Synthesis of the dysiherbaine tetrahydropyran core employing a tethered aminohydroxylation reaction

Article abstract of DOI:10.1016/j.tetlet.2007.02.016

A stereocontrolled and scalable synthesis of an advanced intermediate of the dysiherbaine tetrahydropyran core has been achieved in 11 steps and 27% overall yield. The key feature of this synthetic approach is the application of the Donohoe tethered amino

Full text of DOI:10.1016/j.tetlet.2007.02.016

Tetrahedron Letters 48 (2007) 2533–2536
Synthesis of the dysiherbaine tetrahydropyran core employing
a tethered aminohydroxylation reaction
Jamie L. Cohen and A. Richard Chamberlin*
Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA
Received 24 January 2007; accepted 6 February 2007
Available online 9 February 2007
Abstract—A stereocontrolled and scalable synthesis of an advanced intermediate of the dysiherbaine tetrahydropyran core has been
achieved in 11 steps and 27% overall yield. The key feature of this synthetic approach is the application of the Donohoe tethered
aminohydroxylation reaction to install the amino diol and establish the four contiguous syn stereocenters on the tetrahydropyran
ring.
Ó 2007 Elsevier Ltd. All rights reserved.
Since its isolation in 1997, (ꢀ)-dysiherbaine (1) has at-
tracted attention in the chemical and biological commu-
nities due to its interesting structure and unique
biological activity.1 The molecular architecture of dysi-
herbaine (DH), characterized by a cis fused hexahydrof-
uro[3,2-b]pyran ring system displaying a glutamic acid
appendage, has generated a great deal of interest as a
synthetic target.2,3 Our own synthetic efforts were moti-
vated by dysiherbaine’s impressive biological profile.4
Radioligand binding assays of DH activity at ionotropic
glutamate receptors have demonstrated that DH is a
potent agonist of non-NMDA type glutamate receptors,
with a particularly high affinity for the KA receptor:
IC50 = 33 and 230 nM for KA and AMPA, respec-
tively.1 Furthermore, DH induces epilepsy-like seizures
in mice and has been shown to be the most potent
epileptogenic excitatory amino acid yet identified. Both
the kainate receptor selectivity and potency of DH make
it a valuable pharmacological tool for investigating the
physiological roles of the various glutamate receptors
in the CNS.4e Furthermore, as a neurotoxin and potent
convulsant, DH may also provide insight as to targets
for therapeutic intervention in the treatment of seizures.
The low natural abundance of DH, however, has limited
its availability, thereby impeding further studies on its
mode of action. As a consequence, total synthesis of
DH is required for further physiological studies.
Since the initial elucidation of the dysiherbaine struc-
ture, several research groups, including our own, have
independently accomplished the total synthesis of DH.
The synthesis of DH previously developed in our labo-
ratory featured a Fleet-inspired ring contraction of d-
lactone 3 to construct the bicyclic ring system and estab-
lish the stereochemistry at the tetrasubstituted c-carbon
of the glutamate side chain (Scheme 1).2d
Overall, the synthetic route was highly convergent and it
provided sufficient quantities of DH for biological eval-
uation; however, the final stages of the synthesis were
plagued by difficulties encountered with an oxidation
and reductive amination sequence that ultimately
produced the N-Me amino alcohol of 1 in poor yield.
To circumvent this low yielding amination step, we have
NH2CH3
OH
OH
H
H
OH
O
O
O2C
MeO2C
Ring
Contraction
Reductive
Amination
O
O
H3N
CO2
BocHN
CO2Me
O
2
Dysiherbaine (1)
O
O
O
I
O
O
BnO
O
O
OH
3
4
BocHN
CO2Me
*
Corresponding author. Tel./fax: +1 949 824 7089; e-mail:
archambe@uci.edu
Scheme 1. Retrosynthetic strategy for previous dysiherbaine synthesis.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.016

2534
J. L. Cohen, A. R. Chamberlin / Tetrahedron Letters 48 (2007) 2533–2536
O
O
the tethered aminohydroxylation reaction figured prom-
inently in our synthetic planning.
MeN
O
I
O
Dysiherbaine
(1)
Our approach to 6 thus began with the preparation of
the tethered aminohydroxylation substrate, allylic
carbamate 11 (Scheme 3). The microwave accelerated
indium catalyzed Ferrier rearrangement8 of tri-O-acetyl-
D-galactal (8) in the presence of triethylsilane consis-
tently provided good yields (85%) of olefin 99 on scales
ranging from 100 mg to 20 g. Deacetylation of 9 was
accomplished using NaOMe in MeOH to afford diol 7,
which was selectively protected at the primary alcohol
as TBS silyl ether 10. Sequential treatment of allylic
alcohol 10 with trichloroacetylisocyanate and K2CO3/
MeOH afforded multi-gram quantities of carbamate
11, the substrate for the key tethered aminohydroxyl-
ation reaction, in 96% yield after purification.
O
5
BocHN
CO2Me
HO
O
O
MeN
BnO
O
O
OH
OH
7
6
Scheme 2. Revised retrosynthetic strategy for dysiherbaine featuring
early installation of amino alcohol.
explored an alternative approach to DH in which an
analogous but more highly functionalized tetrahydro-
pyran derivative, 6, would be carried through a similar
sequence in place of intermediate 4 (Scheme 2), with the
critical installation of the N-Me amino alcohol moiety
occurring prior to the lactone ring contraction. More-
over, we believe that the route we have developed to
tetrahydropyran 6 has considerable merit in its own
right-independent of its potential as a DH intermedi-
ate-as one of the few examples of a tethered amino
hydroxylation reaction applied to natural product struc-
tures, and more importantly, as a caveat in the applica-
tion of this exceptionally selective and high-yielding
reaction to construct vicinal amino alcohols. We thus
describe herein an efficient and scalable synthesis of
the highly functionalized intermediate 6 that embodies
the tetrahydropyran (THP) core of dysiherbaine.
Following the successful synthesis of carbamate 11, the
key tethered aminohydroxylation reaction was investi-
gated. We first examined the tethered aminohydroxyl-
ation conditions reported by Donohoe, which were
modeled after the traditional Sharpless asymmetric
aminohydroxylation procedures. Satisfyingly, exposure
of carbamate 11 to the standard tethered aminohydr-
oxylation conditions (t-BuOCl, NaOH, K2OsO2(OH)4,
(DHQ)2PHAL, nPrOH/H2O) cleanly installed the syn
amino diol motif on the DH tetrahydropyran core in
75% yield. The remainder of the mass balance for this
transformation consisted of recovered starting material
that could be easily recycled through the hydroxyamin-
ation sequence. To our surprise, however, the amino-
hydroxylation product was not isolated as the single
anticipated hydroxy oxazolidinone isomer 12. On the
contrary, a 1:1 mixture of hydroxy oxazolidinone iso-
mers 12 and 13 was observed in the crude reaction mix-
ture. Following careful chromatography to separate the
two isomers, 12 and 13 were independently resubjected
to the tethered aminohydroxylation reaction conditions.
Previous syntheses of advanced DH intermediates iden-
tified the four contiguous syn stereocenters and amino
diol functionality of the tetrahydropyran core as a
significant synthetic challenge.2,3 The strategy reported
herein was motivated by the view that a new synthetic
approach to the DH pyran core would need to provide
greater efficiency and implement high yielding processes
in strategic roles. With this in mind, we recognized that
the hydroxyamination of an unsaturated pyran deriva-
tive (7) might be ideally suited for this application.
While the Sharpless asymmetric aminohydroxylation
reaction of olefins has emerged as a powerful method
to construct vicinal amino alcohols in the context of nat-
ural product synthesis,5 it has not been employed to
introduce the amino alcohol of dysiherbaine—possibly
because of concerns regarding the regioselectivity of this
transformation, which may detract from its potential
synthetic utility. In 2002, Donohoe and co-workers
introduced an innovative method of controlling amino-
hydroxylation regioselectivity, in which the nitrogen
source is tethered to the olefin substrate. This tethered
aminohydroxylation of olefins was reported to proceed
with complete control of regioselectivity and was highly
diastereoselective in cyclic substrates.6,7 These charac-
teristics, in conjunction with a substitution pattern in
dysiherbaine ideally suited for this process, suggested
that the Donohoe aminohydroxylation reaction might
be an ideal means of achieving the desired levels of
regio- and stereoselectivity in the synthesis of 6. Thus,
OAc
AcO
AcO
HO
b
a
88%
97%
O
O
O
7
8
OAc
OAc
OH
9
O
NH2
HO
O
4
e
d
75%
12:13 = (1:1)
96%
1
O
O
OTBS
OTBS
10
11
O
O
O
NH
HN
O
OH
HO
O
O
OTBS
OTBS
12
13
Scheme 3. Reagents and conditions: (a) Et3SiH, InCl3, CH3CN,
lwave; (b) NaOMe, MeOH; (c) TBSCl, imidazole, DMF; (d) (i)
Cl3CCONCO, CH2Cl2; (ii) K2CO3, MeOH/H2O; (e) t-BuOCl, NaOH,
K2OsO2(OH)4, (DHQ)2PHAL, nPrOH/H2O.

J. L. Cohen, A. R. Chamberlin / Tetrahedron Letters 48 (2007) 2533–2536
2535
Both reactions afforded identical 1:1 product mixtures
regardless of the starting isomer, confirming that equili-
bration is quite facile and has reached thermodynamic
equilibrium under the reaction conditions. The hydroxy
oxazolidinone isomers 12 and 13 also undergo equilibra-
tion upon exposure to NaOMe/MeOH or NaH/THF.
in energetically preferred conformers of the initially
formed product. A related example describing oxazolid-
inone migration during the tethered aminohydroxyl-
ation reaction of a homoallylic carbamate11 has recently
appeared, supporting this contention.
Despite a considerable effort, conditions for preventing
the equilibration of 12 could not be found; however,
the problem was circumvented by processing both oxa-
zolidinone isomers into a single advanced intermediate
(17) by sequential treatment with Boc2O, TBAF, and
Cs2CO3 in MeOH.12 Employing this optimized three-
step protocol, the conversion of 12 and 13 into THP
17 was realized on an 11 g scale in 81% overall yield
(Scheme 4). In order to strategically differentiate
between the two secondary axial alcohols on pseudo-
symmetric 17, the DH tetrahydropyran core was
selectively functionalized using benzaldehyde dimethyl-
acetal and CSA (cat.) at 0 °C to exclusively provide
the six-membered ring benzylidene acetal 18 in 78%
yield. Sequential treatment of 18 with KOtBu and MeI
then afforded N-Me oxazolidinone 19 as a crystalline
solid in 95% yield. X-ray crystallographic analysis of
19 verified the structure and unambiguously established
the all syn stereochemistry of the substituents on the
THP ring (Fig. 2).13 Finally, regioselective reductive
cleavage of the benzylidene acetal14 was best accom-
plished using PhBCl2 and Et3SiH at ꢀ78 °C to furnish
multi-gram quantities of tetrahydropyran (6).
The few reports in the literature of tethered aminohydr-
oxylation reactions of allylic carbamates do not include
any examples of related equilibrations, which clearly
might diminish the synthetic utility of the reaction to
some extent. We believe, however, that this side reaction
is substrate dependent, and in this specific instance
occurs because of the overwhelmingly axial disposition
of the secondary alcohols in both the initially formed
product (12) and in the migration product (13). Both
alcohols are ideally positioned for direct acyl transfer;
thus a plausible mechanism for equilibration in the spe-
cific case of 11!12 + 13 is the direct attack of the axial
alkoxide on the urethane carbonyl group followed by a
regioselectively arbitrary collapse of the tetrahedral
intermediate and facile equilibration of the two ure-
thanes. Significantly, carbamate migrations were not ob-
served during the tethered aminohydroxylation reaction
on an analogous cyclic substrate (C4-epi-11!14, Fig. 1)
in which the allylic alcohol occupies an equatorial
position.6
Indeed, molecular modeling10 indicates that the equato-
rial alkoxide of 14 is poorly aligned for addition to
p*C@O, while the axial alkoxide of 12 is well positioned
for attack at the Burgi–Dunitz angle. An alternative
equilibration pathway might involve deprotonation of
the carbamate N–H to form an isocyanate that is at-
tacked indiscriminately by the flanking hydroxyl groups.
This pathway, however, does not account for the differ-
ence in the migratory propensity of 12 and 14 under the
reaction conditions, because one would not expect a sig-
nificant difference in the rates of isocyanate formation
from diastereomers 12 and 14. This analysis suggests
more generally that carbamate equilibration in the teth-
ered aminohydroxylation reaction is a consequence of
relative stereochemistry, and may be facile if the partic-
ipating groups are favorably positioned for acyl transfer
In summary, we have developed an efficient, stereocon-
trolled, and scalable synthesis of a highly functionalized
amino hydroxy tetrahydropyran derivative in 11 steps
and 27% overall yield. The key feature of this approach
is the application of the Donohoe tethered aminohydr-
oxylation reaction to install the syn amino diol motif
found in dysiherbaine. We also observed, consistent
with a recent literature report, that the initially formed
product of this reaction can undergo facile acyl transfer
to give a thermodynamic mixture of cyclic urethanes,
although this process appears to be highly substrate
O
O
O
O
NBoc
BocN
O
OBoc BocO
c
a, b
12 + 13
96%
86%
O
O
15
16
OH
OH
NH
NHBoc
OH
NHBoc
O
OH
H
H
HO
Ph
O
O
OH
d
e
O
O
17
78%
95%
O
18
OTBS
12
OH
O
O
O
O
O
MeN
O
MeN
O
NH
Ph
O
BnO
f
OH
O
92%
O
O
19
6
OH
OTBS
14
Scheme 4. Reagents and conditions: (a) Boc2O, Et3N, DMAP, THF;
Figure 1. Comparison of oxazolidinone equilibration substrates (TBS
group omitted for clarity).
(b) TBAF, AcOH, DMF; (c) Cs2CO3, MeOH; (d) PhCH(OMe)2, CSA,
CH2Cl2; (e) KO Bu, MeI, THF; (f) PhBCl2, Et3SiH, 4 A, CH2Cl2.
t
˚

2536
J. L. Cohen, A. R. Chamberlin / Tetrahedron Letters 48 (2007) 2533–2536
Naito, T.; Nair, S.; Nishiki, A.; Yamashita, K.; Kiguchi,
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Figure 2. Single crystal X-ray structure of 19.
dependent and in the case reported here, easily
circumvented.
Acknowledgments
6. Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M.
J. Am. Chem. Soc. 2002, 124, 12934–12935.
We acknowledge Professor Robert Doedens and Erin
Tappan for solving the X-ray crystal structure of com-
pound 19. We are grateful for the support from the Na-
tional Institute of Neurological Disorders and Stroke
(NS-27600 to A.R.C.) and the National Institute of
General Medical Sciences (GM07311, training grant
support for J.L.C.).
7. Examples of tethered aminohydroxyalations of allylic
carbamates: (a) Donohoe, T. J.; Johnson, P. D.; Helliwell,
M.; Keenan, M. Chem. Commun. 2001, 2078–2079; (b)
Donohoe, T. J.; Johnson, P. D.; Pye, R. J.; Keenan, M.
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Taylor, R. J. . Tetrahedron Lett. 2004, 45, 6661–6664; (e)
Donohoe, T. J.; Johnson, P. D.; Pye, R. J.; Keenan, M.
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Supplementary data
8. Das, S. K.; Reddy, K. A.; Abbineni, C.; Das, S. K.;
Reddy, K. A.; Abbineni, C.; Roy, J.; Narasimha Rao, K.
V. L.; Sachwani, R.; Iqbal, J. Tetrahedron Lett. 2003, 44,
4507–4509.
9. Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy,
A. L. J. Org. Chem. 2000, 65, 8499–8509.
Complete experimental procedures, product character-
ization, and spectral data. Supplementary data associ-
ated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.02.016.
10. Molecular modeling was performed using Spartan ’02
(WaveFunctionF, Irvine, CA) and conformations 12 and
14 were optimized using Molecular Mechanics MMFF
method.
References and notes
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13. Crystallographic data (excluding structure factors) for the
structures in this Letter have been deposited with the
Cambridge Crystallographic Data Centre as Supplemen-
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