Stereocontrolled synthesis of (+)-lycoperdic acid based on a palladium catalyzed reaction using a serine-derived organozinc reagent

Article abstract of DOI:10.1016/S0040-4039(00)00719-X

An efficient stereocontrolled synthesis of (+)-lycoperdic acid has been achieved based on palladium catalyzed cross-coupling reaction of (Z)-1-(tert- butyldimethylsiloxy)-3-iodo-6-(p-methoxybenzyl)oxy-2-hexene with the organozinc reagent, prepared from N-Boc-β-iodoalanine methyl ester. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00719-X

Tetrahedron Letters 41 (2000) 4801±4804
Stereocontrolled synthesis of (+)-lycoperdic acid based on a
palladium catalyzed reaction using a serine-derived
organozinc reagent
Hidekazu Masaki, Tomoko Mizozoe, Tomoyuki Esumi, Yoshiharu Iwabuchi
and Susumi Hatakeyama*
Faculty of Pharmaceutical Sciences, Nagasaki University, Nagasaki 852-8131, Japan
Received 28 March 2000; revised 24 April 2000; accepted 28 April 2000
Abstract
An ecient stereocontrolled synthesis of (+)-lycoperdic acid has been achieved based on palladium catalyzed
cross-coupling reaction of (Z)-1-(tert-butyldimethylsiloxy)-3-iodo-6-(p-methoxybenzyl)oxy-2-hexene with
the organozinc reagent, prepared from N-Boc-b-iodoalanine methyl ester. # 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: amino acids; palladium catalyzed reactions; coupling reactions; organozinc compounds.
In connection with a project directed towards a total synthesis of dysiherbaine (2), a novel
neuroexitotoxin occurring in a Micronesian marine sponge Dysidea herbacea,1 we became inter-
ested in lycoperdic acid (1), a non-proteinogenic a-amino acid isolated from the mushroom
Lycoperdon perlatum (Fig. 1).2,3 This amino acid is the 50-oxo analogue of 2-amino-3-(20-carboxy-
50-tetrahydrofuranyl)propanoic acid which is the core structure of dysiherbaine (2). Although
there has been no report concerning biological activity, lycoperdic acid (1) is expected to possess
neuroexcitatory activity because of structural similarity with glutamic acid, a major neuroexcitatory
substance in the mammalian central nerve system. This combination of structural features and
potential biological activity prompted us to investigate a total synthesis of (+)-lycoperdic acid (1).
Our strategy leading to lycoperdic acid (1) relies on palladium catalyzed cross-coupling reac-
tion of an alkenyl iodide or tri¯ate 5 (XˆI or OTf) with the organozinc reagent 4, prepared from
3, based on Jackson's method4 originated from Tamaru's protocol5 (Scheme 1). We envisaged
that total synthesis of 1 would be achieved stereoselectively from the coupling product 6 through
three major transformations; (i) diastereoselective epoxidation; (ii) acid catalyzed cyclization; (iii)
oxidation.
* Corresponding author. Tel: +81 95 847 1111; fax: +81 95 848 4286; e-mail: susumi@net.nagasaki-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00719-X

4802
Figure 1.
Although various examples of the palladium catalyzed coupling reactions using organozinc
reagents derived from l-serine have already been described in the literature,4,6 aryl halides were
predominantly used as a coupling partner and little attention has been paid to acyclic alkenyl
halides or tri¯ates. Therefore, we ®rst undertook experiments summarized in Table 1. Coupling
reactions of 5a±d were carried out using 0.2 equivalents of Pd(PPh3)4 and organozinc reagent 4,
prepared in situ from 3 equivalents of 3 (R=Bn).y As can be seen from Table 1, this reaction was
found to be applicable to both alkenyl iodides and tri¯ates and the corresponding coupling
products 6a±d were obtained in moderate to excellent yields, except for the example listed in entry
3. In the case of the alkenyl tri¯ate, addition of LiCl turned out to produce better results (entries
5 and 6).
Scheme 1.
Table 1
Palladium catalyzed reactions of the organozinc reagent prepared from 3 (R=Bn) with 5
y
Since benzyl 2-(methoxycarbonylamino)acrylate was also formed under these conditions, the use of 3±5 equiv. of
N-Boc-b-iodoalanine was required for sucient production of the organozinc reagent.

4803
Scheme 2 illustrates the synthesis of (+)-lycoperdic acid (1) based on the above-mentioned
strategy. Alkylation of tetrahydro-2-(2-propynyloxy)-2H-pyran (7) with 1-iodo-3-(p-methoxy-
benzyl)oxypropane, followed by removal of the THP ether protecting group gave propargyl
alcohol 8. Reaction of 8 with Red-Al1,7 followed by treatment of the resulting alkenylaluminum
complex with iodine allowed stereo- and regioselective formation of the corresponding (Z)-iodo-
alkene which was protected as its TBS ether to give 5b.
Scheme 2. (a) n-BuLi, 1-iodo-3-(p-methoxybenzyl)oxypropane, THF±HMPA, ^25ꢀC to rt; (b) PPTS, MeOH, re¯ux;
(c) NaH2Al(OCH2CH2OMe)2, Et2O, then I2; (d) tert-BuMe2SiCl, Et3N±DMAP, CH2Cl2; (e) 3 (2.5 equiv.), Zu±Cu (2.8
equiv.), benzene±DMA (10:1), sonication, 45ꢀC, then 5b in benzene±HMPA (5:2), Pd(PPh3)4 (5 mol%), 80ꢀC; (f)
AcOH±H2O±THF (3:1:1); (g) diisopropyl l-tartrate (10 mol%), Ti(O-i-Pr)4 (8 mol%), t-BuOOH (2 equiv.), 4A
molecular sieves, CH2Cl2, ^30ꢀC; (h) DDQ, CH2Cl2±H2O (20:1); (i) PPTS, CH2Cl2; (j) Pb(OAc)4, THF, ^20ꢀC; (k)
H2CrO4, acetone; (l) RuCl3 (10 mol%), NaIO4 (4 equiv.), CCl4±MeCN±H2O (2:2:3); (m) 6 M HCl, re¯ux
Upon reaction of 5b with the organozinc reagent, prepared in situ from 3 (R=Me, see entry 2
in Table 1), palladium catalyzed coupling reaction took place very cleanly and, after desilylation,
allylic alcohol 9, ‰ꢀŠ21 +2.9 (c 1.18, CHCl3), was obtained in good yield. Katsuki±Sharpless catalytic
D
asymmetric epoxidation8 of 9 proceeded with complete diastereoselectivity to give epoxide 10,
23
D
‰ꢀŠ ^4.6 (c 1.40, CHCl3), which was then subjected to oxidative removal9 of the MPM ether
protecting group to a€ord diol 11, ‰ꢀŠ22 +2.8 (c 1.55, CHCl3). Treatment of 11 with PPTS brought
D
about stereoselective cyclization with complete inversion of stereochemistry at the quaternary
center to give tetrahydrofuran 12 which was directly subjected to Pb(OAc)4-oxidation and Jones
oxidation to provide lactam 13, ‰ꢀŠ20 ^44.6 (c 0.55, CHCl3), in 50% overall yield. RuO4-oxidation10{
21
D
27
D
of 13 gave known lactone 14, mp 144±146ꢀC, ‰ꢀŠ ^70.4 (c 1.05, CHCl3) {lit.3 mp 143±145ꢀC,
‰ꢀŠ ^68.2 (c 1.10, CHCl3)}, almost quantitatively. Finally, acidic hydrolysis of 14 according to
D
the reported procedure3 furnished (+)-lycoperdic acid (1), mp 200±202ꢀC, ‰ꢀŠ28 +12.7 (c 0.21, H2O)
D
{
RuO4-oxidation of 12 gave 14 directly but in poor yield (20%).

4804
{lit.3 mp 200±201ꢀC, ‰ꢀŠ20 +14.9 (c 0.47, H2O)}. The synthetic substance exhibited spectral properties
D
(1H and 13C NMR) in accord with those reported.3
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