57, 2768–2771.
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K. Tetrahedron Lett. 2002, 43, 4175–4178; (c) Mizutani, H.;
1
9. The optical purity was determined by 400MHz H NMR
spectra of the corresponding MTPA ester.