Highly enantioselective catalytic asymmetric Claisen rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers

Article abstract of DOI:10.1016/j.tetlet.2004.03.047

Progress in the catalytic asymmetric Claisen rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ether is reported. Application of a more Lewis acidic catalyst, [Cu{(S,S)-t-Bu-box}](H₂O) ₂(SbF₆)₂, afforded

Full text of DOI:10.1016/j.tetlet.2004.03.047

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3647–3650
Highly enantioselective catalytic asymmetric Claisen
rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers
z
*
€
Lars Abraham, Marleen Korner and Martin Hiersemann
Technische Universit€at Dresden, Institut f€ur Organische Chemie, D-01062 Dresden, Germany
Received 9 January 2004; revised 18 February 2004; accepted 8 March 2004
Abstract—Progress in the catalytic asymmetric Claisen rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ether is reported.
Application of a more Lewis acidic catalyst, [Cu{(S,S)-t-Bu-box}](H2O)2(SbF6)2, afforded b-chiral a-keto ester with an enantiomeric
excess up to 99%. We suggest a highly polarized transition state for the Lewis acid-catalyzed Claisen rearrangement in order to
explain the experimental results.
ꢀ 2004 Elsevier Ltd. All rights reserved.
We have recently communicated the first catalytic
O
asymmetric Claisen rearrangement of acyclic 2-alkoxy-
carbonyl-substituted allyl vinyl ether 1.1;2 The catalyzed
rearrangement proceeded at room temperature yielding
highly substituted a-keto ester 2 in a remarkable chemo-
and an acceptable enantioselectivity (Fig. 1). The tert-
butyl- and phenyl-substituted copper(II) bis(oxazolines)
3a,b containing triflate counterions were employed as
Lewis acid catalysts for the rearrangement (Fig. 2).3;4 In
this letter, we present the results of further work aimed
at the improvement of the enantioselectivity to a syn-
thetically useful level. We will illustrate that the varia-
O
O
O
N
N
N
N
Cu
Cu
Ph
Ph
tBu
tBu
TfO OTf
TfO OTf
3b
3a
O
O
O
O
Ph
Ph
N
N
N
N
Cu
Cu
Ph
Ph
TfO OTf
TfO OTf
3c
3d
iPrO
R1E
O
O
Figure 2. Catalysts for the catalytic asymmetric Claisen rearrange-
ment.
0.5-10 mol% catalyst 3a,b
CH2Cl2, rt, 1-72 h
R1Z
tion of the catalyst structure can significantly increase
the enantioselectivity of the catalyzed Claisen rear-
rangement.
R1
O
R6
R6
1
OiPr
R6
R6
R1= H, Alkyl
R6= H, Me
O
In order to evaluate the influence of the ligand structure
on the enantioselectivity of the rearrangement, a small
number of commercially available bis(oxazoline) ligands
were combined with Cu(OTf)2 to afford the corre-
sponding Lewis acid catalysts 3a–d (Fig. 2). Employing
these catalysts for the catalytic asymmetric Claisen rea-
rangement of the allyl vinyl ether (Z)-1a did not signifi-
cantly improve the enantioselectivity compared to our
previous results (Table 1). In accordance with our earlier
observations,1 the tert-butyl-substituted [Cu{(S,S)-t-
Bu-box}](OTf)2 (3b) afforded the rearrangement product
with the highest enantioselectivity but at the same time
exerted the lowest reactivity (Table 1, entry 2).
2
Figure 1. Previous work1 afforded 94–100% yield and 72–88% ee,
depending on the substrate and the catalyst structure (3a,b). For cat-
alyst structures see Figure 2.
Keywords: Claisen rearrangement; Asymmetric catalysis; Lewis acid;
Copper(II)bis(oxazoline).
* Corresponding author. Tel.: +49-351-463-35480; fax: +49-351-463-
33661; e-mail: martin.hiersemann@chemie.tu-dresden.de
Deceased on September 28, 2003.
Undergraduate research participant.
z
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.047

3648
L. Abraham et al. / Tetrahedron Letters 45 (2004) 3647–3650
Table 1. Influence of the catalyst structure on reactivity and diastereoselectivity––a case study
CO2iPr
O
Ph
catalyst
CH2Cl2, rt
O
3
OiPr
Ph
O
2a
(Z)-1a
Entrya
Catalyst
t [h]
0.5
72
Yield [%]
3S:3Rb
1
2
3
4
(R,R)-3a
(S,S)-3b
100
100
99
88:12
93:7
(4R,5S)-3c
(4S,5R)-3d
24
24
86:14
90:10
100
a All reactions were carried out on a 0.4 mmol scale. The catalyst was removed by filtrating the reaction mixture through a 4 · 5 cm silica gel column
to obtain a colorless oil that was analytically pure.
b Determined by chiral HPLC: Chiracel OD 14025.
The next objective was to maintain the capability of the
[Cu(t-Bu-box)](OTf)2-complex (3a) to differentiate
between the enantiotopic faces of the vinyl ether double
bond and at the same time to improve the reactivity
by increasing the Lewis acidity of the copper cation.
Therefore, we decided to exchange the triflate counter-
ion for the less coordinating hexafluoroantimonate.
For this purpose, we selected the bench stable aqua
complex [Cu(t-Bu-box)](H2O)2(SbF6)2 (3e), which
was originally described by Evans et al.,5 as potential
catalyst.
Initially, the 3e-catalyzed rearrangement of allyl vinyl
ether (E)- and (Z)-1b was investigated. We switched the
substrate structure from 1a to 1b because the rear-
rangement product 2b represents the more useful syn-
thetic building block and 1b is available in both vinyl
ether double bond configurations.6
Compound 1b represents a sterically challenging system
since its rearrangement would generate a quaternary
carbon atom vicinal to the new chiral center at C-3.
Furthermore, the gem-dimethyl group at C-30 of the allyl
vinyl ether could support the ionization of the allyl vinyl
ether to an oxallylic anion and an allylic cation in the
presence of the strong Lewis acid 3e. For the sake of
comparison, the rearrangement of (Z)-1b was catalyzed
under identical conditions with (S,S)-3b and (S,S)-3e.
The results are summarized in Table 2. The comparison
of reaction time and enantioselectivity clearly demon-
strates that the application of 3e led to a faster and more
2
O
O
2
2 SbF6
N
N
Cu
tBu
tBu
H2O OH2
3e
Table 2. Highly enantioselective Claisen rearrangement of allyl vinyl ether 1b
O
3'
3
OiPr
iPrO
O
O
3, mol sieves
CH2Cl2, rt
O1
3
2b
1'
O
3'
1'
3
OiPr
1b
O
4b
Entrya
AVE
Catalyst
t [h]
Yield [%]
Ee [%]b
1
2
3
4
(Z)-1b
(Z)-1b
(Z)-1b
(E)-1b
10 mol % (S,S)-3b
10 mol % (S,S)-3e
5 mol % (S,S)-3e
5 mol % (S,S)-3e
24c
24
2
100
95d
94d
100
94 (3S)-2b
99 (3S)-2b
99 (3S)-2b
99 (3R)-2b
2c
AVE¼allyl vinyl ether.
a All reactions were performed on a 0.4 mmol scale. The catalyst was removed by filtrating the reaction mixture through a 4 · 0.5 cm silica gel column
to obtain a colorless oil that was analytically pure.
b Determined by chiral HPLC: Chiracel OD 14025.
c Optimized reaction time and catalyst loading.
d 5% 4b, separated by chromatography. Enantiomeric ratio not determined.

L. Abraham et al. / Tetrahedron Letters 45 (2004) 3647–3650
3649
enantioselective Claisen rearrangement compared to the
3b-catalyzed rearrangement (Table 2, entries 1–3).
However, due to the increased Lewis acidity and the
carbenium ion-stabilizing ability of the gem-dimethyl
group, we observed up to 5% of the undesired [1,3]-
rearrangement product 4b (Table 2, entries 2 and 3). The
formation of 4b is most likely a consequence of the
homogenous cleavage of the O-1 to C-10 bond, which
generated an a-keto ester enolate and an allylic cation.
The a-keto ester enolate then attacked the allylic cation
at C-10, the sterically less hindered position. It is how-
ever surprising, that the formation of the [1,3]-rear-
rangement product 4b was not observed from the
3e-catalyzed rearrangement of the (E)-configured allyl
vinyl ether 1b (Table 2, entry 4). Nevertheless, from
these initial experiments we concluded that the appli-
cation of [Cu(t-Bu-box)](H2O)2(SbF6)2 (3e) does indeed
represent a significant progress compared to our previ-
ous results.
carbonyl-substituted allyl vinyl ethers 1 are easily
accessible according to our previously published
procedure.6
We next turned our attention to the allyl vinyl ether 1c
featuring a nonstereogenic, mono-substituted allylic
ether double bond (Table 3). Compound 1c represents a
challenging substrate due to the absence of alkyl-sub-
stituents at C-30. Lack of substituents on the allylic ether
segment may cause a decreased reactivity due to a less
efficiently stabilized positive partial charge in the pro-
posed highly polarized transition state of the Lewis acid-
catalyzed Claisen rearrangement. Consequently, the
application of 3b as the catalyst led to disappointing
results. Generally, reaction times of several days and
catalyst loadings up to 20 mol % of 3b were not sufficient
to obtain a complete conversion and consistently high
ꢀ
enantioselectivities, even in the presence of 4 A molec-
ular sieves (Table 3, entry 1). Although the sterically less
demanding 3a catalyzed the rearrangement within an
acceptable reaction time, the corresponding enantio-
selectivity remained improvable (Table 3, entry 2).7
Finally, due to its increased Lewis-acidity, 3e was found
to be the most efficient catalyst affording the corre-
sponding rearrangement product 2c in high yield and
enantioselectivity (Table 3, entry 3).8
The catalysis of the rearrangement of (E)- and (Z)-1b
with 3e proceeded equally well in the presence or
ꢀ
absence 4 A molecular sieves. However, the 3b-catalyzed
rearrangement was significantly slower (80–85% con-
version after 4 d with 10 mol % 3b) in the absence of
molecular sieves but afforded identical enantioselectivi-
ties.
The ability to introduce further functional groups in the
allyl vinyl ether 1 would significantly increase the utility
of the catalytic asymmetric Claisen rearrangement for
the synthesis of a-keto esters 2 as synthetic building
blocks. Consequently, the protected hydroxymethyl-
substituted allyl vinyl ether 1d was synthesized. The
highly Lewis acidic catalyst 3e tolerated the protecting
group and afforded the rearrangement product, the
functionalized a-keto ester 2d, in a remarkable chemo-
and enantioselectivity (Table 3, entries 5 and 6).9
As can be seen from Table 2, it is possible to control the
absolute configuration of the newly generated chiral
center at C-3 by changing the vinyl ether double bond
configuration (Table 2, entries 3 and 4). Therefore, the
availability of one enantiomer of the catalyst is sufficient
in order to gain access to both enantiomeric rearrange-
ment products. This fact further increases the utility of
our catalytic asymmetric Claisen rearrangement,
because a variety of (E)- and (Z)-configured 2-alkoxy-
Table 3. Highly enantioselective Claisen rearrangement of allyl vinyl ether 1c,d
iPrO
O
R
O
3
CH2Cl2, rt
R
O1
3
OiPr
3
1'
3'
O
R= H: 1c
R= OTPS: 1d
R= H: 2c
R= OTPS: 2d
Entrya
AVE
Catalyst
t [d]
Yield [%]
Ee [%]b
1
2
3
4
5
6
(Z)-1c
(Z)-1c
(Z)-1c
(E)-1c
(Z)-1d
(E)-1d
10 mol % (S,S)-3b
6
55c
95
98
96
99
98
24 (3S)-2c
84 (3S)-2c
95 (3S)-2c
97 (3R)-2c
99 (3R)-2d
99 (3S)-2d
10 mol % (R,R)-3ad
10 mol % (S,S)-3e
10 mol % (S,S)-3e
10 mol % (S,S)-3e
10 mol % (S,S)-3e
2
1
1
1.5 he
1.5 he
AVE¼allyl vinyl ether.
a
ꢀ
All reactions were performed on a 0.4 mmol scale in the presence of 100 mg pulverized and activated 4 A molecular sieves. The catalyst was removed
by filtrating the reaction mixture through a 4 · 0.5 cm silica gel column to obtain a colorless oil that was analytically pure.
b Enantiomeric excess determined by GC (2c: 50 m · 0.25 mm hydrodex (R)-b-6-TBDM (heptakis-(6-O-tert-butyl-2,3-di-O-methyl)-b-cyclodextrine),
65 ꢁC) or HPLC (2d: Chiracel OD 14052, 1 mL/min hexane/i-PrOH 99.5/0.5).
c 45% recovered starting material.
d Performed in the absence of molecular sieves. The presence of molecular sieves did not increase the enantioselectivity.
e Optimized reaction time.

3650
L. Abraham et al. / Tetrahedron Letters 45 (2004) 3647–3650
Risgaard, T.; Gothelf, K. V.; Jørgensen, K. A. Org.
H3C CH3
H3C
Biomol. Chem. 2003, 1, 153–156; (d) Yang, D.; Yang, M.;
Zhu, N. Org. Lett. 2003, 5, 3749–3752; For recent reviews,
see: (e) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1–45; (f) Johnson, J. S.;
Evans, D. A. Acc. Chem. Res. 2000, 33, 325–335.
O
O
N
N
Cu
O
O
H3C
OiPr
δ
4. For a less successful Lewis acid-catalyzed asymmetric
Claisen rearrangement, see: Helmboldt, H.; Hiersemann,
M. Tetrahedron 2003, 59, 4031–4038.
R1Z
R1E
CH3
H3C
δ
5. Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.;
Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936–7943.
6. 2-Alkoxycarbonyl-substituted allyl vinyl ethers 2 were
synthesized according to our previously published proce-
dure: Hiersemann, M. Synthesis 2000, 1279–1290, The
vinyl ether double bond isomers have been separated by
preparative HPLC. Details will be published elsewhere.
7. We had previously reported a low reactivity and a moderate
enantioselectivity (68%) for the (S,S)-3b-catalyzed Claisen
rearrangement of (Z)-1c.1 A careful reinvestigation using a
new charge of ligand and allyl vinyl ether (Z)-1c in the
presence of molecular sieves afforded the rearrangement
product 2c with an increased enantioselectivity.
R6
R6
5
Figure 3. Proposed model for the transition state of the [Cu{(S,S)-t-
Bu-box}]-catalyzed Claisen rearrangement.
The majority of the experimental data from this and
from earlier studies support the assumption that the
[Cu(box)]-catalyzed Claisen rearrangement proceeds
through a highly polarized but nevertheless concerted
pericyclic transition state 5 (Fig. 3). Based on extensive
computational work,
a polarized transition state
8. General procedure: (S,S)-3e was dissolved in dry CH2Cl2
(5 mL/mmol allyl vinyl ether) in a round bottom flask under
an atmosphere of argon. After 5 min of stirring, pulverized
has also been suggested for the noncatalyzed, thermal
Claisen rearrangement.10 Furthermore, the observation
of the [1,3]-rearrangement product 4b illustrated the
existence of a rather small line between a highly polar-
ized transition state 5 and the formation of an allylic
cation/oxallylic anion ionpair that will recombine to the
corresponding [1,3]-rearrangement product.
ꢀ
and activated 4 A molecular sieves (250 mg/mmol ave) was
added. After an additional 5 min of stirring, a solution of
the allyl vinyl ether in dry CH2Cl2 (5 mL/mmol ave) was
added. The flask was then sealed with a rubber septum and
the reaction mixture was stirred for the appropriate time.
The reaction mixture was then diluted with a 20/1 mixture
of heptane and ethyl acetate. The molecular sieves were
removed subsequently by filtration and the filtrate was
filtered again, then through a 4 · 0.5 cm plug of silica gel in
order to remove the catalyst. The solvents were evaporated
and the colorless oil was dried at reduced pressure to
provide the analytical pure a-keto ester 2c: 1H NMR
(CDCl3, 300 MHz) d 5.41 (ddd, J ¼ 17:0, 10.0, 7.1 Hz, 1H),
5.14 (sept, J ¼ 6:3 Hz, 1H), 5.09–5.04 (m, 1H), 5.02 (s, 1H),
3.28 (qdd, J ¼ 13:5, 7.3 Hz, 1H), 2.39–2.51 (m, 1H), 2.09–
2.21 (m, 1H), 1.34 (d, J ¼ 6:2 Hz, 3H), 1.33 (d, J ¼ 6:4 Hz,
6H), 1.13 (d, J ¼ 7:1 Hz, 3H); 13C NMR (CDCl3,
The stereochemical result of the 3e-catalyzed rearrange-
ment may be explained assuming an idealized square
planar coordination sphere around the copper(II) ion
(Fig. 3). The allylic ether segment will then approach the
vinyl ether double bond from the face opposite to the
tert-butyl group on the bis(oxazoline) ligand. Further
experimental and theoretical work is currently underway
to support our assumptions concerning the nature of the
transition state and to further broaden the scope of the
Lewis acid-catalyzed Claisen rearrangement.
75.5 MHz) d 197.7, 161.4, 134.7, 117.4, 70.4, 41.8, 36.0,
25
21.5, 14.8; IR (in substance) 2980–2940, 1720; ½aꢀ (3S)-2c
D
25
D
ꢁ23, (c 1.52, CHCl3, 95% ee), ½aꢀ (3R)-2c þ24, (c 1.90,
Acknowledgements
CHCl3, 97% ee); analyt. GC (50 m · 0.25 mm hydrodex (R)-
b-6-TBDM (heptakis-(6-O-tert-butyl-2,3-di-O-methyl)-b-
cyclodextrine), 65 ꢁC) Rt (3S)-2c¼76.2 min, Rt (3R)-
2c¼74.7 min; Anal. Calcd for C10H16O3: C, 65.19; H,
8.75. Found: C, 65.22; H, 8.84.
Financial support from the German Research Founda-
tion (DFG) is gratefully acknowledged. The generous
gift of (S)-tert-leucine by Degussa is gratefully
acknowledged. This letter is dedicated to the memory of
Lars Abraham who died in a motorcycle accident on
September 28, 2003.
9. 2d: 1H NMR (300 MHz, CDCl3) d 7.64–7.57 (m, 4H),
7.46–7.33 (m, 6H), 5.44 (ddt, J ¼ 17:1, 10.2, 7.0 Hz, 1H),
5.11 (sept, J ¼ 6:3 Hz, 1H), 5.03–4.93 (m, 2 H), 3.88 (d,
J ¼ 5:8 Hz, 2H), 3.59 (dt, J ¼ 12:9, 6.5 Hz, 1H), 2.51–2.40
(m, 1H), 2.32–2.20 (m, 1H), 1.32 (d, J ¼ 6:2 Hz, 3H), 1.31
(d, J ¼ 6:2 Hz, 3H), 1.00 (s, 9H); 13C (75 MHz, CDCl3) d
196.1, 184.5, 161.0, 135.6, 134.6, 133.1, 129.8, 127.7, 117.2,
References and notes
1. Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew.
Chem., Int. Ed. 2001, 40, 4700–4703.
70.5, 63.7, 49.8, 31.6, 26.7, 21.6, 19.2; IR (in substance)
25
D
3070–2860, 1720, 1470, 1425 cmꢁ1; ½aꢀ (3S)-2d ꢁ14, (c
25
D
2. Asymmetric Claisen rearrangements have been reviewed,
see: (a) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron:
Asymmetry 1996, 7, 1847–1882; (b) Ito, H.; Taguchi, T.
Chem. Soc. Rev. 1999, 28, 43–50; (c) Nubbemeyer, U.
Synthesis 2003, 961–1008.
3. For recent applications of [Cu(II){box}]X2 in asymmetric
catalysis, see: (a) Evans, D. A.; Seidel, D.; Rueping, M.;
Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2003, 125, 12692–12693; (b) Morao, I.; McNamara, J.
P.; Hillier, I. H. J. Am. Chem. Soc. 2003, 125, 628–629; (c)
1.02, CHCl3, 98% ee), ½aꢀ (3R)-2d þ15, (c 0.95, CHCl3,
99% ee); analyt. HPLC (Chiracel OD 14052, flow 1 mL/
min, 99.5% n-hexane/0.5% iso-propanol) Rt (3S)-
2d¼5.2 min, Rt (3R)-2d¼4.7 min; Anal. Calcd for
C26H34O4Si: C, 71.19; H, 7.81. Found: C, 71.01, H, 7.84.
10. For selected references, see: (a) Yoo, H. Y.; Houk, K. N.
J. Am. Chem. Soc. 1997, 119, 2877–2884; (b) Aviyente, V.;
Yoo, H. Y.; Houk, K. N. J. Org. Chem. 1997, 62, 6121–
6128; (c) Wiest, O.; Houk, K. N. J. Am. Chem. Soc. 1995,
117, 11628–11639.