A highly stereocontrolled total synthesis of (-)-neodysiherbaine A

Article abstract of DOI:10.1021/jo060410r

Neodysiherbaine A, a neuroexitotoxin occurring in a Micronesian marine sponge Dysidea herbacea, was synthesized from tri-O-acetyl-D-glucal with excellent stereocontrol. The method established enables us to obtain gram quantities of neodysiherbaine A and i

Full text of DOI:10.1021/jo060410r

A Highly Stereocontrolled Total Synthesis of (-)-Neodysiherbaine A
Keisuke Takahashi, Takashi Matsumura, Graeme R. M. Corbin, Jun Ishihara, and
Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki UniVersity, Nagasaki 852-8521, Japan
susumi@net.nagasaki-u.ac.jp
ReceiVed February 27, 2006
Neodysiherbaine A, a neuroexitotoxin occurring in a Micronesian marine sponge Dysidea herbacea, was
synthesized from tri-O-acetyl-D-glucal with excellent stereocontrol. The method established enables us
to obtain gram quantities of neodysiherbaine A and its related compounds.
Introduction
Dysiherbaine (1) and neodysiherbaine A (2) are novel amino
acids isolated from the Micronesian sponge Dysidea herbacea
by Sakai et al.1,2 These amino acids are known to be highly
selective agonists of AMPA-KA-type glutamate receptors and
exhibit the most potent convulsant activity among the excitatory
amino acids known to date such as kainic acid and domoic acid.3
Due to the low availability from natural sources as well as the
intriguing biological activity and characteristic structures involv-
ing a cis-fused hexahydrofuro[3,2-b]pyran ring system contain-
ing a glutamic acid appendage, this family of natural amino
acids are good targets for synthesis. Thus, there have been a
number of synthetic studies including four total syntheses of
dysiherbaine (1)4,5 and two total syntheses of neodysiherbaine
A (2) (Figure 1).2,6,7 However, all methods are not efficient
enough to obtain gram quantities of these amino acids as well
FIGURE 1. Neuroexcitatory amino acids of Dysidea herbacea.
as their derivatives, except for the one just recently reported by
Lygo et al.6 In addition, the stereocontrolled construction of
the C4 quaternary stereogenic center has remained an unsolved
problem despite the significance of the C4 configuration for
the biological activity.2,4ab For this stereocontrol issue, Lygo et
al.6 successfuly provided one solution using RuO4-mediated
oxidative cyclization of a 1,5-diene. We herein report a novel
synthesis of (-)-neodysiherbfaine A (2) where all stereogenic
centers including the C4 quaternary center were constructed in
highly stereocontrolled manner over 98% de.
(1) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem.
Soc. 1997, 119, 4112-4116.
Results and Discussion
(2) Sakai, R.; Koike, T.; Sasaki, M.; Shimamoto, K.; Oiwa, C.; Yano,
A.; Suzuki, K.; Tachibana, K.; Kamiya, H. Org. Lett. 2001, 3, 1479-1482.
(3) (a) Sasaki, M.; Maruyama, T. Sakai, R.; Tachibana, K. Tetrahedron
Lett. 1999, 40, 3195-3198. (b) Sakai, R.; Swanson, G. T.; Shimamoto, K.;
Green, T.; Contractor, A.; Ghetti, A.; Tamura-Horikawa, Y.; Oiwa, C.;
Kamiya, H. J. Pharm. Exp. Ther. 2001, 296, 650-658. (c) Swanson, G.
T.; Green, T.; Sakai, R.; Contractor, A.; Che, W.; Kamiya, H.; Heinemann,
S. F. Neuron 2002, 34, 589-598. (d) Sanders, J. M.; Ito, K.; Settimo, L.;
Pentika¨inen, O. T.; Shoji, M.; Sasaki, M.; Johnson, M. S.; Sakai, R.;
Swanson, G. T. J. Pharm. Exp. Ther. 2005, 314, 1068-1078.
(4) (a) Masaki, H.; Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. J. Am. Chem. Soc. 2000, 122, 5216-5217. (b) Sasaki, M.;
Koike, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett. 2000, 41, 3923-
3926. (c) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2000, 2, 635-638. (d)
Phillips, D.; Chamberlin, A. R.; J. Org. Chem. 2002, 67, 3194-3201.
Our synthetic plan is illustrated in Scheme 1. Based on the
methodology we have demonstrated in the total synthesis of
(5) For synthetic studies on dyshiherbaine, see: (a) Miyata, O.; Iba, R.;
Hashimoto, J.; Naito, T. Org. Biomol. Chem. 2003, 1, 772-774. (b) Kang,
S. H.; Lee, Y. M. Synlett 2003, 7, 993-994. (c) Huang, J.-M.; Xu, K.-C.;
Loh, T.-P. Synthesis 2003, 5, 755-764. (d) Naito, T.; Nair, J. S.; Nishiki,
A.; Yamashita, K.; Kiguchi, T. Heterocycles 2000, 53, 2611-2615.
(6) Lygo, B.; Slack, D.; Wilson, C. Tetrahedron Lett. 2005, 46, 6629-
6632.
(7) For the synthesis of 8,9-diepineodysiherbaine A, see: Shoji, M.;
Shiohara, K.; Oikawa, M.; Sakai, R.; Sasaki, M.; Tetrahedron Lett. 2005,
46, 5559-5562.
10.1021/jo060410r CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/29/2006
J. Org. Chem. 2006, 71, 4227-4231
4227

Takahashi et al.
SCHEME 1. Retrosynthetic Analysis
SCHEME 3. Synthesis of Alkenyl Iodide 22
SCHEME 2. Preparation of the Pyran Ring Moiety
high diastereoselectivity is assumed to be attributable to the
stereoelectronic effect of the allylic silyloxy system.12 After
protection of 12 as its acetonide, addition of 1.3 equiv of
methanol to the reaction mixture allowed selective removal of
the primary tert-butyldimethylsilyl ether protecting group of 13
to give alcohol 14 cleanly. It is important to note that all
reactions were carried out without purification during the
transformation from 9 to 14.
According to the method established by Kotsuki et al.,13
alcohol 14 was triflated and then the resulting triflate was
directly reacted with the lithium acetylide derived from p-
methoxybenzyl propargyl ether to give 15 in excellent yield
(Scheme 3). After desilylation of 15, the hydroxyl group of 16
was inverted via 17 in a completely steteoselective manner by
an oxidation14-reduction15 procedure to give 18 possessing four
contiguous all-cis stereogenic centers. Protection of 18 as its
triethylsilyl ether, followed by removal of the p-methoxybenzyl
ether protecting group of 19, gave propargyl alcohol 20.
Reaction11b of 20 with sodium bis(2-methoxyethoxy)aluminum
hydride (Red-Al), followed by treatment of the resulting
alkenylaluminate complex with iodine, allowed stereo- and
regioselective formation of (Z)-iodoalkene 21 which was
protected as its tert-butyldimethylsilyl ether to give alkenyl
iodide 22, the required precursor for the next crucial cross-
coupling reaction.
Alkenyl iodide 22 thus prepared was subjected to cross-
coupling reaction with organozinc reagent 24, according to the
procedure we have established in the previous syntheses of
dysiherbaine4a and lycoperdic acid7 (Scheme 4). Thus, iodoala-
nine 2316 was sonicated in the presence of Zn-Cu to generate
24, which was reacted with 22 using 3 mol % of (Ph3P)4Pd as
catalyst. The coupling reaction completed within 2 h to furnish
dysiherbaine4a and lycoperdic acid,8 we envisaged allylic alcohol
4 as a precursor of neodysiherbaine A (2), which would be
accessible via a cross-coupling reaction9 of alkenyl iodide 6
and organozinc reagent 5. We assumed that the C4 quaternary
stereogenic center would be assembled in stereocontrolled
manner via Katsuki-Sharpless asymmetric epoxidation10 of 4
followed by 5-exo-tet cyclization of 3 with inversion of the
configuration. Stereoselective construction of alkenyl iodide 6
could be achieved from 8 employing modified Corey’s reductive
iodination methodology.11
The required pyran ring moiety was first synthesized from
tri-O-acetyl-D-glucal (9) in 54% overall yield (Scheme 2). Thus,
according to the procedure established by Sasaki et al.,2 9 was
first converted to diol 10 by triethylsilane-promoted reduction
followed by methanolysis. After protection of 10 as its tert-
butyldimethylsilyl ether, exposure of 11 to OsO4-NMO condi-
tions allowed highly diastereoselective dihydroxylation to afford
diol 12 as the sole product. Since dihydroxylation of the
corresponding benzylidene acetal was reported to exhibit lower
diastereofacial selectivity (66% de),2 the observed extremely
(12) Arjona, O.; de Dios, A.; Plumet, J.; Saez, B. J. Org. Chem. 1995,
60, 4932-4935.
(8) Masaki, H.; Mizozoe, T.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Tetrahedron Lett. 2000, 41, 4801-4804.
(13) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1990, 31, 4609-
4612.
(9) For a review, see: Rilatt, I.; Caggiano, L.; Jackson, R. F. W. Synlett
2005, 2701-2719.
(14) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(10) For a review, see: Johnson, R. A.; Sharpless, K. B. In Compre-
hensiVe Organic Synthesis; Trost B M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 7, pp 389-436.
(11) (a) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem.
Soc. 1967, 89, 4245-4247. (b) Denmark, S. E.; Jones, T. K. J. Org. Chem.
1982, 47, 4595-4597.
(15) The use of Dess-Martin periodinane (DMPI) instead of SO3‚
pyridine/DMSO/Et3N resulted in the quantitative conversion of 16 to 17 in
less than one gram scale. However, DMPI turned out to be less effective in
large scale due to lack of reproducibility and dificulty in purification.
(16) Jackson, R. F. W.; Perez-Gonzalez, M. Org. Synth. 2005, 81, 77-88.
4228 J. Org. Chem., Vol. 71, No. 11, 2006

Total Synthesis of (-)-Neodysiherbaine A
SCHEME 4. Cross-Coupling Reaction
cleanly to give diol 28. In the cases of the stronger acids (e.g.,
CSA, Et2AlCl, BF3‚Et2O, Sc(OTf)3), the reaction became rather
complex, possibly due to the competitive attack of the carbamate
group to the polarized C4 center. Since purification of 28 was
found to be difficult because of its polar nature, crude 28 was
successively subjected to NaIO4 oxidation and TPAP oxidation19
to afford 2920 in 56% overall yield. In this case, the correspond-
ing C4 epimer was not obtained at all, suggesting that the
cyclization occurred with complete inversion of stereochemistry
at the quaternary center. Finally, upon acidic hydrolysis,
neutralization, and demineralization using ion-exchange chro-
matography, 29 furnished (-)-neodysiherbaine A (2), [R]23
D
-6.5 (c 0.75, H2O),21 quantitatively. The spectral data (1H and
13C NMR, CD, and FAB-Mass) exhibited good agreement with
those reported for the natural specimen.
SCHEME 5. Completion of the Total Synthesis
In conclusion, we have achieved a highly stereocontrolled
total synthesis of (-)-neodysiherbaine A (2) from tri-O-acetyl-
D-glucal (9) in 14% overall yield. This synthesis enables us to
obtain even gram quantities of neodysiherbaine A (2). The
synthetic method is of general value in approaches to related
neuroexcitatory amino acids.
Experimental Section
(3aR,6R,7R,7aR)-6-(4-(p-Methoxybenzyloxy)but-2-ynyl)-7-
(tert-butyldimethylsilyl)oxy-tetrahydro-2,2-dimethyl-3aH-[1,3]-
dioxolo[4,5-c]pyran (15). To a stirred solution of 14 (25.0 g, 78.6
mmol) in CH2Cl2 (250 mL) at -65 °C were added 2,6-lutidine
(12.6 g, 117.9 mmol) and trifluoromethanesulfonic anhydride (28.8
g, 102.1 mmol). After being stirred at -65 °C for 2 h, the reaction
mixture was diluted with Et2O and washed with saturated NaHCO3.
The organic layer was washed with 1 M HCl to remove 2,6-lutidine,
saturated NaHCO3, and brine, dried, and evaporated to give the
corresponding triflate (36.0 g) as a brown oil, which was used for
the next reaction without purification.
To a stirred solution of p-methoxybenzyl propargyl ether (27.7
g, 157.2 mmol) in THF (300 mL) at -65 °C was added
n-butyllithium (2.55 M in hexane, 61 mL, 157.2 mmol), and the
mixture was stirred at -65 °C for 2 h. N,N-Dimethylpropylene urea
(DMPU) (60 mL) was added, and then a solution of crude triflate
(36.0 g) in THF (30 mL) was added via a cannula over 10 min.
After being stirred at -65 °C for 2.5 h, the reaction mixture was
diluted with Et2O and washed with saturated NaHCO3 and brine,
dried, and evaporated. Purification of the residue by column
chromatography (SiO2 600 g, hexane/AcOEt ) 10/1-4/1) gave 15
25, and after desilylation using tetra-n-butylammonium fluoride
(TBAF) together with acetic acid, diol 26 was obtained in good
yield. In this desilylation step, the use of either TBAF without
acetic acid or HF-pyridine turned out to cause decomposition
of coupling product 25.
Having obtained key intermediate 26 possessing the entire
carbon framework of neodysiherbaine A (2), we then proceeded
to the final stage involving stereoselective construction of the
C4 quaternary stereogenic center, one of the most difficult issues
in this synthesis (Scheme 5).
(36.0 g, 96%) as a colorless oil: [R]24 -21.8 (c 1.00, CHCl3);
D
1
FTIR (neat) 2937, 2854, 1511, 1375, 1247, 1133, 1079 cm-1; H
NMR (400 MHz, CDCl3) δ 7.28 (d, J ) 8.5 Hz, 2H), 6.87 (d, J )
8.5 Hz, 2H), 4.52 (s, 2H), 4.26 (d, J ) 13.5 Hz, 1H), 4.17 (dd, J
) 2.2, 6.0 Hz, 1H), 4.14 (t, J ) 2.2 Hz, 2H), 3.96 (t, J ) 6.1 Hz,
1H), 3.80 (s, 3H), 3.74 (dd, J ) 2.2, 13.5 Hz, 1H), 3.63 (dd, J )
6.6, 9.3 Hz, 1H), 3.16 (ddd, J ) 3.6, 6.6, 9.3 Hz, 1H), 2.75 (ddt,
J ) 3.68, 16.8, 2.2 Hz, 1H), 2.50 (ddt, J ) 4.2, 16.8, 2.2 Hz, 1H),
1.52 (s, 3H), 1.36 (s, 3H), 0.90 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.1, 129.6, 113.7, 109.2, 83.1,
79.6, 77.6, 77.5, 74.0, 73.2, 70.8, 66.7, 57.3, 55.2, 28.1, 26.4, 25.9,
25.8, 22.4, 18.1, -4.0, -5.0; HRMS (FAB) calcd for C26H40O6Si
(M+) 476.2594, found 476.2581.
To introduce a scaffold for the construction of the C4 center
in desirable fashion, we undertook Katsuki-Sharpless asym-
metric epoxidation of 26. Upon exposure of 26 to the conditions
using a catalytic amount of Ti(OiPr)4 (9 mol %) and (+)-
diisopropyl L-tartrate (10 mol %),17 the epoxidation proceeded
with excellent diastereoselectiviy (>98% de)18 to give epoxide
27 in good yield. In this particular case, when stoichiometric
amounts of Ti(OiPr)4 and (+)-diisopropyl L-tartrate were
employed, the reaction became dirty due to the instability of
27 under the conditions.
(3aR,6R,7R,7aS)-6-(4-(p-Methoxybenzyloxy)but-2-ynyl)-tet-
rahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol (16). To
an ice-cooled solution of 15 (21.3 g, 44.7 mmol) in THF (100 mL)
The crucial 5-exo-tet cyclization of epoxide 27 was investi-
gated using various Lewis acids and Brønsted acids. As a result,
when epoxide 27 was treated with 1 equiv of PPTS in
dichloromethane at room temperature, the cyclization took place
(19) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625-1627.
(20) Compound 29 was found to be stable enough to be purified by silica
gel chromatography (hexane/AcOEt), although Chamberlin et al.4d reported
that 29 was decomposed during silica gel chromatography.
(21) The specific rotation of natural neodyshiherbaine A was not reported
previously.
(17) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
1
(18) Determined by comparison of the H NMR spectrum with that of
the corresponding isomeric epoxide prepared by Katsuki-Sharpless asym-
metric epoxidation of 26 using (-)-diisopropyl D-tartrate.
J. Org. Chem, Vol. 71, No. 11, 2006 4229

Takahashi et al.
was added tetra-n-butylammonium fluoride (TBAF) (1 M in THF,
53.7 mL, 53.7 mmol). After being stirred at 0 °C for 5 h, the reaction
mixture was diluted with Et2O, washed with water and brine, dried,
and concentrated. Purification of the residue by column chroma-
tography (SiO2 500 g, hexane/AcOEt ) 3/1-2/1) gave 16 (16.0 g,
quant) as a colorless oil: [R]24D -35.5 (c 1.05, CHCl3); FTIR (neat)
and the mixture was stirred at 0 °C for 2 h. The reaction mixture
was diluted with CH2Cl2, filtered through Celite, washed with
saturated NaHCO3, water, and brine, dried, and concentrated.
Purification of the residue by column chromatography (SiO2 30 g,
hexane/AcOEt ) 3/1-2/1) gave 20 (542 mg, 98%) as a colorless
oil: [R]26D +38.4 (c 0.96, CHCl3); FTIR (neat) 3424, 2954, 2877,
1380, 1213, 1135, 1058, 1002 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.27 (t, J ) 2.2 Hz, 2H), 4.20-4.29 (m, 2H), 4.06 (dd, J ) 3.9,
4.6 Hz, 1H), 3.84 (dt, J ) 9.8, 4.6 Hz, 1H), 3.69 (dd, J ) 5.6, 11.9
Hz, 1H), 3.63 (dd, J ) 7.3, 11.9 Hz, 1 H), 2.93 (ddt, J ) 9.8, 17.6,
2.2 Hz, 1H), 2.69 (ddt, J ) 17.6, 4.6, 2.2 Hz, 1H), 1.55 (s, 3H),
1.35 (s, 3H), 0.98 (t, J ) 8.0 Hz, 9H), 0.66 (q, J ) 8.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 110.0, 83.6, 79.4, 75.1, 74.1, 72.0,
67.0, 61.9, 51.4, 27.6, 25.4, 18.9, 6.9, 4.9; HRMS (EI) calcd for
C18H32O5Si (M+) 356.2019, found 356.2002.
(Z)-4-((3aR,6R,7S,7aR)-7-Triethylsilyloxy-tetrahydro-2,2-di-
methyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)-3-iodobut-2-en-1-ol
(21). To an ice-cooled solution of 20 (200 mg, 0.56 mmol) in Et2O
(2.2 mL) was added sodium bis(2-methoxyethoxy)aluminum hy-
dride (Red-Al) (3.2 M in toluene, 0.38 mL, 1.22 mmol), and the
mixture was stirred at room temperature for 2 h. Additional Red-
Al (3.2 M in tolulene, 0.20 mL, 0.64 mmol) was added at 0 °C,
and the mixture was stirred at room temperature for 1 h. AcOEt
(112 mg, 1.2 mmol) was added at 0 °C and the mixture was stirred
at 0 °C for 10 mim. Then solid I2 (213 mg, 0.84 mmol) was added
to the mixture at -40 °C, and the mixture was allowed to warm to
room temperature. After being stirred at room temperature for 12
h, the reaction was quenched with saturated Na2S2O3 (5 mL) at 0
°C, and the reaction mixture was diluted with AcOEt, filtered
through Celite, washed with brine, dried, and concentrated.
Purification of the residue by column chromatography (SiO2 5 g,
hexane/AcOEt ) 5/1-4/1) gave 21 (206 mg, 76%) as a colorless
oil: [R]26D +23.5 (c 0.86, CHCl3); FTIR (neat) 3438, 2954, 2877,
1457, 1380, 1216, 1134, 1008 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.95 (t, J ) 5.6 Hz, 1H), 4.31 (m, 1H), 4.22-4.23 (m, 3H), 4.07
(m, 2H), 3.62 (dd, J ) 5.0, 12.4 Hz, 1H), 3.56 (dd, J ) 6.8, 12.4
Hz, 1H), 3.22-3.28 (m, 1H), 2.80 (d, J ) 15.6 Hz, 1H), 1.57 (s,
3H), 1.36 (s, 3H), 1.00 (t, J ) 8.0 Hz, 9H), 0.67 (q, J ) 8.0, 6H);
13C NMR (100 MHz, CDCl3) δ 135.9, 110.1, 107.0, 75.3, 73.4,
72.3, 67.3, 67.1, 61.8, 43.1, 27.8, 25.6, 6.9, 4.8; HRMS (EI) calcd
for C18H33IO5Si (M+) 484,1142, found 484.1134.
1
3448, 2985, 2933, 1722, 1612, 1514, 1381, 1250, 1078 cm-1; H
NMR (400 MHz, CDCl3) δ 7.28 (d, J ) 8.6 Hz, 2 H), 6.87 (d, J
) 8.6 Hz, 2H), 4.52 (s, 2H), 4.30 (d, J ) 13.2 Hz, 1H), 4.20 (dd,
J ) 2.0, 6.0 Hz, 1H), 4.13 (t, J ) 2.0 Hz, 2H), 4.02 (t, J ) 6.0 Hz,
1H), 3.80 (s, 3H), 3.77 (dd, J ) 2.1, 14.0 Hz, 1H), 3.67 (ddd, J )
3.6, 7.2, 10.4 Hz, 1H), 3.19 (ddd, J ) 4.0, 6.4, 10.4 Hz, 1H), 2.77
(tdd, J ) 2.0, 4.0, 16.8 Hz, 1H), 2.60 (tdd, J ) 2.0, 6.4, 16.8 Hz,
1H), 2.52-2.50 (br, 1H), 1.53 (s, 3H), 1.38 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.2, 129.7, 129.5, 113.7, 109.7, 82.7, 79.4, 77.9,
76.4, 73.9, 73.9, 72.9, 71.0, 66.6, 57.3, 55.3, 28.2, 26.3, 22.3; HRMS
(EI) calcd for C20H26O6 (M+) 362.1729, found 362.1709.
(3aR,6R,7S,7aS)-6-(4-(p-Methoxybenzyloxy)but-2-ynyl)-tet-
rahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol (18). To
an ice-cooled solution of 16 (27.3 g, 75.6 mmol) in CH2Cl2 (150
mL) and DMSO (150 mL) were added triethylamine (69 g, 680
mmol) and SO3‚pyridine (36 g, 227 mmol). After being stirred at
0 °C for 4 h, the reaction mixture was diluted with Et2O, washed
with saturated NaHCO3, water, and brine, dried, and concentrated
to give 17 (31 g) as a yellow oil, which was used for the next
reaction without purification. Pure 17, a colorless oil, obtained by
preparative TLC (hexane/AcOEt ) 1/1) showed the following
spectral and analytical data: [R]24 +7.6 (c 1.34, CHCl3); FTIR
D
(neat) 2987, 2935, 2235, 1743, 1612, 1513, 1382, 1253, 1130, 1072
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.25 (d, J ) 8.4 Hz, 2H),
6.85 (d, J ) 8.4 Hz, 2H), 4.58 (dd, J ) 2.0, 6.0 Hz, 1H), 4.48 (s,
2H), 4.43 (d, J ) 6.0 Hz, 1H), 4.27 (d, J ) 12.6 Hz, 1H), 4.09 (t,
J ) 2.0 Hz, 2H), 3.95 (dd, J ) 4.4, 7.8 Hz, 1H), 3.91 (dd, J ) 2.0,
12.6 Hz, 1H), 3.78 (s, 3H), 2.82 (tdd, J ) 2.0, 7.8, 16.8 Hz, 1H),
2.61 (tdd, J ) 2.0, 7.8, 16.8 Hz, 1H), 1.44 (s, 3H), 1.38 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 202.1, 158.8, 129.3, 129.1, 113.3,
110.7, 81.8, 80.0, 77.0, 76.5, 76.4, 70.6, 66.5, 56.9, 54.9, 26.7, 25.5,
19.7; HRMS (EI) calcd for C20H24O6 (M+) 360.1573, found
360.1584.
Crude ketone 17 (31 g) thus obtained was dissolved into a
mixture of MeOH (150 mL) and THF (150 mL). To this solution
NaBH4 (3.7 g, 98.2 mmol) was added at -78 °C, and the mixture
was stirred at -78 °C for 2 h. The reaction was quenched with
saturated NH4Cl (150 mL), and the reaction mixture was extracted
with Et2O. The extract was washed with water, saturated NaHCO3,
and brine, dried, and concentrated. Purification of the residue by
column chromatography (SiO2 300 g, hexane/AcOEt ) 4/1-2/1)
(3aR,6R,7S,7aR)-6-((Z)-4-tert-Butyldimethylsilyloxy-2-iodobut-
2-enyl)-7-triethylsilyloxy-tetrahydro-2,2-dimethyl-3aH-[1,3]di-
oxolo[4,5-c]pyran (22). To an ice-cooled stirred solution of 21 (615
mg, 1.25 mmol) in CH2Cl2 (10 mL) were added triethylamine (315
mg, 3.12 mmol), tert-butyldimethylsilyl chloride (318 mg, 2.12
mmol), and DMAP (15 mg, 0.125 mmol). After the mixture was
stirred at 0 °C for 5 h, the reaction was quenched by MeOH (2
mL), and the reaction mixture was extracted with Et2O. The extract
was washed with 10% Na2S2O3, saturated NaHCO3, water, and
brine, dried, and concentrated. Purification of the residue by column
chromatography (SiO2 20 g, hexane/AcOEt ) 10/1-4/1) gave 22
(747 mg, quant.) as a colorless oil: [R]26D +39.4 (c 1.60, CHCl3);
gave 18 (25.0 g, 93%) as a colorless oil: [R]24 -67.2 (c 1.05,
D
CHCl3); FTIR (neat) 3498, 2937, 2840, 1612, 1513, 1380, 1249,
1
1068 cm-1; H NMR (400 MHz, CDCl3) δ 7.27 (d, J ) 8.0 Hz,
2H), 6.87 (d, J ) 8.0 Hz, 2H), 4.50 (s, 2H), 4.32 (d, J ) 14.4 Hz,
1H), 4.16-4.11 (m, 2H), 4.11 (t, J ) 2.2 Hz, 2H), 3.85-3.80 (m,
1H), 3.81 (s, 3H), 3.80 (dd, J ) 3.0, 14.4 Hz), 3.34 (t, J ) 7.1 Hz,
1H), 2.69 (tt, J ) 2.2, 7.1 Hz, 2H), 2.25 (d, J ) 7.1 Hz, 1H), 1.61
(s, 3H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 129.5,
129.4, 113.6, 109.2, 82.5, 77.7, 76.7, 75.7, 73.1, 71.0, 71.0, 66.6,
65.2, 57.2, 55.1, 25.8, 25.3, 21.5; HRMS (EI) calcd for C20H26O6
(M+) 362.1729, found 362.1717.
1
FTIR (neat) 2924, 2858, 1460, 1375, 1248, 1101, 1007 cm-1; H
NMR (400 MHz, CDCl3) δ 5.86 (t, J ) 5.2 Hz, 1H), 4.31 (dd, J
) 3.6, 5.6 Hz, 1H), 4.24 (dd, J ) 1.2, 5.2 Hz, 2H), 4.24-4.18 (m,
1H), 4.07-4.00 (m, 2H), 3.61 (dd, J ) 5.2, 12.8 Hz, 1H), 3.53
(dd, J ) 5.2, 18.2 Hz, 1H), 3.22 (dd, J ) 10.0, 16.0 Hz, 1H), 2.76
(d, J ) 16.0, Hz, 1H), 1.57 (s, 3H), 1.36 (s, 3H), 0.99 (t, J ) 8.0
Hz, 9H), 0.90 (s, 9H), 0.67 (q, J ) 8.0 Hz, 6H), 0.09 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 137.0, 110.0, 103.8, 75.4, 73.6, 72.3,
68.5, 67.2, 61.6, 42.8, 27.9, 26.0, 25.9, 25.7, 18.3, 6.9, 6.6, 5.9,
4.9, -5.0; HRMS (EI) calcd for C23H44IO5Si [(M - Me)+]
583.1772, found 583.1746.
tert-Butyl (S,E)-1-(Methoxycarbonyl)-3-(((3aR,6R,7S,7aS)-tet-
rahydro-7-hydroxy-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-
6-yl)methyl)-5-hydroxypent-3-enylcarbamate (26). A mixture of
N-Boc-â-iodoalanine methyl ester (23) (1.40 g, 4.26 mmol) and
Zn-Cu couple (1.36 g) in benzene (8 mL) and N,N-dimethyl-
acetamide (DMA) (0.8 mL) was sonicated at 45 °C until the starting
4-((3aR,6R,7R,7aR)-7-Triethylsilyloxy-tetrahydro-2,2-dimeth-
yl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)but-2-yn-1-ol (20). To a
stirred solution of 18 (560 mg, 1.55 mmol) in DMF (3 mL) at room
temperature were added imidazole (421 mg, 6.19 mmol) and
triethylsilyl chloride (465 mg, 3.1 mmol). After being stirred at
room temperature for 50 min, the reaction was quenched by the
addition of MeOH (2 mL). The reaction mixture was diluted with
Et2O, washed with water and brine, dried, and concentrated to give
19 (793 mg) as a pale yellow oil, which was used for the next
reaction without purification.
To an ice-cooled solution of crude 19 (793 mg) in CH2Cl2 (17
mL) were added water (0.8 mL) and DDQ (982 mg, 4.33 mmol),
4230 J. Org. Chem., Vol. 71, No. 11, 2006

Total Synthesis of (-)-Neodysiherbaine A
material disappeared on TLC. This mixture of the organozinc
reagent was added to a degassed mixture of 22 (641 mg, 1.076
mmol) and (Ph3P)4Pd (37 mg, 0.032 mmol) in benzene (8 mL) and
HMPA (0.8 mL), and the mixture was heated at 80 °C for 1 h.
After cooling, the reaction mixture was diluted with AcOEt, filtered
through Celite, washed with saturated NaHCO3 and brine, dried,
concentrated, and chromatographed (SiO2 40 g, hexane/AcOEt )
6/1, then SiO2 20 g, toluene/AcOEt )1/0-7/1) gave 25 (845 mg)
as a yellow oil, which contained compounds derived from 23. Pure
25, a colorless oil, obtained by 2× silica gel column chromatog-
raphy (toluene/AcOEt ) 1/0-10/1, H/A)8/1-4/1) followed by
recycling preparative HPLC (CHCl3) showed the following spectral
(100 MHz, CDCl3) δ 172.5, 155.2, 109.2, 80.2, 73.2, 73.1, 70.9,
67.1, 66.2, 61.2, 60.2, 59.6, 52.5, 51.1, 36.3, 33.9, 28.3, 25.8, 25.4;
HRMS (EI) calcd for C21H35NO10 (M+) 461.2261, found 461.2249.
Lactam 29. To a stirred solution of 27 (520 mg, 1.12 mmol) in
CH2Cl2 (10 mL) was added pyridinium p-toluenesulfonate (PPTS)
(283 mg, 1.12 mmol), and the mixture was stirred for 2 h. The
reaction was quenched with saturated NaHCO3 (30 mL), and the
reaction mixture was extracted with AcOEt. The extract was washed
with water and brine, dried over Na2SO4, and concentrated to give
28 (540 mg), which was used for the next reaction without
purification.
To a solution of crude 28 (540 mg) in 20% aqueous THF (12.5
mL) was added NaIO4 (480 mg, 2.25 mmol) at room temperature.
After being stirred at room temperature for 50 min, the reaction
was quenched with 10% Na2S2O3 (10 mL), and the reaction mixture
was extracted with AcOEt. The extract was washed with saturated
NaHCO3 and brine, dried, and concentrated to give the correspond-
ing aminal (500 mg) as a pale yellow oil, which was used for the
next reaction without purification.
To a solution of crude aminal (500 mg) in MeCN (10 mL) were
added 4 A molecular sieves (500 mg) and N-methylmorpholine
oxide (NMO) (263 mg, 2.25 mmol) at room temperature. After 10
min, tetra-n-propylammonium perruthenate (TPAP) (79 mg, 0.23
mmol) was added to the mixture, and stirring was continued at
room temperature for 80 min. The reaction mixture was filtered
through Celite, concentrated, and chromatograped (SiO2 20 g,
hexane/AcOEt ) 1/2-0/1) to give 29 (269 mg, 56%) as a colorless
solid: [R]24D -10.8 (c 0.60, MeOH); FTIR (neat) 2981, 1791, 1752,
1442, 1369, 1307, 1211, 1149 cm-1; 1H NMR (500 MHz, C6D6) δ
4.44 (dd, J ) 2.5, 9.0 Hz, 1H), 4.01 (dd, J ) 4.5, 12.5 Hz, 1H),
3.95 (dd, J ) 4.5, 7.5 Hz, 1H), 3.83 (dt, J ) 7.5, 4.5 Hz, 1H), 3.76
(dt, J ) 7.0, 6.0 Hz, 1H), 3.38 (s, 3H), 3.34 (dd, J ) 4.5, 6.0 Hz,
1H), 3.25 (dd, J ) 4.5, 12.5 Hz, 1H), 2.72 (dd, J ) 6.0, 13.5 Hz,
1H), 1.93 (dd, J ) 2.5, 13.5 Hz, 1H), 1.59 (s, 3H), 1.49 (dd, J )
7.0, 13.0 Hz, 1H), 1.41 (s, 9H), 1.21 (s, 3H), 1.12 (dd, J ) 9.0,
13.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.5, 169.8, 149.4,
110.4, 83.9, 83.1, 75.7, 75.5, 72.0, 71.2, 65.7, 55.6, 52.6, 41.5, 36.0,
27.9, 26.3 25.6; HRMS (EI) calcd for C20H29NO9 (M+) 427.1842,
found 427.1831.
Neodysiherbaine A (2). A solution of 29 (283 mg, 0.662 mmol)
in 6 M HCl (20 mL) was heated at 60 °C for 10 h. The reaction
mixture was evaporated and the residue was treated with 1 N NaOH
followed by IRC-76 and then evaporated. The residue (300 mg)
was subjected to ion-exchange chromatography using Dowex
50WX4-200 (30 mL of resin, H2O then 5% NH4OH) and lyo-
philization to give neodysiherbaine A (2) (199 mg, quant) as a pale
yellow solid: [R]23D -6.5 (c 0.75, H2O); 1H NMR (500 MHz, D2O)
δ 4.06 (dd, J ) 1.5, 3.0 Hz, 1H), 3.98 (brs, 1H), 3.74 (m, 1H),
3.69 (dd, J ) 2.5, 13.0 Hz, 1H), 3.53 (brs, 1H), 3.41 (d, J ) 13.0
Hz, 1H), 3.38 (dd, J ) 2.5, 12.0 Hz, 1H), 2.48 (dd, J ) 2.5, 15.0
Hz, 1H), 2.41 (d, J ) 14.0 Hz, 1H), 1.99 (dd, J ) 3.0, 14.0 Hz,
1H), 1.78 (dd, J ) 12.0, 15.0 Hz, 1H); 13C NMR (100 MHz, D2O
+ CD3OD) δ 108.9, 174.5, 88.2, 81.1, 77.4, 70.3, 68.5, 67.9, 54.4,
45.3, 39.9; MS (FAB) m/z 292 [(M + H)+], 314 [(M + Na)+];
HRMS (FAB) calcd for C11H18NO8 [(M + H)+] 292.1032, found
292.1054; CD (H2O) λext 204 nm. These spectral data was in good
agreement with those for natural neodyshiherbaine A.2
and analytical data: [R]23 +19.5 (c 0.84, CHCl3); FTIR (neat)
D
1
3354, 2954, 1716, 1506, 1365, 1249, 1164, 1058 cm-1; H NMR
(400 MHz, CDCl3) δ 5.64 (t, J ) 6.4 Hz, 1H), 5.50 (d, J ) 6.8
Hz, 1H), 4.29 (dd, J ) 4.0, 5.6 Hz, 1H), 4.27-4.35 (m, 1H), 4.22
(dd, J ) 6.8, 12.8 Hz, 1H), 4.18 (dd, J ) 6.8, 12.8 Hz, 1H), 4.10
(dd, J ) 6.8, 12.8 Hz, 1H), 3.99 (dd, J ) 4.0, 5.6 Hz, 1H), 3.80
(ddd, J ) 2.0, 5.6, 10.8 Hz, 1H), 3.71 (s, 3H), 3.66 (dd, J ) 7.2,
12.4 Hz, 1H), 3.60 (dd, J ) 6.0, 12.4 Hz, 1H), 2.73 (dd, J ) 10.8,
16.0 Hz, 1 H), 2.54 (m, 2H), 2.38 (d, J ) 16.0 Hz, 1H), 1.56 (s,
3H), 1.41 (s, 9H), 1.36 (s, 3H), 0.98 (t, J ) 7.8 Hz, 9 H), 0.92 (s,
9H), 0.66 (q, J ) 7.8 Hz, 6H), 0.10 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 173.3, 155.3, 136.4, 129.1, 110.0, 79.5, 77.2, 75.5, 77.2,
75.5, 75.4, 72.2, 67.9, 61.6, 59.3, 52.1, 33.6, 33.2, 28.4, 27.8, 26.1,
25.6, 18.5, 6.9, 4.9, -5.0, -5.1; HRMS (EI) calcd for C33H63NO9-
Si2 (M+) 673.4041, found 673.4034.
To a stirred solution of 25 (845 mg) thus obtained in THF (10
mL) were added AcOH (323 mg, 5.38 mmol) and TBAF (4.3 mmol)
at room temperature, and stirring was continued at room temperature
for 10 h. The reaction mixture was diluted with AcOEt, washed
with water, saturated NaHCO3, and brine, dried, and concentrated.
Purification of the residue by column chromatography (SiO2 15 g,
hexane/AcOEt ) 1/1-0/1) gave 26 (382 mg, 80%) as a colorless
oil: [R]23D -29.1 (c 2.04, CHCl3); FTIR (neat) 3369, 2979, 1749,
1
1712, 1519, 1367, 1251, 1214, 1169, 1024 cm-1; H NMR (400
MHz, CDCl3) δ 5.73 (t, J ) 7.0 Hz, 1H), 5.40 (d, J ) 7.5 Hz,
1H), 4.42 (m, 1H), 4.26 (d, J ) 13.7 Hz, 1H), 4.11 (m, 4H), 3.75
(d, J ) 13.7 Hz, 1H), 3.74 (s, 3H), 3.59 (s, 1H), 3.27 (t, J ) 5.4
Hz, 1 H), 2.53-2.60 (m, 3H), 2.31 (dd, J ) 5.1, 14.6 Hz, 1H),
1.61 (s, 3H), 1.42 (s, 9H), 1.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.7, 155.2, 134.8, 130.0, 109.1, 79.8, 76.0, 73.3, 71.0,
66.4, 66.3, 58.0, 52.1, 38.0, 33.3, 28.2, 25.7, 25.4; MS (EI) m/z
57, 345, 389, 430, 445 (M+); HRMS (EI) calcd for C21H35NO9
(M+) 445.2312, found 445.2311.
tert-Butyl (S)-1-(Methoxycarbonyl)-2-((2S,3S)-2-(((3aR,6R,7S,
7aS)-tetrahydro-7-hydroxy-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-
c]pyran-6-yl)methyl)-3-(hydroxymethyl)oxiran-2-yl)ethylcar-
bamate (27). To a suspension of powdered 4 A molecular sieves
(560 mg) in CH2Cl2 (15 mL) were added (+)-diisopropyl L-tartrate
(DIPT) (30 mg, 0.126 mmol), and Ti(OiPr)4 (32 mg, 0.112 mmol)
at -35 °C, and the mixture was stirred at -35 °C for 50 min. tert-
Butyl hydroperoxide (TBHP) (2.76 M in CH2Cl2, 0.91 mL, 2.52
mmol) was added, and then, 70 min later, a solution of allyl alcohol
26 (562 mg, 1.26 mmol) in CH2Cl2 (10 mL) was added to the
reaction mixture at -35 °C. After the mixture was stirred at -30
°C for 67 h, 17% aqueous acetone (20 mL) was added, and the
mixture was stirred for 30 min at room temperature. The reaction
mixture was filtered through Celite and concentrated. The residue
was dissolved into toluene, evaporated to remove the remaining
TBHP by azeotropic distillation, and chromatographed (SiO2 20 g,
hexane/AcOEt ) 1/1-0/1) to give 27 (520 mg, 90%) as a colorless
amorphous: [R]22D -27.9 (c 0.90, CHCl3); FTIR (neat) 3342, 2977,
Acknowledgment. We thank Professor Makoto Sasaki
(Graduate School of Life Sciences, Tohoku University) for
giving us valuable information and spectral data of neodysi-
herbaine A. This work was partly supported by a Grant-in-Aid
for Scientific Research on Priority Areas (16073213) from The
Ministry of Education, Culture, Sports, Science and Technology
(MEXT).
1
1702, 1511, 1444, 1373, 1162, 1031 cm-1; H NMR (400 MHz,
CDCl3) δ 5.31 (d, J ) 7.2 Hz, 1H), 4.50 (m, 1H), 4.28 (d, J )
13.6 Hz, 1H), 4.13 (m, 2H), 3.75(s, 3H), 3.73-3.75 (m, 4H), 3.57
(m, 1H), 3.22 (m, 1H), 3.12 (t, J ) 5.6 Hz, 1 H), 2.35 (dd, J )
8.0, 15.2 Hz, 1H), 2.27 (d, J ) 7.2 Hz, 2H), 2.15 (dd, J ) 5.2,
14.4 Hz, 1H), 1.98 (dd, J ) 9.2, 14.4 Hz, 1H), 1.88 (dd, J ) 3.2,
15.2 Hz, 1H), 1.67 (s, 3H), 1.45 (s, 9H), 1.40 (s, 3H); 13C NMR
Supporting Information Available: General experimental
procedures, experimental details for compound 14 from 9, and 1H
and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060410R
J. Org. Chem, Vol. 71, No. 11, 2006 4231