Total synthesis and biological evaluation of neodysiherbaine A and analogues

Article abstract of DOI:10.1021/jo0605593

Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogue

Full text of DOI:10.1021/jo0605593

Total Synthesis and Biological Evaluation of Neodysiherbaine A and
Analogues
Muneo Shoji,† Nobuyuki Akiyama,† Koichi Tsubone,† L. Leanne Lash,‡ James M. Sanders,‡
Geoffrey T. Swanson,‡ Ryuichi Sakai,§ Keiko Shimamoto,| Masato Oikawa,† and
Makoto Sasaki*,†
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku UniVersity,
Sendai 981-8555, Japan, Department of Pharmacology and Toxicology, UniVersity of Texas Medical
Branch, GalVeston, Texas 77555-1031, School of Fisheries Sciences, Kitasato UniVersity, Sanriku-cho,
Iwate 022-0101, Japan, and Suntory Institute for Bioorganic Research, Mishima-gun,
Osaka 618-8503, Japan
masasaki@bios.tohoku.ac.jp
ReceiVed March 13, 2006
Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids
with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the
total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a
branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities,
which would not have been accessible through manipulations of the natural product itself. The synthesis
of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise
synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-
olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring
closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid
appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and
binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9
functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic
acid receptor family.
Introduction
of their pharmacological preference toward selective agonists:
R-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA),
kainate, and N-methyl-D-aspartic acid (NMDA) receptors.1
Molecular cloning studies demonstrated that ionotropic glutamate
receptors are encoded by at least six NMDA (NR1, NR2A-D,
and NR3A), four AMPA (GluR1-4), and five kainate (GluR5-
7, KA1, and KA2) receptor genes.2 Understanding the complex
roles that ionotropic glutamate receptors play in physiological
Glutamate receptors play a central role in the mammalian
central nervous system (CNS), not only in excitatory neu-
rotransmission but also in complex brain functions such as
learning and memory. Glutamate receptors are broadly divided
into ionotropic and metabotropic receptors. Ionotropic glutamate
receptors are further subdivided into three subtypes on the basis
* To whom correspondence should be addressed. Phone: +81-22-717-8897.
Fax: +81-22-717-8897.
(1) Watkins, J. C.; Evans, R. H. Annu. ReV. Pharmacol. Toxicol. 1981,
21, 165-204.
(2) (a) Seeburg, P. Trends Neurosci. 1993, 16, 359-365. (b) Hollmann,
M.; Heinemann, S. Annu. ReV. Neurosci. 1994, 17, 31-108. (c) Dingledine,
R.; Borges, K.; Bowie, D.; Traynelis, S. F. Pharmacol. ReV. 1999, 51, 7-45.
† Tohoku University.
‡ University of Texas Medical Branch.
§ Kitasato University.
| Suntory Institute for Bioorganic Research.
10.1021/jo0605593 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/17/2006
5208
J. Org. Chem. 2006, 71, 5208-5220

Total Synthesis of Neodysiherbaine A and Analogues
FIGURE 1. Structures of dysiherbaine (1), neodysiherbaine A (2),
and simplified analogue 3.
FIGURE 2. Structures of dysiherbaine analogues 4-8.
and pathological processes in the brain has been facilitated by
the presence of selective pharmacological agents. However,
pharmacological characterization of kainate receptors has for
many years been hampered by the lack of selective ligands,
both agonists and, particularly, antagonists.3
amino acids and their designed analogues are anticipated to serve
as useful tools for understanding the structure and functions of
ionotropic glutamate receptors in the CNS. Therefore, dysi-
herbaine and neodysiherbaine A have attracted a great deal of
attention as synthetic targets, and seven total syntheses7,10 and
several synthetic approaches11 have been described to date.
To reveal further the detailed structure-activity relationship
profiles of dysiherbaines, we set out to develop a flexible route
to a series of dysiherbaine analogues. We describe herein the
details of a concise total synthesis of 2 and its structural
analogues 8,9-epi-neodysiherbaine A (4),12 8-epi-neodysi-
herbaine A (5), 9-epi-neodysiherbaine A (6), 8-deoxyneodysi-
herbaine A (7), and 9-deoxyneodysiherbaine A (8) (Figure 2)
from a common key intermediate. These analogues, easily
accessible through efficient synthesis, allowed us to test the
hypothesis that the C8 and C9 functional groups are the critical
determinants of pharmacological activity of dysiherbaines. The
preliminary biological evaluation described herein revealed that
both the type and stereochemistry of these functional groups
strongly affected the subtype selectivity of dysiherbaine ana-
logues for members of the kainate receptor family.
Dysiherbaine (1), isolated from the Micronesian sponge
Dysidea herbacea, is a novel excitatory amino acid with potent
convulsant activity4 (Figure 1). The unprecedented molecular
structure consists of a cis-fused hexahydrofuro[3,2-b]pyran ring
system containing a glutamic acid substructure. Dysiherbaine
activates neuronal AMPA and kainate receptors, with a higher
affinity for kainate receptors, but shows no detectable affinity
for NMDA receptors.5 Pharmacological characterization of the
affinity of dysiherbaine for recombinant GluR5, GluR6, and
KA2 kainate receptor subunits revealed that it had extremely
high affinity for GluR5 or GluR6 but very low affinity for KA2
subunits, which produced unusual biophysical behavior from
heteromeric kainate receptors.6
Neodysiherbaine A (2), isolated as a minor congener from
the same sponge, differs from 1 in the C8 functional group7
(Figure 1) and is also a selective agonist for AMPA and kainate
receptors. Most recently, we characterized the pharmacological
action of neodysiherbaine A and a simplified synthetic analogue,
3,8 on glutamate receptors.9 These studies revealed that neo-
dysiherbaine A is similar to dysiherbaine in its pharmacological
activity on kainate receptors, albeit with slightly different
binding affinities for individual receptor types. In contrast,
compound 3, lacking the C8 and C9 functional groups, was a
selective, competitive antagonist for GluR5-containing kainate
receptors. In addition, homology modeling of kainate receptor
subunits generated a conceptual framework for understanding
the interaction between the C8 and C9 functional groups and
residues in the ligand-binding domains that confer selectivity
and specificity to the marine toxins.9
Results and Discussion
Overall Synthetic Strategy. We have previously reported
the synthesis of 4 via a key intermediate, 16,12 which was settled
on a branching point for a flexible entry into the dysiherbaine
analogues not accessible from the natural product itself. The
key features of the synthesis of 16 involved (i) stereoselective
C-glycosylation of allylsilane 1013 with di-O-acetyl-L-arabinal
(9)14 to set the C6 stereocenter, (ii) chemoselective oxidation
of bisolefin 11, (iii) epoxide ring opening/5-exo ring closure of
(10) For the total synthesis of dysiherbaine, see: (a) Snider, B. B.;
Hawryluk, N. A. Org. Lett. 2000, 2, 635-638. (b) Sasaki, M.; Koike, T.;
Sakai, R.; Tachibana, K. Tetrahedron Lett. 2000, 41, 3923-3926. (c)
Masaki, H.; Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.; Hatakeya-
ma, S. J. Am. Chem. Soc. 2000, 122, 5216-5217. (d) Phillips, D.;
Chamberlin, A. R. J. Org. Chem. 2002, 67, 3194-3201. For the total
synthesis of neodysiherbaine A, see: (e) Reference 7. (f) Lygo, B.; Slack,
D.; Wilson, C. Tetrahedron Lett. 2005, 46, 6629-6632. (g) Takahashi, K.;
Matsumura, T.; Corbin, G. R. M.; Ishihara, J.; Hatakeyama, S. J. Org. Chem.
2006, 71, 4227-4231.
Due to these unusual pharmacological properties of dysi-
herbaines and their potent epileptogenic activity, these excitatory
(3) Bra¨uner-Osborne, H.; Egebjerg, J.; Nielsen, E. Ø.; Madsen, U.;
Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609-2645.
(4) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem.
Soc. 1997, 119, 4112-4116.
(5) Sakai, R.; Swanson, G. T.; Shimamoto, K.; Contractor, A.; Ghetti,
A.; Tamura-Horikawa, Y.; Oiwa, C.; Kamiya, H. J. Pharm. Exp. Ther. 2001,
296, 650-663.
(6) Swanson, G. T.; Green, T.; Sakai, R.; Contractor, A.; Che, W.;
Kamiya, H.; Heinemann, S. F. Neuron 2002, 34, 589-598.
(7) Sakai, R.; Koike, T.; Sasaki, M.; Shimamoto, K.; Oiwa, C.; Yano,
A.; Suzuki, K.; Tachibana, K.; Kamiya, H. Org. Lett. 2001, 3, 1479-1482.
(8) Sasaki, M.; Maruyama, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett.
1999, 40, 3195-3198.
(9) Sanders, J. M.; Ito, K.; Settimo, L.; Pentikainen, O. T.; Shoji, M.;
Sasaki, M.; Jonson, M. S.; Sakai, R.; Swanson, G. T. J. Pharm. Exp. Ther.
2005, 314, 1068-1078.
(11) For synthetic studies on dysiherbaine, see: (a) Naito, T.; Nair, J.
S.; Nishiki, A.; Yamashita, K.; Kiguchi, T. Heterocycle 2000, 53, 2611-
2615. (b) Huang, J.-M.; Xu, K.-C.; Loh, T.-P. Synthesis 2003, 755-764.
(c) Miyata, O.; Iba, R.; Hashimoto, J.; Naito, T. Org. Biomol. Chem. 2003,
1, 772-774. (d) Kang, S. H.; Lee, Y. M. Synlett 2003, 993-994.
(12) For a preliminary communication, see: Shoji, M.; Shiohara, K.;
Oikawa, M.; Sakai, R.; Sasaki, M. Tetrahedron Lett. 2005, 46, 5559-5562.
(13) Konosu, T.; Furukawa, Y.; Hata, T.; Oida, S. Chem. Pharm. Bull.
1991, 39, 2813-2818.
(14) Hullomer, F. L. Methods in Carbohydrate Chemistry; Academic
Press: New York, 1962; Vol. I, pp 83-88.
J. Org. Chem, Vol. 71, No. 14, 2006 5209

Shoji et al.
TABLE 1. Asymmetric Dihydroxylation of Diene 11
SCHEME 1. Our First Total Synthesis of
8,9-epi-Neodysiherbaine A (4)
osmium
sourcea
time
(h)
yield
(%)
entry
ligandb
drc
1
2
3
AD-mix-R
AD-mix-â
K2OsO2(OH)2 (DHQD)2AQN
OsO4 (DHQD)2AQN
K2OsO2(OH)2 (DHQD)2PYR
K2OsO2(OH)2 (DHQ)2PYR
12
12
12
3
12
12
85
1:1.3
quantitative 1.2:1
58
80
78
59
3:1
3:1
1:2.3
2.3:1
4d,e
5
6
a A 1 mol % concentration of K2OsO2(OH)2 was used. b A 10 mol %
concentration of ligand was used. c Determined by 500 MHz 1H NMR.
d Performed on a gram scale. e A 5 mol % concentration of OsO4 was used.
assigned at a later stage. The use of pseudoenantiomeric reagent
AD-mix-â resulted in reversed but poor diastereoselectivity
(entry 2). The highest diastereoselectivity (dr ) 3:1) was
observed when (DHQD)2AQN19 was used as a ligand (entry
3), and these conditions showed good reproducibility even on
a gram scale (entry 4). When the (DHQD)2PYR20 ligand was
used, the diastereoselectivity was reversed with a moderate ratio
(entry 5), and the selectivity was reversed again by changing
the ligand to (DHQ)2PYR (entry 6). The diastereomeric mixture
thus obtained in entry 4 was carried forward without separation
through the subsequent transformations.
Selective monosilylation of diol 19 was performed under
standard conditions (TBDMSOTf, triethylamine, CH2Cl2) to
afford the corresponding TBDMS ether 20 (Scheme 3). After
methanolysis of the acetyl group (95%), treatment of the
resultant allylic alcohol with m-chloroperbenzoic acid (m-CPBA)
led exclusively to the â-epoxide 21. When the crude epoxide
21 was subjected to purification by flash chromatography on
silica gel, epoxide ring opening by an intramolecular attack of
the tertiary alcohol occurred in a 5-exo-trig mode, leading to
bicyclic ether 22 in high yield. After protection of the diol as
the acetonide (85%), the benzyl group of the resultant 23 was
removed under hydrogenolysis to afford alcohols 24a and 24b
in 75% and 20% yield, respectively, which were readily
separable by flash column chromatography. Thus, the synthesis
of the bicyclic ether skeleton was realized in only seven steps
from 9. In addition, both alcohols 24a and 24b are considered
to be potentially identical compounds, just being different in
the position of the TBDMS protection. Therefore, these
compounds were expected to be transformed to the single
compound in a convergent manner.
12 to form the bicyclic ring skeleton 13, and (iv) construction
of the amino acid side chain through stereoselective introduction
of the C2 amino group following the procedure of Kishi et al.15
(14 f 15) (Scheme 1).
While highly concise to construct the bicyclic ether skeleton,
this first-generation route required a multistep sequence of
reactions for the C2 amino group. Accordingly, we decided to
explore an alternative approach for the efficient synthesis of
the amino acid appendage. In this context, we focused on an
asymmetric hydrogenation of enamide esters, which has been
recently utilized for the synthesis of various functionalized
amino acid derivatives.16,17 Thus, the key intermediate 16 was
envisioned to be prepared by catalytic asymmetric hydrogenation
of the precursor enamide ester 17, which, in turn, could be
readily derived from alcohol 18 through oxidation followed by
Horner-Wadsworth-Emmons (HWE) olefination (Scheme 2).
We first reinvestigated chemo- and diastereoselective oxida-
tion of the exo-olefin within 11 under Sharpless asymmetric
dihydroxylation conditions.18 In the previous study,12 oxidation
of 11 with AD-mix-R (CH3SO2NH2, t-BuOH/H2O, 0 °C f room
temperature) proceeded in a completely chemoselective manner
to produce diol 19 in 85% yield; however, the diastereoselec-
tivity proved to be low (ca. 1.3:1) by 500 MHz 1H NMR (Table
1, entry 1). The stereochemistry at the C4 stereocenter was
Introduction of an Amino Acid Appendage. Oxidation of
the major alcohol 24a to the corresponding acid by a two-step
sequence (SO3‚pyridine/DMSO and NaClO2 oxidations)
followed by esterification with trimethylsilyldiazomethane
(TMSCHN2) provided methyl ester 25 in 85% overall yield
(Scheme 4). At this stage, the stereochemistry at the C4 position
was determined by NOE experiments as shown. Removal of
the TBDMS group with TBAF gave the desired alcohol 18 in
85% yield.
(15) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
1109-1111.
(16) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125-10138. (b) Burk, M. J. Acc. Chem. Res.
2000, 33, 363-372.
(17) (a) Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J. J.
Am. Chem. Soc. 1997, 119, 9897-9898. (b) Debenham, S. D.; Cossrow,
J.; Toone, E. J. J. Org. Chem. 1999, 64, 9153-9163. (c) Allen, J. R.; Harris,
C. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 1890-1897. (d)
Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J.
Am. Chem. Soc. 2002, 124, 6552-6554.
On the other hand, the minor diastereomeric alcohol 24b was
also converted to 18 as depicted in Scheme 5. Thus, protection
(18) For a review, see: Kolb, H. C.; VanNieuwehze, M. S.; Sharpless,
K. B. Chem. ReV. 1994, 94, 2483-2547.
(19) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 448-451.
5210 J. Org. Chem., Vol. 71, No. 14, 2006

Total Synthesis of Neodysiherbaine A and Analogues
SCHEME 2. New Approach for Key Intermediate 16
SCHEME 3a
SCHEME 5a
a Reagents and conditions: (a) ethyl vinyl ether, p-TsOH‚H2O, CH2Cl2,
rt, 97%; (b) TBAF, THF, rt, quantitative; (c) SO3‚pyridine, DMSO, Et3N,
CH2Cl2, 0 °C; (d) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/H2O, rt;
(e) (TMS)CHN2, MeOH, rt, 80% (three steps); (f) HCl, Et2O, 0 °C, 91%.
SCHEME 6a
a Reagents and conditions: (a) TBDMSOTf, Et3N, DMAP, CH2Cl2, rt,
85%; (b) K2CO3, MeOH, rt, 95%; (c) m-CPBA, CH2Cl2/pH 7 phosphate
buffer, 0 °C f rt, then silica gel, 89%; (d) Me2C(OMe)2, CSA, CH2Cl2, 0
°C, 85%; (e) H2, Pd/C, hexane, rt, (24a) 75%, (24b) 20%.
SCHEME 4a
a Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C
f rt; (b) 28a or 28b, tetramethylguanidine, CH2Cl2, rt, (17a) 81% (two
steps), (17b) 80% (two steps).
followed by HWE olefination using phosphonates 28a and 28b21
and N,N,N′,N′-tetramethylguanidine (TMG) generated enamide
esters 17a and 17b in 81% and 80% yield for the two steps,
respectively.
With the desired enamide esters 17 now available, we were
positioned to investigate the asymmetric hydrogenation (Table
2). The reaction was first attempted on the N-Cbz-protected 17a
in the presence of 0.5 mol % [RhI(COD)-(S,S)-EtDuPHOS]+OTf-
catalyst16 in methanol under pressurized hydrogen (0.4 MPa)
at room temperature; however, the desired amino acid derivative
29a was not obtained (entry 1). When the reaction was
performed under higher pressure (0.8 MPa) in THF, the desired
product 29a was obtained, albeit in a low yield (22%), with
complete stereoselectivity (entry 2). The yield of 29a was further
improved by using 1 mol % catalyst (entry 3). When the reaction
was carried out at 40 °C, no improvement of the yield was
observed (entry 4). Finally, the best result was obtained by using
5 mol % catalyst to give the desired 29a in 85% yield and with
a diastereomeric ratio of >20:1 (entry 5). The corresponding
diastereomer could not be detected in entries 2-5 in the 500
MHz 1H NMR spectra. The stereochemistry of the product 29a
a Reagents and conditions: (a) SO3‚pyridine, DMSO, Et3N, CH2Cl2, 0
°C; (b) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/H2O, rt; (c)
TMSCHN2, MeOH, rt, 85% (three steps); (d) TBAF, THF, rt, 85%.
of 24b as the ethoxyethyl (EE) ether followed by removal of
the TBDMS group provided alcohol 26. The primary hydroxy
group was oxidized to the corresponding carboxylic acid by a
two-step procedure and esterified with TMSCHN2 to give
methyl ester 27. Removal of the EE group by treatment with
hydrochloric acid in diethyl ether then delivered 18. Thus,
diastereomeric alcohols 24a and 24b were convergently used
for the synthesis of hydroxy ester 18.
We next converted alcohol 18 to the requisite enamide esters
N-Cbz-protected 17a and N-Boc-protected 17b in a two-step
procedure (Scheme 6). Oxidation of 18 under Swern conditions
(20) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
(21) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis, 1984, 53-59.
J. Org. Chem, Vol. 71, No. 14, 2006 5211

Shoji et al.
TABLE 2. Asymmetric Hydrogenation of Enamide Ester 17
enamide
ester
catalyst concn
(mol %)
H2
time
(h)
yield
(%)
entry
pressure (MPa)
solvent
temp
rt
rt
rt
40 °C
rt
rt
dr (2S:2R)a
1
2
3
4
5
6
17a
17a
17a
17a
17a
17b
0.5
0.5
1.0
1.0
5.0
5.0
0.4
0.8
0.8
0.8
0.8
0.8
MeOH
THF
THF
THF
THF
THF
48
48
120
120
96
0
-
22b
53c
55d
85
>20:1
>20:1
>20:1
>20:1
6:1
96
90
1
a Determined by 500 MHz H NMR. b 17a was recovered in 70% yield. c 17a was recovered in 32%. d 17a was recovered in 30% yield.
SCHEME 7a
SCHEME 8a
a Reagents and conditions: (a) H2, Pd(OH)2/C, Boc2O, hexane/MeOH,
quantitative; (b) DDQ, CH3CN/H2O, 55 °C, 80%.
was tentatively assigned on the basis of Burk’s empirical rule,16
and was confirmed later. In contrast to the case of 17a,
hydrogenation of N-Boc-protected enamide ester 17b under the
optimized conditions resulted in a moderate selectivity (dr )
6:1, entry 6). This result is apparently caused by the steric
demand of the bulky Boc protective group, which would
interfere in the diastereoselective interaction of the olefin moiety
with the rhodium catalyst. Hydrogenation of 17b under achiral
conditions (H2, Pd(OH)2/C, hexane/methanol) produced a 1:1
mixture of diastereomers, providing a comparison for diaster-
eomeric ratio determination.
The Cbz group of 29a was replaced with the Boc group by
hydrogenolysis in the presence of Boc2O to furnish 29b in
quantitative yield, which was completely identical with that
previously synthesized (Scheme 7). After several experiments,
selective removal of the acetonide group within 29b was realized
by the action of DDQ (MeCN/H2O, 55 °C),22 and the desired
16 was obtained in 80% yield without any loss of the Boc group.
Thus, the advanced key intermediate 16 was concisely prepared
from 9 in 12% overall yield over 16 steps.
a Reagents and conditions: (a) SOCl2, Et3N, CH2Cl2, -20 °C; (b)
catalytic RuCl3, NaIO4, CCl4/MeCN/H2O, rt, 91% (two steps); (c) CsOAc,
DMF, 65 °C; (d) catalytic H2SO4, THF, rt, 83% (two steps); (e) catalytic
TPAP, NMO, 4 Å molecular sieves, CH2Cl2, rt; (f) NaBH4, MeOH, -40
°C, 30-77% (two steps); (g) Tf2O, pyridine, DMAP, CH2Cl2, -20 °C; (h)
CsOAc, DMF, rt, 71% (two steps); (i) 6 M HCl, 85 °C, 93%.
31 in 83% yield after acid hydrolysis of the resultant sulfate
ester. Inversion of the C8 hydroxy group was next attempted
by an oxidation-reduction sequence; however, this protocol
lacked reproducibility (30-77% yield). Therefore, we decided
to undertake inversion of the C8 alcohol by nucleophilic
substitution. Triflation of 31 using triflic anhydride and pyridine
proceeded cleanly to give the corresponding triflate. Subsequent
treatment with cesium acetate led to alcohol 32 with the inverted
C8 stereochemistry in 71% yield over the two steps, and the
expected diacetate 33 was not obtained at all. Although this
transformation can be rationalized by neighboring group par-
ticipation of the C9 acetoxy group, we do not have an
explanation of why the acetyl group remains at the C9 position
(Scheme 9). In addition, since the use of DMAP instead of
cesium acetate also effected this inversion of the C8 configu-
ration, the role of cesium acetate was just that of an acid
scavenger. Finally, acidic hydrolysis of alcohol 32 completed
the synthesis of 2 in 93% yield, which was identical to the
natural sample.7
Total Synthesis of Neodysiherbaine A. Having established
a concise synthetic route to 16, we next set out to synthesize 2
from this advanced intermediate. Thus, cis-diol 16 was converted
to cyclic sulfate ester 30 in 91% yield by a two-step sequence,
including cyclic sulfite formation with SOCl2 and triethylamine
followed by oxidation using RuCl3/NaIO4 (Scheme 8).23 Treat-
ment of 30 with cesium acetate (DMF, 65 °C) effected
regioselective substitution at the C9 position to produce acetate
(22) (a) Fernandez, J. M. G.; Mellet, C. O.; Martin, A. M.; Fuentes, J.
Carbohydr. Res. 1995, 274, 263-268. (b) Tu, Y.; Wang, Z.-X.; Frohn,
M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475-
8485. (c) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002,
67, 2435-2446.
(23) For a review of cyclic sulfates, see: Byun, H.-S.; He, L.; Bittman,
R. Tetrahedron 2000, 56, 7051-7079.
5212 J. Org. Chem., Vol. 71, No. 14, 2006

Total Synthesis of Neodysiherbaine A and Analogues
SCHEME 9
SCHEME 12a
SCHEME 10a
a Reagents and conditions: (a) PhOC(S)Cl, DMAP, toluene, reflux, 73%;
(b) n-Bu3SnH, AIBN, toluene, reflux, 78%; (c) 6 M HCl, 85 °C, 92%.
SCHEME 13a
a Reagents and conditions: (a) 6 M HCl, 65 °C, 94%; (b) 6 M HCl, 85
°C, 90%.
SCHEME 11a
a Reagents and conditions: (a) NaBH4, DMA, rt; (b) catalytic H2SO4,
THF, rt, 51% (two steps); (c) catalytic TPAP, NMO, 4 Å molecular sieves,
CH2Cl2, rt; (d) NaBH4, MeOH, -20 °C, 88% (two steps); (e) 6 M HCl, 65
°C, 90%.
The C8 stereochemistry of 35 was determined by the observed
NOE between 6-H and 8-H as shown. Finally, global depro-
tection of 35 with 6 M HCl at 100 °C afforded 6 in quantitative
yield.
Analogue 7 was prepared as shown in Scheme 12. Alcohol
31 was converted to the corresponding phenyl thiocarbonate
37 by the action of phenyl chlorothionoformate and DMAP in
refluxing toluene (73% yield). Subsequent deoxygenation
proceeded smoothly under radical conditions (Bu3SnH, AIBN,
toluene, reflux) to deliver 38 in 78% yield. Acidic hydrolysis
of 38 generated 7 in 92% yield.
The synthesis of 8 is summarized in Scheme 13. Treatment
of 30 with sodium borohydride effected reductive ring opening
of the cyclic sulfate to yield, after acid hydrolysis of the resultant
sulfate monoester, alcohol 39 in 51% yield over the two steps.
The â-oriented hydroxy group of 39 was then inverted by an
oxidation-reduction sequence to produce R-alcohol 40 in 88%
yield for the two steps. Finally, global deprotection by acid
hydrolysis furnished 8 in 90% yield.
Analogue 3, which was a selective, competitive antagonist
for GluR5-containing kainate receptors,8,9 was also prepared
from diol 16 (Scheme 14). Treatment of diol 16 with thiocar-
bonyldiimidazole and DMAP in refluxing toluene generated
cyclic thiocarbonate 41 in 80% yield without epimerization at
the C2 position. Subsequent reductive deoxygenation of the C8
and C9 oxygen functionalities was performed by the Corey-
Winter method using 1,3-dimethyl-2-phenyl-1,3,2-diazaphos-
a Reagents and conditions: (a) PivCl, Et3N, DMAP, CH2Cl2, -50 °C,
82%; (b) Tf2O, pyridine, DMAP, CH2Cl2, -20 °C; (c) CsOAc, DMF, 50
°C, (35) 37% (two steps), (36) 11% (two steps); (d) 6 M HCl, 100 °C,
quantitative.
Synthesis of Analogues. Analogues 4 and 6 were prepared
by acid hydrolysis of intermediates 29b and 31, respectively
(Scheme 10).
Synthesis of analogue 6 is summarized in Scheme 11.
Selective protection of the C9 hydroxy group of 16 was
performed with pivaloyl chloride, triethylamine, and DMAP in
CH2Cl2 to provide pivalate ester 34 in 82% yield. The remaining
C8 hydroxy group was triflated (triflic anhydride, pyridine), and
subsequent nucleophilic substitution by cesium acetate provided
acetate 35 in 37% yield over the two steps. In this reaction,
elimination product 36 was produced as a significant byproduct.
Formation of 36 could not be avoided under various conditions.
J. Org. Chem, Vol. 71, No. 14, 2006 5213

Shoji et al.
SCHEME 14a
TABLE 4. Receptor Binding Affinities of Natural Dysiherbaines 1
and 2 and Synthetic Analogues 4-8 for Native AMPA and Kainate
Receptorsa
entry
compd
[3H]AMPA
[3H]kainic acid
1b
2c
3
4
5
DH (1)
NDH (2)
0.153 ( 0.01110
0.227 ( 0.0405
>100
0.026 ( 0.004
0.066 ( 0.005
>100
4
5
6
7
8
9.7 ( 2.3
24.1 ( 6.8
91 ( 35
32 ( 11
6
7
4.2 ( 1.6
1.4 ( 0.35
31.8 ( 14.1
68.1 ( 17.9
a Affinities for receptors (IC50, µM) were determined by the displacement
of [3H]AMPA and [3H]kainic acid from rat synaptic membrane preparations.
b Ki values (µM), reference 5. c Ki values (µM), reference 9.
TABLE 5. Receptor Binding Affinities of Natural Dysiherbaines 1
and 2 and Synthetic Analogues 4, 5, 7, and 8 for Recombinant
Kainate Receptorsa,b
a Reagents and conditions: (a) (imidazole)2CdS, DMAP, toluene, 70
°C, 80%; (b) 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine, THF, 40 °C,
73%; (c) H2, Pd(OH)2/C, hexane/MeOH, rt, 94%; (d) 6 M HCl, 65 °C,
85%.
entry
compd
GluR5
GluR6
KA2
1
2
3
4
5
6
DH (1)
NDH (2)
4
5
7
8
0.48c
7.7e
48000
34
1.1
168
1.28c
4300d
TABLE 3. Epileptogenic Activity of Natural Dysiherbaines 1 and
33e
600e
2 and Synthetic Analogues 4-8
>100000
22000
42
>100000
>100000
36000
ED50
(nmol/mouse,
icv)
ED50
(nmol/mouse,
icv)
entry
compd
entry
compd
>100000
>100000
1.3 × 10-2
1.6 × 10-2
no activitya
0.23
5
6
7
6
7
8
9.4
0.17
6.7
a Affinities for receptors (Ki, nM) were determined by the radioligand
binding assays using HEK 293 cells expressing the appropriate KA receptor
subunits. b [3H]Kainic acid was used as a radioligand. c Reference 5.
d Reference 6. e Reference 9.
1
2
3
4
DH (1)
NDH (2)
4
5
a Did not induce convulsant behaviors at 69 nmol/mouse.
kainate receptors, whereas analogue 4 had no significant affinity.
These results were consistent with the behavioral activity
described above. Among active analogues with binding affini-
ties, 8-deoxy analogue 7 showed the highest affinity for both
AMPA and kainate receptors, but was 20-fold less potent than
the natural product 2. Interestingly, 5 and 6 displaced [3H]-
AMPA more potently than [3H]kainic acid from the receptors.
None of the analogues exhibited a detectable affinity for NMDA
receptors.
To estimate the binding affinities of analogues 4, 5, 7, and 8
to the kainate receptor subunits, the radioligand binding assay
was next performed using recombinant homomeric kainate
receptor subunits (GluR5, GluR6, and KA2 receptors) expressed
in HEK 293 cells. The results are summarized in Table 5.
Although 4 did not bind detectably to native kainate receptors,
it displaced [3H]kainic acid from homomeric GluR5 kainate
receptors. The binding affinity of analogues 4, 5, 7, and 8 for
GluR5 kainate receptors correlated well with their epileptogenic
potency in mice, suggesting that activation of the GluR5 kainate
receptor subunit directly results in seizure behaviors. In contrast,
the affinity for the GluR6 or KA2 subunits poorly correlates
with the epileptogenic potency. Especially, the potently con-
vulsant 8-deoxy analogue 7 exhibited a high affinity for GluR5
receptors comparable to that of the natural product 2, but its
affinity for GluR6 receptors was greatly reduced. These results
suggest that the R-oriented C9 hydroxy group is a critical
structural element required for highly selective binding to the
GluR5 kainate receptors.
pholidine24 to give olefin 42 in 73% yield. Finally, hydroge-
nation of the double bond followed by acid hydrolysis furnished
analogue 3 in 80% yield for the two steps. According to the
newly developed procedures, analogue 3 was prepared even on
a 100 mg scale with good reproducibility.
Biological Evaluation of Dysiherbaine Analogues. The in
vivo toxicity of analogues 4-8 against mice was determined
by intracerebroventricular injection. Among the analogues tested,
9-epi, 8-deoxy, and 9-deoxy analogues (6, 7, and 8, respectively)
elicited behavior in a dose-dependent manner. The seizure
behavior observed after injection of these analogues cor-
responded well to that observed in 1, with the exception that
such behavior seldom recurred. The ED50 values for analogues
6, 7, and 8 were 9.4, 0.17, and 6.7 nmol/mouse, respectively
(Table 3). 8,9-epi analogue 4 did not induce noticeable
convulsant behavior even at a higher dose (69 nmol/mouse),
although mice became relatively hypoactive for a while.
Injection of 5 also resulted in the induction of seizures with an
ED50 value of 0.23 nmol/mouse. Interestingly, the behavioral
profile of 5 was substantially different from that of 1. Stereo-
typed behaviors, such as persistent scratching or clonic convul-
sions, frequently observed after administration of 1, were absent
in the case of 5. Instead, transient jumping and running behaviors
were apparent.
The binding affinities of analogues 4-8 were first evaluated
with native ionotropic glutamate receptors by radioligand
binding assays using rat synaptic membrane preparation (Table
4).5 Analogues 5-8, which possess a hydroxy group with at
least the same configuration as that of the natural product on
the C8 and/or C9 position, showed affinities for AMPA and
Conclusion. We have developed an efficient synthetic route
to 2 and its analogues 3-8, which features (i) a concise synthesis
of the bicyclic ether skeleton through stereoselective C-
glycosylation to set the C6 stereocenter and 5-exo cyclization
for constructing the tetrahydrofuran ring and (ii) stereoselective
construction of the amino acid appendage through catalytic
asymmetric hydrogenation of enamide ester. The preliminary
(24) (a) Corey, E. J.; Winter, A. E. J. Am. Chem. Soc. 1963, 85, 2677-
2678. (b) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 1979-
1982.
5214 J. Org. Chem., Vol. 71, No. 14, 2006

Total Synthesis of Neodysiherbaine A and Analogues
(80 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by flash column
chromatography on silica gel (100 g, ethyl acetate:hexanes ) 1:4)
afforded TBDMS ether 20 (10.6 g, 85%, an inseparable 3:1 mixture
of diastereomers) as a colorless oil: [R]D26 -66.2 (c 0.72, CHCl3);
IR (film) 3522, 2928, 2856, 1736, 1237, 1094, 837 cm-1; 1H NMR
(500 MHz, CDCl3) (major diastereomer) δ 7.35-7.25 (m, 5 H),
5.88 (d, J ) 10.0 Hz, 1 H), 5.81 (dt, J ) 10.5, 2.5 Hz, 1 H), 5.15
(d, J ) 3.0 Hz, 1 H), 4.55 (d, J ) 9.0 Hz, 1 H), 4.53 (dd, J ) 10.0,
2.5 Hz, 1 H), 4.51 (d, J ) 9.0 Hz, 1 H), 4.04 (dd, J ) 12.0, 3.5
Hz, 1 H), 3.57 (dd, J ) 4.0, 2.0 Hz, 1 H), 3.55-3.54 (m, 2 H),
3.45-3.44 (m, 2 H), 3.12 (s, 1H), 2.06 (s, 3 H), 1.85 (dd, J )
14.5, 5.0 Hz, 1 H), 1.62 (dd, J ) 14.5, 2.5 Hz, 1 H), 0.85 (s, 9 H),
0.02 (s, 6 H); 13C NMR (125 MHz, CDCl3) (major diastereomer)
δ 169.1, 135.6 (×2), 128.6, 127.9 (×2), 126.5 (×2), 123.3, 78.9,
73.7, 73.2, 70.4, 66.2, 65.0, 64.3, 36.9, 25.9 (×3), 21.3, 18.2, -4.5
(×2); HRMS (FAB) m/z calcd for C24H39O6Si [(M + H)+]
451.2516, found 451.2520.
structure-activity relationship studies described herein revealed
that the R-oriented C9 hydroxy group is a critical element
required for selective binding to the GluR5 kainate receptor
subunit. More detailed neurophysiological studies of analogues
4-8 and newer analogues will not only facilitate an in-depth
understanding of the structure-function relationship between
dysiherbaine analogues and glutamate receptors but also lead
us to the development of compounds with therapeutic utility.
Further investigations along these lines are currently under way
and will be reported in due course.
Experimental Section
C-Glycoside 11. To a solution of 3,4-di-O-acetyl-L-arabinal (9;
11.92 g, 59.6 mmol) and allylsilane 10 (16.8 g, 71.5 mmol) in CH2-
Cl2 (300 mL) at 0 °C was added Yb(OTf)3 (5.54 g, 8.94 mmol).
The reaction mixture was stirred at room temperature for 2.5 h
and treated with water (50 mL). The mixture was extracted with
CH2Cl2 (2 × 100 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography on silica gel (150 g,
triethylamine:ethyl acetate:hexanes ) 0.1:1:10) afforded C-glyco-
Acetonide 23. To a solution of TBDMS ether 20 (11.5 g, 25.5
mmol) in methanol (150 mL) at room temperature was added K2-
CO3 (702 mg, 5.00 mmol). The reaction mixture was stirred at room
temperature for 12 h and then concentrated under reduced pressure
to give an oily solid. The residue was purified by flash column
chromatography on silica gel (100 g, ethyl acetate:hexanes ) 1:1)
to afford allylic alcohol (9.73 g, 95%, an inseparable 3:1 mixture
of diastereomers) as a colorless oil: [R]D26 -58.6 (c 0.72, CHCl3);
26
side 11 (15.7 g, 87%) as a colorless oil: [R]D -110.1 (c 0.25,
CHCl3); IR (film) 2927, 2857, 2359, 2342, 1734, 1370, 1236, 1092
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.25 (m, 5 H), 5.92 (d,
J ) 10.0 Hz, 1 H), 5.82 (d, J ) 10.0 Hz, 1 H), 5.19 (s, 1 H), 5.16
(s, 1 H), 5.03 (s, 1 H), 4.48 (s, 2 H), 4.31 (s, 1 H), 4.07 (dd, J )
12.0, 5.0 Hz, 1 H), 4.02 (d, J ) 16.0 Hz, 1 H), 3.99 (d, J ) 16.0
Hz, 1 H), 3.53 (dd, J ) 12.0, 6.0 Hz, 1 H), 2.37 (dd, J ) 14.5, 8.0
Hz, 1 H), 2.29 (dd, J ) 14.5, 5.0 Hz, 1 H), 2.05 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 170.6, 142.1, 138.2, 128.4 (×2), 127.8, 127.6,
124.0, 123.9, 115.0, 73.0, 72.0, 71.8, 64.9, 64.8, 64.7, 37.6, 21.2;
HRMS (FAB) m/z calcd for C18H23O4 [(M + H)+] 303.1596, found
303.1604.
IR (film) 3410, 2927, 2359, 2341 cm-1 1H NMR (500 MHz,
;
CDCl3) (major diastereomer) δ 7.33-7.25 (m, 5 H), 5.86 (dt, J )
10.0, 3.0 Hz, 1 H), 5.74 (d, J ) 10.0 Hz, 1 H), 4.55 (d, J ) 11.5
Hz, 1 H), 4.52 (d, J ) 11.5 Hz, 1 H), 4.46 (d, J ) 10.0 Hz, 1 H),
4.10 (m, 1 H), 3.99 (dd, J ) 11.5, 4.0 Hz, 1 H), 3.56 (s, 2 H), 3.45
(s, 2 H), 3.44 (dd, J ) 11.0, 5.5 Hz, 1 H), 3.25 (s, 1H), 1.82 (dd,
J ) 14.5, 5.0 Hz, 1 H), 1.67 (d, J ) 8.5 Hz, 1H), 1.63 (dd, J )
15.0, 6.0 Hz, 1 H), 0.84 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H); 13C
NMR (125 MHz, CDCl3) (major diastereomer) δ 138.2, 133.3,
128.3 (×2), 127.6 (×2), 127.5, 127.4, 73.6, 73.4, 72.8, 70.4, 67.6,
66.2, 62.6, 36.4, 25.8 (×3), 18.2, -5.5 (×2); HRMS (FAB) m/z
calcd for C22H37O5Si [(M+H)+] 409.2410, found 409.2416.
To a solution of allylic alcohol (8.70 g, 21.3 mmol) in CH2Cl2
and pH 7 phosphate buffer (9:1, v/v, 150 mL) at 0 °C was added
m-CPBA (65%, 8.5 g, 32 mmol). The reaction mixture was stirred
at room temperature for 12 h, quenched with saturated aqueous
Na2SO3 (100 mL), and then stirred for an additional 30 min. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 300 mL). The combined organic layers were
washed with brine (100 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by flash column
chromatography on silica gel (100 g, ethyl acetate:hexanes ) 1:1)
afforded diol 22 (8.10 g, 89%, an inseparable 3:1 mixture of
diastereomers) as a colorless oil.
Diol 19. To a solution of OsO4 (1% solution in tert-butyl alcohol,
19.0 mL, 0.750 mmol), (DHQD)2AQN (1.29 g, 1.50 mmol), K2-
CO3 (6.22 g, 45.0 mmol), and K2[Fe(CN)6] (14.8 g, 45.0 mmol) in
water (40 mL) at 0 °C were successively added diene 11 (4.53 g,
15.0 mmol) in tert-butyl alcohol (40 mL) and methanesulfonamide
(4.28 g, 45.0 mmol). The reaction mixture was stirred for 3 h and
then quenched with saturated aqueous Na2SO3 (40 mL). The
resulting mixture was stirred at room temperature for an additional
30 min. The organic phase was separated, and the aqueous layer
was extracted with CH2Cl2 (5 × 300 mL). The combined organic
layers were washed with brine (100 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification by
flash column chromatography on silica gel (150 g, ethyl acetate:
hexanes ) 1:1) afforded diol 19 (4.07 g, 80%, an inseparable 3:1
mixture of diastereomers) as a colorless oil: [R]D26 -67.0 (c 1.03,
1
CHCl3); IR (film) 3446, 2925, 2359, 1733, 1418 cm-1; H NMR
To a solution of the above diol 22 (8.09 g, 19.0 mmol) in CH2-
Cl2 (150 mL) at 0 °C were added CSA (882 mg, 3.80 mmol) and
2,2-dimethoxypropane (23 mL, 190 mmol). The reaction mixture
was stirred at 0 °C for 2 h and then quenched with triethylamine
(5 mL). The solution was concentrated under reduced pressure, and
the residue was purified by flash column chromatography on silica
gel (100 g, ethyl acetate:hexanes ) 1:9) to afford acetonide 23
(7.50 g, 85%, an inseparable 3:1 mixture of diastereomers) as a
(500 MHz, CDCl3) (major diastereomer) δ 7.35-7.26 (m, 5 H),
5.82-5.79 (m, 2 H), 5.21 (dd, J ) 4.0, 2.0 Hz, 1 H), 4.54 (d, J )
11.5 Hz, 1 H), 4.49 (d, J ) 11.5 Hz, 1 H), 4.46-4.43 (m, 1 H),
4.09 (d, J ) 5.5 Hz, 1 H), 3.55 (d, J ) 6.5 Hz, 2 H), 3.51 (dd, J
) 11.0, 6.5 Hz, 1 H), 3.49 (d, J ) 9.0 Hz, 1 H), 3.46 (s, 1H), 3.45
(d, J ) 12.0 Hz, 1 H), 3.41 (d, J ) 9.0 Hz, 1 H), 2.62 (t, J ) 14.0
Hz, 1 H), 2.06 (s, 3 H), 1.76-1.74 (m, 2 H); 13C NMR (125 MHz,
CDCl3) (major diastereomer) δ 170.5, 137.8, 134.0, 128.4, 127.8
(×2), 127.7 (×2), 124.1, 73.4, 73.2, 70.5, 66.8, 64.6, 60.3, 37.1,
20.9, 14.1; HRMS (FAB) m/z calcd for C18H25O6 [(M + H)+]
337.1651, found 337.1654.
TBDMS Ether 20. To a solution of diol 19 (9.21 g, 27.6 mmol),
triethylamine (9.30 mL, 66.2 mmol), and DMAP (674 mg, 5.52
mmol) in CH2Cl2 (150 mL) at 0 °C was added TBDMSOTf (6.90
mL, 30.3 mmol). The reaction mixture was stirred at room
temperature for 12 h. The mixture was diluted with ethyl acetate
(500 mL) and washed successively with water (80 mL), aqueous 1
M HCl (80 mL), saturated aqueous NaHCO3 (80 mL), and brine
26
colorless oil: [R]D -5.5 (c 0.66, CHCl3); IR (film) 2928, 2857,
2359, 2342, 1085, 1062 cm-1; 1H NMR (500 MHz, CDCl3) (major
diastereomer) δ 7.34-7.25 (m, 5H), 4.53 (d, J ) 13.0 Hz, 1 H),
4.50 (d, J ) 13.0 Hz, 1 H), 4.42 (s, 1 H), 4.19 (dt, J ) 11.0, 7.0
Hz, 1 H), 4.16 (s, 1 H), 4.07 (dd, J ) 12.0, 2.5 Hz, 1 H), 3.73 (q,
J ) 6.0 Hz, 1 H), 3.65 (d, J ) 9.0 Hz, 1 H), 3.61 (d, J ) 11.0 Hz,
1 H), 3.52 (d, J ) 15.0 Hz, 1 H), 3.45 (d, J ) 15.0 Hz, 1 H), 3.10
(t, J ) 11.0 Hz, 1 H), 2.23 (dd, J ) 14.5, 5.5 Hz, 1 H), 1.99 (d, J
) 14.5 Hz, 1 H), 1.44 (s, 6 H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.02
(s, 3 H); 13C NMR (125 MHz, CDCl3) (major diastereomer) δ 138.0,
128.2, 127.5 (×2), 127.4 (×2), 108.4, 84.1, 78.1, 76.2, 73.5, 73.3,
J. Org. Chem, Vol. 71, No. 14, 2006 5215

Shoji et al.
72.9, 72.4, 68.9, 65.7, 65.5, 37.0, 27.9, 25.8 (×3), 18.2, -5.4 (×2);
HRMS (FAB) m/z calcd for C25H41O6Si [(M + H)+] 465.2672,
found 465.2672.
68.2, 66.4, 64.9, 51.9, 51.8, 38.5, 27.8, 25.7, 25.6 (×3), -5.7, -5.6;
HRMS (FAB) m/z calcd for C19H35O7Si [(M + H)+] 403.2152,
found 403.2156.
Alcohols 24a and 24b. A suspension of acetonide 23 (3.77 g,
8.12 mmol) and 10% Pd/C (377 mg) in hexane (80 mL) at room
temperature was stirred under a hydrogen atmosphere for 2 h. The
reaction mixture was filtered through a short pad of Celite, and the
filtrate was concentrated under reduced pressure. Purification by
flash column chromatography on silica gel (100 g, ethyl acetate:
hexanes ) 1:9) afforded (4R)-alcohol 24a (2.27 g, 75%) and its
diastereomeric (4S)-alcohol 24b (609 mg, 20%) as colorless oils.
Data for (4R)-alcohol 24a: [R]D26 -21.8 (c 0.18, CHCl3); IR (film)
Alcohol 18. To a solution of TBDMS ether 25 (528 mg, 1.30
mmol) in THF (9.0 mL) at room temperature was added TBAF
(1.0 M in THF, 4.0 mL, 4.0 mmol). The reaction mixture was stirred
at room temperature for 30 min and then concentrated under reduced
pressure. Purification by flash column chromatography on silica
gel (20 g, ethyl acetate:hexanes ) 3:7) afforded alcohol 18 (313
26
mg, 85%) as a pale yellow oil: [R]D -20.4 (c 0.67, CHCl3); IR
1
(film) 3479, 2985, 1732, 1218, 1086, 1060 cm-1; H NMR (500
MHz, CDCl3) δ 4.55 (d, J ) 5.5 Hz, 1 H), 4.25 (dt, J ) 10.5, 6.0
Hz, 1 H), 4.23 (s, 1 H), 4.09 (s, 1 H), 3.82 (dd, J ) 12.0, 7.0 Hz,
1 H), 3.73 (s, 3 H), 3.72 (dd, J ) 18.0, 6.0 Hz, 1 H), 3.63 (dd, J
) 12.0, 6.5 Hz, 1 H), 3.07 (t, J ) 10.5 Hz, 1 H), 2.49 (d, J ) 14.0
Hz, 1 H), 2.23 (dd, J ) 7.0, 5.5 Hz, 1 H), 1.44 (s, 3 H), 1.35 (s, 3
H); 13C NMR (125 MHz, CDCl3) δ 173.4, 108.8, 86.5, 79.3, 75.0,
72.7, 68.7, 66.3, 65.3, 52.5, 39.4, 28.2, 26.1; HRMS (FAB) m/z
calcd for C13H21NO7 [(M + H)+] 289.1287, found 289.1288.
Cbz-Protected Enamide Ester 17a. To a solution of DMSO
(4.05 mL, 57.2 mmol) in CH2Cl2 at -78 °C was added oxalyl
chloride (3.81 mL, 42.9 mmol). The resultant mixture was stirred
at -78 °C for 15 min, and then a solution of alcohol 18 (4.11 g,
14.3 mmol) in CH2Cl2 (140 mL) was introduced via cannula. The
reaction mixture was stirred at the same temperature for 45 min
and then treated with triethylamine (11.9 mL, 85.8 mmol). The
resultant mixture was allowed to warm to room temperature over
1 h and quenched with saturated aqueous NH4Cl (100 mL). The
mixture was extracted with ethyl acetate (3 × 250 mL), and the
combined organic extracts were washed with brine (100 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure to
give a crude aldehyde as a yellow solid.
1
3481, 2952, 2359, 1085, 1062, 837 cm-1; H NMR (500 MHz,
CDCl3) δ 4.38 (d, J ) 5.5 Hz, 1 H), 4.20 (dt, J ) 11.0, 5.5 Hz, 1
H), 4.09 (s, 1 H), 4.07 (dd, J ) 5.0, 2.5 Hz, 1 H), 3.77 (q, J ) 6.0
Hz, 1 H), 3.69 (d, J ) 9.5 Hz, 1 H), 3.62 (dd, J ) 12.0, 7.0 Hz, 1
H), 3.59 (d, J ) 9.5 Hz, 1 H), 3.56 (dd, J ) 12.0, 6.0 Hz, 1 H),
3.10 (t, J ) 11.0 Hz, 1 H), 2.25 (t, J ) 6.5 Hz, 1 H), 2.07 (d, J )
15.0 Hz, 1 H), 1.99 (dd, J ) 15.0, 5.0 Hz, 1 H), 1.44 (s, 3 H), 1.33
(s, 3 H), 0.86 (s, 9 H), 0.04 (s, 6 H); 13C NMR (125 MHz, CDCl3)
δ 108.9, 85.0, 78.2, 76.5, 72.4, 68.8, 66.3, 66.1, 65.9, 36.7, 28.3,
26.5, 26.0 (×3), 18.4, -5.2, -5.3; HRMS (FAB) m/z calcd for
C18H35O6Si [(M + H)+] 375.2203, found 375.2209. Data for (4S)-
alcohol 24b: [R]D26 -12.1 (c 0.56, CHCl3); IR (film) 3481, 2929,
2359, 1085, 1063, 838 cm-1; 1H NMR (CDCl3) δ 4.40 (d, J ) 5.5
Hz, 1 H), 4.24 (dt, J ) 11.0, 5.5 Hz, 1 H), 4.11 (s, 1 H), 4.07 (dd,
J ) 5.0, 2.0 Hz, 1 H), 3.80 (q, J ) 6.0 Hz, 1 H), 3.55 (d, J ) 6.0
Hz, 2 H), 3.54 (s, 2 H), 3.14 (t, J ) 11.0 Hz, 1 H), 2.61 (t, J ) 5.3
Hz, 1 H), 2.23 (dd, J ) 14.0, 5.3 Hz, 1 H), 1.98 (d, J ) 14.0 Hz,
1 H), 1.44 (s, 3 H), 1.34 (s, 3 H), 0.87 (s, 9 H), 0.04 (s, 6 H); 13
C
NMR (125 MHz, CDCl3) δ 108.6, 83.8, 77.7, 76.2, 72.4, 68.9, 66.9,
66.4, 65.7, 37.2, 28.0 (×2), 25.9, 25.8 (×2), 18.1, -5.5 (×2);
HRMS (FAB) m/z calcd for C18H35O6Si [(M + H)+] 375.2203,
found 375.2207.
To a stirred solution of the above aldehyde in CH2Cl2 (140 mL)
at 0 °C were added (MeO)2P(O)CH(NHCbz)CO2Me (28a; 14.17
g, 42.90 mmol) and N,N,N′,N′-tetramethylguanidine (7.20 mL, 57.2
mmol). The reaction mixture was stirred at room temperature for
1 h and then quenched with saturated aqueous NH4Cl (40 mL).
The mixture was extracted with CH2Cl2 (3 × 50 mL), and the
combined organic layers were washed with brine (30 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography on silica gel (300 g,
ethyl actetate:hexanes ) 3:7) afforded enamide ester 17a (5.65 g,
Methyl Ester 25. To a solution of alcohol 24a (3.26 g, 9.40
mmol) in CH2Cl2/DMSO (4:1, v/v, 80 mL) at 0 °C were succes-
sively added triethylamine (6.50 mL, 47.0 mmol) and SO3‚pyridine
(5.98 g, 37.6 mmol). The resultant mixture was stirred at room
temperature for 1.5 h. The mixture was then extracted with ethyl
acetate (3 × 200 mL), and the combined organic layers were
successively washed with aqueous 1 M HCl (80 mL), saturated
aqueous NaHCO3 (80 mL), and brine (80 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated under reduced
pressure to give a crude aldehyde as a colorless oil.
To a solution of the above aldehyde in tert-butyl alcohol/water
(5:1, v/v, 70 mL) at 0 °C were added 2-methyl-2-butene (17.0 mL),
NaH2PO4 (1.24 g, 10.3 mmol), and NaClO2 (2.81 g, 31.0 mmol).
The resultant mixture was stirred at room temperature for 2 h and
then poured into CHCl3/water (3:1, v/v, 200 mL). The mixture was
acidified to pH 2 with aqueous 1 M HCl. The organic layer was
separated, and the aqueous layer was extracted with CHCl3 (5 ×
200 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under reduced pressure to give a crude
carboxylic acid as a colorless oil.
26
81% for the two steps) as a colorless solid: [R]D -8.0 (c 0.61,
CHCl3); IR (film) 3365, 2986, 2952, 2359, 2341, 1733, 1653, 1219,
1062 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.58 (br s, 1 H), 7.35-
7.29 (m, 5 H), 6.02 (s, 1 H), 5.14 (s, 2 H), 4.50 (d, J ) 5.5 Hz, 1
H), 4.26 (s, 1 H), 4.19 (dt, J ) 10.5, 5.5 Hz, 1 H), 4.05 (s, 1 H),
3.72 (m, 1 H), 3.69 (s, 6 H), 3.04 (t, J ) 11.0 Hz, 1 H), 2.92 (d,
J ) 13.5 Hz, 1 H), 2.23 (dd, J ) 13.5, 4.0 Hz, 1 H), 1.43 (s, 3 H),
1.36 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 172.2, 164.3, 153.4,
135.6, 130.5, 128.4 (×2), 128.1 (×2), 128.0, 108.6, 83.8, 78.9, 74.2,
72.3, 68.3, 67.4, 65.9, 60.2, 52.9, 52.5, 43.9, 27.9, 25.9; HRMS
(FAB) m/z calcd for C24H30NO10 [(M + H)+] 492.1870, found
492.1867.
Boc-Protected Enamide Ester 17b. To a solution of DMSO
(0.28 mL, 3.0 mmol) in CH2Cl2 (2.0 mL) at -78 °C was added
oxalyl chloride (0.26 mL, 4.0 mmol). The resultant mixture was
stirred at -78 °C for 15 min, and then a solution of alcohol 18
(288 mg, 1.00 mmol) in CH2Cl2 (8.0 mL) was introduced via
cannula. The reaction mixture was stirred at the same temperature
for 45 min and then treated with triethylamine (0.86 mL, 6.00
mmol). The mixture was allowed to warm to room temperature
over 1 h and then quenched with saturated aqueous NH4Cl (10 mL).
The reaction mixture was extracted with ethyl acetate (3 × 30 mL),
and the combined organic layers were washed with brine (10 mL),
dried over Na2SO4, filtered, and concentrated under reduced pressure
to give a crude aldehyde as a yellow solid.
To a solution of the above carboxylic acid in methanol/benzene
(1:1, v/v, 80 mL) at room temperature was added TMSCHN2 (2 M
in Et2O, 14.0 mL, 28 mmol). The reaction mixture was stirred at
room temperature overnight and then concentrated under reduced
pressure. Purification by flash column chromatography on silica
gel (200 g, ethyl acetate:hexanes ) 1:4) afforded methyl ester 25
26
(10.6 g, 85% for the three steps) as a colorless oil: [R]D -11.0
(c 0.44, CHCl3); IR (film) 2953, 2929, 2362, 1733, 1249, 1086,
1
838 cm-1; H NMR (500 MHz, CDCl3) δ 4.54 (d, J ) 5.5 Hz, 1
H), 4.24 (dt, J ) 10.5, 5.5 Hz, 1 H), 4.19 (s, 1 H), 4.06 (s, 1 H),
3.82 (d, J ) 11.0 Hz, 1 H), 3.71 (dd, J ) 13.0, 6.5 Hz, 1 H), 3.70
(s, 3 H), 3.67 (d, J ) 10.0 Hz, 1 H), 3.08 (t, J ) 10.5 Hz, 1 H),
2.45 (d, J ) 14.0 Hz, 1 H), 2.31 (dd, J ) 14.0, 4.5 Hz, 1 H), 1.44
(s, 3 H), 1.35 (s, 3 H), 0.85 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H);
13C NMR (125 MHz, CDCl3) δ 172.9, 108.3, 86.4, 78.9, 74.8, 72.3,
To a stirred solution of the above aldehyde in CH2Cl2 (10 mL)
at 0 °C were added (MeO)2P(O)CH(NHBoc)CO2Me (28b; 892 mg,
5216 J. Org. Chem., Vol. 71, No. 14, 2006

Total Synthesis of Neodysiherbaine A and Analogues
3.00 mmol) and N,N,N′,N′-tetramethylguanidine (0.52 mL, 4.0
mmol). The reaction mixture was stirred at room temperature for
1 h and then quenched with saturated aqueous NH4Cl (10 mL).
The mixture was extracted with ethyl acetate (3 × 30 mL), and
the combined extracts were washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifica-
tion by flash column chromatography on silica gel (15 g, CH2Cl2:
ethyl acetate:hexanes ) 1:2:7) afforded enamide ester 17b (365
mg, 80% for the two steps) as a pale yellow foam: [R]D19 +2.9 (c
0.48, CHCl3); IR (film) 3391, 2982, 1728, 1655, 1459, 1245, 1162,
methanol:CHCl3 ) 3:97) afforded diol 16 (163 mg, 80%) as a white
19
solid: [R]D +24.5 (c 0.28, CHCl3); IR (film) 3435, 2977, 2953,
1734, 1716, 1506, 1164, 1082 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.41 (d, J ) 7.0 Hz, 1 H), 4.23 (dd, J ) 7.5, 5.0 Hz, 1 H), 4.16
(s, 1 H), 4.15 (br s, 2 H), 4.01 (s, 1 H), 3.72 (s, 3 H), 3.70 (s, 3 H),
3.52 (dd, J ) 11.0, 5.0 Hz, 1 H), 3.44 (t, J ) 10.5 Hz, 1 H), 2.95
(br s, 1 H), 2.61 (d, J ) 14.0 Hz, 1 H), 2.59 (dd, J ) 7.0, 5.5 Hz,
1 H), 2.16 (dd, J ) 14.0, 5.5 Hz, 1 H), 2.06 (dd, J ) 13.0, 3.5 Hz,
1 H), 1.40 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ 174.2, 172.2,
154.8, 83.3, 82.4, 79.7, 72.7, 66.4, 63.8, 63.5, 52.3, 52.1, 50.2, 43.7,
39.7, 27.9 (×3); HRMS (FAB) m/z calcd for C18H30NO10 [(M +
H)+] 420.1870, found 420.1869.
1
1084, 1063, 858 cm-1; H NMR (500 MHz, CDCl3) δ 7.21 (br s,
1 H), 5.83 (s, 1 H), 4.42 (d, J ) 7.0 Hz, 1 H), 4.17 (s, 1 H), 4.11
(dt, J ) 10.0, 6.0 Hz, 1 H), 3.99 (s, 1 H), 3.66 (s, 3 H), 3.62 (s, 3
H), 3.60 (dd, J ) 12.0, 6.5 Hz, 1H), 2.96 (t, J ) 11.0 Hz, 1 H),
2.84 (d, J ) 14.5 Hz, 1 H), 2.17 (dd, J ) 14.5, 3.5 Hz, 1 H), 1.34
(s, 3 H), 1.34 (s, 9 H), 1.27 (s, 3 H); 13C NMR (125 MHz, CDCl3)
δ 172.7, 163.2, 152.9, 131.1, 123.6, 109.4, 84.2, 81.4, 79.9, 74.7,
72.7, 68.7, 65.5, 53.2, 52.7, 44.2, 28.4 (×3), 28.3, 26.2; HRMS
(FAB) m/z calcd for C21H32NO10 [(M + H)+] 458.2026, found
458.2029.
Cyclic Sulfate 30. To a solution of diol 16 (254 mg, 0.61 mmol)
in CH2Cl2 (7.0 mL) at -20 °C were added triethylamine (0.23 mL,
1.71 mmol) and thionyl chloride (0.100 mL, 1.46 mmol). The
resultant mixture was stirred at -20 °C for 30 min and then poured
into ice-water (5 mL). The mixture was extracted with Et2O (3 ×
20 mL), and the combined organic layers were washed with brine
(10 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure to give a cyclic sulfite (265 mg) as a white solid.
To a solution of the above cyclic sulfite in CH3CN/CCl4 (4:5,
v/v, 9.0 mL) at room temperature were added NaIO4 (487 mg, 2.28
mmol) and RuCl3 (24 mg, 0.11 mmol) followed by water (4.0 mL).
The resultant mixture was stirred at room temperature for 1 h and
then extracted with Et2O (3 × 20 mL). The combined organic layers
were washed with brine (10 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by flash column
chromatography on silica gel (10 g, ethyl acetate:hexanes ) 3:7)
afforded cyclic sulfate 30 (245 mg, 91% for the two steps) as a
Cbz-Protected Amino Acid Derivative 29a. A degassed mixture
of [RhI(COD)-(S,S)-EtDuPHOS]OTf (41.0 mg, 0.060 mmol) and
enamide ester 17a (564 mg, 1.14 mmol) in freshly distilled THF
(6.0 mL) was placed in a hydrogenation bottle and pressurized with
hydrogen to an initial pressure of 0.8 MPa. The reaction mixture
was stirred at room temperature for 96 h. The mixture was
concentrated under reduced pressure, and the residue was purified
by flash column chromatography on silica gel (10 g, CH2Cl2:ethyl
acetate:hexanes ) 1:2:7) to afford Cbz-protected glutamic acid
26
26
derivative 29a (486 mg, 85%) as a white solid: [R]D +8.4 (c
white solid: [R]D +66.8 (c 0.11, CHCl3); IR (film) 3421, 2954,
1
0.67, CHCl3); IR (film) 3348, 2986, 2952, 2359, 2341, 1729, 1244,
2359, 1746, 1714, 1392, 1213, 985 cm-1; H NMR (500 MHz,
1
1085 cm-1; H NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 5 H),
CDCl3) δ 5.26 (d, J ) 4.5 Hz, 1 H), 5.21 (d, J ) 7.5 Hz, 1 H),
5.02 (dt, J ) 11.0, 5.5 Hz, 1 H), 4.32 (s, 1 H), 4.33 (dd, J ) 7.5,
5.0 Hz, 1 H), 4.19 (t, J ) 3.5 Hz, 1 H), 3.97 (dd, J ) 12.0, 6.5 Hz,
1H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.52 (t, J ) 11.0 Hz, 1 H), 2.61
(d, J ) 14.0 Hz, 1 H), 2.59 (dd, J ) 7.0, 5.5 Hz, 1 H), 2.18 (dd,
J ) 14.0, 4.0 Hz, 1 H), 2.13 (dd, J ) 15.0, 5.5 Hz, 1 H), 1.38 (s,
9 H); 13C NMR (125 MHz, CDCl3) δ 173.4, 171.9, 154.9, 84.0,
80.1, 76.6, 74.9, 74.7, 61.9 (× 2), 52.5, 52.4, 50.5, 43.9, 39.3, 28.3
(×3); HRMS (FAB) m/z calcd for C18H28NO12S [(M + H)+]
482.1332, found 482.1335.
5.64 (d, J ) 7.0 Hz, 1 H), 5.11 (d, J ) 12.5 Hz, 1 H), 5.07 (d, J
) 12.5 Hz, 1 H), 4.42 (d, J ) 5.0 Hz, 1 H), 4.34 (dd, J ) 7.5, 5.5
Hz, 1 H), 4.20 (dt, J ) 10.5, 5.5 Hz, 1 H), 4.15 (s, 1 H), 4.03 (s,
1 H), 3.73 (s, 3 H), 3.68 (dd, J ) 11.5, 6.0 Hz, 1 H), 3.59 (s, 3 H),
3.03 (t, J ) 10.5 Hz, 1 H), 2.59 (d, J ) 14.0 Hz, 1 H), 2.58 (dd,
J ) 14.0, 6.5 Hz, 1 H), 2.18 (dd, J ) 14.5, 6.5 Hz, 1 H), 2.11 (dd,
J ) 14.5, 4.0 Hz, 1 H), 1.42 (s, 3 H), 1.34 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 174.1, 172.1, 155.8, 136.4, 128.6 (×2), 128.3, (×2),
128.2, 108.8, 83.6, 78.9, 77.5, 72.8, 68.7, 67.0, 65.2, 52.6, 52.4,
51.6, 44.9, 39.6, 28.2, 26.1; HRMS (FAB) m/z calcd for C24H32-
NO10 [(M + H)+] 494.2026, found 494.2026.
Acetoxy Alcohol 31. To a solution of cyclic sulfate 30 (76.0
mg, 0.160 mmol) in DMF (2.0 mL) at room temperature was added
cesium acetate (45.0 mg, 0.230 mmol). The resultant suspension
was stirred at 65 °C for 6 h and then concentrated under reduced
pressure to give an acetoxy sulfate as a pale yellow solid.
To a stirred suspension of the above acetoxy sulfate in THF (2.0
mL) at room temperature was added concentrated H2SO4 (4 drops).
The mixture was stirred at room temperature for 1 h and then
partitioned between ethyl acetate (5 mL) and ice-water (5 mL).
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (3 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (5 g, methanol:CHCl3 ) 3:97)
afforded acetoxy alcohol 31 (68.0 mg, 83% for the two steps) as a
Boc-Protected Amino Acid Derivative 29b. To a solution of
29a (486 mg, 0.97 mmol) in hexane/methanol (3:2, v/v, 10 mL) at
room temperature were added Boc2O (0.89 mL, 3.80 mmol) and
10% Pd(OH)2/C (50.0 mg). The mixture was stirred at room
temperature under a hydrogen atmosphere for 2 h and then filtered
through a pad of Celite. The filtrate was concentrated under reduced
pressure, and the residue was purified by flash column chroma-
tography on silica gel (20 g, ethyl acetate:hexanes ) 1:1) to afford
19
29b (458 mg, 100%) as a colorless solid: [R]D +19.2 (c 0.29,
CHCl3); IR (film) 3365, 2981, 2952, 2359, 2342, 1749, 1717, 1246,
1164, 1062 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.33 (d, J ) 7.0
Hz, 1 H), 4.43 (d, J ) 4.5 Hz, 1 H), 4.30 (dd, J ) 7.5, 5.5 Hz, 1
H), 4.24 (dt, J ) 6.5, 4.5 Hz, 1 H), 4.16 (s, 1 H), 4.04 (s, 1 H),
3.72 (dd, J ) 13.0, 6.5 Hz, 1 H), 3.70 (s, 3 H), 3.69 (dd, J ) 12.0,
6.0 Hz, 1 H), 3.03 (t, J ) 11.0 Hz, 1 H), 2.59 (d, J ) 14.5 Hz, 1
H), 2.55 (dd, J ) 15.0, 5.0 Hz, 1 H), 2.17 (dd, J ) 14.5, 5.5 Hz,
1 H), 2.14 (dd, J ) 12.0, 4.5 Hz, 1 H), 1.42 (s, 3 H), 1.41 (s, 9 H),
1.39 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 173.8, 172.1, 154.8,
108.3, 83.2, 79.6, 78.5, 74.4, 72.4, 68.3, 64.8, 60.1, 52.1, 50.6, 44.3,
39.4, 28.3 (×3), 27.8, 25.7; HRMS (FAB) m/z calcd for C21H34-
NO10 [(M + H)+] 460.2183, found 460.2188.
26
white solid: [R]D +18.3 (c 0.36, CHCl3); IR (film) 3437, 2978,
1
2360, 1729, 1368, 1245, 1163, 1073 cm-1; H NMR (500 MHz,
CDCl3) δ 5.36 (d, J ) 6.5 Hz, 1 H), 4.55 (s, 1 H), 4.26 (s, 1 H),
4.14 (s, 1 H), 4.07 (d, J ) 4.0 Hz, 1 H), 3.79 (s, 1 H), 3.78 (dd, J
) 10.5, 3.0 Hz, 1 H), 3.69 (s, 3 H), 3.68 (s, 3 H), 3.67 (m, 1H),
2.56 (d, J ) 14.0 Hz, 1 H), 2.44 (dd, J ) 14.5, 5.5 Hz, 1 H),
2.19-2.15 (m, 2 H), 2.11 (s, 3 H), 1.84 (br s, 1H), 1.41 (s, 9 H);
13C NMR (125 MHz, CDCl3) δ 173.4, 172.6, 171.3, 155.1, 83.7,
83.6, 74.7, 69.9, 66.1, 64.9, 55.5, 52.6, 52.4, 50.8, 42.9, 40.6, 28.3
(×3), 20.9; HRMS (FAB) m/z calcd for C20H32NO11 [(M + H)+]
462.1975, found 462.1979.
Advanced Key Intermediate 16. A solution of 29b (225 mg,
0.49 mmol) and DDQ (22 mg, 0.098 mmol) in CH3CN/H2O (9:1,
v/v, 5.0 mL) was stirred at 55 °C for 12 h. The mixture was cooled
to room temperature and then concentrated under reduced pressure.
Purification by flash column chromatography on silica gel (30 g,
Alcohol 32. To a solution of alcohol 31 (51.4 mg, 0.111 mmol)
in CH2Cl2 (1.0 mL) at -20 °C were added pyridine (36.0 µL, 0.444
J. Org. Chem, Vol. 71, No. 14, 2006 5217

Shoji et al.
mmol) and DMAP (2.7 mg, 0.022 mmol), followed by trifluo-
romethanesulfonic acid anhydride (56.0 µL, 0.333 mmol). The
resultant mixture was stirred at -20 °C for 2 h and then partitioned
between ice-water (3.0 mL) and ethyl acetate (3.0 mL). The
organic layer was separated, and the aqueous layer was extracted
with ethyl acetate (3 × 5 mL). The combined organic layers were
successively washed with saturated aqueous NaHCO3 (5 mL) and
brine (5 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure to give a triflate as a yellow oil.
To a stirred solution of the above triflate in DMF (1.0 mL) at
room temperature was added cesium acetate (63.90 mg, 0.333
mmol). The resultant mixture was stirred at room temperature for
4 h and then poured into a mixed solution of water and ethyl acetate
(1:1, v/v, 10 mL). The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (3 × 5 mL). The combined
organic layers were successively washed with saturated aqueous
NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (5 g, methanol:CHCl3 ) 3:97)
afforded alcohol 32 (36.4 mg, 71% for the two steps) as a colorless
oil: [R]D20 -6.6 (c 0.12, CHCl3); IR (film) 3365, 2977, 2954, 2359,
2341, 1733, 1792, 1653, 1245 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.29 (d, J ) 7.0 Hz, 1 H), 4.85 (d, J ) 2.0 Hz, 1 H), 4.33 (d, J
) 6.0 Hz, 1 H), 4.03 (s, 1 H), 4.02 (s, 1 H), 3.97 (dd, J ) 12.5, 3.5
Hz, 1 H), 3.90 (s, 1 H), 3.77 (s, 3 H), 3.72 (s, 3 H), 3.40 (d, J )
12.5 Hz, 1 H), 2.66 (d, J ) 13.5 Hz, 1 H), 2.58 (dd, J ) 14.5, 5.5
Hz, 1 H), 2.24 (dd, J ) 14.5, 5.5 Hz, 1 H), 2.17 (s, 3 H), 2.15 (dd,
J ) 13.5, 4.5 Hz, 1 H), 1.42 (s, 9 H); 13C NMR (125 MHz, CDCl3)
δ 173.5, 172.4, 171.2, 154.9, 83.5, 80.1, 78.7, 76.3, 68.4, 66.7,
65.8, 65.1, 52.7, 52.5, 43.8, 40.6, 28.3 (×3), 21.0; HRMS (FAB)
m/z calcd for C20H32NO11 [(M + H)+] 462.1975, found 462.1979.
Pivalate 34. To a solution of diol 16 (24.2 mg, 0.0580 mmol)
in CH2Cl2 (0.5 mL) at -78 °C were added triethyamine (32.0 µL,
0.232 mmol) and DMAP (1.4 mg, 0.011 mmol) followed by
pivaloyl chloride (21.0 µL, 0.173 mmol). The reaction mixture was
stirred at -50 °C for 12 h and then poured into ice-water (ca. 1
mL). The mixture was extracted with ethyl acetate (3 × 3 mL),
and the combined organic layers were washed with aqueous 1 M
HCl (1 mL), saturated aqueous NaHCO3 (1 mL), and brine (1 mL).
The organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification by flash column chromatog-
raphy on silica gel (5 g, methanol:CHCl3 ) 3:97) afforded pivalate
34 (23.1 mg, 79%) as a colorless oil: [R]D17 +23.3 (c 0.06, CHCl3);
IR (film) 3446, 2973, 2359, 2342, 1733, 1717, 1162 cm-1; 1H NMR
(500 MHz, CDCl3) δ 5.33 (d, J ) 7.0 Hz, 1 H), 5.19 (m, 1 H),
4.32 (d, J ) 7.0 Hz, 1 H), 4.22 (s, 1 H), 4.14 (s, 1 H), 4.02 (s, 1
H), 3.75 (s, 3 H), 3.71 (s, 3 H), 3.61 (dd, J ) 11.0, 5.5 Hz, 1 H),
3.49 (t, J ) 11.0 Hz, 1 H), 2.58-2.54 (m, 2 H), 2.17 (dd, J )
14.5, 5.5 Hz, 1 H), 2.08-2.04 (m, 2 H), 1.40 (s, 9 H), 1.18 (s, 9
H); 13C NMR (125 MHz, CDCl3) δ 177.3 (×2), 172.6, 155.3, 84.4,
82.7, 80.2, 73.8, 67.7, 66.4, 61.4, 52.7, 52.6, 51.1, 44.5, 40.3, 39.1,
28.5 (×3), 27.4 (×3); HRMS (FAB) m/z calcd for C23H38NO11 [(M
+ H)+] 504.2445, found 504.2452.
Acetate 35. To a solution of 34 (22.0 mg, 0.0430 mmol) in CH2-
Cl2 (0.5 mL) at -20 °C were added pyridine (14.0 µL, 0.172 mmol)
and DMAP (1.2 mg, 0.0080 mmol) followed by trifluoromethane-
sulfonic acid anhydride (22.0 µL, 0.133 mmol). The reaction
mixture was stirred at -20 °C for 2 h and then partitioned between
ice-water (1.5 mL) and ethyl acetate (1.5 mL). The organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate (3 × 3 mL). The combined organic layers were successively
washed with saturated aqueous NaHCO3 (1 mL) and brine (1 mL),
dried over Na2SO4, filtered, and concentrated under reduced pressure
to give a triflate as a yellow oil.
Neodysiherbaine A (2). A solution of alcohol 32 (12.7 mg, 0.028
mmol) in aqueous 6 M HCl (0.5 mL) was heated at 85 °C overnight.
The mixture was cooled to room temperature and lyophilized to
To a solution of the above triflate in DMF (0.5 mL) at room
temperature was added cesium acetate (75.0 mg, 0.387 mmol). The
resultant mixture was stirred at 50 °C for 48 h and then poured
into a mixed solution of water and ethyl acetate (1:1, v/v, 5.0 mL).
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate (3 × 3 mL). The combined organic
layers were successively washed with saturated aqueous NaHCO3
(3 mL) and brine (3 mL). The organic layer was dried over Na2-
SO4, filtered, and concentrated under reduced pressure. Purification
by flash column chromatography on silica gel (5 g, ethyl acetate:
hexanes ) 3:7) afforded acetate 35 (8.6 mg, 37% for the two steps)
and 36 (2.1 mg, 11% for the two steps) as colorless oils. Data for
20
afford 2 (8.5 mg, 93%) as a colorless solid: [R]D +1.4 (c 0.07,
1
H2O); H NMR (500 MHz, D2O) δ 4.08 (br s, 1 H), 4.00 (br s, 1
H), 3.76 (t, J ) 3.7 Hz, 1 H), 3.68 (dd, J ) 13.0, 2.5 Hz, 1 H),
3.57 (br s, 1 H), 3.46 (d, J ) 11.5 Hz, 1 H), 3.41 (d, J ) 13.0 Hz,
1 H), 2.55 (dd, J ) 15.0, 2.0 Hz, 1 H), 2.42 (d, J ) 14.5 Hz, 1 H),
2.04 (dd, J ) 14.3, 3.3 Hz, 1 H), 1.84 (dd, J ) 15.0, 11.5 Hz, 1
H); 13C NMR (125 MHz, D2O:CD3OD ) 15:1) δ 180.4, 174.1,
87.6, 81.6, 77.5, 70.4, 68.6, 67.8, 54.0, 45.3, 39.8; HRMS (FAB)
m/z calcd for C11H18NO8 [(M + H)+] 292.1032 found 292.1037.
8,9-epi-Neodysiherbaine A (4). A solution of 29b (73.1 mg,
0.159 mmol) in aqueous 6 M HCl (1.0 mL) was heated at 65 °C
overnight. The reaction mixture was cooled to room temperature
17
35: [R]D +98.8 (c 0.085, CHCl3); IR (film) 2974, 2876, 2359,
1733, 1717, 1161 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.50 (d, J
) 7.0 Hz, 1 H), 5.35 (dt, J ) 10.5, 5.0 Hz, 1 H), 5.13 (dd, J )
10.5, 3.5 Hz, 1 H), 4.31 (s, 1 H), 4.29 (d, J ) 7.0 Hz, 1 H), 4.09
(s, 1H), 3.89 (dd, J ) 10.5, 5.0 Hz, 1 H), 3.81 (s, 3 H), 3.67 (s, 3
H), 3.11 (t, J ) 10.5 Hz, 1 H), 2.64 (d, J ) 13.0 Hz, 1 H), 2.58
(dd, J ) 14.5, 4.5 Hz, 1 H), 2.16 (dd, J ) 14.5, 5.5 Hz, 1 H), 2.12
(s, 3H), 2.05 (m, 1 H), 1.41 (s, 9 H), 1.13 (s, 9 H); 13C NMR (125
MHz, CDCl3) δ 177.6, 174.9, 174.3, 172.3, 155.1, 84.9, 79.6, 71.4,
66.6, 66.0 (×2), 60.3, 52.6, 52.2, 51.0, 44.7, 39.9, 38.7, 28.3 (×3),
26.9 (×3), 20.9; HRMS (FAB) m/z calcd for C25H40NO12 [(M +
H)+] 546.2551, found 546.2557. Data for 36: 1H NMR (500 MHz,
CDCl3) δ 5.17 (d, J ) 4.5 Hz, 1H), 5.39 (d, J ) 6.0 Hz, 1H), 4.37
(m, 1H), 4.31 (d, J ) 5.5 Hz, 1H), 4.12 (d, J ) 15.0 Hz, 1H), 4.06
(s, 1H), 3.86 (d, J ) 15.0 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 2.62
(d, J ) 13.5 Hz, 1H), 2.53 (dd, J ) 14.5, 5.5 Hz, 1H), 2.23 (dd, J
) 13.5, 4.5 Hz, 1H), 2.19 (dd, J ) 14.5, 5.5 Hz, 1H), 1.41 (s, 9H),
1.21 (s, 9H).
25
and lyophilized to afford 4 (46.0 mg, 94%) as a white foam: [R]D
1
-40.0 (c 0.05, H2O); H NMR (600 MHz, D2O) δ 4.13 (m, 1 H),
4.09 (m, 1 H), 4.05 (m, 1 H), 3.93 (ddd, J ) 10.6, 5.0, 3.2 Hz, 1
H), 3.61 (dd, J ) 10.6, 2.3 Hz, 1 H), 3.47 (dd, J ) 10.6, 5.0 Hz,
1 H), 3.39 (dd, J ) 10.6, 10.6 Hz, 1 H), 2.54 (d, J ) 14.1 Hz, 1
H), 2.53 (dd, J ) 15.6, 2.3 Hz, 1 H), 2.09 (dd, J ) 14.1, 3.8 Hz,
1 H), 2.00 (dd, J ) 15.6, 10.6 Hz, 1 H); 13C NMR (125 MHz,
D2O:CD3OD ) 15:1) δ 178.6, 174.1, 86.9, 84.0, 74.2, 67.4, 65.1,
64.4, 53.8, 44.3, 39.7; HRMS (FAB) m/z calcd for C11H16NO8 [(M
- H)-] 290.0876, found 290.0881.
8-epi-Neodysiherbaine A (5). A solution of 31 (50.0 mg, 0.108
mmol) in aqueous 6 M HCl (1.0 mL) was heated at 85 °C overnight.
The mixture was cooled to room temperature and lyophilized to
20
afford 5 (32.0 mg, 90%) as a white solid: [R]D -20.6 (c 0.02,
1
H2O); H NMR (500 MHz, D2O) δ 4.17 (s, 1 H), 4.05 (s, 1 H),
3.93 (s, 1 H), 3.73 (d, J ) 12.5 Hz, 1 H), 3.69 (d, J ) 10.5 Hz, 1
H), 3.59 (d, J ) 13.0 Hz, 1 H), 3.51 (s, 1 H), 2.68 (d, J ) 15.0 Hz,
1 H), 2.49 (d, J ) 14.0 Hz, 1 H), 2.19 (d, J ) 13.5 Hz, 1 H), 2.02
(t, J ) 12.5 Hz, 1 H); 13C NMR (125 MHz, D2O/CD3OD ) 15:1)
δ 180.5, 174.5, 88.0, 81.9, 75.1, 68.7, 67.0, 66.4, 54.5, 46.3, 40.3;
HRMS (FAB) m/z calcd for C11H18NO8 [(M - H)-] 290.0876,
found 290.0876.
9-epi-Neodysiherbaine A (6). A solution of 35 (6.00 mg, 0.0109
mmol) in aqueous 6 M HCl (1.0 mL) was heated at 100 °C
overnight. The mixture was cooled to room temperature and
22
lyophilized to afford 6 (4.4 mg, 100%) as a white foam: [R]D
1
+33.1 (c 0.12, H2O); H NMR (500 MHz, D2O) δ 4.29 (m, 1 H),
4.17 (s, 1 H), 3.88 (dd, J ) 11.0, 3.0 Hz, 1 H), 3.82 (dt, J ) 11.0,
5218 J. Org. Chem., Vol. 71, No. 14, 2006

Total Synthesis of Neodysiherbaine A and Analogues
4.5 Hz, 1 H), 3.69 (dd, J ) 11.0, 4.5 Hz, 1 H), 3.65 (dd, J ) 10.5,
4.5 Hz, 1 H), 3.07 (t, J ) 10.5 Hz, 1 H), 2.63 (dd, J ) 13.0, 2.5
Hz, 1 H), 2.62 (d, J ) 13.5 Hz, 1 H), 2.15 (dd, J ) 13.0, 3.5 Hz,
1 H), 2.10 (dd, J ) 13.5, 11.0 Hz, 1 H); 13C NMR (125 MHz,
D2O:CD3OD ) 15:1) δ 181.0, 175.9, 89.0, 78.8, 77.3, 71.4, 65.1,
54.9, 46.9, 40.5, 31.6; HRMS (FAB) m/z calcd for C11H16NO8 [(M
- H)-] 290.0876, found 290.0883.
was stirred at room temperature for 4.5 h and then concentrated
under reduced pressure to give a sulfate monoester as a white solid.
To a suspension of the above sulfate in THF (2.0 mL) at room
temperature was added concentrated H2SO4 (9 drops). The resultant
mixture was stirred at room temperature for 1 h and then partitioned
between ethyl acetate (5 mL) and ice-water (5 mL). The organic
layer was separated, and the aqueous layer was extracted with ethyl
acetate (3 × 10 mL). The combined organic layers were washed
with brine (5 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification by flash column chromatog-
raphy on silica gel (5 g, methanol:CHCl3 ) 2:98) afforded 8â-
Thiocarbonate 37. To a solution of alcohol 31 (46.0 mg, 0.0990
mmol) in toluene (2.0 mL) at room temperature were added DMAP
(24.0 mg, 0.198 mmol) and phenyl chlorothionoformate (0.0210
mL, 0.149 mmol). The resultant mixture was heated at reflux for
3 h and then cooled to room temperature. Water (5 mL) was added,
and the mixture was extracted with ethyl acetate (3 × 20 mL).
The combined organic layers were successively washed with
aqueous 1 M HCl (5 mL), saturated aqueous NaHCO3 (5 mL), and
brine (5 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (5 g, ethyl acetate:hexanes
) 1:1) afforded thiocarbonate 37 (41.0 mg, 70%) as a white solid:
20
alcohol 39 (37.0 mg, 51% for the two steps) as a white solid: [R]D
+1.3 (c 0.08, CHCl3); IR (film) 3441, 2953, 2359, 2341, 1734,
1714, 1164, 1074 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.38 (d, J
) 7.0 Hz, 1 H), 4.31 (dd, J ) 7.5, 5.0 Hz, 1 H), 4.17 (s, 1 H), 4.13
(s, 1 H), 3.72 (s, 1H), 3.71 (s, 3 H), 3.70 (s, 3 H), 3.67 (dd, J )
13.0, 1.5 Hz, 1 H), 3.55 (ddd, J ) 11.0, 4.0, 1.5 Hz, 1 H), 2.55 (d,
J ) 14.0 Hz, 1 H), 2.49 (dd, J ) 14.0, 5.0 Hz, 1 H), 2.21 (dt, J )
13.0, 4.0 Hz, 1 H), 2.15 (dd, J ) 15.0, 6.0 Hz, 1 H), 2.05 (dd, J )
10.0, 4.0 Hz, 1 H), 1.82 (dd, J ) 14.5, 3.5 Hz, 1 H), 1.41 (s, 9 H);
13C NMR (125 MHz, CDCl3) δ 172.7, 171.5, 155.4, 84.2, 81.2,
80.2, 73.3, 64.1, 60.4, 52.5, 52.4, 51.1, 44.5, 40.4, 28.6, 28.3 (×3);
HRMS (FAB) m/z calcd for C18H30NO9 [(M + H)+] 404.1942,
found 404.1942.
8r-Alcohol 40. To a solution of alcohol 39 (37.0 mg, 0.0920
mmol) in CH2Cl2 (2.0 mL) at room temperature were added
powdered 4 Å molecular sieves (50.0 mg), NMO (32.0 mg, 0.28
mmol), and TPAP (6.50 mg, 0.018 mmol). The resultant mixture
was stirred at room temperature for 30 min and then passed through
a short pad of silica gel (5 g, ethyl acetate). The filtrate was
concentrated under reduced pressure to give a ketone (22.6 mg) as
a white solid.
26
[R]D +25.3 (c 0.06, CHCl3); IR (film) 3365, 2951, 2359, 1734,
1
1717, 1276, 1200 cm-1; H NMR (500 MHz, CDCl3) δ 7.40 (t, J
) 8.0 Hz, 2 H), 7.28 (t, J ) 7.5 Hz, 1 H), 7.03 (d, J ) 8.5 Hz, 2
H), 5.68 (s, 1 H), 5.26 (d, J ) 7.5 Hz, 1 H), 4.81 (d, J ) 1.5 Hz,
1 H), 4.32 (dd, J ) 7.5, 5.0 Hz, 1 H), 4.14 (s, 1 H), 3.99 (s, 1 H),
3.89 (d, J ) 13.0 Hz, 1 H), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.72 (dd,
J ) 10.5, 3.0 Hz, 1 H), 2.77 (d, J ) 14.0 Hz, 1 H), 2.46 (dd, J )
14.0, 4.5 Hz, 1 H), 2.21 (dd, J ) 15.0, 6.0 Hz, 1 H), 2.17 (dd, J )
13.5, 4.5 Hz, 1 H), 2.16 (s, 3 H), 1.41 (s, 9 H); 13C NMR (125
MHz, CDCl3) δ 193.1, 172.7, 172.1, 170.5, 155.1, 153.3, 129.6
(×2), 126.7, 121.7 (×2), 84.2, 79.9, 76.7, 74.8, 74.4, 65.7, 64.7,
52.6, 52.4, 50.6, 43.5, 40.4, 28.2 (×3), 20.9; HRMS (FAB) m/z
calcd for C27H36NO12S [(M + H)+] 598.1958, found 598.1960.
To a stirred solution of the above ketone in methanol (1.0 mL)
at -20 °C was added NaBH4 (6.10 mg, 0.16 mmol). The resultant
mixture was stirred at -20 °C for 15 min and then poured into a
mixed solution of CH2Cl2 and pH 7 phosphate buffer (3:1, v/v, 4.0
mL). The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (10 g, methanol:CHCl3 )
3:97) afforded 8R-alcohol 40 (23.0 mg, 88% for the two steps) as
a white solid: [R]D20 +115.3 (c 0.045, CHCl3); IR (film) 3375, 2955,
2359, 2341, 1734, 1717, 1164 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.34 (d, J ) 7.5 Hz, 1 H), 4.32 (dd, J ) 12.5, 5.0 Hz, 1 H), 3.99
(s, 1 H), 3.96 (s, 1 H), 3.78 (ddd, J ) 11.0, 4.0, 2.0 Hz, 1 H), 3.75
(s, 3 H), 3.72 (s, 3 H), 3.23 (t, J ) 11.0 Hz, 1 H), 3.72 (m, 1 H),
2.66 (dd, J ) 14.0, 5.0 Hz, 1 H), 2.61 (d, J ) 13.0 Hz, 1 H), 2.28
(d, J ) 11.0 Hz, 1 H), 2.21 (dd, J ) 14.0, 4.0 Hz, 1 H), 2.08 (dd,
J ) 14.0, 4.0 Hz, 1 H), 1.95 (dq, J ) 12.5, 5.0 Hz, 1 H), 1.67 (dd,
J ) 12.0, 5.0 Hz, 1 H), 1.41 (s, 9 H); 13C NMR (125 MHz, CDCl3)
δ 172.8, 172.7, 154.9, 83.5, 80.4, 79.9, 76.4, 67.6, 64.9, 52.6, 52.3,
50.9, 45.8, 40.8, 29.4, 28.3 (×3); HRMS (FAB) m/z calcd for
C18H30NO9 [(M + H)+] 404.1942, found 404.1923.
Acetate 38. A solution of thiocarbonate 37 (41.0 mg, 0.069
mmol) and AIBN (23.0 mg, 0.138 mmol) in toluene (3.0 mL) was
degassed by bubbling of argon under sonication for 30 min. To
the mixture heated at 130 °C was added Bu3SnH (0.110 mL, 0.414
mmol). The resultant mixture was stirred at 130 °C for 1 h, cooled
to room temperature, and then concentrated under reduced pressure.
Purification by flash column chromatography on silica gel (5 g,
ethyl acetate:hexanes ) 7:3) afforded acetate 38 (24.0 mg, 78%)
26
as a white solid: [R]D +34.4 (c 0.05, CHCl3); IR (film) 3365,
2952, 2359, 1728, 1247 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.34
(d, J ) 7.0 Hz, 1 H), 4.68 (s, 1 H), 4.28 (dd, J ) 7.5, 5.0 Hz, 1 H),
3.90 (dd, J ) 13.0, 3.0 Hz, 1 H), 3.89 (d, J ) 9.0 Hz, 1 H), 3.88
(m, 1H), 3.73 (s, 3 H), 3.69 (s, 3 H), 3.44 (dd, J ) 11.0, 1.5 Hz,
1 H), 2.67 (d, J ) 15.0 Hz, 1 H), 2.40 (dd, J ) 14.0, 4.5 Hz, 1 H),
2.34 (d, J ) 17.0 Hz, 1 H), 2.16 (dd, J ) 16.0, 7.0 Hz, 1 H), 2.15
(d, J ) 7.0 Hz, 1 H), 2.11 (s, 3 H), 1.92 (dt, J ) 11.5, 4.0 Hz, 1
H), 1.40 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ 173.3, 172.3,
171.3, 155.1, 83.7, 76.2, 74.7, 67.5 (×2), 64.8, 52.4 (×2), 50.9,
43.8, 40.2, 28.3 (×3), 28.2, 21.3; HRMS (FAB) m/z calcd for
C20H32NO10 [(M + H)+] 446.2026, found 446.2029.
8-Deoxyneodysiherbaine A (7). A solution of acetate 38 (35.0
mg, 0.079 mmol) in aqueous 6 M HCl (1.0 mL) was heated at 85
°C overnight. The mixture was cooled to room temperature and
9-Deoxyneodysiherbaine A (8). A solution of alcohol 40 (41.0
mg, 0.101 mmol) in aqueous 6 M HCl (1.0 mL) was heated at 65
°C overnight. The mixture was cooled to room temperature and
20
20
lyophilized to afford 7 (22.0 mg, 92%) as a white solid: [R]D
lyophilized to afford 8 (30.0 mg, 90%) as a brown solid: [R]D
-37.0 (c 0.016, H2O); 1H NMR (500 MHz, D2O) δ 4.16 (s, 1 H),
4.08 (s, 1 H), 3.89 (dd, J ) 11.0, 3.0 Hz, 1 H), 3.76 (s, 1 H), 3.69
(d, J ) 13.0 Hz, 1 H), 3.53 (d, J ) 12.5 Hz, 1 H), 2.74 (dd, J )
15.5, 3.0 Hz, 1 H), 2.46 (d, J ) 15.0 Hz, 1 H), 2.26 (dd, J ) 14.5,
3.5 Hz, 1 H), 2.19 (dd, J ) 14.5, 2.0 Hz, 1 H), 2.08 (dd, J ) 15.0,
10.5 Hz, 1 H), 1.95 (dt, J ) 15.5, 3.0 Hz, 1 H); 13C NMR (125
MHz, D2O:CD3OD ) 15:1) δ 178.9, 174.8, 87.6, 83.6, 78.5, 74.1,
69.7, 68.0, 54.5, 45.3, 40.3; HRMS (FAB) m/z calcd for C11H16-
NO8 [(M - H)-] 274.0927, found 274.0923.
1
+18.4 (c 0.026, H2O); H NMR (500 MHz, D2O) δ 4.13 (s, 1H),
4.05 (s, 1H), 3.89 (ddd, J ) 12.0, 5.0, 3.5 Hz, 1H), 3.74 (ddd, J )
12.5, 3.0, 1.5 Hz, 1H), 3.65 (dd, J ) 12.0, 2.0 Hz, 1H), 3.30 (t, J
) 12.0 Hz, 1H), 2.57 (d, J ) 13.0 Hz, 1H), 2.54 (dd, J ) 14.5, 2.5
Hz, 1H), 2.08 (dd, J ) 14.0, 3.0 Hz, 1H), 2.03 (dd, J ) 15.0, 12.0
Hz, 1H), 1.83 (dq, J ) 12.0, 4.5 Hz, 1H), 1.57 (dd, J ) 12.5, 5.0
Hz, 1H); 13C NMR (125 MHz, D2O:CD3OD ) 15:1) δ 178.5, 174.6,
87.4, 82.3, 77.9, 73.4, 68.8, 66.5, 54.3, 45.5, 40.3; HRMS (FAB)
m/z calcd for C11H16NO8 [(M - H)-] 274.0927, found 274.0927.
Cyclic Thiocarbonate 41. To a solution of diol 16 (624 mg,
1.49 mmol) in toluene (15 mL) at 0 °C were added DMAP (182
mg, 1.49 mmol) and thiocarbonyl diimidazole (320 mg, 1.79 mmol).
8â-Alcohol 39. To a solution of cyclic sulfate 30 (89.9 mg, 0.180
mmol) in N,N-dimethylacetamide (2.0 mL) at room temperature
was added NaBH4 (17.0 mg, 0.450 mmol). The resultant mixture
J. Org. Chem, Vol. 71, No. 14, 2006 5219

Shoji et al.
The resultant mixture was heated at 70 °C for 30 min and then
concentrated under reduced pressure. Purification by flash column
chromatography on silica gel (20 g, ethyl aceate:hexanes ) 3:7)
afforded cyclic thiocarbonate 41 (523 mg, 76%) as a colorless
2952, 2359, 1750, 1716, 1167 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.13 (d, J ) 7.0 Hz, 1 H), 4.38 (d, J ) 5.5 Hz, 1 H), 3.89 (s, 1
H), 3.83 (s, 1 H), 3.69 (s, 3 H), 3.60 (s, 3 H), 3.75 (ddt, J ) 10.5,
4.0, 2.0 Hz, 1 H), 3.26 (dt, J ) 13.0, 2.0 Hz, 1 H), 2.54 (d, J )
14.0 Hz, 1 H), 2.31 (dd, J ) 14.0, 4.5 Hz, 1 H), 2.16 (dd, J )
14.0, 6.0 Hz, 1 H), 2.06-2.03 (m, 2 H), 1.96 (dq, J ) 13.0, 4.0
Hz, 1 H), 1.64 (tt, J ) 13.5, 4.0 Hz, 1 H), 1.38 (s, 9 H), 1.27 (d,
J ) 13.0 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 174.5, 172.4,
155.1, 83.9, 79.7, 77.2, 77.1, 75.6, 66.2, 52.2, 52.1, 50.9, 44.9, 40.1,
28.2 (×2), 25.3, 19.5; HRMS (FAB) m/z calcd for C18H30NO8 [(M
+ H)+] 388.1971, found 388.1971.
20
solid: [R]D +36.9 (c 0.79, CHCl3); IR (film) 3421, 2978, 1745,
1713, 1499, 1353, 1320, 1164, 1095, 991, 736 cm-1; 1H NMR (500
MHz, CDCl3) δ 5.22 (d, J ) 6.5 Hz, 1 H), 5.12 (d, J ) 7.0 Hz, 1
H), 5.02 (ddd, J ) 8.0, 6.0, 2.5 Hz, 1 H), 4.34 (s, 2 H), 4.27 (t, J
) 4.5 Hz, 1 H), 3.98 (dd, J ) 12.5, 6.0 Hz, 1 H), 3.72 (s, 3 H),
3.70 (s, 3 H), 3.28 (dd, J ) 12.5, 8.0 Hz, 1 H), 2.61 (dd, J ) 14.5,
5.5 Hz, 1 H), 2.56 (d, J ) 14.0 Hz, 1 H), 2.27 (dd, J ) 14.0, 5.0
Hz, 1 H), 2.17 (dd, J ) 14.5, 4.5 Hz, 1 H), 1.41 (s, 9 H); 13C NMR
(125 MHz, CDCl3) δ 190.4, 173.6, 172.2, 155.2, 109.9, 84.1, 80.4,
75.4, 75.1, 74.2, 62.2, 52.9, 52.8, 50.9, 44.9, 39.4, 28.5 (×3); HRMS
(FAB) m/z calcd for C19H28NO10S [(M + H)+] 462.1434, found
462.1434.
A solution of the above product (155 mg, 0.40 mmol) in aqueous
6 M HCl (1.0 mL) was heated at 65 °C overnight. The mixture
was cooled to room temperature and lyophilized to afford compound
20
3 (100 mg, 85%) as a brown solid: [R]D -21.7 (c 0.026, H2O);
1H NMR (500 MHz, D2O) δ 4.07 (s, 1 H), 3.97 (s, 1 H), 3.88 (dd,
J ) 10.5, 3.0 Hz, 1 H), 3.72 (d, J ) 7.5 Hz, 1 H), 3.69 (dd, J )
10.5, 3.5 Hz, 1 H), 3.29 (t, J ) 11.0 Hz, 1 H), 2.62 (dd, J ) 15.5,
3.0 Hz, 1 H), 2.52 (d, J ) 14.0 Hz, 1 H), 2.15-2.09 (m, 2 H),
1.97 (d, J ) 11.0 Hz, 1 H), 1.71-1.69 (m, 2 H), 1.30 (d, J ) 8.0
Hz, 1 H); 13C NMR (125 MHz, D2O:CD3OD ) 15:1) δ 178.8,
173.5, 86.4, 79.9, 77.0, 67.8, 53.3, 46.1, 39.8, 25.8, 20.8; HRMS
(FAB) m/z calcd for C11H17NO6Cl [(M - H)-] 294.0774, found
294.0750.
Olefin 42. To a solution of cyclic thiocarbonate 41 (525 mg,
1.13 mmol) in THF (0.6 mL) at room temperature was added 1,3-
dimethyl-2-phenyl-1,3,2-diazaphospholidine (0.62 mL, 3.41 mmol).
The resultant mixture was stirred at 40 °C for 12 h. The mixture
was cooled to room temperature and purified by flash column
chromatography on silica gel (20 g, ethyl acetate:hexanes ) 1:1)
to afford olefin 42 (319 mg, 73%) as colorless oil: [R]D20 -143.7
(c 0.41, CHCl3); IR (film) 3375, 2977, 2359, 2342, 1748, 1733,
1716, 1166, 1089 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.96-5.91
(m, 2 H), 5.39 (d, J ) 6.5 Hz, 1 H), 4.20 (m, 1 H), 4.04 (m, 1 H),
4.00-3.86 (m, 3 H), 3.63 (s, 3 H), 3.60 (s, 3 H), 2.51 (d, J ) 14.0
Hz, 1 H), 2.42 (dd, J ) 14.0, 5.0 Hz, 1 H), 2.14 (dd, J ) 14.0, 5.0
Hz, 1 H), 2.11 (dd, J ) 14.0, 6.5 Hz, 1 H), 1.32 (s, 9 H); 13C NMR
(125 MHz, CDCl3) δ 174.1, 172.2, 154.9, 130.4, 121.9, 84.0, 79.6,
74.6, 73.5, 63.5, 52.2, 52.1, 50.7, 43.9, 39.4, 28.0 (×3); HRMS
(FAB) m/z calcd for C18H28NO8 [(M + H)+] 386.1815, found
386.1816.
Acknowledgment. This work was financially supported by
the Yamada Science Foundation, a Grant-in-Aid for Scientific
Research on Priority Area “Creation of Biologically Functional
Molecules” (No. 16073202) from the Ministry of Education,
Science, Sports, Culture and Technology, Japan (M.Sa.), a
predoctoral National Research Service Award (J.M.S.), and
Grant R01 NS44322 from the National Institute for Neurological
Diseases and Stroke (G.T.S.).
Compound 3. To a solution of olefin 42 (167 mg, 0.430 mmol)
in hexane/methanol (2:1, v/v, 6 mL) at room temperature was added
Pd(OH)2/C (10 wt %, 16.7 mg). The mixture was stirred at room
temperature under a hydrogen atmosphere for 4 h and then filtered
through a short pad of Celite. The filtrate was concentrated under
reduced pressure, and the residue was purified by flash column
chromatography on silica gel (10 g, ethyl acetate:hexanes ) 1:1)
to afford fully protected glutamic acid derivative (158 mg, 94%)
Supporting Information Available: Experimental procedures
and characterization data for compounds in Scheme 5 and copies
of 1H and 13C NMR spectra for compounds 2-8, 11, 16-20, 23-
27, 29-32, 34, 35, and 37-42. This material is available free of
charge via the Internet at http://pubs.acs.org.
20
as a white solid: [R]D +107.0 (c 0.22, CHCl3); IR (film) 3375,
JO0605593
5220 J. Org. Chem., Vol. 71, No. 14, 2006