3
For the synthesis of natural (2S,4S)–LPA (1), amine 11a was
reprotected with Boc group (Boc O, NaHCO ) to give rise to 13a
Scheme 3). Next we tried chemoselective removal of
isopropylidene group of 13a over the N–Boc group. While
attempts using standard procedure (80% AcOH or Amberlyst–15
References and notes
2
3
(
1. G. Riedel, B. Platt, J. Micheau, Behav. Brain. Res. 140 (2003) 1-
4
7.
2
.
G.T. Swanson, R. Sakai, in Marine Toxins as Research Tools; N.
Fusetani, W. Kem (Eds.), Springer Berlin Heidelberg, Berlin,
Heidelberg (2009) pp. 123-157.
(EtOH, water)) [28] met with failure, we found that Inoue’s
procedure (TfOH, CF CH OH, THF) [29,30] effected selective
3
2
3. R. Sakai, H. Kamiya, M. Murata, K. Shimamoto, J. Am. Chem.
Soc. 119 (1997) 4112-4116.
deprotection of the isopropylidene group and concomitant
lactonization without affecting the acid-labile N–Boc group to
afford γ–butyrolactone (2S,4S)–14a in 47% yield, whose
spectroscopic data were in good accord with those reported [14].
4
.
R. Sakai, T. Koike, M. Sasaki, K. Shimamoto, C. Oiwa, A. Yano,
K. Suzuki, K. Tachibana, H. Kamiya, Org. Lett. 3 (2001) 1479-
482.
S. Murakami, T. Takemoto, Z. Shimizu, YAKUGAKU ZASSHI
3 (1953) 1026-1028.
1
5
.
7
The primary hydroxy group of 14a was then oxidized with
RuO to furnish carboxylic acid 15a in 83% yield. To complete
4
6
7
.
.
T. Takemoto, K. Daigo, Chem. Pharm. Bull. 6 (1958) 578b-580.
K. Konno, H. Shirahama, T. Matsumoto, Tetrahedron Lett. 24
(1983) 939-942.
the synthesis, protective group manipulation and lactone
construction at the correct position were first attempted according
to the reported two-step procedure [14] (procedure A) as follows.
Thus, exposure of carboxylic acid 15a to NaOH in MeOH and
water at rt induced translactonization smoothly in 1 h. Then
8. K. Shin-ya, J.-S. Kim, K. Furihata, Y. Hayakawa, H. Seto,
Tetrahedron Lett. 38 (1997) 7079-7082.
9
.
J. Lamotte, B. Oleksyn, L. Dupont, O. Dideberg, H. Campsteyn,
M. Vermeire, N. Rhugendabanga, Acta Crystallogr., Sect. B:
Struct. Sci. 34 (1978) 3635-3638.
removal of the Boc group was carried out with HCO
HCl, to afford LPA (1) in 94% yield (86% purity) [31] for 2 steps
32% after recrystallization from water). Spectroscopic data of
the synthetic LPA (1) were in good accord with those reported
11,14]. For these transformations, however, we found that a
2
H and 1 M
10. M. Kaname, S. Yoshifuji, Tetrahedron Lett. 33 (1992) 8103-8104.
11. S. Yoshifuji, M. Kaname, Chem. Pharm. Bull. 43 (1995) 1617-
1
620.
(
1
1
2. H. Masaki, T. Mizozoe, T. Esumi, Y. Iwabuchi, S. Hatakeyama,
Tetrahedron Lett. 41 (2000) 4801-4804.
3. K. Makino, K. Shintani, T. Yamatake, O. Hara, K. Hatano, Y.
Hamada, Tetrahedron 58 (2002) 9737-9740.
[
simple one-step procedure (B, 1 M HCl, 90 °C) is also effective
to furnish LPA (1) in 69% yield (25% yield after
recrystallization). By the latter one-step procedure B, no
epimerization at the C2 position took place, which we observed
in the former two-step procedure A in approximately 13% (see
above) [31]. 4–epi–LPA (2) was also synthesized from (2S,4R)–
14. O. Tamura, T. Shiro, M. Ogasawara, A. Toyao, H. Ishibashi, J.
Org. Chem. 70 (2005) 4569-4577.
1
5. J.L. Cohen, A.R. Chamberlin, J. Org. Chem. 72 (2007) 9240-
247.
9
1
6. G. Kachkovskyi, C. Faderl, O. Reiser, Adv. Synth. Catal. 355
(2013) 2240-2248.
1
1b (see Scheme 2) after the same sequence of reaction in 6.2%
17. A. Paju, D. Kostomarova, K. Matkevitš, M. Laos, T. Pehk, T.
Kanger, M. Lopp, Tetrahedron 71 (2015) 9313-9320.
yield (see the Supplementary data). The total yields for LPA (1)
and 4–epi–LPA (2) were 5.7% and 1.2%, respectively, for 11
steps each from ketone 3.
1
1
8. M.B. Gill, S. Frausto, M. Ikoma, M. Sasaki, M. Oikawa, R. Sakai,
G.T. Swanson, Br. J. Pharmacol. 160 (2010) 1417-1429.
9. L. Juknaite, Y. Sugamata, K. Tokiwa, Y. Ishikawa, S.
Takamizawa, A. Eng, R. Sakai, D.S. Pickering, K. Frydenvang,
G.T. Swanson, J.S. Kastrup, M. Oikawa, J. Med. Chem. 56 (2013)
In conclusion, we have achieved enantiospecific syntheses of
mushroom-derived lycoperdic acid (1) and the 4–epi–congener 2
for development of glutamate analogs with diverse
neuroactivities. The key reaction was enantioselective
hydrogenation of enamide ester rac–9 mediated by (R,S)–
MeBoPhoz. From the enantioselectivity profile shown in Scheme
2
283-2293.
20. E.M. González-García, J. Grognux, D. Wahler, J.-L. Reymond,
Helv. Chim. Acta 86 (2003) 2458-2470.
2
1. D. Enders, I. Breuer, E. Drosdow, Synthesis 2005 (2005) 3239-
244.
2. A.J. Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 43 (1978)
480-2482.
3
2
2
, (4S)–9 and (R,S)–MeBoPhoz are stereochemically rather
2
mismatched, and hydrogenation of (4R)–9 with (R,S)–MeBoPhoz
is a matched double asymmetric reaction [32,33]. The synthetic
route reported herein is reasonably expected to provide other
isomers of LPA. Works on the synthesis and evaluation are
currently underway, and the results will be reported in due
course.
23. U. Schmidt, A. Lieberknecht, J. Wild, Synthesis 1984 (1984) 53-
60.
2
4. N.W. Boaz, E.B. Mackenzie, S.D. Debenham, S.E. Large, J.A.
Ponasik, J. Org. Chem. 70 (2005) 1872-1880.
2
2
5. N. Grimblat, A.M. Sarotti, Chem. Eur. J. 22 (2016) 12246-12261.
6. K. Tanaka, H. Manabe, R. Irie, M. Oikawa, Bull. Chem. Soc. Jpn.
9
2 (2019) in press.
7. S.G. Smith, J.M. Goodman, J. Am. Chem. Soc. 132 (2010) 12946-
2959.
2
1
Acknowledgments
2
2
3
8. J. Zhu, D. Ma, Angew. Chem. Int. Ed. 42 (2003) 5348-5351.
9. J.L. Holcombe, T. Livinghouse, J. Org. Chem. 51 (1986) 111-113.
0. M. Inoue, T. Sasaki, S. Hatano, M. Hirama, Angew. Chem. Int.
Ed. 43 (2004) 6500-6505.
This work was supported by the grant for Academic Research
Promotion (No. SG2803) of Yokohama City University, Japan.
3
1. The impurity in crude LPA prepared by the procedure A is a
Appendix A. Supplementary data
(2R,4S)–isomer. The details will be reported in the full account of
this work.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.########.
32. M. Chen, W.R. Roush, J. Am. Chem. Soc. 134 (2012) 10947-
10952.
3. L. Huang, Y. Zhang, R.J. Staples, R.H. Huang, W.D. Wulff,
Chem. Eur. J. 18 (2012) 5302-5313.
3
Configuration was analyzed by experimental and
1
3
calculated C NMR data.
Lycoperdic acid and the 4–epi–congener have been
enantiospecifically synthesized.
Asymmetric hydrogenation by (R,S)–MeBoPhoz
ligand was employed for the amino acid.