Enantiocontrolled synthesis of C-19 tetrahydrofurans isolated from the marine alga Notheia anomala

Article abstract of DOI:10.1016/S0040-4039(00)00595-5

The stereocontrolled synthesis of (2S,3S,5R)-5-[(1R)-1-hydroxy-9- decenyl]-2-pentyltetrahydro-3-furanol and (2S,3S,5S)-5-[(1S)-1-hydroxy-9- decenyl]-2-pentyltetrahydro-3-furanol, both isolated from the brown alga Notheia anomala has been achieved. The req

Full text of DOI:10.1016/S0040-4039(00)00595-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4127–4130
Enantiocontrolled synthesis of C-19 tetrahydrofurans isolated
from the marine alga Notheia anomala
Celina García, Marcos A. Soler and Víctor S. Martín ∗
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Universidad de La Laguna, C/Astrofísico Francisco Sánchez, 2,
38206 La Laguna, Tenerife, Spain
Received 25 February 2000; accepted 7 April 2000
Abstract
The stereocontrolled synthesis of (2S,3S,5R)-5-[(1R)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol and
(2S,3S,5S)-5-[(1S)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol, both isolated from the brown alga Notheia
anomala has been achieved. The requisite configurations of the stereogenic centres were established by Sharpless
asymmetric dihydroxylation and Katsuki–Sharpless asymmetric epoxidation. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: marine metabolites; asymmetric synthesis; enantiopure functionalized tetrahydrofurans.
(2S,3S,5R)-5-[(1R)-1-Hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol (1)1 and (2S,3S,5S)-5-[(1S)-
1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol (2),2 which have a characteristic substitution pat-
tern in their tetrahydrofuran ring system, are C19 diols isolated from Notheia anomala, a member
of the Notheiaceae family, a taxonomically unique brown alga found along the southern Australian
coasts. These tetrahydrofurans have been considered to be biosynthesized via a cyclization of a natu-
ral methylene-interrupted bisepoxide and, within this context, a biomimetic synthesis of the racemic
compounds has been reported.3 On the other hand, both 1 and 2 are potent and selective inhibitors of the
larval development of parasitic nematodes.
Considerable efforts have been directed to the synthesis of 14 but, to the best of our knowledge,
no enantiomeric synthesis of 2 has hitherto been reported. Within our general program directed at the
enantiomeric synthesis of bioactive substances of marine origin,5 we focused our attention on the above-
mentioned compounds as examples of metabolites containing a highly functionalized tetrahydrofuran
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00595-5
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ring. In this communication, we describe our approach to the enantiomeric synthesis of these compounds,
based on the retrosynthetic analysis outlined in Scheme 1. We considered a general methodology that
would permit the selection of the stereochemistry in the ring formation in a simple manner. Thus, we
first disconnected the unsaturated chain to the terminal epoxide 3, bearing in mind the possibility of
introducing such a chain by a nucleophilic opening of the terminal ring. This epoxide with the correct
stereochemistry would be built from suitable 2,3-epoxy alcohol 4, available by a Katsuki–Sharpless
asymmetric epoxidation (AE)6 of the corresponding allylic alcohol obtained by homologation from a
γ-lactone such as 5, which should be easily synthesized by Sharpless asymmetric dihydroxylation (AD)7
of the corresponding β,γ-unsaturated ester 6.8
Scheme 1.
Our synthesis of 1 and 2 started with the unsaturated ester 6, available by a modified Knoevenagel
condensation of malonic acid and n-heptanal (Scheme 2).9 The application to 6 of the AD reaction using
AD-mix-α provided the γ-lactone 5 in 96% ee, in accordance with the NMR analysis of the correspon-
ding Mosher’s esters.10 With these steps we simultaneously achieved two important goals: firstly, we
introduced the correct stereochemistry in two stereocentres of the final molecules, and secondly, by the
lactonization we performed the chemical differentiation between the two hydroxy groups. The protection
of the free secondary hydroxy group led to the silyl ether 7 that was converted to the E-unsaturated ester
8 by selective reduction to the corresponding lactol followed by a Horner–Wadsworth–Emmons reaction.
The reduction of 8 provided the allylic alcohol 9, useful to introduce the remaining stereocentres.
Scheme 2. Reagents and conditions: (a) (i) malonic acid, piperidine (cat.), xylene, reflux, 3 h; (ii) TMSCl, MeOH, rt, 2 h, 80%
overall; (b) AD-mix-α, CH3SO2NH2, t-BuOH:H2O (1:1), 0°C, 20 h, 82%; (c) TBDPSCl, imidazole, CH2Cl2, rt, overnight,
96%; (d) (i) DIBAL-H (1 equiv.), ether, −78 °C, 5 min; (ii) Ph3P_CHCO2Et, benzene, 50°C, 2 h, 89% overall; (e) DIBAL-H,
ether, 0°C, 5 min, 77%
At this step of the synthesis we pondered a divergent strategy to access either 1 or 2, simply choosing
the suitable reagent in the next stereoselective reaction. Thus, the asymmetric epoxidation of 9 using
(R,R)-(+)-DET provided by concomitant epoxide opening11 the anti-tetrahydrofuran 10 as the sole
detected stereoisomer, while the use of the enantiomeric chiral auxiliary provided the corresponding
syn-diastereoisomer 11.12 In both cases, we constructed the desired tetrahydrofurans having controlled
three of the required stereocentres (Scheme 3).
Scheme 3. Reagents and conditions: (a) Ti(OPr-i)4, (R,R)-(+)-DET, TBHP, CH2Cl2, −20°C, 2 h, 82%; (b) Ti(OPr-i)4,
(S,S)-(−)-DET, TBHP, CH2Cl2, −20°C, 2 h, 82%
In order to fulfil the synthesis of natural compounds, first we addressed our efforts to the synthesis of 1.
Thus, the diol 10 was monoprotected as the benzoyl ester and the secondary free alcohol was transformed

4129
into the corresponding mesylate 12. Basic hydrolysis of the ester then provided the terminal epoxide 13
by intramolecular displacement of the secondary mesylate group with the primary alkoxide. Opening of
the terminal epoxide with the Grignard reagent derived from commercially available 8-bromo-1-octene,
in the presence of CuI, furnished compound 14 that after cleavage of the silyl protecting group provided
25
(2S,3S,5R)-5-[(1R)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol (1), mp 50–52°C, [α] =+15.2
D
(c 0.8, CHCl3).13
With these satisfactory results in our hands, the synthesis of the diastereoisomer 2, mp 35–37°C,
25
[α] =+20.5 (c 0.4, CHCl3),14 was performed in a straightforward and similar manner from 11 (Scheme
D
4).
Scheme 4. Reagents and conditions: (a) (i) BzCl (1.2 equiv.), TEA, CH2Cl2, 0°C, 2 h, (ii) MsCl, TEA, 0°C, 15 min, 75%; (b)
NaH, MeOH, CH2Cl2, 0°C, 30 min, 80%; (c) H2C_CH–(CH2)7MgBr, CuI, THF, –30°C; (d) TBAF, THF, rt, 1 h, 78%
In summary, we have developed
a
divergent route to anti- or syn-2-hydroxy-2,5-
dialkyltetrahydrofurans from a common precursor. The application of two consecutive enantioselective
reactions ensures very high enantiomeric purity in the final products. Moreover, the described
methodology can be applied to other natural products with a similar structure.
Acknowledgements
This research was supported by the DGES (PB95-0751) of Spain, FEDER-1FD97-0747-C04-01 and
the Consejería de Educación, Cultura y Deportes del Gobierno de Canarias. C.G. thanks the Spanish
MEC for an FPI fellowship. Special thanks are given to Professor Robert J. Capon for helpful discussions
related to compound 2.
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study.