Oxidative fragmentation of bicyclic hydroxy silanes and stannanes: a strategy for the stereoselective synthesis of kainoids

Article abstract of DOI:10.1016/j.tetlet.2007.09.150

The addition of tin or silicon nucleophiles to bicyclic enones generated by dearomatising cyclisation gives stannanes and silanes stereoselectively. These compounds may be fragmented under oxidative conditions to generate substituted pyrrolidines bearing

Full text of DOI:10.1016/j.tetlet.2007.09.150

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Tetrahedron Letters 48 (2007) 8550–8553
Oxidative fragmentation of bicyclic hydroxy silanes and stannanes:
a strategy for the stereoselective synthesis of kainoids
Jonathan Clayden,* Katherine R. Hebditch, Benjamin Read and Madeleine Helliwell
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 6 September 2007; accepted 18 September 2007
Available online 29 September 2007
Dedicated to Professor Miguel Yus, University of Alicante, on the occasion of his 60th birthday
Abstract—The addition of tin or silicon nucleophiles to bicyclic enones generated by dearomatising cyclisation gives stannanes and
silanes stereoselectively. These compounds may be fragmented under oxidative conditions to generate substituted pyrrolidines bear-
ing C2 and C3 substituents closely related to those found in the kainoid series of cyclic amino acids.
Ó 2007 Elsevier Ltd. All rights reserved.
Bicyclic enones generated by dearomatising cyclisation
of aromatic amides have proved to be useful starting
materials for the synthesis of kainoids.1,2 For example,
asymmetric dearomatising cyclisation of 1 to yield 2
was the key step in the first total synthesis of (À)-isodo-
moic acid C (Scheme 1).3 Similar reactions have been
used to make (À)-kainic acid,4,5 its a-methyl derivative,6
and an important hydroxyphenyl analogue of acromelic
acid.7 The kainoids, which can be viewed as conforma-
tionally constrained glutamate analogues, have impor-
tant biological activity at neurotransmitter receptors.8
However some, especially the 10 or so members of the
(iso)domoic acid family, are obtained only scarcely from
their natural source (in the case of the isodomoic acids,
the dinoflagellate alga Pseudonitzschia), increasing the
value of synthetic routes to them.2,8
Kainoids are characterised by the substitution pattern
around a pyrrolidine ring shown in 3, with a cis relation-
ship between the C2 and C3 substituents being essential
for biological activity. This relative stereochemistry can
be assured by generating C2 and C3 substituents by
cleavage of a ring, and in this letter we report our inves-
tigation of the use of oxidative fragmentations of stann-
anes9–12 and silanes13,14 for this purpose. Unlike our
previous methods, which used a Baeyer–Villiger reac-
tion,4,3,7 fragmentation offers scope for the control of
the trisubstituted double bond found in many of the
domoic acid family.
Initial studies were carried out using racemic bicyclic
enone 5, generated by treating 4 with LDA.15 Tin
(Bu3SnLi)16 and silicon (PhMe2SiLi/Et2Zn)17 nucleo-
philes underwent conjugate addition to 5 to yield the
ketones 6 and 8 as single diastereoisomers in 60% and
90% yield, respectively, with the nucleophiles attacking
the exo face of the bicyclic system.18 In order to provide
starting materials for a study described below, the addi-
tion of the silyl zinc reagent was also quenched with
O-deuterio-2,4,6-tri-tert-butylphenol19 to provide d-8.
The ketones were reduced with L-SelectrideÒ or sodium
borohydride to mixtures of alcohols 7a and b and 9a and
b (Scheme 2). Stereochemistry was assigned to these
alcohols by the analysis of the coupling constants
around the six-membered ring, along with the X-ray
crystal structure of 9a (Fig. 1).20 This structure also
ring cleavage
1.
required
O
O
H
H
N
Li
Ph
N
Ph
N
Ph
MeO
Ph 2. H3O+
O
1
2
Ph
kainic acid: R = Me
H
steps
[refs 3-5]
R
isodomoic acid C:
R = HO2C
NH
HO2C
H
CO2H
3
Scheme 1. Bicyclic enones in the synthesis of kainoids.
*
Corresponding author. Fax: +44 161 275 4939; e-mail: clayden@
man.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.150

J. Clayden et al. / Tetrahedron Letters 48 (2007) 8550–8553
8551
X
O
4
O
O
O
O
H
H
H
H
H
H
H
t
-Bu
a or b
c
a
N
N
t-Bu
N
t-Bu
N
t
-Bu
Nt-Bu
OHC
HO
HO
MeO
Ph
O
H
Ph
Ph
Ph
5
Ph
b
c, e
c, d
O
10 (31%)
7a
9a
11(51%)
Bu3Sn
PhMe2Si
PhMe2Si
D
-Bu
O
O
H
H
H
Scheme 3. Fragmentation to a vinyl kainoid analogue. Reagents and
conditions: (a) (for 7a) Pb(OAc)4, PhH, D, 1 h; (b) (for 9a) 1.
PhI(OAc)2, I2, CH2Cl2, 0 °C to D, 2 h, 2. Na2S2O3 (satd aq.); (c)
NaBH4, MeOH, 21.5 h.
N
t-Bu
N
t
N
t-Bu
O
O
O
H
H
H
H
H
H
Ph
O
Ph
O
Ph
O
6
8
d-8
f
g
g
Bu3Sn
PhMe2Si
PhMe2Si
D
N
t
-Bu
HO
9a
PhMe2Si
N
t
-Bu
HO
N
t-Bu
method for the formation of compounds bearing the rel-
ative stereochemistry and alkenyl substitution pattern
displayed by the domoic/isodomoic acid family of kai-
noid amino acids, along with kainic acid itself.8
HO
H
+
H
H
+
H
H
+
H
Ph
O
Ph
O
Ph
O
7a
d-9a
Bu3Sn
PhMe2Si
D
Nt-Bu
Nt-Bu
Nt-Bu
HO
HO
HO
Kainic acid bears an isopropenyl group at the C3
carbon, and we were able to introduce this group by
starting with the b-methyl enone 13, available by dearo-
matising cyclisation15 with acid work-up of o-toluamide
12 (which interestingly yielded also the product 14 from
cyclisation onto the substituted ortho position). The
addition of Bu3SnLi gave ketone 15 in 51% yield and
hence alcohols 16a and b. The comparable additions
of silyl nucleophiles gave yields of <20%. Furthermore,
while fragmentation of 16b gave some of the kainic
acid-like 17, the yield was low, with destannylation as
a major side reaction (Scheme 4).
H
H
H
Ph
Ph
Ph
7b
9b
d-9b
Scheme 2. Synthesis of fragmentation precursors. Reagents and
conditions: (a) 1. LDA, THF, 0–20 °C, 1.5 h; 2. 2 M HCl (63%)
(Ref. 15); (b) Bu3SnLi, THF, 0 –20 °C (60%); (c) premix Et2Zn,
PhMe2SiLi, THF, 0 °C, 5 min; add 5, THF, À78 °C, 40 min; Me3SiCl,
À78 °C, 30 min and +20 °C, 1.5 h; (d) NH4Cl (aq.); 80% AcOH/H2O,
1 h (90% from 5); (e) 2,4,6-tri-t-BuC6H3OD (86% from 5, 17% d); (f) L-
SelectrideÒ, THF (65%; 1:1 dias); (g) NaBH4, MeOH, 20 °C (100%, 2:1
dias).
A synthetic challenge in the domoic/isodomoic acid
series is the control of double bond stereochemistry in
the diene sidechain at C3. Isoe11 has shown that the
stereospecificity of the fragmentation can transform
relative stereochemistry in a fragmentation precursor
into alkene geometry in the fragmentation product. We
Bu3Sn
O
O
H
H
+
H
H
H
c
N
t-Bu
Nt-Bu
O
O
O
O
Ph
O
Ph
15
t
-Bu
a, b
13 47%
N
MeO
Ph
12
Figure 1. X-ray crystal structure of 9a.
Nt-Bu
Me
14 10%
Ph
indicated that, in the solid state at least, the six-mem-
bered ring adopts a chair conformation with axial silyl,
carbonyl and hydroxyl groups. Other X-ray crystal
structures reported below also display axial silyl groups.
Bu3Sn
HO
O
H
N
t
-Bu
H
+
Ph
O
16a
d
15
Following the procedures of Posner,10,13 alcohols 7a and
9a were treated with oxidants lead tetraacetate or diac-
etoxyiodosobenzene, respectively. Fragmentation pro-
ceeded somewhat slowly and messily, but gave the
vinyl substituted aldehyde 10 from 7a. The isolation of
10 from 9a proved problematic but its reduction product
11 was obtained in 51% yield (Scheme 3). The fragmen-
tation of the epimers 7b and 9b proceeded even more
slowly, and gave very poor yields of ring-opened prod-
ucts. Nonetheless, this strategy provides an efficient
Bu3Sn
O
H
H
H
e
N
t-Bu
Nt-Bu
OHC
17
HO
H
Ph
Ph
16b
Scheme 4. Synthesis and fragmentation to a pyrrolidinone bearing
kainic acid substitution. Reagents and conditions: (a) LDA, DMPU,
THF, 0–20 °C; (b) 3 M HCl (aq.) (47% 13, 10% 14); (c) Bu3SnLi, THF,
0–20 °C, 30 min (51%); (d) NaBH4, MeOH, 20 °C (83%) (2:1 dias); (e)
Pb(OAc)4, PhH, D, 30 min (13%).

8552
J. Clayden et al. / Tetrahedron Letters 48 (2007) 8550–8553
accordingly made the ketones 18a and 19a by methyl-
ating the enolate produced during the conjugate
addition of the silicon or tin nucleophile to enone 5.
Methylation occurred trans to the bulky and electron-
rich Si/Sn substituent, but epimerisation of 19a in a base
allowed a low yield of the syn methyl epimer 19b to be
isolated. The reduction of the ketones yielded alcohols
20a and b and 21a and c, with the stereochemistries of
21a and c being confirmed by X-ray crystallography
(Figs. 2 and 3).20 The six-membered ring of 21c adopts
a chair conformation, but that of 21a, which would
have four axial substituents, flips into a twist-boat
(Scheme 5).
X
O
H
H
Me
HO
Nt-Bu
X
O
Ph
H
H
Me
O
20a (X = SnBu3)
a, b
d
5
21a (X = SiPhMe2)
Nt-Bu
X
O
H
Me
Ph
18a (X = SnBu3)
19a (X = SiPhMe2)
Nt-Bu
HO
H
Ph
20b (X = SnBu3)
c
21b (X = SiPhMe2)
PhMe2Si
PhMe2Si
O
H
O
H
Me
Me
d
N
t-Bu
Nt-Bu
The alcohols 20 and 21 were subjected to the standard
fragmentation conditions and yielded alkenes 22 or 23,
whose geometry was identified by their 3JHH alkene cou-
pling constants. Both hydroxy epimers 20a and b of the
stannane yielded, as expected, the E isomer of the alde-
hyde 22, with 20b fragmenting more slowly and requir-
ing the addition of further Pb(OAc)4 during the
reaction. The silanes 21a and c did not fragment cleanly,
and alkene products could be isolated cleanly only after
the reduction of the reaction mixture. Interestingly, in
this case the sole isolated alkenic products were 23, con-
taining a Z double bond. Given the low yield of this
product, we are reluctant to draw conclusions about
the mechanism, but it appears that the silane fragmenta-
tion is not stereospecific (both methyl epimers give the
same product) and is instead stereoselective for the Z
double bond (Scheme 6).
O
HO
H
19b
H
Ph
Ph
21c
Scheme 5. Precursors to disubstituted alkenes. Reagents and condi-
tions: (a) 1. Bu3SnLi, THF, À78 °C, 5 h; 2. MeI, À78 to +20 °C, (46%);
(b) 1. premix Et2Zn, PhMe2SiLi, THF, 0 °C, 5 min; add 5, THF,
À78 °C, 40 min; MeI, 0–20 °C (61%); (c) DBU, ClCH2CH2Cl, D,
22.5 h (68:32 19a:19b); (d) NaBH4, MeOH, 20 °C (20: 61%, 1:1 dias;
21: 90%; 2:1 dias).
O
H
a
b
N
t
-Bu
20a
21a
22
H
H
Ph
O
b
a
OHC
OHC
20b
21c
O
H
H
c
Nt
-Bu
Nt-Bu
H
Ph
Ph
HO
23
Scheme 6. Fragmentation to 1,2-disubstituted alkenes. Reagents and
conditions: (a) Pb(OAc)4, CaCO3, PhH, D, 90 min (41–47%); (b)
PhI(OAc)2, I2, CH2Cl2, 0–40 °C, 2–3.5 h; (c) NaBH4, MeOH, 20 °C,
18 h (5–10% from 21).
To gain further insight into the fragmentation, deuter-
ated alcohols d-9a and d-9b were similarly treated with
PhI(OAc)2. Both yielded the Z-deuterated alcohol
(Scheme 7).
Figure 2. X-ray crystal structure of 21a.
The unexpected formation of Z alkenes from the silanes
is, we propose, possibly due to fragmentation via a tri-
cyclic transition state, in which the proposed hypoiodite
(ROI) intermediate sustains a Si–I interaction as the
C–C bond breaks.
D
H
D
H
PhMe2Si
D
O
O
O
H
H
a
b
Nt-Bu
Ph
Nt-Bu
Nt-Bu
Ph
OHC
HO
HO
H
H
Ph
d
d
-9a
-9b
Z-d-11
Scheme 7. Fragmentation of deuterated silanes. Reagents and condi-
tions: (a) 1. PhI(OAc)2, I2, CH2Cl2, 0 °C to D, 2 h, 2. Na2S2O3 (satd
aq.); (b) NaBH4, MeOH, 2 h (21% from d-9).
Figure 3. X-ray crystal structure of 21c.

J. Clayden et al. / Tetrahedron Letters 48 (2007) 8550–8553
8553
5. Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron
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In summary, silicon and tin-directed fragmentations
have potential value for the synthesis of pyrrolidine-
based structures containing kainoid-like alkene substitu-
tion patterns. Tin-directed substitutions proceed in higher
yield than the silicon equivalents, and have the potential
to be stereospecific.
Acknowledgements
We are grateful to Eli Lilly and Co., Merck Sharp and
Dohme and the EPSRC for support of this work.
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Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.09.150.
17. Crump, R. A. N. C.; Fleming, I.; Urch, C. J. J. Chem.
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References and notes
18. The stereoselectivity (exo face attack) of this addition was
deduced from the X-ray crystal structures of later
derivatives.
19. Goldsmith, C. R.; Jonas, R. T.; Stack, T. D. P. J. Am.
Chem. Soc. 2002, 124, 83.
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20. X-ray crystallographic data has been deposited with the
Cambridge Crystallographic Data Centre: Deposition
numbers: 9a 658992; 21a 658993; 21c 658994.
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