Stereocontrol of palladium(ii)-catalysed aza-Claisen rearrangements using a combination of 1,3-allylic strain and a solvent mediated directing effect

Article abstract of DOI:10.1039/b613271e

A non-coordination solvent was used for the aza-Claisen rearrangement of δ,ε-disubstituted acetimidates that generates a substrate directing effect, providing excellent stereoselectivity. The aza-Claisen rearrangement of allylic trichloroacetimidates was

Full text of DOI:10.1039/b613271e

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Stereocontrol of palladium(II)-catalysed aza-Claisen rearrangements using a
combination of 1,3-allylic strain and a solvent mediated directing effect†
Michael D. Swift and Andrew Sutherland*
Received 13th September 2006, Accepted 14th September 2006
First published as an Advance Article on the web 28th September 2006
DOI: 10.1039/b613271e
The use of a non-coordinating solvent for the aza-Claisen
rearrangement of d,e-disubstituted acetimidates switches on a
substrate directing effect that gives excellent stereoselectivity.
synthesis of b-hydroxy-a-amino acids.6g,8 Our current studies
have focused on the rearrangement of allylic trichloroacetim-
idates derived from d,e-disubstituted allylic alcohols. In this
communication we demonstrate that, while the stereoselective
rearrangement of these compounds in THF is controlled solely
by 1,3-allylic strain, the use of a non-coordinating solvent (such as
toluene) results in the switching on of a substrate directing effect
which significantly enhances the diastereoselective outcome of the
reaction allowing the efficient synthesis of the natural products,
(2S,4R)-c-hydroxynorvaline and (2S,3S,4R)-c-hydroxyisoleucine.
For investigating the effects of 1,3-allylic strain on the stereo-
chemical outcome of this rearrangement, allylic trichloroacetimi-
dates 16–18 were prepared as outlined in Scheme 2.
[3,3]-Sigmatropic rearrangements have found widespread applica-
tion in synthesis for the preparation of organic molecules.1 An
important reaction from this class is the aza-Claisen rearrange-
ment of allylic trichloroacetimidates (commonly known as the
Overman rearrangement), which allows the allylic interchange
of alcohol and amine functional groups.2 Traditionally, these
transformations have been carried out thermally3 taking place
via a concerted, suprafacial reaction pathway according to the
Woodward–Hoffmann rules.4 The discovery of the metal-catalysed
reaction, which proceeds via a cyclisation-induced mechanism
(Scheme 1) under mild conditions,5 has led to its widespread
use in the synthesis of biologically active compounds and natural
products.6 Lately, efforts have focused on developing an asym-
metric version of the Pd(II)-catalysed process using either chiral
substrates or chiral palladium catalysts.2,6,7 For example, Overman
and others have reported a number of chiral Pd(II) complexes
which catalyse the rearrangement giving allylic amides in high
yields and excellent enantioselectivities.7
Scheme 1 Palladium(II) catalysed aza-Claisen rearrangement.
With the goal of utilizing this reaction for the asymmetric
synthesis of complex amino acids, we became interested in
developing an understanding of how the rearrangement of chiral
substrates is influenced intramolecularly by stereogenic centres
and functional groups. This led to the development of an ether
directed, Pd(II)-catalysed process which has been used for the
Scheme 2 Reagents and conditions: (i) LDA (2.0 eq), THF, −78 ◦C,
MeI or BnBr; (ii) MOMCl, NEt(iPr)2, CH2Cl2; (iii) DIBAL-H (2.2 eq.),
Et2O, −78 ◦C; (iv) DMSO, (COCl)2, NEt3, CH2Cl2, −78 ◦C to RT, then
LiCl, DBU, triethyl phosphonoacetate, MeCN; (v) DBU, Cl3CCN, 0 ◦C,
CH2Cl2.
WestCHEM, Department of Chemistry, The Joseph Black Building, Univer-
sity of Glasgow, Glasgow, UK G12 8QQ. E-mail: andrews@chem.gla.ac.uk;
Fax: +44 (0)141 330 4888; Tel: +44 (0)141 330 5936
† Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for the rearrangement reactions and
formation of the a-amino acids. See DOI: 10.1039/b613271e
The methyl and benzyl derivatives 2 and 3 were synthesised
from ethyl (R)-3-hydroxybutanoate 1 using a LDA mediated
stereoselective alkylation which gives excellent levels of the
desired erthyro product.9 The MOM-ethers were formed under
standard conditions6g and this was followed by reduction of
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1,3-allylic strain between the 2-H and the R-group.11 This leads to
the preferred formation of diastereomer a in increasing amounts
as the steric bulk of the R-group increases, thereby effectively
demonstrating stereocontrol of the rearrangement by 1,3-allylic
strain.
Table 1 Palladium(II) catalysed rearrangement of acetimidates 16, 17 and
18 in THF and toluene
We have previously reported a highly diastereoselective, sub-
strate directed aza-Claisen rearrangement in a non-coordinating
solvent where the facial coordination of the Pd(II)-catalyst is
controlled by an adjacent MOM-ether.8b Thus, in an effort to
improve the diastereoselectivity of the aza-Claisen rearrangement
of acetimidates, 16–18, the reactions were repeated using toluene
as a solvent. As can be seen from Table 1, the change in solvent
leads to cleaner reactions producing the allylic amides in higher
yields. More importantly, the diastereoselective outcome of each
rearrangement is greatly enhanced. Without the competition of
THF, the MOM-ether group can now coordinate to the catalyst
and direct the stereoselective outcome of the rearrangement. The
different ratios of diastereomers can again be rationalized by the
transition states (Scheme 4). For acetimidate 16, transition state
23b is destabilised due to the action of the directing effect, causing
the methyl group to adopt an axial position and leading to the
preferred formation of 20a in a 3 : 1 ratio of diastereomers. In the
case of acetimidates 17 and 18, where transition state 23b is already
destabilised by 1,3-allylic strain, the positioning of the axial methyl
group adds to this destabilization leading to an enhancement of
diastereoselectivity. Thus, the combination of both the 1,3-allylic
strain and the MOM-ether directing effect led to an excellent
13 : 1 and 11 : 1 ratio for diastereomers 21 and 22, respectively.
Entry
R
Solvent
Yielda (%)
Ratiob (a : b)
1
2
3
4
5
6
H (20)
THF
THF
THF
Toluene
Toluene
Toluene
50%
49%
72%
71%
66%
82%
1 : 1
3 : 1
6 : 1
3 : 1
13 : 1
11 : 1
Me (21)
Bn (22)
H (20)
Me (21)
Bn (22)
a Isolated combined yields of a and b from allylic alcohols 13–15. b Ratio
in crude reaction mixture.
the ester functional groups using DIBAL-H. A one-pot Swern
oxidation/Horner–Wadsworth–Emmons reaction10 then gave (E)-
a,b-unsaturated esters 10–12 in good yields and these were
converted to the corresponding allylic alcohols 13–15 again using
DIBAL-H. Finally, treatment of the allylic alcohols with DBU
and trichloroacetonitrile gave the desired substrates 16–18.
The aza-Claisen rearrangement of allylic trichloroacetimidates
16–18 was then carried out at room temperature in THF using
bis(acetonitrile)palladium(II) chloride as the catalyst (Table 1).
Unsurprisingly, rearrangement of the mono-substituted analogue,
16 gave only a 1 : 1 mixture of diastereomers in 50% yield.
Rearrangement of 17 and 18 which have increasing steric bulk
at the d-position gave the corresponding alyllic amides in ratios of
3 : 1 and 6 : 1, respectively.
Analysis of the transition states for acetimidate 16 show that
both reaction pathways are equally likely, leading to the observed
1 : 1 ratio of diastereomers 20a and 20b (Scheme 3). However,
introduction of substituents at the d-position as for acetimidates
17 and 18 results in the destabilisation of transition state 19b due to
Scheme 4
To confirm our stereochemical assignment of the products of
these aza-Claisen rearrangements, the major diasteromers 20a
and 21a were converted to the corresponding amino acid using
a ruthenium(III) trichloride catalysed oxidation12 followed by an
acid mediated deprotection step (Scheme 5). This gave the natural
products, (2S,4R)-c-hydroxynorvaline,13 24, and (2S,3S,4R)-c-
hydroxyisoleucine,14 25, which showed optical activity and NMR
spectra consistent with published values. In a similar fashion,
Scheme 3
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3 (a) L. E. Overman, J. Am. Chem. Soc., 1974, 96, 597; (b) L. E. Overman,
J. Am. Chem. Soc., 1976, 98, 2901.
4 R. B. Woodward and R. Hoffmann, J. Am. Chem. Soc., 1965, 87, 2511.
5 (a) T. Ikariya, Y. Ishikawa, K. Hirai and S. Yoshikawa, Chem. Lett.,
1982, 1815; (b) L. E. Overman, Angew. Chem., Int. Ed. Engl., 1984, 23,
579; (c) T. G. Schenck and B. Bosnich, J. Am. Chem. Soc., 1985, 107,
2058.
6 For recent examples see: (a) H. Ovaa, J. D. C. Code´e, B. Lastdrager,
H. S. Overkleeft, G. A. van der Marel and J. H. van Boom, Tetrahedron
Lett., 1999, 40, 5063; (b) G. Mehta, S. Lakshminath and P. Talukdar,
Tetrahedron Lett., 2002, 43, 335; (c) M. Reilly, D. R. Anthony and C.
Gallagher, Tetrahedron Lett., 2003, 44, 2927; (d) A. E. Lurain and P. J.
Walsh, J. Am. Chem. Soc., 2003, 125, 10677; (e) A. G. Jamieson, A.
Sutherland and C. L. Willis, Org. Biomol. Chem., 2004, 2, 808; (f) S.
Kim, T. Lee, E. Lee, J. Lee, G.-J. Fan, S. K. Lee and D. Kim, J. Org.
Chem., 2004, 69, 3144; (g) K. N. Fanning, A. G. Jamieson and A.
Sutherland, Org. Biomol. Chem., 2005, 3, 3749.
7 (a) M. Calter, T. K. Hollis, L. E. Overman, J. Ziller and G. G. Zipp,
J. Org. Chem., 1997, 62, 1449; (b) T. K. Hollis and L. E. Overman,
Tetrahedron Lett., 1997, 38, 8837; (c) Y. Uozumi, K. Kato and T.
Hayashi, Tetrahedron: Asymmetry, 1998, 9, 1065; (d) J. Kang, T. H.
Kim, K. H. Yew and W. K. Lee, Tetrahedron: Asymmetry, 2003, 14,
415; (e) L. E. Overman, C. E. Owen, M. M. Pavan and C. J. Richards,
Org. Lett., 2003, 5, 1809; (f) C. E. Anderson and L. E. Overman, J. Am.
Chem. Soc., 2003, 125, 12412; (g) S. F. Kirsch, L. E. Overman and
M. P. Watson, J. Org. Chem., 2004, 69, 8101; (h) C. E. Anderson, Y.
Donde, C. J. Douglas and L. E. Overman, J. Org. Chem., 2005, 70,
648.
Scheme 5 Reagents and conditions: (i) RuCl3·xH2O, NaIO4, H2O, CCl4,
MeCN, R = H (65%), Me (62%), Bn (82%); (ii) 6 M HCl, D, R = H (74%),
Me (55%), Bn (55%).
allylic amide 22a was converted to the novel benzyl derived c-
hydroxy-a-amino acid 26 (Scheme 5).
In conclusion, we have demonstrated that while the aza-
Claisen rearrangement of allylic acetimidates derived from d,e-
disubstituted allylic alcohols in THF is controlled solely using
1,3-allylic strain the use of a non-coordinating solvent results in
the switching on of a substrate directing effect which substantially
enhances the stereochemical outcome. Studies are currently un-
derway on the modelling of these reaction pathways and further
applications of the allylic amides.
8 (a) A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2005, 3,
735; (b) A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2006,
4, 2932.
The authors wish to thank EPSRC (studentship to MDS) and
the University of Glasgow for funding.
9 (a) G. Frater, Helv. Chim. Acta, 1979, 62, 2825; (b) D. Seebach and D.
Wasmuth, Helv. Chim. Acta, 1980, 63, 197.
References
10 R. E. Ireland and D. W. Norbeck, J. Org. Chem., 1985, 50, 2198.
11 The general effects of the 1,3-allylic strain in controlling stereochem-
istry have been reviewed: R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.
12 P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org.
Chem., 1981, 46, 3936.
1 (a) F. E. Ziegler, Acc. Chem. Res., 1977, 10, 227; (b) R. P. Lutz,
Chem. Rev., 1984, 84, 205; (c) D. Enders, M. Knopp and R. Schiffers,
Tetrahedron: Asymmetry, 1996, 7, 1847; (d) H. Ito and T. Taguchi,
Chem. Soc. Rev., 1999, 28, 43; (e) A. M. Mart´ın Castro, Chem. Rev.,
2004, 104, 2939; (f) K. N. Fanning, A. G. Jamieson and A. Sutherland,
Curr. Org. Chem., 2006, 10, 1007.
13 J. Ariza, J. Font and R. M. Ortuno, Tetrahedron, 1990, 46, 1931 and
references therein.
14 R. F. Raffauf, T. M. Zennie, K. D. Onan and P. W. Le Quesne, J. Org.
Chem., 1984, 49, 2714.
2 L. E. Overman and N. E. Carpenter, Org. React., 2005, 66, 1 and
references therein.
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The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3889–3891 | 3891
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