The first enantioselective synthesis of the amino acid, (2S,3S,4R)-γ-hydroxyisoleucine using a palladium(ii) catalysed 3,3-sigmatropic rearrangement

Article abstract of DOI:10.1039/b401076k

A synthetic route towards the synthesis of (2S,3S,4R)-γ- hydroxyisoleucine, the amino acid component of the natural product, funebrine has been developed using as the key step, a palladium(II) catalysed 3,3-sigmatropic rearrangement to create the (2S)-stereogenic centre.

Full text of DOI:10.1039/b401076k

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The first enantioselective synthesis of the amino acid,
(2S,3S,4R)-ꢀ-hydroxyisoleucine using a palladium(II) catalysed
3,3-sigmatropic rearrangement
Andrew G. Jamieson,a Andrew Sutherland*a and Christine L. Willisb
a Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow,
UK G12 8QQ. E-mail: andrews@chem.gla.ac.uk; Fax: 0141 330 4888; Tel: 0141 330 5936
b School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK BS8 1TS
Received 22nd January 2004, Accepted 13th February 2004
First published as an Advance Article on the web 19th February 2004
A synthetic route towards the synthesis of (2S,3S,4R)-
ꢀ-hydroxyisoleucine, the amino acid component of the
natural product, funebrine has been developed using
as the key step, a palladium(II) catalysed 3,3-sigmatropic
rearrangement to create the (2S)-stereogenic centre.
The Zapotec tribes of southeastern Mexico accorded particular
cultural significance to the tree, Quararibea funebris (Llave)
Vischer (Bombacaceae). As well as conducting funeral rites
beneath its branches, the plant was used as a cough remedy, an
antipyretic, and to control menstrual disorders and psycho-
pathic fears.1 Investigation of the natural products contained
within the flowers identified a series of compounds, including
the novel pyrrole alkaloid, funebrine 1.2 Also isolated was the
amino acid component of 1, (2S,3S,4R)-γ-hydroxyisoleucine 2.
Scheme 1
Other stereoisomers of γ-hydroxyisoleucine have been iso-
lated from organisms such as Trigonella foenum-graecum
(Leguminosae)3 and Amanita phalloides,4 and this has led to the
development of methodology towards the synthesis of these
isomers of the amino acid.5 Le Quesne and co-workers com-
pleted the first total synthesis and conformational studies of
( )-funebrine.6 However, as yet, there is no reported synthesis
of (2S,3S,4R)-γ-hydroxyisoleucine 2. Recently we initiated a
research programme to investigate 3,3-sigmatropic rearrange-
ments of chiral molecules. We now report the first enantio-
selective synthesis of (2S,3S,4R)-γ-hydroxyisoleucine 2 using
allylic 1,3-strain to control the stereoselectivity in the key
step, which involves a palladium() catalysed 3,3-sigmatropic
rearrangement.
Scheme 2 Reagents and conditions: i. H2SO4, ClCH2CH2Cl, EtOH,
∆, 82%; ii. LDA (2 equiv.), MeI, THF, Ϫ78 ЊC, 84%; iii. TBDPSCl,
imidazole, THF, 96%; iv. DIBAL-H, Et2O, Ϫ78 ЊC, 94%; v.
Our retrosynthesis of (2S,3S,4R)-γ-hydroxyisoleucine 2 is
shown in Scheme 1. The key intermediate, trichloroacetimidate
4 was to be prepared from readily available ethyl (R)-hydroxy-
butanoate 5. Stereoselective rearrangement of 4 would then
allow the formation of the allylic trichloroamide 3 introducing
the (2S)-stereogenic centre. Finally, oxidative cleavage of the
alkene and deprotection would give the target amino acid.
The first stage of the synthesis involved the preparation of
the trichloroacetimidate 9 (Scheme 2). Acid hydrolysis of poly
(R)-hydroxybutanoate gave ethyl (R)-hydroxybutanoate 57 and
this was used to install the (3S)-stereogenic centre of the target
amino acid using a stereoselective alkylation. Treatment of 5
with two equivalents of LDA forms a di-lithiated chair-like
enolate which undergoes alkylation from the least hindered face
Ph3P᎐CHCO2Me, THF, 90%; vi. DIBAL-H (2.2 equiv.), Et2O, Ϫ78 ЊC,
89%; vii. NaH, Cl3CCN, 0 ЊC, 83%.
᎐
to give the erythro product 6.8 Protection of the hydroxyl group
as the TBDPS silyl ether followed by reduction of the ester to
the aldehyde and subsequent coupling with the stabilized ylide,
methyl (triphenylphosphoranylidene)acetate gave solely the
trans-alkene 7 in excellent yield. Reduction of 7 with DIBAL-H
afforded (2E,4S,5R)-allylic alcohol 8 in 5 steps and 61% overall
yield from ethyl (R)-3-hydroxybutanoate 5. Alcohol 8 was con-
verted to the trichloroacetimidate 9 using sodium hydride and
trichloroacetonitrile.9
The next stage was to investigate the proposed 3,3-sigma-
tropic rearrangement to introduce the (2S)-stereogenic centre
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 0 8 – 8 0 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
808

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Table 1 Rearrangement of trichloroacetimidate 9
Entry
Conditions
Ratio (10a : 10b)
Yield (%)
1
2
3
p-xylene, ∆, 24 h
PdCl2[MeCN]2, r.t., 3 h
PdCl2[PhCN]2, r.t., 3 h
3 : 2
1 : 6
1 : 7
54
65
71
Scheme 3 Reagents and conditions: i. O3, NaOH, MeOH, Ϫ78 ЊC,
74%; ii. 6 M HCl, ∆, 24 h, 88%.
of the amino acid. We initially carried out a thermal
rearrangement using Overman conditions in refluxing p-xylene
(Table 1).10a This gave the two diastereomeric rearranged prod-
ucts 10a and 10b in a very modest 3 : 2 ratio (entry 1). More
importantly the major product was the unwanted (3R)-isomer.
However, treatment of trichloroacetimidate 9 with either
bis(acetonitrile)- or bis(benzonitrile)palladium() catalysts10b at
room temperature (entries 2 and 3) led to a complete reversal in
the stereochemical outcome of the reaction to give the desired
(3S)-isomer as the major product.11
The stereoselectivity of both the thermal and the palladium
catalysed rearrangement can be explained by considering the
transition states (Fig. 1). In both cases a chair-like transition
state is formed in which allylic 1,3-strain is minimised.12 This
causes the bulky TBDPS containing side chain to block the
back face of the alkene and thus, during the thermal
rearrangement, intramolecular attack by the trichloro-
acetimidate nitrogen occurs at the least hindered face of the
alkene to give predominantly the (3R)-isomer. Alternatively,
during the palladium catalysed reaction, initial coordination of
the catalyst to the least hindered face of the alkene effectively
blocks this side. Hence, intramolecular attack of the trichloro-
acetimidate nitrogen has to now take place from the back face
of the alkene giving rise to the desired (3S)-isomer as the major
product.
chemical assignment of the rearrangement products 10a and
10b.
In conclusion, the first enantioselective synthesis of
(2S,3S,4R)-γ-hydroxyisoleucine 2 by consecutive introduction
of the (3S)- and (2S)-stereogenic centres respectively has been
accomplished in 10 steps and in 19.3% overall yield from poly
(R)-hydroxybutanoate. We have previously reported an efficient
synthesis of the enantiomer of allylic alcohol 8 in which a
stereocontrolled aldol reaction of propionyl camphorsultam
with acetaldehyde was used to create the stereogenic centres.14
Hence the approach described herein may be readily adapted
for the synthesis of (2R,3R,4S)-γ-hydroxyisoleucine. Further
studies on the 3,3-sigmatropic rearrangement of chiral mole-
cules for natural product synthesis are currently in progress.
Acknowledgements
The authors would like to thank Dr Richard C. Hartley for
helpful and insightful discussions. Financial support from
EPSRC (studentship to AGJ) and the University of Glasgow is
gratefully acknowledged.
Notes and references
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2 R. F. Raffauf, T. M. Zennie, K. D. Onan and P. W. Le Quesne, J. Org.
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3 L. Fowden, H. M. Pratt and A. Smith, Phytochemistry, 1973, 12,
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4 A. Gieren, P. Narayanan, W. Hoppe, M. Hasan, K. Michl,
T. Wieland, H. O. Smith, G. Jung and E. Breitmaier, Justus Liebigs
Ann. Chem., 1974, 1561.
5 For example see: Q. Wang, J. Ouazzani, N. A. Sasaki and P. Potier,
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Fulcrand, M. Roland, M.-L. Roumestant and J. Martinez,
Tetrahedron: Asymmetry, 2001, 12, 2657; T. Inghardt, T. Frejd and
G. Svensson, Tetrahedron, 1991, 47, 6469.
6 Y. Dong, N. N. Pai, S. L. Ablaza, S.-X. Yu, S. Bolvig, D. A. Forsyth
and P. W. Le Quesne, J. Org. Chem., 1999, 64, 2657.
7 D. Seebach and M. F. Züger, Tetrahedron Lett., 1985, 25, 2747.
8 G. Frater, Helv. Chim. Acta, 1979, 62, 2825; D. Seebach and
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9 L. E. Overman, J. Am. Chem. Soc., 1974, 96, 597; L. A. Clizbe and
L. E. Overman, Org. Synth., 1978, 58, 4.
Fig. 1 Transition states for the thermal and palladium catalysed
rearrangement of 9.
10 (a) L. E. Overman, J. Am. Chem. Soc., 1976, 98, 2901; (b) L. E.
Overman, Angew. Chem., Int. Ed. Engl., 1984, 23, 579.
11 Representative procedure for the palladium catalysed rearrange-
ments: The trichloroacetimidate 9 (1 mmol) was dissolved in THF
The 7 : 1 mixture of diastereomers obtained from the bis-
(benzonitrile)palladium() catalysed reaction was elaborated to
(2S,3S,4R)-γ-hydroxyisoleucine 2 (Scheme 3). Oxidative cleav-
age of 10a and 10b in the presence of methanolic NaOH gave
the corresponding methyl esters 11a and 11b in 74% yield.13 At
this stage the two diastereomers were separated using column
chromatography. Deprotection of the major (2S)-isomer under
acidic conditions followed by purification with ion exchange
chromatography gave (2S,3S,4R)-γ-hydroxyisoleucine 2 in 88%
yield. Spectroscopic data was entirely consistent with that pub-
lished for the natural product2 thereby confirming our stereo-
(10 ml) under
a nitrogen atmosphere and bis(benzonitrile)-
palladium() chloride (10 mol%) was added. After 3 h, the solvent
was evaporated under reduced pressure. The resulting residue was
purified by column chromatography, eluting with 20% diethyl ether
in petroleum ether to give the rearranged products as a colourless
oil.
12 U. Nubbemeyer, Synthesis, 2003, 961; R. W. Hoffmann, Chem. Rev.,
1989, 89, 1841.
13 J. A. Marshall and A. W. Garofalo, J. Org. Chem., 1993, 58, 3675.
14 C. McKay, T. J. Simpson, C. L. Willis, A. K. Forrest and P. J. O’Han-
lon, Chem. Commun., 2000, 1109.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 0 8 – 8 0 9
809