Asymmetric formation of allylic amines with N-substituted quaternary stereocenters by PdII-catalyzed aza-Claisen rearrangements

Article abstract of DOI:10.1002/anie.200702086

(Chemical Equation Presented) With the ferrocene imidazoline palladacycle FIP-Cl as precatalyst, quaternary N-substituted stereocenters can be generated in an asymmetric aza-Claisen rearrangement. Excellent enantioselectivities are obtained even if R and R′ have a similar or identical size (see scheme: e.g. 96% ee for CH₃/CD₃).

Full text of DOI:10.1002/anie.200702086

Communications
DOI: 10.1002/anie.200702086
Asymmetric Rearrangements
Asymmetric Formation of Allylic Amines with N-Substituted
Quaternary Stereocenters by PdII-Catalyzed Aza-Claisen
Rearrangements**
Daniel F. Fischer, Zhuo-qun Xin, and RenØ Peters*
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
Enantiomerically pure allylic amines are valuable building
blocks, as they possess two highly versatile functional groups.
Two widely used methods for their preparation are the
transition-metal-catalyzed allylic substitution[1] and the aza-
Claisen rearrangement of trihaloacetimidates (Overman
rearrangement).[2] A longstanding problem is the catalytic
enantioselective formation of quaternary stereocenters by
either of these methodologies. Since quaternary carbon atoms
bearing a nitrogen substituent are a widespread structural
motif for bioactive natural and non-natural compounds,[3] the
asymmetric construction of those stereocenters by means of
asymmetric catalysis is an important challenge. Enantiopure
allylic amines possessing a quaternary N-substituted stereo-
center are particularly attractive for the synthesis of quater-
nary amino acids,[4] which are important targets owing to their
ability to induce helical peptide structures[5] and owing to the
fact that peptides incorporating quaternary amino acid
residues possess enhanced stability toward proteases.[6]
Recently, we have developed a
nature of the five phenyl substituents, which enhance the
Lewis acidity of the Pd center in 1-X.
This excellent catalytic activity has prompted us to
investigate the formation of quaternary stereocenters by the
rearrangement of 3,3-disubstituted allylic trifluoroacetimi-
dates 4, which were prepared from the corresponding allylic
alcohols 2 [Eq. (1)].[7]
The isomerically almost pure 3,3-disubstituted allylic
alcohols 2 were formed by CuI-mediated 1,4-additions to
methyl- or ethyl-2-ynoates 6 and subsequent reduction with
DIBAL [Eq. (2)].
planar-chiral ferrocenyl imidazoline
palladacycle catalyst 1-X (FIP-X),
which displays unprecedented levels
of activity for the highly enantioselec-
tive aza-Claisen rearrangement of E-
configured allylic PMP-trifluoroaceti-
midates (PMP = p-methoxyphenyl).[2h]
Compound 1-X is in fact about 50–100
times more active for the rearrange-
ment of this class of substrates than
the best previously reported catalysts.
The exceptionally high catalytic activity is attributed to the
pentaphenylcyclopentadienyl (CpF) ligand and can be
explained at least in part by the electron-withdrawing
Functionalized derivatives were prepared starting from
geranyl acetate (7) by regioselective epoxidation and subse-
quent treatment with periodic acid, leading to the corre-
sponding aldehyde, which was reduced to alcohol
8
(Scheme 1).[8] The alcohol was then used to synthesize a
silylether, carbonate, and BOC-protected amine derivative
(2d–f). Alternatively, ester 2g (R = Me, R’ = (CH2)2CO2Et)
was prepared by Johnson–Claisen rearrangement (see the
Supporting Information). The allylic alcohols were then
condensed with iminochloride 3 [Eq. (1)].
[*] D. F. Fischer, Z.-q. Xin, Prof. Dr. R. Peters
Laboratory ofOrganic Chemistry
ETH Zürich
Wolfgang-Pauli-Strasse 10, Hönggerberg HCI E 111
8093 Zürich (Switzerland)
Fax: (+41)44-633-1226
E-mail: peters@org.chem.ethz.ch
Homepage: http://www.peters.ethz.ch
2.0 mol% of the catalyst precursor FIP-Cl (1-Cl, X = Cl),
activated in situ with 3.75 equivalents AgTFA (relative to 1-
Cl, TFA = trifluoroacetate),[2h] was generally sufficient to give
high conversion after 2.5 days at 508Cusing substrates in
which one of the substituents R or R’ is a methyl group. The
allylic trifluoroacetamides were formed with high to excellent
ee values and in good yield (Table 1, entries 1–10). As
expected, the rearrangement of 3,3-disubstituted substrates
[**] This work was financially supported by ETH Research Grant TH-30/
04-2, Novartis (Ph.D. fellowship to Z.-q.X.) and F. Hoffmann-La
Roche.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
7704
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Chemie
formed under identical conditions with very high ee values (96
and 98%, respectively; Table 1, entries 5 and 9), but with the
opposite configuration.[9] Whenever the smaller of the two
substituents R and R’ was larger than a methyl group,
4.0 mol% of 1-Cl was employed to obtain synthetically useful
yields. Excellent enantioselectivities were even obtained in
those cases in which R and R’ have a similar size (Table 1,
entries 12–14, for example). Gratifyingly, the rearrangement
is compatible with important functional groups such as olefin,
ester, carbonate, silylether, benzylether, or Boc-protected
amino moieties.
Acid-catalyzed elimination of PMP trifluoroacetamide 10
is a significant side reaction for the 3,3-disubstituted sub-
strates 4, since the additional electron-donating substituent
(Me in Scheme 2) leads to an additional stabilization of the
Scheme 1. Synthesis ofthe isomerically pure 3,3-disubstituted allylic
alcohols.
Table 1: Highly enantioselective rearrangement of3,3-disubstituted allylic
imidates 4.[a]
Entry
4
R’
R
Cat.
Yield
ee [%][c]
[mol%] [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
a
b
c
d
e
f
g
h
i
(CH2)2Ph
(CH2)2Ph
nBu
(CH2)2CH CMe2 Me
(CH2)3OSi(iPr)3 Me
(CH2)3O(CO)OBn Me
(CH2)3NBnBoc
(CH2)2CO2Et
Me
Me
Me
Me
Me
2
0.5
2
2
2
2
2
2
2
2
4
4
4
94[d]
79[e,f]
63
74
73
84
64
50
74
99.6 (R)
97 (R)
93 (R)
98 (R)
96 (R)
98 (R)
93 (R)
96 (R)
98 (S)
99 (R)
91 (R)[g]
=
Scheme 2. Elimination as side reaction.
Me
Me
allylic cation 9.[10] However, by the use of proton sponge (PS,
1,8-bis(dimethylamino)naphthalene) as a Brønsted acid scav-
enger this competitive reaction pathway can be suppressed to
a large degree, thus allowing the preparation of allylic amides
5 in good yield.
(CH2)3OSi(iPr)3
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
84
68
j
k
l
Et
nPr
63[h] >99.5 (R)
nBu
(CH2)3OSi(iPr)3
61[h]
51[h]
98 (R)
97 (R)
Since the enantioselectivity of the rearrangement is
apparently largely independent of the steric differentiation
of the two residues R and R’ at the imidate 3-position, it
appeared that the enantioselectivity-determining step is the
enantioface-selective coordination of the olefin moiety to the
PdII center (Figure 1).[11] Assuming
m
4
[a] The reactions were performed on a 0.03–0.08-mmol scale (reaction time
2.5 days) unless otherwise noted. [b] Yield ofthe isolated product. [c] ee
value determined by chiral column HPLC (Daicel OD-H). [d] 0.3-mmol
scale. [e] Reaction time: 10 days. [f] 1.0-mmol scale. [g] E/Z ratio of 4j=
4:96. [h] Reaction time: 3.5 days.
that the olefin will coordinate (in
analogy to PPh3)[2h] trans to the imida-
4 is significantly slower than for substrates with R = H, for
zoline N atom owing to the trans
which only 0.05 mol% leads to full conversion after 1–3 days
effect,[12] the imidate N atom will
[2h]
at 408Cin most cases.
The lower turnover frequency is
attack the olefin at the face remote
À
attributed to the additional substituent at the C Cdouble
bond, which hampers the attack of the imidate nitrogen atom
on the olefin. Decreasing the precatalyst amount to 0.5 mol%
required a reaction time of 10 days, yet provided the
rearrangement product in good yield and with excellent
enantioselectivity (Table 1, entry 2).
to the Pd atom. In the preferential
orientation of the olefin part parallel
Figure 1. Explanation
ofthe enantioselectiv-
ity by enantioface-
selective olefin coordi-
nation.
to the ferrocene axis, the sterically
undemanding C1 methylene moiety
should point towards the bulky CpF
spectator ligand to minimize unfavor-
able steric interactions. Coordination
of the enantiotopic olefin face should
be less favorable, again owing to steric
crowding. Even substrates in which R and R’ have an identical
size should consequently provide high enantioselectivities.
To verify this hypothesis, the use of a geometrically pure
allylic imidate in which R and R’ have practically the same
Whereas Z-configured 3-monosubstituted imidates had
given significantly lower reaction rates than E-configured
substrates in previous experiments with 1-X, this difference
vanishes if both R and R’ are larger than H.[2h] For example,
both the E- and Z-configured substrates 4d and 4h bearing a
bulky (CH2)3OTIPS moiety as substituent gave practically the
same yield and conversion. In both cases the product was
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size, namely CH3 and CD3 (Scheme 3), was investigated. Also
Keywords: asymmetric synthesis · aza-Claisen rearrangement ·
imidates · imidazolines · palladacycles
.
in this case the product is formed with an ee value of 96%,
thus confirming the mechanistic hypothesis.[13]
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Scheme 3. Highly enantioselective formation of CH3/CD3-substitituted
allylic amide 5n.
[2] a) Review about enantioselective aza-Claisen rearrangements:
T. K. Hollis, L. E. Overman, J. Organomet. Chem. 1999, 576, 290;
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1260.
To showcase the utility of the rearrangement products,
allylic amide 5a was employed to synthesize Fmoc-protected
a,a-disubstituted a-amino acid 12 and b,b-disubstituted b-
amino acid 13 (Scheme 4) by oxidative cleavage of the vinyl
[3] Selected examples: a) B. J. Burreson, P. J. Scheuer, J. Chem. Soc.
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54, 557; d) J. Kobayashi, F. Kanda, M. Ishibashi, H. Shigemori, J.
Org. Chem. 1991, 56, 4574; selected books and reviews: e) S.
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Elsevier, Amsterdam, 2003; h) J. Kobayashi, H. Morita, Alka-
loids 2003, 60, 165; i) D. J. Ramon, M. Yus, Curr. Org. Chem.
2004, 8, 149; j) I. Moldvai, E. Temesvari-Major, M. Incze, G.
Doernyei, E. Szentirmay, C. Szantay, Helv. Chim. Acta 2005, 88,
1344; k) Y. Ohfune, T. Shinada, Eur. J. Org. Chem. 2005, 5127;
l) T. Reynolds, Phytochemistry 2005, 66, 1399.
[4] a) Recent reviews about the stereoselective formation of a,a-
disubstituted a-amino acids: H. Vogt, S. Brꢀse, Org. Biomol.
Chem. 2007, 5, 406; b) C. Cativiela, M. D. Dꢁaz-de-Villegas,
Tetrahedron: Asymmetry 2007, 18, 569; c) review about the
catalytic asymmetric synthesis of a-branched chiral amines: S.
Brꢀse, T. Baumann, S. Dahmen, H. Vogt, Chem. Commun. 2007,
1881; d) review about the catalytic asymmetric synthesis of
quaternary carbon centers by nucleophilic addition on ketones
and ketimines: O. Riant, J. Hannedouche, Org. Biomol. Chem.
2007, 5, 873; e) for the catalytic asymmetric formation of N-
substituted quaternary stereocenters, see, for example: X. Liu,
H. Li, L. Deng, Org. Lett. 2005, 7, 167, and references therein.
[5] a) A. Aubry, D. Bayeul, G. Precigoux, M. Pantano, F. Formaggio,
M. Crisma, C. Toniolo, W. H. J. Boesten, H. E. Schoemaker, J.
Kamphuis, J. Chem. Soc. Perkin Trans. 2 1994, 525; b) T. S.
Yokum, T. J. Gauthier, R. P. Hammer, M. L. McLaughlin, J. Am.
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F. N. M. Kuhnle, C. Braun, D. Seebach, Liebigs Ann./Recl. 1997,
1697.
Scheme 4. Use ofallylic amide 5a for the preparation of a,a-disubsti-
tuted a-amino acid 12 and b,b-disubstituted b-amino acid 13.
system and hydroboration, respectively. The absolute config-
uration of a-amino acid 12 was determined after removal of
the Fmoc protecting group by comparison of the specific
optical rotation with reported data[14] (see the Supporting
Information).[15]
In summary, we have developed a highly enantioselective
and functional-group-compatible catalytic method to form
allylic amines with quaternary N-substituted stereocenters.
We have shown that the enantioselectivity-determining step is
the enantioface-selective olefin coordination to the PdII
center, allowing high enantioselectivities also for 3,3-disub-
stituted substrates in which the two substituents at the 3-
position can even have an identical size.
Experimental Section
See the Supporting Information.
[6] M. C. Khosla, K. Stachowiak, R. R. Smeby, F. M. Bumpus, F.
Piriou, K. Lintner, S. Fermandjian, Proc. Natl. Acad. Sci. USA
1981, 78, 757.
Received: May 11, 2007
Published online: August 23, 2007
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[7] This type of rearrangement has previously been performed in
non-enantioselective manner utilizing [PdCl2(NCMe)2] as an
achiral catalyst: D. B. Berkowitz, B. Wu, H. Li, Org. Lett. 2006, 8,
971.
[8] K. Tago, M. Arai, H. Kogen, J. Chem. Soc. Perkin Trans. 1, 2000,
2073.
pletely to 4-methoxytrifluoroacetanilide and the corresponding
diene.
[11] For the kinetic and computational analysis of the asymmetric
rearrangement of related 3-monosubstituted allylic trichloro-
acetimidates, see: M. P. Watson, L. E. Overman, R. G. Bergman,
J. Am. Chem. Soc. 2007, 129, 5031.
[12] F. R. Hartley, Chem. Soc. Rev. 1973, 2, 163.
[9] Z-Configured substrate 4h was prepared in analogy to E-
configured 4d, but starting from neryl acetate.
[13] The ee value of 5n was determined by 1H NMR after removal of
the trifluoroacetamide and PMP protecting groups and con-
densation of the free amine with Mosherꢂs acid chloride (see the
Supporting Information).
[10] We assume that traces of acid may be formed in the reaction
mixture by partial hydrolysis of AgTFA in the presence of traces
of moisture. Whereas 3-monosubstituted imidates decompose
only slowly on a slightly acidic HPLCcolumn (less than 0.1%
(Bu4N)HSO4), 3,3-disubstituted imidates 4 decompose com-
[14] L. M. Harwood, K. J. Vines, M. G. B. Drew, Synlett 1996, 1051.
[15] Since a uniform reaction pathway can be assumed, the absolute
configuration can be assigned to all rearrangement products 5.
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