Total synthesis of dysiherbaine

Article abstract of DOI:10.1021/jo0107610

A convergent total synthesis of the marine natural product dysiherbaine was accomplished. The key steps of the synthesis are an alkylation at the γ-carbon of a protected glutamate with a highly substituted pyran derived from mannose, which was followed by a ring-contraction cascade reaction, which simultaneously gave the tetrasubstituted carbon and the hexahydrofuro[3,2-b]pyran ring system of the natural product.

Full text of DOI:10.1021/jo0107610

3194
J . Org. Chem. 2002, 67, 3194-3201
Tota l Syn th esis of Dysih er ba in e
Dean Phillips and A. Richard Chamberlin*
Department of Chemistry, University of California, Irvine, Irvine, California 92697-2025
Received J uly 26, 2001
A convergent total synthesis of the marine natural product dysiherbaine was accomplished. The
key steps of the synthesis are an alkylation at the γ-carbon of a protected glutamate with a highly
substituted pyran derived from mannose, which was followed by a ring-contraction cascade reaction,
which simultaneously gave the tetrasubstituted carbon and the hexahydrofuro[3,2-b]pyran ring
system of the natural product.
In tr od u ction
Advances in the study of the mammalian central
nervous system (CNS) have been highly dependent on
the design, synthesis, and discovery of new pharmaco-
logical probes.1-3 For example, the excitatory amino acid
(EAA) l-glutamate, the principle excitatory neurotrans-
mitter in the mammalian CNS, is known to bind to a
number of receptors that have been pharmacologically
differentiated by their interaction with selective agonists
and antagonists.4 In addition, our group5 and others6-8
have reported the discovery of a number of confor-
mationally constrained glutamate analogues that bind
selectively to specific subclasses of EAA receptors and
transporters. There are also a number of glutamate-
like natural products, such as the kainoids, that are
among the most selective glutamate receptor agonists
known. The availability of these selective probes has
contributed to the identification/differentiation of five
major subclasses of glutamate receptors: kainic acid
(KA), DL-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA), N-methyl-D-aspartate (NMDA), (1R,3R)-
1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), and
(S)-2-amino-4-phosphonobutyric acid (AP-4) receptors
(Figure 1).4
The KA, AMPA, and NMDA receptors are ionotropic
glutamate receptors (iGluRs) that mediate fast excitatory
synaptic transmission in the CNS, whereas the ACPD
and AP-4 receptors are metabotropic glutamate receptors
(mGluRs) that mediate neuronal signaling processes in
the CNS. The result of glutamate binding to iGlurRs is
ion channel opening, the influx of Na+ and Ca2+, and the
efflux of K+. Normally, this process leads to cell de-
polarization, neurotransmission, and intracellular signal-
ing;4 however, when it is not properly regulated, the
result is neuronal overactivation and eventually cell
F igu r e 1. Partial list of glutamate receptor agonists.
death. This phenomenon, known as glutamate excito-
toxicity, is a common final pathway of such conditions
as Huntington’s disease, stroke, hypoglycemia, Alz-
heimer’s disease, ALS, and multiple sclerosis.9-16 Glutam-
ate receptor antagonists have been shown to ameliorate
the symptoms of excitotoxicity, implying that antagonists
are potential neuroprotectants.15,16 More generally, the
discovery of new selective glutamate receptor agonists,
antagonists, and neuromodulators will further advance
the mechanistic understanding of these receptors, which
in turn may lead to therapeutic intervention for diseases
involving dysfunctional glutamate receptors.1-3,5-8
* To whom correspondence should be addressed. E-mail:
archambe@uci.edu.
(1) Moloney, M. G. Nat. Prod. Rep. 1998, 15, 205-219.
(2) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485-498.
(3) Brauner-Osborne, H.; Egebjerg, J .; Nielsen, E. O.; Madsen, U.;
Krogsgaard-Larsen, P. J . Med. Chem. 2000, 43, 2609-2645.
(4) Monaghan, D. T.; Bridges, R. J .; Cotman, C. W. Annu. Rev.
Pharmacol. Toxicol. 1989, 29, 365-402.
(9) Choi, D. W. Neuron 1988, 1, 623-634.
(10) Greene, J . G.; Greenamyre, J . T. Prog. Neurobiol. 1996, 48,
613-634.
(5) Bridges, R. J .; Chamberlin, A. R. In Drug Design for Neuro-
science; Kozikowski, A. P., Ed.; Raven Press: Hagerstown, MD, 1993;
pp 231-259.
(11) Whetsell, W. O.; Shapira, N. A. Lab. Invest. 1993, 68, 372-
387.
(12) Whetsell, W. O. J . Neuropathol. Exp. Neurol. 1996, 55, 1-13.
(13) Turski, L.; Turski, W. A. Experientia 1993, 49, 1064-1072.
(14) Leist, M.; Nicotera, P. Exp. Cell Res. 1998, 239, 183-201.
(15) Doble, A. Pharmacol. Ther. 1999, 81, 163-221.
(16) Smith, T.; Groom, A.; Zhu, B.; Turski, L. Nat. Med. (N.Y.) 2000,
6, 62-66.
(6) Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 1989, 30, 3803-
3804.
(7) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J . Org.
Chem. 1991, 56, 4167-4176.
(8) Shimamoto, K.; Ohfune, Y. J . Med. Chem. 1996, 39, 407-423.
10.1021/jo0107610 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/30/2002

Total Synthesis of Dysiherbaine
J . Org. Chem., Vol. 67, No. 10, 2002 3195
Sch em e 1
A truly novel agonist, dysiherbaine, was isolated from
extracts of the Micronesian sponge Dysidea herbacea and
its structure reported in 1997 by Sakai and co-workers.
This natural product binds specifically to the KA and
AMPA glutamate receptor subtypes (IC50 ) 26 and 153
nM for the KA and AMPA receptors, respectively) and
has been shown not to bind to NMDA glutamate receptor
subtypes (IC50 > 10000 nM).17,18 Dysiherbaine is particu-
larly interesting as a lead compound for the discovery of
new iGluR agonists and antagonists because the substi-
tution pattern of the embedded glutamate moiety differs
dramatically from that of other known EAA ligands.
Because the structure is so dissimilar to that of previ-
ously known iGluR ligands, it is likely that the bicyclic
ring system makes contacts in the binding sites of the
KA and AMPA receptors that other agonists do not; thus,
dysiherbaine SAR studies could provide new insights into
glutamate receptor structure and function.
struction of the tetrahydrofuran ring is the key step,
requiring a leaving group at the γ-carbon of glutamate
that would be displaced by an oxygen nucleophile on the
pyran 2 in an SN2 fashion. Establishing the correct C-4
stereochemistry would then be predicated upon a stereo-
selective enolate halogenation of 3 at the γ-position.
Intermediate 3 would in turn be obtained via an alkyl-
ation of a protected glutamate (4) with a glycosyl elec-
trophile (5). This overall synthetic strategy is reasonably
convergent and, at the same time, could give access to
an interesting group of uniquely substituted glutamate
analogues for SAR studies.
Several protecting groups (phenylfluorenyl (PhFl),
trityl (Tr), trifluroacetamide, p-nitrophenylamide, and
carbamates) may be employed for the γ-alkylation of
glutamate without epimerization at the R-center. PhFl
and Tr completely protect the R-stereocenter from epimer-
ization, but alkylations are often not very stereoselec-
tive,30,31 except in alkylations of PhFl-protected aspar-
tates.32 Pyroglutamate is an internally protected form of
glutamate, and alkylations of protected pyroglutamates
have been shown to produce good stereoselectivities.33,34
More recently, however, Hanessian35-37 and others24,25
have shown that amides and carbamates of glutamate
diesters undergo efficient and highly diastereoselective
alkylations without epimerizing the R-stereocenter. We
envisioned a route to dysiherbaine employing two se-
quential stereoselective enolate reactions of an appro-
priately protected glutamate, one to form the C-C bond
and the other to close the tetrahyrofuran ring via C-O
bond formation. Although there were to our knowledge
no reports of Hanessian-type reactions of γ-substituted
glutamates, there appeared to be no a priori reason that
the same model would not apply in such a case.
Resu lts a n d Discu ssion
Syn th etic P la n n in g. The structure of dysiherbaine
is that of a hexahydrofuro[3,2-b]pyran ring system with
a glutamate appendage that presumably occupies the
endogenous glutamate active site on the receptor. Dysi-
herbaine could also be viewed as a γ,γ-disubstituted
glutamate; many γ-substituted glutamates are known to
show increased receptor selectivity compared to glutamate
itself, so from this perspective it is perhaps not surprising
that dysiherbaine is an active and selective glutamate
receptor ligand.19-25
One of the synthetically demanding features of this
target is the tetrasubstituted C-4 center. Several groups
have developed syntheses of dysiherbaine and sim-
plified analogues, and in all cases procuring the C-4
center stereoselectively posed a significant synthetic chal-
lenge.26-29 A highly stereoselective method, therefore,
figured prominently in our synthetic planning, as did
increased convergence.
One way to address both of these issues simultaneously
would be to dissect the molecule into an appropriately
functionalized glutamate (4) and a pyran (5), which would
be joined by a tetrahydrofuran-ring-forming reaction
(Scheme 1). In this approach, the stereoselective con-
(17) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J . Am. Chem.
Soc. 1997, 119, 4112-4116.
(18) Sakai, R.; Swanson, G. T.; Shimamoto, K.; Green, T.; Contractor,
A.; Ghetti, A.; Tamura-Horikawa, Y.; Kamiya, H. J . Pharmacol. Exp.
Ther. 2001, 296, 650-658.
Tota l Syn th esis. The first stage of this plan required
the acquisition of the pyran core. Styractitol (6) was
prepared from D-(+)-mannose according to known litera-
ture procedures38 and converted into 7 via a TBDPS
protection of the primary C-6 alcohol, followed by iso-
(19) Vandenberg, R. J .; Mitrovic, M.; Chebib, M.; Balcar, V. J .;
J ohnston, G. A. R. Mol. Pharmacol. 1997, 809-815.
(20) Wermuth, C. G.; Mann, A.; Schoenfelder, A.; Wright, R. A.;
J ohnson, B. G.; Burnett, J . P.; Mayne, N. G.; Schoepp, D. D. J . Med.
Chem. 1996, 39, 814-816.
(21) Hon, Y.-S.; Chang, Y.-C.; Gong, M.-L. Heterocycles 1990, 2, 191-
195.
(22) Escribano, A.; Ezquerra, J .; Pedregal, C.; Rubio, A.; Yruteta-
goyena, B.; Baker, S. R.; Wright, R. A.; J ohnson, B. G.; Schoepp, D. D.
Bioorg. Med. Chem. Lett. 1998, 8, 765.
(30) Koskinen, A. M. P.; Rapoport, H. J . Org. Chem. 1989, 54, 1859-
1866.
(31) Rapoport, H.; Sardina, F. J . Chem. Rev. 1996, 96, 1825-1872.
(32) Humphrey, J . M.; Hart, J . A.; Chamberlin, A. R. Bioorg. Med.
Chem. Lett. 1995, 5, 1315-1320.
(33) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245-
2303.
(34) Ezquerra, J .; Pedregal, C.; Rubio, A. J . Org. Chem. 1994, 59,
4327-4331.
(35) Hanessian, S.; Vanasse, B. Can. J . Chem. 1993, 71, 1401-1406.
(36) Hanessian, S.; Schaum, R. Tetrahedron Lett. 1997, 38, 163-
166.
(23) Ezquerra, J .; Pedregal, C.; Mico, I.; Najera, C. Tetrahedron:
Asymmetry 1994, 5, 921-926.
(24) Gu, Z.-Q.; Hesson, D. P. Tetrahedron: Asymmetry 1995, 6,
2101-2104.
(25) Gu, Z. Q.; Lin, X.-F.; Hesson, D. P. Bioorg. Med. Chem. Lett.
1995, 5, 1973-1976.
(26) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2000, 2, 635-638.
(27) Masaki, H.; Maeyama, J .; Kamada, K.; Esumi, T.; Iwabuchi,
Y.; Hatakeyama, S. J . Am. Chem. Soc. 2000, 122, 5216-5217.
(28) Sasaki, M.; Koike, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett.
2000, 41, 3923-3926.
(37) Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39, 5887-
(29) Sasaki, M.; Maruyama, T.; Sakai, R.; Tachibana, K. Tetrahedron
Lett. 1999, 40, 3195-3198.
5890.
(38) Kocienski, P.; Pant, C. Carbohydr. Res. 1982, 110, 330-332.

3196 J . Org. Chem., Vol. 67, No. 10, 2002
Phillips and Chamberlin
Sch em e 2
propylidene ketal formation with 2-methoxypropene
(Scheme 2).39 Benzylation of 7 with sodium hydride and
benzyl bromide proved to be quite sluggish. Combinations
of elevated temperatures, excess electrophile, excess base,
and the use of TBAI produced poor yields; however, upon
addition of 15-crown-5 to a THF solution of 7, benzyl
bromide, and NaH at 0 °C, the reaction was nearly
complete in 1 h.40 The crude product was deprotected
with TBAF to give the alcohol 8, which was then
converted into the triflate 9.41 In the next step, the
alkylation that brings together the two major fragments
of the target, the LHMDS-generated enolate of 11 was
treated with the triflate electrophile 9 to give a single
diastereomer (12) in excellent yield. The stage was thus
set for the crucial γ-functionalization step necessary to
carry out the key ring closure.
The ring-closing strategy required the stereoselective
installation of a leaving group at the γ-position, as
discussed above. Despite the absence of precedents for
preparing γ,γ-disubstituted glutamates from the corre-
sponding γ-substituted enolates, this simple strategy
appeared to be worth exploring as a means of obtaining
the desired γ-halo derivative required for tetrahydrofuran
ring closure. However, it quickly became apparent that
this strategy was untenable, most likely because the
selective deprotonation of 12 failed.
engineer this intermediate so that the distal carboxyl
group is in the form of a δ-lactone. This modification in
turn suggested the possibility of employing an interesting
variant of the original strategy for tetrahydrofuran ring
formation that would rely on the ring contraction of
R-halo-, R-mesyl-, and R-triflyl-δ-lactones developed by
Fleet.43-53 Specifically, when such lactones are treated
with a nucleophile, attack at the carbonyl group pre-
dominates, leading to ring opening followed by attack of
the newly unveiled alkoxide on the R-center that bears
the leaving group. Since the SN2 reaction proceeds with
clean inversion, this method would offer a simple and
convenient means of controlling the stereochemistry of
the C-4 position in dysiherbaine, assuming that the
R-leaving group could be introduced diastereoselectively.
To implement this revised plan, the C-7 alcohol group
on the pyran ring would be internally acylated to form
the lactone, but before that it would have to be inverted.
Both steps were readily accomplished by treatment of 12
(43) Choi, S. S.; Myerscough, P. M.; Fairbanks, A. J .; Skead, B. M.;
Bichard, C. J . F.; Mantell, S. J .; Son, J . C.; Fleet, G. W. J .; Saunders:
J .; Brown, D. J . Chem. Soc., Chem. Commun. 1992, 1605-1607.
(44) Wheatley, J . R.; Bichard, C. J . F.; Mantell, S. J .; Son, J . C.;
Hughes, D. J .; Fleet, G. W. J .; Brown, D. J . Chem. Soc., Chem.
Commun. 1993, 1065-1067.
(45) Bichard, C. J . F.; Wheatley, J . R.; Fleet, G. W. J . Tetrahedron:
Asymmetry 1994, 5, 431-440.
(46) Bichard, C. J . F.; Brandstetter, T. W.; Estevez, J . C.; Fleet, G.
W. J .; Hughes, D. J .; Wheatley, J . R. J . Chem. Soc., Perkin Trans. 1
1996, 2151-2156.
This setback prompted us to consider related systems
in which the γ-deprotonation might be more facile. Since
lactones are considerably more acidic than their ester
counterparts,42 one such possibility would be to re-
(47) Skead, B. M.; Fleet, G. W. J .; Saunders, J .; Lamont, R. B.
Tetrahedron Lett. 1993, 34, 6115-6118.
(48) Estevez, J . C.; Fairbanks, A. J .; Hsia, K. Y.; Ward, P.; Fleet, G.
W. J . Tetrahedron Lett. 1994, 35, 3361-3364.
(39) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E. J . Am. Chem.
Soc. 1989, 111, 6682-6690.
(49) Estevez, J . C.; Fairbanks, A. J .; Fleet, G. W. J . Tetrahedron
1998, 54, 13591-13620.
(40) Aspinall, H. C.; Greeves, N.; Lee, W.-M.; McIver, E. G.; Smith,
P. M. Tetrahedron Lett. 1997, 38, 4679-4682.
(41) Shen, Q.; Sloss, D. G.; Berkowitz, D. B. Synth. Commun. 1994,
24, 1519-1530.
(50) Mantell, S. J .; Ford, P. S.; Watkin, D. J .; Fleet, G. W. J .; Brown,
D. Tetrahedron 1993, 49, 3343-3358.
(51) Frank, H.; Lundt, I. Tetrahedron 1995, 51, 5397-5402.
(52) Redlich, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 1345-1347.
(53) Kappes, D.; Gerlach, H. Synth. Commun. 1990, 20, 581-587.
(42) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.

Total Synthesis of Dysiherbaine
J . Org. Chem., Vol. 67, No. 10, 2002 3197
F igu r e 2. Conformation of the enolate of lactone 21.
with Pd/C and H2 in THF to give 13 (Scheme 2), which
was followed by TPAP/NMO oxidation54 to give 14, and
reduction of the ketone with NaBH4 in methanol at -20
°C to give 15. Treatment with a catalytic amount of acid
then gave the requisite lactone 16.6,7
then undergo halide displacement by the newly unveiled
alkoxide, leading to the tetrahydrofuran 24 (Scheme 3,
pathway 1). This possibility also raises the issue of
whether the carbamate anion might attack the lactone
carbonyl before the lactone enolate is formed, leading to
the pyroglutamate 19 (Scheme 3, pathway 2). Enolization
of 19 would then give the corresponding enolate 20, a
species for which there is ample precedent for excellent
diastereoselectivity in reactions with electrophiles.34 In
this case, halogenation would be expected to occur on the
opposite face relative to the C-2 ester group to give 23,
the penultimate intermediate in pathway 1. Ring closure
of 23, regardless of which pathway is followed, would
then give 24 with good control of C-4 stereochemistry.
All of these factors provided substantial encourage-
ment to forge ahead with the Fleet ring-contraction plan.
It was therefore gratifying to find that our stereochemical
prediction for the halogenation was correct (on the basis
of the conversion of this intermediate into dysiherbaine;
see below), and that the initial reaction did proceed in
situ to form the desired bicyclic acid 25. When the lactone
16 was treated with 2 equiv of base followed by any of a
variety of halogen sources (i.e., I2,57,58 CBr4,59,60 NBS), the
tetrahydrofuroic acid 25 was isolated directly, along with
unreacted starting material and compound 26 in varying
amounts (Scheme 4). When the reaction was quenched
under anhydrous acidic conditions (HOAc/THF), the
tetracyclic imide 24 could be isolated, but it decomposed
when silica gel chromatography was attempted. This
material could, however, be converted into the more
stable methyl ester with methanol/methoxide.61-63 The
best conditions for this one-pot, multistep cascade are
NaHMDS, I2, and an alkaline bisulfite workup, which
gives 25 in 48% yield and 26 in 14% yield.
Obtaining the natural C-4 stereochemistry in this
sequence is clearly contingent on selective enolate halo-
genation in the correct stereochemical sense, but it
initially appeared that this reaction would likely occur
on the “wrong” face of the lactone enolate 21; one might
expect attack from the seemingly less hindered convex
side (Figure 2), which would ultimately produce the
epimer of the desired tetrahydrofuran product. Although
this stereochemical conundrum might seem to doom this
route, there is precedent suggesting that more subtle
factors might intervene in this system to give the desired
result. Tomioka et al. have shown that the dominant
factor in determining the stereochemical outcome of
similar δ-lactone alkylations is the size of the R-substitu-
ent.55 In the specific case of the enolate derived from 16,
according to the Tomioka model, there would be several
low-energy conformations in which the aminopropanoic
ester moiety essentially blocks the top face of the enol-
ate.56 The validity of this model aside, the pseudoaxial
pyran oxygen is not sterically demanding, and the ketal
group does not appear to play a key role in biasing attack
on the enolate; hence, stereoselective halogenation might
result from stereoelectronically favored axial attack to
give the desired diastereomer.
In a further interesting complication, because of the
presence of the internal carbamate anion in this particu-
lar lactone enolate, the initially formed R-halolactone
could proceed directly to the desired bicyclic ring system
without isolation of the R-halide itself. Specifically,
halogenation of the lactone enolate in the presence of the
internal carbamate anion could trigger the intramolecu-
lar opening of this lactone (22) to give 23, which would
We were then poised to complete the synthesis of
dysiherbaine by converting the equatorial C-8 oxygen into
(57) Rathke, M. W.; Lindert, A. Tetrahedron Lett. 1971, 3995-3998.
(58) Murakata, M.; Tsutsui, H.; Hoshino, O. J . Chem. Soc., Chem.
Commun. 1995, 481-482.
(54) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(55) Tomioka, K.; Kawasaki, H.; Yasuda, K.; Koga, K. J . Am. Chem.
Soc. 1988, 110, 3597-3601.
(59) Arnold, R. T.; Kulenovic, S. T. J . Org. Chem. 1978, 43, 3687-
3689.
(56) The conformation shown in Figure 2 was minimized using the
MM2 force field with the Chem3D software package (CambridgeSoft).
The conformation shown is simply our interpretation of the Tomioka
model discussed in the text. There are clearly other conformations in
which the steric differentiation of the two faces of the enolate is less
pronounced.
(60) Boiadjiev, S. E.; Lightner, D. A. Synlett 1997, 1277-1278.
(61) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.
(62) Schoenfelder, A.; Mann, A. Synth. Comm. 1990, 20, 2585-2588.
(63) Molina, M. T.; del Valle, C.; Escribano, A. M.; Ezquerra, J .;
Pedregal, C. Tetrahedron 1993, 49, 3801-3808.

3198 J . Org. Chem., Vol. 67, No. 10, 2002
Phillips and Chamberlin
Sch em e 3
the required methylamino group. The acid 25 was
converted into 27 with (TMS)CHN2, followed by ketal
deprotection with ferric chloride adsorbed on silica gel
to give the diol 28 in near quantitative yield. NMR
analysis of 28 (NOE and COSY) confirmed that the
correct C-4 stereochemistry had been obtained, as did
subsequent conversion into dysiherbaine. Although it has
not been determined which of the alternative pathways
is being followed, halogenation clearly does occur from
the face predicted by either model to give the stereo-
chemistry leading to dysiherbaine.
At this point, with the diol unveiled, chemoselective
oxidation of the equatorial alcohol 28 was required for
introducing the methylamino group by reductive amina-
tion. A number of oxidation conditions were tested,
including conversion into the stannyl acetal followed by
bromine oxidation,64 Swern oxidation,65 PCC oxidation,66
and Dess-Martin periodinane,67,68 but TPAP/NMO54 gave
consistently higher yields of the intermediate ketol than
any other conditions surveyed. The resultant hydroxy
ketone intermediate proved to be unstable to both silica
gel and alumina chromatography, which made a one-pot
oxidation/reductive amination sequence necessary.
The one-pot oxidation/reductive amination was carried
out by performing the TPAP/NMO oxidation following
standard conditions; when the reaction was complete,
ethanol was added to quench the oxidant and act as a
cosolvent for the reductive amination reaction.69 Isolation
of the very polar amino alcohol proved to be difficult, so
upon completion of the one-pot oxidation/reductive ami-
nation and workup, the crude amino alcohol was Boc-
protected to give 29 in 18% yield (three steps + 8%
recovered 28), a three-step yield that suffers most likely
from the instability of the hydroxy ketone intermediate.
(67) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
(68) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287.
(69) Neidigh, K. A.; Avery, M. A.; Williamson, J . S.; Bhattacharyya,
S. J . Chem. Soc., Perkins Trans. 1 1998, 2527-2531.
(64) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663.
(65) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185.
(66) Piancatelli, G.; Scettri, A.; D’Auria, M. Synthesis 1982, 245-
258.

Total Synthesis of Dysiherbaine
J . Org. Chem., Vol. 67, No. 10, 2002 3199
Sch em e 4
magnesium sulfate (MgSO4), filtered, and concentrated in
vacuo on a rotary evaporator. Abbreviations: ethyl acetate
(EtOAc), camphorsulfonic acid (CSA), N-methylmorpholine
N-oxide (NMO), tetrapropylammonium perruthenate (TPAP),
magnesium sulfate (MgSO4) 2,6-di-tert-butyl-4-methylpyridine
(DTBMP). All other reagents were used as purchased from
Aldrich, Sigma-Aldrich, or Acros unless otherwise stated.
Finally, hydrolysis of 29 with 6 M HCl and ion exchange
chromatography gave 1, which proved identical in all
respects to the natural material (1H NMR, 13C NMR,
HRMS, and optical rotation).
Con clu sion
P r otection of 6 (7). Compound 6 (7.50 g, 45.7 mmol) was
dissolved in dry DMF (230 mL) and cooled in an ice bath.
Imidazole (3.42 g, 50.2 mmol) and (TBDPS)Cl (13.2 mL, 47.9
mmol) were added, and the solution was stirred at 0 °C for 3
h, followed by the addition of 2-methoxypropene (5.47 mL, 57.1
mmol) and CSA (2.12 g, 9.1 mmol). After an additional 2 h
the reaction was treated with a solution of 5% bicarbonate (100
mL) and then extracted with diethyl ether (3 × 125 mL). The
combined organic layers were washed with water (5 × 100
mL), concentrated, and purified by flash chromatography (50%
ether/hexanes) to yield the title compound (16.9 g, 84%) as a
white solid: 1H NMR (400 MHz, CDCl3) δ 7.69 (m, 4H), 7.42
(m, 6H), 4.24 (d, J ) 13.6 Hz, 1H), 4.18 (dd, J ) 5.7, 2.2 Hz,
1H), 4.03 (dd, J ) 7.0, 5.7 Hz, 1H), 3.93 (dd, J ) 10.7, 4.6 Hz,
1H), 3.88-3.83 (m, 2H), 3.69 (dd, J ) 13.5, 2.4 Hz, 1H), 3.14
(app quintet, J ) 4.9 Hz, 1H), 2.92 (br s, 1H), 1.46 (s, 3H),
1.38 (s, 3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.6,
135.5, 132.8, 132.6, 129.9, 129.8, 127.8, 127.7, 109.6, 79.1, 77.1,
73.6, 72.4, 66.4, 65.1, 28.2, 26.8, 26.3, 19.2; IR (thin film) 3448,
3070, 2932, 2856, cm-1; HRMS (CI) calcd for C24H31O5 [M -
CH3]+ 427.1940, found 427.1923; [R]D25 -41.282° (c 5, MeOH).
A convergent synthesis of the glutamate receptor
agonist dysiherbaine was achieved by applying a novel
and stereoselective one-pot halogenation-ring-contrac-
tion reaction to prepare the bicyclic ring system with
excellent stereochemical control of the C-4 center. This
extension of the Fleet ring-contraction reaction allowed
us to prepare the natural product in fewer steps and with
greater control of stereochemistry than in previously
reported syntheses. The route is also amenable to ana-
logue preparation SAR analysis, which is currently under
way.
Exp er im en ta l Section
Gen er a l P r oced u r es. Anhydrous tetrahydrofuran (THF),
dichloromethane (DCM), and diethyl ether were filtered
through two columns of activated basic alumina and trans-
ferred under Ar(g) in a solvent purification system designed
and manufactured in house by J . C. Meyer. Dry toluene was
obtained similarly on the system by filtering through two
columns of Q5. Dry dimethylformamide (DMF) was obtained
by passing through two columns of activated molecular sieves.
Triethylamine (TEA), hexamethylphosphoramide (HMPA),
hexamethyldisilazane (HMDS), and methanol (MeOH) were
purified by distillation from calcium hydride. Unless otherwise
noted, all crude reaction mixtures were dried over solid
Alcoh ol 8. Compound 7 (15.85 g, 35.8 mmol) was dissolved
in dry THF (140 mL) and cooled to 0 °C. Sodium hydride (1.576
g (60 wt %), 39.4 mmol) was then added portionwise over 2
min. After the mixture was stirred for 10 min, benzyl bromide
(5.0 mL, 39.4 mmol) was added slowly, followed 5 min later
by dropwise addition of 15-crown-5 (7.11 mL, 35.8 mmol). The

3200 J . Org. Chem., Vol. 67, No. 10, 2002
Phillips and Chamberlin
reaction mixture was stirred at 0 °C for 30 min and then room
temperature for 2 h. It was then poured onto ice (∼200 g) and
extracted with EtOAc (2 × 100 mL). The organic layer was
washed with brine (100 mL) and then concentrated to give the
crude product as an oil, which was dissolved in THF (140 mL)
and treated with a 1 M TBAF solution (40 mL, 40 mmol). After
2 h the reaction was concentrated and purified by flash
chromatography (50% EtOAc/hexanes) to give the title com-
pound (6.88 g, 65%) as a clear, colorless oil. Upon prolonged
standing the material became a white semisolid: 1H NMR (400
MHz, CDCl3) δ 7.37-7.27 (m, 5H), 4.88 (d, J ) 11.5 Hz, 1H),
4.62 (d, J ) 11.5 Hz, 1H), 4.29-4.27 (m, 3H), 3.87 (dd, J )
11.5, 2.38 Hz, 1H), 3.74 (dd, J ) 13.5, 2.1 Hz, 1H), 3.66 (dd, J
) 11.6, 6.0 Hz, 1H), 3.51 (dd, J ) 9.7, 6.3 Hz, 1H), 3.20 (ddd,
J ) 9.5, 5.8, 3.5 Hz, 1H), 2.04 (br s, 1H), 1.53 (s, 3H), 1.39 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 137.9, 128.3, 128.0, 127.7,
109.4, 79.2, 77.9, 76.7, 73.9, 72.7, 66.6, 62.9, 27.9, 26.2; HRMS
(CI) calcd for C16H22O5 [M+] 294.1467, found 294.1473; IR (thin
39.3, 34.9, 33.8, 28.3, 28.0, 26.3; IR (thin film) 3354, 3033, 2979,
2923, 1735, 1710, 1506 cm-1; HRMS (CI) calcd for C28H41NO10
[M + H]+ 552.2802, found 552.2810; [R]D -7.3° (c 1.4,
25
CH2Cl2).
Alcoh ol 13. Compound 12 (3.43 g, 6.21 mmol) was dissolved
in THF (100 mL) and charged with 10% Pd/C (660 mg, 0.62
mmol, 10 mol %). The reaction vessel was fitted with a balloon
containing H2 (approximately 1 atm). After 1 h the reaction
mixture was filtered on a pad of Celite, rinsed with EtOAc,
and concentrated to dryness to give the title compound (2.85
g, 99%) as a white foam that was used without further
purification: 1H NMR (400 MHz, CDCl3) δ 5.02 (d, J ) 8.6
Hz, 1H), 4.36 (m, 1H), 4.20 (d, J ) 13.7 Hz, 1H), 4.16 (dd, J )
5.8, 2.4 Hz, 1H), 3.94 (dd, J ) 6.4, 6.4 Hz, 1H), 3.72 (s, 3H),
3.68-3.64 (m, 1H ovrlp with OCH3), 3.66 (s, 3H), 3.43-3.37
(m, 1H), 3.02 (ddd, J ) 9.0, 9.0, 2.5 Hz, 1H), 2.70 (app quintet,
J ) 6.7 Hz, 1H), 2.44, (br s, 1H), 2.07-1.99 (m, 3H), 1.86 (ddd,
J ) 15.3, 15.3, 7.9, 1H), 1.52 (s, 3H), 1.43 (s, 9H), 1.36 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 176.1, 172.7, 155.3, 109.5, 79.9,
79.4, 76.6, 73.9, 73.6, 66.4, 52.3, 52.1, 51.8, 39.1, 34.2, 34.0,
film) 3448, 3072, 3025, 2989, 1450 cm-1; [R]D -9.5° (c 0.7,
25
CH2Cl2).
Tr ifla te 9. Alcohol 8 (3.12 g, 10.6 mmol) was placed in an
oven-dried flask, concentrated from toluene (2 × 25 mL) under
high vacuum, and then dissolved in DCM (75 mL), treated with
DTBMP (2.65 g, 12.9 mmol), and cooled to -55 °C. Trifluoro-
methanesulfonic anhydride (2.14 mL, 12.7 mmol) was added
dropwise, and after being stirred at -55 °C for 1 h, the reaction
mixture was warmed to room temperature and stirred for an
additional 30 min. Diethyl ether (80 mL, purified) was added,
and the mixture was filtered on a Hirsch funnel to remove
white pyridinium triflate. The filter cake was rinsed with
ether, and the filtrate was then filtered once again, washed
successively with 5% aqueous bicarbonate (1 × 25 mL) and
brine (1 × 25 mL), and then concentrated to give a slightly
colored oil. Flash chromatography (30% ether/70% light pe-
troleum ether) gave 4.252 g (94%) of the title compound as a
white solid, which was used immediately in the subsequent
reaction without further purification: 1H NMR (500 MHz,
CDCl3) δ 7.38-7.20 (m, 5H), 4.90 (d, J ) 11.5 Hz, 1H), 4.58
(d, J ) 11.5 Hz, 1H), 4.51 (dd, J ) 10.7, 6.2 Hz, 1H), 4.29 (d,
J ) 13.7 Hz, 1H), 4.25 (d, J ) 5.7 Hz, 1H), 4.24 (dd, J ) 5.8,
2.0 Hz, 1H), 3.74 (dd, J ) 13.6, 2.2 Hz, 1H), 3.49-3.39 (m,
2H), 1.54 (s, 3H), 1.40 (s, 3H); IR (thin film) 3000, 2998, 1451,
28.2, 28.1, 26.2; IR (thin film) 3445, 3356, 2981, 1716, cm-1
;
HRMS (CI) calcd for C21H35NO10 [M + H]+ 462.2339, found
25
462.2327; [R]D -37.3° (c 2.1, CH2Cl2).
Keton e 14. Alcohol 13 (2.32 g, 5.0 mmol) was dissolved in
DCM (35 mL) and added via cannula to a flame-dried flask
containing freshly activated 4 Å molecular sieves (∼2.8 g).
NMO (755 mg, 6.25 mmol) was added followed by TPAP (68
mg, 0.25 mmol, 5 mol %) and the reaction mixture stirred for
1 h. The reaction mixture was filtered on a pad of silica gel,
rinsed with EtOAc, concentrated, and purified by flash chro-
matography (70% EtOAc/hexanes) to give the title compound
(2.00 g, 87%) as a pure white powder: 1H NMR (400 MHz,
CDCl3) δ 5.00 (d, J ) 9.0 Hz, 1H), 4.60 (d, J ) 6.2 Hz, 1H),
4.41 (d, J ) 6.2 Hz, 1H), 4.34 (m, 1H), 4.17 (d, J ) 12.4 Hz,
1H), 3.85 (m, 2H signals ovrlp), 3.73 (s, 3H), 3.66 (s, 3H), 2.66
(app quintet, J ) 6.5 Hz, 1H), 2.12-1.99 (m, 4H), 1.46 (s, 3H),
1.44 (s, 9H), 1.39 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 203.6,
175.5, 172.7, 155.4, 111.2, 80.1, 79.9, 77.5, 77.4, 66.9, 52.5, 52.3,
52.0, 39.0, 34.2, 31.6, 28.4, 27.1, 25.9; IR (thin film) 3356, 2980,
1738 cm-1; HMS (CI) calcd for C21H33NO10 [M + H]+ 460.2182,
25
found 460.2181; [R]D +10.9° (4.5, CH2Cl2).
Alcoh ol 15. Ketone 14 (2.48 g, 5.4 mmol) was dissolved in
dry MeOH (30 mL) and cooled to -20 °C. Solid sodium
borohydride (500 mg, 13.5 mmol) was added in one portion,
and the reaction mixture was stirred for 10 min and then
poured into a rapidly stirred solution of DCM (50 mL) and 0.15
M pH 7 phosphate buffer (50 mL). After 10 min, the layers
were separated, the aqueous layer was extracted with DCM
(2 × 30 mL), and the combined organic layers were concen-
trated. Flash chromatography (60% EtOAc/hexanes) gave the
title compound (2.48 g, 100%) as a pure white foam: 1H NMR
(400 MHz, CDCl3) δ 4.99 (d, J ) 8.3 Hz, 1H), 4.34 (m, 1H),
4.25 (d, J ) 13.5 Hz, 1H), 4.11 (m, 2H), 3.72 (s, 3H), 3.66 (s,
3H), 3.58 (app d, J ) 7.4 Hz, 1H), 3.61 (dd, J ) 9.3, 3.8 Hz,
1H), 2.62 (app quintet, J ) 6.9 Hz, 1H), 2.27 (d, J ) 7.6 Hz,
1H), 2.20 (ddd, J ) 14.2, 8.8, 8.8 Hz, 1H), 2.04 (m, 2H), 1.71
(ddd, J ) 12.0, 7.1, 7.1 Hz, 1H), 1.56 (s, 3H), 1.43 (s, 9H, 1.39
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 175.7, 172.6, 155.3,
109.2, 79.9, 75.2, 73.2, 71.0, 66.8, 66.5, 52.3, 52.1, 51.8, 39.4,
34.3, 34.2, 28.2, 25.7, 25.3; IR (thin film) 3550, 3351, 2972,
1730, cm-1; HRMS (CI) calcd for C21H35NO10 [M + H]+
cm-1
.
Glu ta m a te Ad d u ct 12. Compound 11 (4.14 g, 15.0 mmol)
was concentrated from dry toluene (2 × 25 mL) and placed
under high vacuum overnight prior to use. The resultant oil
was dissolved in dry THF (75 mL) and cooled to -78 °C. In a
separate flask 0.64 M LHMDS (32.0 mmol), freshly prepared
from a 1.8 M solution of n-BuLi (17.9 mL 32.3 mmol) and
HMDS (7.50 mL, 35.5 mmol) in 25 mL of THF, was cooled to
-78 °C, and then it was cannulated dropwise into the flask
containing 11 over a 20 min period. After 1 h, HMPA (13.0
mL, 75 mmol) was added dropwise to the solution, and the
solution was stirred for an additional 20 min. A separate flask
containing the triflate 9 (3.50 g, 8.21 mmol) was charged with
THF (20 mL), which was cooled to -78 °C and then added
dropwise via cannula over 20 min to the solution of the dianion.
After 7 h, the reaction was warmed to -30 °C, stirred for
approximately 5 min, and then quenched by adding 1 M HCl
(40 mL), stirring vigorously for 15 min, and warming to 0 °C.
The reaction was then extracted with EtOAc (3 × 50 mL), and
the combined organic layers were washed with saturated
ammonium chloride until the pH of the aqueous layer was
acidic. Successive washes with brine (2 × 25 mL) and
concentration gave the crude product. Flash chromatography
(25% EtOAc/hexanes ramped to 50% EtOAc/hexanes) gave the
title compound (3.41 g, 75%) as a clear oil: 1H NMR (400 MHz,
CDCl3) δ 7.34-7.28 (m, 5H), 4.96 (d, J ) 8.0 Hz, 1H), 4.87 (d,
J ) 11.5 Hz, 1H), 4.58 (d, J ) 11.5 Hz, 1H), 4.31 (m, 1H), 4.17
(m, 3H), 3.71 (s, 3H), 3.63 (s, 3H), 3.60 (m, 1H ovrlp with
OCH3), 3.23 (dd, J ) 9.5, 5.9 Hz, 1H), 3.07 (d, J ) 8.8, 1H),
2.64 (m, 1H), 2.10-1.97 (m, 3H), 1.71 (ddd, J ) 14.3, 9.8, 6.8
Hz, 1H), 1.51 (s, 3H), 1.42 (s, 9H), 1.36 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 176.1, 172.8, 154.8, 138.0, 128.3, 128.0, 127.7,
109.4, 79.8 (×2), 79.4, 75.9, 74.0, 72.7, 66.5, 52.5, 52.3, 51.7,
25
462.2339, found 462.2334; [R]D -26.1° (2.7, CH2Cl2).
La cton e 16. Alcohol 15 (2.45 g, 5.3 mmol) was dissolved in
benzene (260 mL) and treated with CSA (163 mg, 0.70 mmol,
13 mol %) and pyridine (0.05 mL, 0.5 mmol). The flask was
then equipped with a Soxhlet extractor containing activated
5 Å molecular sieves and the reaction mixture heated at reflux
for ∼72 h, cooled to room temperature, treated with 5 mL of
TEA, and concentrated. The crude product was dissolved in
EtOAc (50 mL) and washed successively with 5% aqueous
bicarbonate (1 × 15 mL) and brine (1 × 15 mL). The combined
organic layers were then concentrated. Flash chromatography
(50% EtOAc/hexanes f 70% EtOAc/hexanes) gave the title
compound (1.65 g, 72%) as a white foam. The product was an
inseparable mixture of diastereomers and was used without

Total Synthesis of Dysiherbaine
J . Org. Chem., Vol. 67, No. 10, 2002 3201
further purification: 1H NMR (500 MHz, CDCl3) δ 5.14 (d, J
) 8.8 Hz, 1H), 4.42 (dd, J ) 5.2, 3.0 Hz, 1H), 4.37-4.31 (m,
2H), 4.22 (d, J ) 13.7 Hz, 1H), 4.15 (dd, J ) 5.9, 2.6 Hz, 1H),
3.73 (s, 3H), 3.71-3.66 (m, overlp diastereomer, 2H), 3.01 (m,
1H), 2.44 (m, 1H), 2.29 (ddd, J ) 14.6, 10.3, 4.7 Hz, 1H), 2.01-
1.95 (m, 1H), 1.84-1.70 (m, overlp diastereomer, 1H), 1.63 (s,
3H), 1.42 (s, 9H), 1.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
172.3, 172.1, 155.2, 110.4, 80.1, 73.7, 71.8, 70.8, 68.8, 67.0, 52.5,
50.9, 34.3, 30.9, 28.4, 26.0, 25.8; IR (thin film) 3354, 2981, 1786,
1715 cm-1; HRMS (CI) calcd. for C19H28NO9 [M - Me]+ calcd
414.1764, found 414.1758.
Hz, 1H), 4.03 (m, 1H), 3.99-3.96 (m, 2H), 3.82 (s, 3H), 3.78
(s, 3H), 3.68 (br s, 1H), 3.64 (dd, J ) 3.8, 3.8 Hz, 1H), 3.42 (d,
J ) 11.9 Hz, 1H), 2.81 (dd, J ) 14.5, 5.4 Hz, 1H), 2.53 (d, J )
14.0 Hz, 1H), 2.26 (dd, J ) 14.6, 3.7 Hz, 1H), 2.13 (dd, J )
14.1, 3.6 Hz, 1H), 1.60 (br s, 2H), 1.43 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 175.5, 172.2, 155.0, 83.2, 81.0, 80.0, 76.6, 70.1,
67.7, 67.2, 53.0, 51.0, 4.61, 40.3, 28.3; IR (thin film) 3425, 1741,
1709 cm-1; HRMS (CI) calcd for C18H29NO10 [M + NH4]+
27
437.2135, found 437.2144; [R]D +56.7° (c 1.1, CHCl3).
P r otected Dysih er ba in e 29. A flask containing diol 27
(75 mg, 0.2 mmol) and activated molecular sieves (4 Å beads)
was charged with DCM (3 mL), and the solution was cooled
to 0 °C. NMO (63 mg, 0.54 mmol) and TPAP (10 mg, 0.03
mmol) were added, and the solution was stirred for 10 min.
Dry ethanol (3 mL) was then added, and the reaction mixture
was stirred for an additional 15 min. Methylamine hydro-
chloride (60 mg, 0.9 mmol), TEA (0.13 mL, 0.9 mmol), and
Ti(OiPr)4 (0.25 mL, 0.9 mmol) were added in succession, and
after the solution was stirred for 1.5 h, sodium borohydride
(20 mg, 0.5 mmol) was added. After an additional 1.5 h the
reaction was quenched with 2.5% NH4OH (1 mL) and stirred
for 5 min. The insoluble inorganic precipitate was filtered on
a thin pad of Celite and rinsed with EtOAc. The organic layers
were combined and concentrated to give a light brown solid
that was taken up in EtOAc (5 mL) and filtered through
another narrow pad of Celite. The pad was washed with
EtOAc/MeOH (90:10) and again concentrated to dryness.
Addition of DCM produced a white precipitate that was filtered
off, and the filtrate was refiltered through a cotton plug and
rinsed with DCM. The concentrated organic layers were
dissolved in MeOH (2 mL), treated with NEt3 (0.1 mL) and
Boc2O (0.2 mL), and then stirred overnight. The reaction
mixture was diluted with EtOAc (10 mL) and washed succes-
sively with 2.5% NaHSO4 (2 × 4 mL) and brine (1 × 3 mL).
The combined organic layers were concentrated, and the
resultant product was purified twice by flash chromatography
(2.5% MeOH/DCM) to give the title compound (16 mg, 17%)
as a white solid along with recovered 27 (6 mg, 8%): 1H NMR
(500 MHz, CDCl3) δ 5.50 (br s, 1H), 4.92 (d, J ) 12.6 Hz, 1H),
4.46 (br s, 1H), 4.24 (m, 1H), 4.13 (dd, J ) 1.3, 1.3 Hz, 1H),
4.03 (d, J ) 1 Hz, 1H), 3.84 (d, J ) 11.5 Hz, 1H), 3.80 (s, 3H),
3.80 (ovrlp m, 1H), 3.72 (s, 3H), 3.55 (d, J ) 12.1 Hz, 1H),
3.27 (s, 3H), 2.63 (dd, J ) 14.5, 4.7 Hz, 1H), 2.53 (d, J ) 14.0
Hz, 1H), 2.09 (dd, J ) 14.4, 7.5 Hz, 1H), 2.03 (m, 1H), 1.47 (s,
9H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 174.7, 172.1,
155.6, 155.2, 85.3, 82.4, 79.9, 77.7, 73.1, 69.0 53.1, 52.6, 52.3,
51.3, 44.7, 39.8, 33.4, 27.7, 28.4, 28.2; IR (thin film) 3443, 2977,
1744, 1716, 1684 cm-1; HRMS (CI) calcd for C24H40N2O11 [M
Acid 25. Lactone 16 (750 mg, 1.74 mmol) was dissolved in
THF (6.5 mL) and cooled to -78 °C. A separate flask was
charged with NaHMDS (1 M in THF, 4.0 mL, 4.0 mmol) in
THF (7.5 mL) and cooled to -78 °C. The solution containing
16 was added dropwise to the NaHMDS solution over 10 min,
resulting in a bright yellow solution that was stirred for an
additional 30 min. A third flask containing I2 (467 mg, 1.84
mmol) in THF (9.0 mL) was cooled to -78 °C, and the yellow
dianion was then added to the I2 solution via cannula over a
10 min period. The reaction mixture was stirred for 1 h at -78
°C and then 30 min at -20 °C. It was quenched with 0.1 N
LiOH (0.5 mL) in THF (5 mL), stirred for 20 min, and then
allowed to warm to room temperature. A dilute alkaline
bisulfite solution (water (8 mL), 5% bisulfite (1 mL), and 1 N
LiOH (1 mL)) was added and the resultant solution stirred
rapidly for an additional 10 min. The reaction mixture was
concentrated in vacuo to approximately one-third of the initial
volume and extracted with EtOAc (30 mL). The organic layer
was washed with a 1% aqueous bicarbonate (2 × 15 mL), and
the combined aqueous layers were acidified to pH 3 with 0.1
N HCl. Solid sodium chloride (∼5 g) was then added to the
aqueous solution, which was then extracted with EtOAc (3 ×
20 mL). The combined organic layers were concentrated and
purified by flash chromatography (60% EtOAc/hexanes f 80%
i
EtOAc/hexanes f 90% EtOAc/10% PrOH) to give the title
compound (376 mg, 48%) as a white foam: 1H NMR (400 MHz,
CDCl3) δ 10.1 (br s, 1H), 5.33 (d, J ) 6.5 Hz, 1H), 4.39-4.35
(m, two ovrlp signals, 2H), 4.24 (d, J ) 14.0 Hz, 1H), 4.16 (app
d, J ) 4.4 Hz), 4.13 (dd, J ) 2.5, 2.5 Hz, 1 H), 4.02 (ddd, J )
4.4, 4.4, 2.3, 1H), 3.74 (s, 3H), 3.63 (dd, 13.9, 2.2 Hz, 1H), 2.76
(dd, J ) 14.5, 5.9 Hz, 1H), 2.57 (d, J ) 13.9 Hz, 1H), 2.22 (dd,
J ) 13.6, 4.0 Hz, 1H), 2.10 (dd, J ) 14.4, 3.10 Hz, 1H), 1.64 (s,
3H), 1.43 (s, 9H), 1.18 (s, 3H);13C NMR (100 MHz, CDCl3) δ
174.1, 172.3, 155.0, 110.5, 83.6, 80.0, 77.2, 75.1, 70.7, 64.9, 52.4,
50.8, 45.7, 39.1, 36.4, 28.3, 25.8, 25.4; IR (thin film) 3400 (br),
2924, 1750, 1708 cm-1; HRMS (FAB) calcd for C20H31NO10 [M
+ Na]+ 468.1845, found 468.1845.
27
+ H] 533.2710, found 533.2697; [R]D +58.0° (c 0.6, CHCl3).
Meth yl Ester 27. Acid 25 (240 mg, 0.53 mmol) was
dissolved in DCM (6 mL) and MeOH (1 mL) and treated with
(TMS)CHN2 (2.0 M in hexanes, 0.5 mL, 1 mmol) for 5 min.
Acetic acid (0.5 mL) was added, followed by EtOAc (10 mL).
Successive washes with 5% bicarbonate (10 mL) and brine (10
mL) were followed by concentration of the combined organic
layers to give the crude ester. Purification by flash chroma-
tography (50% EtOAc/hexanes) gave the title compound (190
mg, 77%) as a pure white foam: 1H NMR (400 MHz, CDCl3) δ
5.50 (d, J ) 6.5 Hz, 1H), 4.39 (dd, J ) 6.6, 4.9 Hz 1H), 4.27
(dd, J ) 11.2, 5.6 Hz, 1H), 4.10 (m, 2H), 3.99 (m, 3H), 3.76 (s,
3H), 3.75 (s, 3H), 3.71 (d, J ) 2.2 Hz, 1H), 3.50 (dd, J ) 13.3,
2.7 Hz, 1H), 2.63 (dd, J ) 13.7, 3.9 Hz, 1H), 2.48 (dd, J ) 14.5,
5.0 Hz, 1H), 2.23 (dd, J ) 13.6, 6.1 Hz, 1H), 2.18 (dd, J ) 14.6,
5.8 Hz, 1H), 1.61 (s, 3H), 1.43 (s, 9H), 1.35 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.5, 172.1, 155.1, 110.5, 83.4, 79.8, 75.6,
75.3, 71.5, 71.2, 66.5, 52.5, 52.3, 51.2, 44.2, 39.9, 28.3, 25.9,
25.8; IR (thin film) 3385, 2979, 1715 cm-1; HRMS (FAB) calcd
Dysih er ba in e (Syn t h et ic) (1). Compound 29 (11.5 mg.
0.02 mmol) was heated in 6 M HCl (1 mL) at 80 °C overnight
and concentrated to dryness in vacuo and then twice more from
water to give a quantitative yield of the bis-HCl salt, which
was then filtered through AG-1-X2 (acetate form) resin, eluting
the neutral product with water. Ninhydrin positive fractions
were lyophilized to give 1 (3.6 mg, 55%) as a pure, white
amorphous solid: 1H NMR (500 MHz, D2O) δ 4.47 (dd, J )
1.8, 1.8 Hz, 1H), 4.33 (s br, 1H), 4.03 (dd, J ) 12.8, 2.3 Hz,
1H), 4.01 (s br, 1H), 3.71-3.69 (m, 2H), 3.67 (dd, J ) 11.7, 2.5
Hz, 1H), 2.95 (s, 3H), 2.75 (dd, J ) 15.2, 2.5 Hz, 1H), 2.74 (d,
J ) 14.0 Hz, 1H), 2.32 (dd, J ) 14.0, 3.4 Hz, 1H), 2.09 (dd, J
) 15.2, 11.7 Hz, 1H); 13C NMR (125 MHz, D2O, referenced to
the chemical shift of C-6 (77.0 ppm) δ 181.0, 174.6, 89.4, 77.0,
75.7, 69.5, 63.0, 57.3, 54.5, 45.2, 40.1, 30.4; HR ESI-MS [M +
Na]+ calcd 327.1168, found 327.1162; [R]D27 -3.6° (c 0.1, H2O).
Ack n ow led gm en t. This work was funded by the
National Institutes of Health (Grant NS-27600). Dupont
Pharmaceuticals is gratefully acknowledged for a Gradu-
ate Research Fellowship (D.P.).
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
for C21H33NO10 [M + H]+ 460.2182, found 460.2190; [R]D
+17.1° (c 0.8, CHCl3).
27
Diol 27. Methyl ester 27 (165 mg, 0.36 mmol) was dissolved
in CHCl3 (7 mL) and treated with FeCl3‚SiO2 (100 mg) and
acetic acid (0.1 mL). After being stirred for 17 h, the reaction
mixture was filtered through a pad of SiO2, washed with
EtOAc, and concentrated. Flash chromatography provided the
title compound (156 mg, 99%) as a white foam: 1H NMR (400
MHz, CDCl3) δ 5.34 (d, J ) 6.2 Hz, 1H), 4.34 (dd, J ) 9.5, 6.0
J O0107610