Application of the asymmetric chelate enolate Claisen rearrangement to the synthesis of unsaturated polyhydroxylated amino acids

Article abstract of DOI:10.1055/s-1998-6104

Ester enolate Claisen rearrangement of chelated N-protected chiral allylic amino acid esters results in the formation of polyhydroxylated γ,δ-unsaturated amino acids in good yields and with a high degree of chirality transfer.

Full text of DOI:10.1055/s-1998-6104

SYNTHESIS
September 1998
1321
Application of the Asymmetric Chelate Enolate Claisen Rearrangement to the
Synthesis of Unsaturated Polyhydroxylated Amino Acids
Uli Kazmaier,* Christiane Schneider
Organisch-Chemisches Institut der Universität, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: ck1@ix.urz.uni-heidelberg.de
Received 10 February 1998
Abstract: Ester enolate Claisen rearrangement of chelated N-pro-
tected chiral allylic amino acid esters results in the formation of
polyhydroxylated γ,δ-unsaturated amino acids in good yields and
with a high degree of chirality transfer.
Key words: allylic esters, chelates, Claisen rearrangement, en-
olates, unsaturated amino acids
Polyhydroxylated amino acids are an important class of
natural products. For example, polyoxamic acid is part of
many polyoxines, which are potent antifungal agents.1
These interesting synthetic targets2 can act as enzyme in-
hibitors or as antimetabolites.3 They are also found as sub-
structures in naturally occurring antibiotics4 and take part
in the biosynthesis of important bioactive substances.5 In
addition, polyhydroxylated amino acids are valuable tools
syntheses of the chiral allylic alcohols 1a–1f used is de-
in the design of polyhydroxylated piperidine alkaloids.6
scribed in the previous paper.13
Polyhydroxylated amino acids can be obtained via intro-
duction of suitable side chains into glycine residues and/
or via functionalization of double bonds.7 The unsaturated
amino acids, needed for this approach, can be obtained
e.g. by sigmatropic rearrangement reactions.8
Esterification of these alcohols with protected amino ac-
ids in the presence of DCC/DMAP14 gave the correspond-
ing chiral allylic esters 2 in high yields (Scheme 2, Table
1). This procedure is suitable for the generation of glycine
esters, and other amino acid esters15 as well. These are of
special interest because they allow the stereoselective
synthesis of functionalized unsaturated α-alkylated amino
acids.16
Recently, we have developed a new variation of the ester
enolate Claisen rearrangement proceeding via chelated al-
lylic ester enolates.9 Deprotonation of N-protected glycine
allyl esters with LDA at –78°C and subsequent addition
of metal salts, such as zinc chloride, presumably results in
the formation of a chelated zinc enolate, which undergoes
Claisen rearrangement upon warming to room tempera-
ture (Scheme 1). Due to the fixed enolate geometry, as a
result of chelate formation, the rearrangement proceeds
with a high degree of diastereoselectivity, independent of
the substitution pattern and the protecting groups used.
This method is suitable for various types of allylic esters
and can also be applied to peptides.10 If the reaction is car-
ried out in the presence of chiral bidentate ligands, chiral
γ,δ-unsaturated amino acids are obtained in high yields
and in a highly stereoselective fashion.11
Scheme 2
For the investigation of the ester enolate Claisen rear-
rangement, a solution of the allylic ester 2 in THF was
deprotonated with an excess of base (2.5 equiv) in the
presence of a chelating metal salt. Best results were ob-
tained when lithium diisopropylamide (LDA) was used as
a base, and ZnCl2 for the chelation of the ester enolate
(Table 2). If other metal salts such as MgCl2 or Al(OiPr)3
were used for chelate formation, generally lower yields
were observed (entries 3 and 4), and the allylic alcohols 1
were obtained as byproducts. After warming the reaction
mixture overnight to room temperature, the mixture was
hydrolyzed with 1 N KHSO4 solution. For this purpose
KHSO4 is superior to HCl, because no cleavage of the
acid labile ketal moieties was observed under these condi-
Scheme 1
Herein we describe the ester enolate Claisen rearrange-
ment of functionalized chiral allylic amino acid esters
which gives rise to the corresponding chiral amino acids
with high enantio- as well as diastereoselectivities.12 The

SYNTHESIS
Papers
Table 1. Preparation of Chiral Allylic Esters 2
1322
Allylic
Alcohol
Y
R
Yield
(%)
Config.
(allyl Pos.)
Ester
1a
ent-1a
1b
1c
1d
1e
1f
1a
ent-1a
1a
Z
Z
Boc
Z
Boc
Z
Z
Z
Z
Z
H
H
H
H
H
H
H
Me
Ph
Bn
Me
Et
83
79
98
83
82
92
93
96
95
80
94
86
S
R
R
S
S
R
S
S
R
S
S
S
2a
ent-2a
2b
2c
2d
2e
2f
2g
2h
2i
2k
2l
1c
1c
Z
Z
Scheme 3
termines the double bond geometry in the rearranged
product. E-Olefins are obtained if the reaction proceeds
via transition state A, while the disfavored transition state
B gives rise to Z-configurated olefins. The exclusive for-
mation of the E-configurated amino acids, obtained in our
reactions, clearly demonstrates the high preference for the
favored transition state A.
Table 2. Chelate Claisen Rearrangement of Chiral Allylic Esters 2
Entry
Ester
MXn
Yield
(%)
Select.
(%)
Amino Acid
Ester
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2a
ent-2a
2b
2b
2b
2c
2d
2e
2f
2g
2h
2i
2k
2l
ZnCl2
ZnCl2
Al(OiPr)3
MgCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
89
93
5
99.3
>99
n.d.
n.d.
>99
>98
99.7
>99
98
>99
>99
>98
>99
>99
(R)-3a
(S)-3a
3b
6
3b
The absolute configuration of the rearrangement products
was determined by ozonolysis of the double bond, giving
rise to the corresponding aspartic acid derivative (Scheme
4). Comparison with derivatives of the natural amino acid
confirms the mechanism proposed.
95
92
77
85
71
95
92
85
82
82
(S)-3b
(R)-3c
(R)-3d
(S)-3e
(R)-3f
(R)-3g
(R)-3h
(S)-3i
(S)-3k
(R)-3l
tions. The rearrangement generally proceeded with very
good yields and selectivities, as shown in Table 2.
Scheme 4
For the determination of the stereoselectivity of the rear-
rangement, the crude reaction products were esterified
with diazomethane, and the resulting methyl esters were
analyzed by HPLC (chiral HPLC column Daicel OD-H).
The observed ee and ds values were, without exception,
≥98% (Table 2).17 This is also true for the rearrangement
of allylic ester 2f. In this case two new stereogenic centers
were formed, and therefore in principle four stereoisomers
should be expected. Out of these four isomers only two
were observed in a syn/anti ratio of 98:2.
In conclusion we have shown that the chelate enolate
Claisen rearrangement is a versatile method for the syn-
thesis of even highly functionalized amino acids. As illus-
trated, the rearrangement is not limited to allylic esters of
glycine, but can also be applied to the synthesis of α-alkyl-
ated amino acids 3g–l without problems. We were also
able to show that allylic esters with sterically highly de-
manding substituents take part in the rearrangement in
good yields (2d,e). Therefore, it is possible to introduce
protected polyhydroxylated substituents into amino acids
in one step and in a highly diastereoselective fashion. The
observed yields and selectivities are almost independent
of the protecting groups. All rearrangements proceeded
with almost 100% trans-selectivity, no cis-configurated
product was observed by HPLC or NMR.
The high degree of chirality transfer of these chelated es-
ter enolates can be explained by a closer look at the corre-
sponding transition states (Scheme 3). Like in most sig-
matropic rearrangements, the chair-like transition state is
highly preferred, whereas two diastereomeric chairs are
possible for esters of secondary allylic alcohols. In the fa-
vored transition state A, the substituent R is orientated in
an equatorial position, while in transition state B strong
steric interactions between the axial R and the chelate-
complex may occur. As a result of the highly ordered tran-
sition state, the [3.3]-sigmatropic rearrangement also de-
All reactions were carried out in oven-dried glassware (100 ˚C) under
argon. All solvents were dried before use. THF was distilled from
sodium benzophenone, CH2Cl2 and i-Pr2NH from CaH2. The starting
materials and the products were purified by flash chromatography on
silica gel (32–63 µm). Mixtures of EtOAc and petroleum ether (40–

SYNTHESIS
September 1998
1323
Table 3. Analytical and Spectroscopic Data of Compounds 2 and 3
Compound
[α]D20
1H NMR (300 MHz, CDCl3)
13C NMR (75 MHz, CDCl3)
(c, Solvent)
δ, J (Hz)
δ
2a
–43.0
3.99 (dd, J = 18.3, 5.5, 1H, CH2N), 4.09 (dd, J = 18.3, 43.00 (t, CH2N), 67.14 (t, PhCH2), 77.45 (d,
(2.0, CHCl3) 5.7, 1H, CH2N), 5.12 (s. 2H, PhCH2), 5.28 (d, J = 10.3, CHOCO), 116.61 (t, CH=CH2), 127.18, 128.11,
2H, CH=CHHt, NH), 5.31 (d, J = 17.1, 1H, CH=CH- 128.20, 128.47,128.55, 128.66 (6d, ArC), 135.62 (d,
Hc), 6.01 (ddd, J = 17.1, 10.6, 6.0, 1H, CH=CH2), 6.21 CH=CH2), 136.26, 138.20 (2s, quart. ArC), 156.23
(m, 1H, CHOCO), 7.35 (sbr, 10H, ArH)
(s, OCON), 169.05 (s, COO)
ent-2a
+ 42.1
3.99 (dd, J = 18.3, 5.5, 1H, CH2N), 4.08 (dd, J = 18.3, 42.99 (t, CH2N), 67.13 (t, PhCH2), 77.45 (d,
(0.5, CHCl3) 5.7, 1H, CH2N), 5.12 (s, 2H, PhCH2), 5.28 (d, J = 10.3, CHOCO), 116.61 (t, CH=CH2), 127.17, 128.10,
2H, CH=CHHt, NH), 5.31 (d, J = 17.3, 1H, CH=CH- 128.20, 128.47, 128.55, 128.65 (6d, ArC), 135.62 (d,
Hc), 6.01 (ddd, J = 17.3, 10.4, 5.9, 1H, CH=CH2), 6.23 CH=CH2), 136.26, 138.20 (2s, quart. ArC), 156.23
(m, 1H, CHOCO), 7.35 (sbr, 10H, ArH)
(s, OCON), 169.04 (s, COO)
2b
–4.3
1.45 [s, 9H, C(CH3)3], 3.52–3.62 (m, 4H, CH2OBn, 28.28 (q, CH3), 42.52 (t, CH2N), 71.07 (t, CH2O),
(1.0, CHCl3) CH2N), 4.53 (d, J = 12.2, 1H, PhCH2), 4.57 (d, J = 73.99 (t, PhCH2), 74.28 (d, CHOCO), 79.93 [s,
12.2, 1H, PhCH2), 5.01 (sbr, 1H, NH), 5.26 (d, J = C(CH3)3], 118.56 (t, CH=CH2), 127.62, 127.74,
11.0, 1H, CH=CHHt), 5.33 (d, J = 17.3, 1H, 128.41 (3d, ArC), 132.68 (d, CH=CH2), 137.75 (s,
CH=CHHc), 5.53 (dd, J = 11.0, 5.9, 1H, CHOCO), quart. ArC), 155.56 (s, OCON), 169.58 (s, COO)
5.82 (ddd, J = 17.1, 10.7, 6.1, 1H, CH=CH2), 7.26–
7.,37 (m, 5H, ArH)
2c
–1.24
1.35 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.80 (dd, J = 26.18 (q, CH3), 26.32 (q, CH3), 42.91 (t, CH2N),
(5.5, CHCl3) 8.4, 6.3, 1H, CH2O), 3.99–4.04 (m, 3H, CH2O, 65.58 (t, CH2O), 67.17 (t, PhCH2), 75.22 (d, CHOC),
CH2N), 4.21 (dt, J = 11.2, 6.2, 1H, CHOC), 5.12 (s, 76.34 (d, CHOCO), 110.05 [s, C(CH3)2], 119.71 (t,
2H, PhCH2), 5.29–5.40 (m, 4H, NH, CHOCO, CH=CH2), 128.11, 128.22, 128.55 (3d, ArC), 131.72
CH=CH2), 5.81 (ddd, J = 17.2, 10.6, 6.6, 1H, (d, CH=CH2), 136.22 (s, quart. ArC), 156.22 (s,
CH=CH2), 7.31–7.35 (m, 5H, ArH)
OCON), 169.02 (s, COO)
2d
–13.8
1.38 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.43 [s, 9H, 26.62 (q, CH3), 26.85 (q, CH3), 28.07 [s, C(CH3)3],
(3.6, CHCl3) C(CH3)3], 3.57 (dd, J = 10.3, 5.2, 1H, CH2OBn), 42.28 (t, CH2N), 70.26 (t, CH2O), 73.31 (t, PhCH2),
3.61 (dd, J = 10.3, 3.7, 1H, CH2OBn), 3.86 (d, J = 74.90 (d, CHOC), 78.48 (d, CHOC), 78.76 (d,
5.4, 2H, CH2N), 3.97 (dd, J = 8.1, 4.0, 1H, CHOC), CHOCO), 79.79 [s, C(CH3)3], 109.85 [s, C(CH3)2],
4.06 (ddd, J = 8.1, 5.2, 2.9, 1H, CHOC), 4.55 (d, J = 119.66 (t, CH=CH2), 127.53, 128.18 (2d, ArC),
12.4, 1H, PhCH2), 4.59 (d, J = 12.4, 1H, PhCH2), 131.38 (d, CH=CH2), 137.64 (s, quart. ArC), 155.31
4.91 (sbr, 1H, NH), 5.28 (d, J = 10.5, 1H, CH=CHHt), (s, OCON), 169.07 (s, COO)
5.32 (ddd, J = 17.4, 1.1, 1.1 Hz, 1H, CH=CHHc),
5.42 (dddd, J = 6.6, 4.4, 1.1, 1.1, 1H, CHOCO), 5.81
(ddd, J = 17.3, 10.5, 6.6, 1H, CH=CH2), 7.27–7.36
(m, 5H, ArH)
2c
2f
+ 5.1 (0.44,
CHCl3)
1.34–1.41 (m, 12H, CH3), 3.68 (t, J = 7.8, 1H, 25.18, 26.60, 26.91, 27.18 (4q, CH3), 42.99 (t,
CH2N), 3.93–4.24 (m, 6H, CH2N, CHO), 5.12 (s, CH2N), 67.13 (t, PhCH2), 67.66 (t, CH2O), 75.87,
2H, PhCH2), 5.29 (sbr, 1H, NH), 5.36–5.42 (m, 2H, 76.93, 78.55, 81.15 (4d, CHO), 109.93, 110.29 [2s,
CH=CH2), 5.52 (dd, J = 7.8, 3.2, 1H, CHOCO), 5.93 C(CH3)2], 121.45 (t, CH=CH2), 128.10, 128.52,
(ddd, J = 17.7, 8.9, 8.9, 1H, CH=CH2), 7.30–7.36 129.19 (3d, ArC), 131.07 (d, CH=CH2), 136.25 (s,
(m, 5H, ArH)
quart. ArC), 156.21 (s, OCON), 169.01 (s, COO)
+ 24.2 (2.5,
CHCl3)
0.88 (t, J = 7.0, 3H, CH2CH3), 1.25–1.33 (m, 4H, 13.96 (q, CH2CH3), 22.20 (t, CH2CH3), 25.40, 26.43
CH2), 1.34 [s, 3H, C(CH3)2], 1.39 [s, 3H, C(CH3)2], [2q, C(CH3)2], 30.99 (t, CH2), 32.12 (t, CH2), 43.14
2.05 (m, 2H, C = CHCH2), 3.77 (dd, J = 7.9, 6.8, 1H, (t, CH2N), 65.72 (t, CH2O), 67.25 (t, PhCH2), 75.54
CH2N), 3.91–4.13 (m, 4H, CH2O, CH2N, CHOC), (d, CHO), 76.83 (d, CHO), 110.06 [2s, C(CH3)2],
5.12 (s, 2H, PhCH2), 5.26 (mc, 1H, NH), 5.33–5.46 123.25 (d, CH=CHCH2), 128.22, 128.32, 128.66 (3d,
(m, 2H, CHOCH=CH, CHOCO), 5.81 (dt, J = 14.3, ArC), 136.42 (s, quart. ArC), 137.97 (d,
7.1, 1H, CH=CHCH2), 7.35 (m, 5H, ArH)
CHOCH=CH), 156.29 (s, OCON), 169.17 (s, COO)
2g
2h
– 40.3 (0.6,
CHCl3)
1.39 (d, J = 7.2, 1.5H, CH3), 1.47 (d, J = 7.2, 1.5H, 18.55, 18.77 (2q, CH3), 49.74 (d, CHN), 68.88 (t,
CH3), 4.47 (mc, 1H, CHN), 5.10 (s, 1H, PhCH2), 5.11 PhCH2), 72.21, 77.32 (2d, CHOCO), 117.41, 117.51
(s, 1H, PhCH2), 5.27 (m, 2H, CH=CHHt, NH), 5.34 (2t, CH=CH2), 126.95, 127.04, 128.05, 128.12,
(mc, 1H, CH=CHHc), 6.00 (ddd, J = 16.1, 10.7, 5.3, 128.31, 128.36, 128.49 (7d, ArC), 135.63 (d,
1H, CH=CH2), 6.28 (m, 1H, CHOCO), 7.34 (sbr, CH=CH2), 136.26, 138.14, 138.20 (3s, quart. ArC),
10H, ArH)
155.52 (s, OCON), 171.85 (s, COO)
– 26.0 (2.7,
CHCl3)
5.06 (d, J = 12.1, 1H, PhCH2), 5.12 (d, J = 12.1, 1H, 67.17 (t, PhCH2), 76.43, 77.85 (2d, CHN, CHOCO),
PhCH2), 5.26 (d, J = 10.4, 1H, CH=CHHt), 5.28 (d, J 117.9 (t, CH=CH2), 126.56, 127.31, 128.09, 128.20,
= 17.1, 1H, CH=CHHc), 5.46 (d, J = 7.5, 1H, CHN), 128.38, 128.55, 128.89 (7d, ArC), 135.58 (d,
5.83 (d, J = 7.3, 1H, NH), 5.97 (ddd, J = 17.0, 10.6, CH=CH2), 136.09, 136.36, 137.94 (3s, quart. ArC),
6.3, 1H, CH=CH2), 6.23 (d, J = 5.9, 1H, CHOCO), 155.33 (s, OCON), 169.67 (s, COO)
6.96 (d, J = 6.1, 2H, ArH), 7.28–7.38 (m, 13H, ArH)

SYNTHESIS
Papers
Table 3. (continued)
1324
Compound
[α]D20
1H NMR (300 MHz, CDCl3)
13C NMR (75 MHz, CDCl3)
(c, Solvent)
δ, J (Hz)
δ
2i
+ 45.3 (3.1,
CHCl3)
3.16 (d, J = 5.9, 2H, PhCH2C), 4.70 (mc, 0.5H, 37.91, 38.28 (2t, PhCH2C), 54.67, 54.89 (2d, CHN),
CHN), 4.74 (mc, 0.5H, CHN), 5.08 (s, 2H, PhCH2O), 66.92 (t, PhCH2O), 77.38, 77.50 (2d, CHOCO),
5.25–5.35 (m, 3H, NH, CH=CH2), 5.95 (ddd, J = 117.50, 117.67 (2t, CH=CH2), 126.96, 127.05,
16.9, 10.7, 6.3, 1H, CH=CH2), 6.25 (d, J = 6.3, 1H, 127.36, 128.03, 128.13, 128.32, 128.48, 128.55,
CHOCO), 7.09–7.35 (m, 15H, ArH)
128.61, 129.32, 129.41 (11d, ArC), 135.29, 135.43
(2d, CH=CH2), 136.23, 138.10, 138.17 (3s, quart.
ArC), 155.58 (s, OCON), 170.51 (s, COO)
2k
2l
–4.4 (2.1,
CHCl3)
1.34 (s, 3H, CH3), 1.41–1.46 [m, 6H, C(CH3)2], 380– 18.66, 18.80 (q, CH3), 25.10, 25.20, 26.38 [3q,
3.82 (m, 1H, CH2O), 4.02 (mc, 1H, CH2O), 4.19 (mc, C(CH3)2], 49.82 (d, CHN), 65.57, 65.75 (2t, CH2O),
1H, CHOC), 4.43 (mc, 1H, CHN), 5.11 (sbr, 2H, 66.96 (t, PhCH2), 109.93, 110.06 [2s, C(CH3)2],
PhCH2O), 5.29–5.36 (m, 4H, NH, CHOCO, 119.34 (t, CH=CH2), 128.12, 128.20, 128.54 (3d,
CH=CH2), 5.77–5.82 (m, 1H, CH=CH2), 7.31–7.35 ArC), 131.95 (d, CH=CH2), 136.26 (s, quart. ArC),
(m, 5H, ArH)
155.54 (s, OCON), 171.95 (s, COO)
–3.7 (3.1,
CHCl3)
0.94 (m, 3H, CH2CH3), 1.34 [s, 3H, C(CH3)2], 1.41 9.37, 9.50 (2q, CH2CH3), 25.12, 25.22 [2q,
[s, 3H, C(CH3)2], 1.71–1.75 (m, 2H, CH2CH3), 3.79 C(CH3)2], 25.79, 25.87 (2t, CH2CH3), 26.34, 26.37
(mc, 1H, CH2O), 3.98–4.08 (m, 1H, CH2O), 4.18– [2q, C(CH3)2], 54.99 (d, CHN), 65.72, 65.82 (2t,
4.22 (m, 1H, CHOC), 4.37–4.39 (m, 1H, CHN), 5.11 CH2O), 75.06, 75.11 (2d, CHOC), 76.27, 76.37 (2d,
(s, 2H, PhCH2O), 5.29–5.38 (m, 4H, NH, CHOCO, CHOCO), 109.93, 110.06 [2s, C(CH3)2], 119.44,
CH=CH2), 5.82 (ddd, J = 17.2, 10.6, 6.5, 1H, 119.71 (2t, CH=CH2), 128.11, 128.20, 128.56 (3d,
CH=CH2), 7.30–7.39 (m, 5H, ArH)
ArC), 132.01 (d, CH=CH2), 136.27 (s, quart. ArC),
155.83 (s, OCON), 171.35 (s, COO)
3a
- 39.9 (1.4,
CHCl3)
2.67–2.76 (m, 2H, CH=CHCH2), 3.77 (s, 3H, 36.13 (t, CH=CHCH2), 52.44 (q, OCH3), 53.67 (d,
OCH3), 4.55 (dd, J = 13.6, 5.9, 1H, CHN), 5.09 (d, J CHN), 67.04 (t, PhCH2), 123.37 (d, CH=CHCH2),
= 12.2, 1H, PhCH2O), 5.14 (d, J = 12.2, 1H, 126.32, 127.01, 128.10, 128.18, 128.53, 128.56 (6d,
PhCH2O), 5.38 (d, J = 7.8, 1H, NH), 6.06 (dt, J = ArC), 134.28 (d, PhCH=CH), 136.11, 136.26 (2s,
15.4, 7.6, 1H, CH=CHCH2), 6.46 (d, J = 15.7, 1H, quart. ArC), 155.74 (s, OCON), 172.15 (s, COO)
PhCH=CH), 7.24–7.33 (m, 10H, ArH)
ent-3a
+ 39.9 (1.3,
CHCl3)
2.68–2.78 (m, 2H, CH=CHCH2), 3.77 (s, 3H, 36.13 (t, CH=CHCH2), 52.44 (q, OCH3), 53.67 (d,
OCH3), 4.55 (dd, J = 13.6, 5.9, 1H, CHN), 5.09 (d, J CHN), 67.04 (t, PhCH2), 123.37 (d, CH=CHCH2),
= 12.2, 1H, PhCH2O), 5.14 (d, J = 12.2, 1H, 126.32, 127.01, 128.10, 128.18, 128.53, 128.56 (6d,
PhCH2O), 5.38 (d, J = 7.8, 1H, NH), 6.06 (dt, J = ArC), 134.28 (d, PhCH=CH), 136.11, 136.26 (2s,
15.4, 7.6, 1H, CH=CHCH2), 6.46 (d, J = 15.7, 1H, quart. ArC), 155.74 (s, OCON), 172.15 (s, COO)
PhCH=CH), 7.24–7.35 (m, 10H, ArH)
3b
+ 16.2 (0.5,
CHCl3)
1.43 [s, 9H, C(CH3)3], 2.47 (ddd, J = 13.5, 6.7, 6.7, 28.30 [q, C(CH3)3], 35.44 (t, CH=CHCH2), 52.21 (q,
1H, CH=CHCH2), 2.57 (ddd, J = 13.5, 6.7, 6.7, 1H, OCH3), 53.10 (d, CHN), 70.23 (t, CH=CHCH2O),
CH=CHCH2), 3.73 (s, 3H, OCH3), 3.97 (J = 5.5, 2H, 72.02 (t, PhCH2), 79.75 [s, C(CH3)3], 127.39 (d,
CH=CHCH2O), 4.37 (mc, 1H, CHN), 4.48 (s, 2H, CH=CHCH2), 127.60, 127.75, 128.37 (3d, ArC),
PhCH2O), 5.03 (sbr, 1H, NH), 5.60 (dt, J = 15.4, 6.7, 131.10 (d, CH=CHCH2O), 138.27 (s, quart. ArC),
1H, CH=CHCH2), 5.70 (dt, J = 15.4, 5.4, 1H, 155.17 (s, OCON), 172.48 (s, COO)
CH=CHCH2O), 7.24–7.37 (m, 5H, ArH)
3c
–9.1 (0.1,
CHCl3)
1.36 [s, 3H, C(CH3)2], 1.40 [s, 3H, C(CH3)2], 2.47– 25.79 [q, C(CH3)2], 26.61 [q, C(CH3)2], 35.20 (t,
2.62 (m, 2H, CH=CHCH2), 3.52 (dd, J = 7.9, 1H, CH=CHCH2), 52.37 (q, OCH3), 53.36 (d, CHN),
CH2O), 3.74 (s, 3H, OCH3), 4.05 (dd, J = 8.1, 6.3, 67.04 (t, PhCH2), 69.32 (t, CH2O), 76.44 (d, CHO),
1H, CH2O), 4.44 (dd, J = 13.6, 6.7, 2H, CHN, 109.32 [s, C(CH3)2], 127.81 (d, CH=CHCH2),
CHOC), 5.10 (sbr, 2H, PhCH2O), 5.34 (d, J = 8.0, 1H, 128.07, 128.18, 128.50 (3d, ArC), 132.45 (d,
NH), 5.56 (dt, J = 15.4, 6.8, 1H, CH=CHCH2), 5.65 CH=CHCHO), 136.22 (s, quart. ArC), 155.64 (s,
(dd, J = 15.3, 6.7, 1H, CH=CHCHO), 7.34 (sbr, ArH) OCON), 171.79 (s, COO)
3d
+ 15.3 (1.1,
CHCl3)
1.40 [s, 3H, C(CH3)2], 1.42 [s, 9H, C(CH3)3], 1.44 [s, 26.89 [q, C(CH3)2], 26.92 [q, C(CH3)2], 28.26 [q,
3H, C(CH3)2], 2.43–2.53 (m, 2H, CH=CHCH2), 3.58 C(CH3)3], 35.30 (t, CH=CHCH2), 52.20 (q, OCH3),
(d, J = 4.0, 2H, CH2O), 3.68 (s, 3H, OCH3), 3.83 (dt, 52.91 (d, CHN), 69.47 (t, PhCH2), 73.52 (t, CH2O),
J = 8.6, 4.0, 1H, OCH2CHO), 4.17 (ddd, J = 8.5, 6.6, 78.61 [s, C(CH3)3], 78.79 (d, CHOC), 80.10 (d,
1.8, 1H, CH=CHCHO), 4.35 (mc, 1H, CHN), 4.59 (s, CHOC), 109.30 [s, C(CH3)2], 12763, 127.65, 127.68
2H, PhCH2O), 5.04 (sbr, 1H, NH), 5.57 (dt, J = 15.4, (3d, ArC), 128.32 (d, CH=CHCH2), 131.63 (d,
6.3, 1H, CH=CHCH2), 5.64 (dd, J = 15.4, 6.6, 1H, CH=CHCHO), 137.92 (s, quart. ArC), 155.06 (s,
CH=CHCHO), 7.24–7.37 (m, 5H, ArH)
OCON), 172.25 (s, COO)

SYNTHESIS
September 1998
1325
Table 3. (continued)
Compound
[α]D20
1H NMR (300 MHz, CDCl3)
13C NMR (75 MHz, CDCl3)
(c, Solvent)
δ, J (Hz)
δ
3e
+ 7.2
1.31 [s, 3H, C(CH3)2], 1.36 [s, 3H, C(CH3)2], 1.38 [s, 25.18, 26.50, 26.89, 26.94 [4q, C(CH3)2], 35.15 (t,
(0.3, CHCl3) 6H, C(CH3)2], 2.57–2.58 (m, 2H, CH=CHCH2), 3.59 CH=CHCH2), 52.40 (q, OCH3), 53.19 (d, CHN),
(dd, J = 7.4, 7.1, 1H, CH2O), 3.75 (s, 3H, OCH3), 67.04 (t, PhCH2), 67.22 (t, CH2O), 76.50, 79.63,
3.87 (mc, 1H, CH2O), 4.04–4.11 (m, 2H, CHOC), 80.15 (3d, CHOC), 109.34 [s, C(CH3)2], 109.85 [s,
4.28 (dd, J = 7.8, 6.0, 1H, CH=CHCHO), 4.50 (dt, J C(CH3)2], 127.50, 128.52, 128.80, 128.81 (4d,
= 8.5, 5.3, 1H, CHN), 5.10 (s, 2H, PhCH2O), 5.35 (d, CH=CHCH2, ArC), 132.51 (d, CH=CHCHO),
J = 8.5, 1H, NH), 5.37–5.80 (m, 2H, CH=CH), 7.26– 136.24 (s, quart. ArC), 155.74 (s, OCON), 171.93 (s,
7.36 (m, 5H, ArH)
COO)
3f
+ 3.7
0.79 (t, J = 6.2, 3H, CH2CH3), 1.20 (m, 6H, CH2), 18.34 (q, CH2CH3), 22.42 (t, CH2CH3), 25.86 [q,
(1.0, CHCl3) 1.31 [s, 3H, C(CH3)2], 1.34 [s, 3H, C(CH3)2], 2.35 C(CH3)2], 26.64 [q, C(CH3)2], 29.22 (t, CH2), 30.17
(mc, 1H, CH=CHCHC), 3.45 (t, J = 7.9, 1H, CH2O), (t, CH2), 45.87 (d, CH=CHCHC), 51.99 (q, OCH3),
3.64 (s, 3H, OCH3), 3.98 (dd, J = 7.9, 6.2, 1H, 57.38 (d, CHN), 67.06 (t, PhCH2), 69.59 (t, CH2O),
CH2O), 4.25–4.40 (m, 2H, CHOC, CHN), 5.00 (d, J 76.44 (d, CHOC), 109.36 [s, C(CH3)2], 128.18,
= 13.0, 1H, PhCH2O), 5.07 (d, J = 13.0, 1H, 128.51, 128.53 (3d, ArC), 131.49 (d, CH=CH),
PhCH2O), 5.16 (d, J = 7.7, 1H, NH), 5.33–5.51 (m, 132.96 (d, CH=CH), 136.21 (s, quart. ArC), 155.73
2H, CH=CH), 7.28 (sbr, 5H, ArH)
(s, OCON), 171.68 (s, COO)
3g
3h
3i
–10.5
1.63 (s, 3H, CH3), 2.75 (dd, J = 14.0, 7.3, 1H, 23.36 (q, CH3), 40.51 (t, CH=CHCH2), 52.71 (q,
(0.7, CHCl3) CH=CHCH2), 2.97 (mc, 1H, CH=CHCH2), 3.76 (s, OCH3), 59.94 (s, CN), 66.51 (t, PhCH2), 123.5 (d,
3H, OCH3), 5.07 (d, J = 12.3, 1H, PhCH2), 5.13 (d, J PhCH=CH), 126.29, 127.50, 128.04, 128.09, 128.51
= 12.3, 1H, PhCH2), 5.57 (sbr, 1H, NH), 6.02 (dt, J = (5d, ArC), 134.44 (d, PhCH=CH), 136.50, 136.98
15.4, 7.7, 1H, PhCH=CH), 6.42 (d, J = 15.8, 1H, (2s, quart. ArC), 154.73 (s, OCON), 174.22 (s, COO)
PhCH=CH), 7.19–7.35 (m, 10H, ArH)
+ 15.3
3.39 (dd, J = 13.6, 7.7, 1H, CH=CHCH2), 3.72 (sbr, 37.27 (t, CH=CHCH2), 53.28 (q, OCH3), 65.49 (s,
(1.0, CHCl3) 4H, CH=CHCH2, OCH3), 5.00 (d, J = 12.3, 1H, CN), 66.55 (t, PhCH2), 123.65 (d, PhCH=CH),
PhCH2), 5.13 (d, J = 12.3, 1H, PhCH2), 6.04 (dt, J = 126.01, 126.33, 127.47, 128.02, 128.06, 128.50,
15.4, 7.7, 1H, PhCH=CH), 6.39 (sbr, 1H, NH), 6.48 128.63 (7d, ArC), 134.55 (d, PhCH=CH), 136.55,
(d, J = 15.4, 1H, PhCH=CH), 7.21–7.90 (m, 15H, 137.15, 139.56 (3s, quart. ArC), 154.15 (s, OCON),
ArH)
172.56 (s, COO)
– 10.5
2.79 (dd, J = 13.9, 7.7, 1H, CH=CHCH2), 3.15 (d, J 39.25 (t, PhCH2C), 40.94 (t, CH=CHCH2), 52.64 (q,
(3.1, CHCl3) = 13.4, 1H, PhCH2C), 3.41 (dd, J = 13.9, 7.7, 1H, OCH3), 65.65 (s, CN), 66.32 (t, PhCH2O), 123.55 (d,
CH=CHCH2), 3.66 (d, J = 13.4, 1H, PhCH2C), 3.76 PhCH=CH), 126.30, 126.95, 127.42, 128.28, 128.52,
(s, 3H, OCH3), 5.11 (d, J = 12.3, 1H, PhCH2O), 5.20 128.77, 129.73 (7d, ArC), 134.12 (d, PhCH=CH),
(d, J = 12.3, 1H, PhCH2O), 5.67 (sbr, 1H, NH), 5.98 135.98, 136.84, 137.12 (3s, quart. ArC), 154.41 (s,
(dt, J = 15.4, 7.7, 1H, PhCH=CH), 6.44 (d, J = 15.4, OCON), 172.69 (s, COO)
1H, PhCH=CH), 6.95–7.88 (m, 15H, ArH)
3k
+ 7.7
1.36 [s, 3H, C(CH3)2], 1.39 [s, 3H, C(CH3)2], 1.56 (s, 23.27 (q, CH3), 25.83 [q, C(CH3)2], 26.66 [q,
(1.0, CHCl3) 3H, CH3), 2.59 (dd, J = 14.0, 6.0, 1H, CH=CHCH2), C(CH3)2], 39.47 (t, CH=CHCH2), 52.72 (q, OCH3),
2.84 (m, 1H, CH=CHCH2), 3.46 (dd, J = 7.9, 7.9, 1H, 59.63 (s, CN), 66.52 (t, PhCH2), 69.36 (t, CH2O),
CH2O), 3.73 (s, 3H, OCH3), 4.02 (dd, J = 8.1, 6.3, 76.18 (d, CHO), 109.29 [s, C(CH3)2], 127.95 (d,
1H, CH2O), 4.41 (mc, 1H, CHO), 5.04 (d, J = 12.3, CH=CHCH2), 128.09, 128.15, 128.52 (3d, ArC),
1H, PhCH2), 5.09 (d, J = 12.3, 1H, PhCH2), 5.45– 132.76 (d, CHOCH=CH), 136.43 (s, quart. ArC),
5.62 (m, 3H, CH=CHNH), 7.30–7.36 (m, 5H, ArH)
154.57 (s, OCON), 174.07 (s, COO)
3l
– 10.9
0.74 (t, J = 7.4, 3H, CH2CH3), 1.33 [s, 3H, C(CH3)2], 8.11 (q, CH2CH3), 25.62 [q, C(CH3)2], 26.44 [q,
(0.7, CHCl3) 1.36 [s, 3H, C(CH3)2], 1.77 (dq, J = 7.4, 7.4, 1H, C(CH3)2], 28.18 (t, CH2CH3), 37.74 (t,
CH2CH3), 2.28 (dq, J = 7.4, 7.4, 1H, CH2CH3), 2.51 CH=CHCH2), 52.56 (q, OCH3), 64.30 (s, CN), 66.08
(dd, J = 14.2, 5.7, 1H, CH=CHCH2), 3.03 (J = 13.8, (t, PhCH2), 69.11 (t, CH2O), 76.38 (d, CHO), 109.98
6.1, 2H, CH=CHCH2), 3.40 (dd, J = 8.1, 7.7, 1H, [s, C(CH3)2], 127.78, 127.90, 128.01, 128.31 (4d,
CH2O), 3.74 (s, 3H, OCH3), 3.97 (dd, J = 8.1, 6.3, CH=CHCH2, ArC), 132.02 (d, CHOCH=CH),
1H, CH2O), 4.36 (mc, 1H, CHO), 4.99–5.09 (m, 2H, 136.33 (s, quart. ArC), 153.80 (s, OCON), 173.27 (s,
PhCH2), 5.45 (dt, J = 15.4, 5.5, 1H, CHOCH=CH), COO)
5.61 (dd, J = 15.4, 6.3, 1H, CHOCH=CH), 5.74 (s,
1H, NH) 7.29–7.34 (m, 5H, ArH)

SYNTHESIS
Papers
1326
60°C) were generally used as eluents. TLC: commercially precoated
Polygram SIL-G/UV 254 plates (Macherey–Nagel). Visualization
(2) Vekemans, J. A. J. M.; de Bruyn, R. G. M.; Caris, R. C. H. M.;
Kokx, A. J. P. M.; Konings, J. J. H. G.; Godefroi, E. F. J. Org.
Chem. 1987, 52, 1093.
1
was accomplished with UV light, I2, and KMnO4 soln. H and 13C
NMR: Bruker AC-300 spectrometer. Enantiomeric and diastereomer-
ic ratios were determined by analytical HPLC using a Knauer Euro-
sphere column (250 × 4 mm, Si80, 5 µm, flow: 2 mL/min), as well as
a Chiracel-OD-H column (Daicel) (0.5 mL/min) and a Knauer UV
detector. Optical rotations were measured on a Perkin–Elmer pola-
rimeter PE 241.
Schmidt, U.; Lieberknecht, A.; Kazmaier, U.; Griesser, H.;
Jung, G.; Metzger, J. Synthesis 1991, 49.
Jackson, R. F. W.; Palmer, N. J.; Wythes, M. J. J. Chem. Soc.,
Chem. Commun. 1994, 95.
Estevez, J. C.; Estevez, R. J.; Ardron, H.; Wormald, M. R.;
Brown, D.; Fleet, G. W. J. Tetrahedron Lett. 1994, 35, 8885.
(3) Barrett, A. G. M.; Edmunds, J. J.; Hendrix, J. A.; Malecha, J.
W.; Parkinson, C. J. J. Chem. Soc., Chem. Commun. 1992,
1240.
Synthesis of Amino Acid Allylic Esters 2; General Procedure:
The allylic ester derivatives used as substrates were synthesized by
the method described by Steglich et al.14 To a solution of allylic alco-
hol 1 (1 mmol) in CH2Cl2 (5 mL) was added DMAP (0.1 mmol). The
mixture was stirred for 5 min, before a solution of DCC (1.1 mmol )
in CH2Cl2 (3 mL) was added, followed by the N-protected amino acid
(1.1 mmol) in CH2Cl2 (5 mL). The mixture was stirred at r.t. over-
night. The precipitate was filtered off, and the filtrate was washed
with 1 N KHSO4, sat. NaHCO3 and brine. After evaporation of the
solvent in vacuo, the residue obtained was purified by flash chroma-
tography (EtOAc/petroleum ether).
Varela, O.; Nin, A. P.; de Lederkremer, R. M. Tetrahedron Lett.
1994, 35, 9359.
Brandstetter, T. W.; Kim, Y.; Son, J. C.; Taylor, H. M.; Lilley,
P. M. de Q.; Watkin, D. J.; Johnson, L. N.; Oikonomakos, N. G.;
Fleet, G. W. J. Tetrahedron Lett. 1995, 36, 2149.
(4) Wagner, I.; Musso, H. Angew. Chem. 1983, 95, 827; Angew.
Chem., Int. Ed. Engl. 1983, 22, 816.
Jackson, R. F. W.; Rettie, A. B.; Wood, A.; Wythes, M. J.
J. Chem. Soc., Perkin Trans. 1 1994, 1719.
Postels, H.-T.; König, W. A. Tetrahedron Lett. 1994, 35, 4535.
Mulzer, J.; Meier, A. J. Org. Chem. 1996, 61, 566.
(5) Baldwin, J. E.; Fieldhouse, R.; Russell, A. T. Tetrahedron Lett.
1993, 34, 5491.
Shioiri, T.; Matsura, F.; Hamada, Y. Pure Appl. Chem. 1994,
66, 2151.
(6) Park, K. H.; Yoon, Y. J.; Lee, S. G. J. Chem. Soc., Perkin Trans.
1 1994, 2621.
Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997, 38, 8009.
Schneider, C.; Kazmaier, U. Tetrahedron Lett. 1998, 39, 817.
(7) Williams, R. M. Synthesis of Optically Active α-Amino Acids;
Pergamon: Oxford, 1989.
Chelate Enolate Claisen Rearrangement; General Procedure:
Freshly prepared LDA solution (2.5 mmol) in THF (7 mL) was added
to a stirred solution of the allylic ester (1 mmol) and ZnCl2 (1.1 mmol)
in anhyd THF at –78°C. The mixture was allowed to warm to r.t.
overnight. The resulting clear solution was diluted with Et2O and hy-
drolyzed with 1 N KHSO4. After separation of the aqueous layer, the
crude rearrangement product was extracted with 1 N NaOH. After
acidification of the aqueous layer with 1 N KHSO4, the product was
extracted twice with Et2O and the solvent was removed in vacuo. For
determination of selectivity the crude product was treated with a so-
lution of diazomethane in Et2O and purified by flash chromatography
on silica gel (EtOAc/petroleum ether).
(8) Bartlett, P. A. Tetrahedron 1980, 36, 3.
Ziegler, F. E. Chem. Rev. 1988, 88, 1423.
Determination of Configuration via Ozonolysis:
Blechert, S. Synthesis 1989, 71.
Starting from allylic ester 2a (S-configuration) (82 mg, 0.25 mmol)
and following the general procedure for the chelate enolate Claisen
rearrangement, the crude amino acid 3a (80 mg) was obtained. This
amino acid was dissolved in MeOH (30 mL), and after addition of
2,3-dimethylbutene (31 mg, 0.37 mmol) the solution was cooled to
–60°C. After ozonolysis for 5 min, the mixture was allowed to warm
to r.t. overnight. The solvent was removed in vacuo, and the residue
obtained was dissolved in EtOAc. After washing the organic layer
with 1 N HCl, the product was extracted twice with 1 N NaOH. The
aqueous solution was acidified with 1 N HCl and extracted twice with
EtOAc. After drying (Na2SO4) and evaporation of the solvent, Z-Asp
was obtained, which was converted into the corresponding dimethyl
ester with diazomethane. HPLC analysis using a Chiracel-OD-H col-
umn (Daicel) (hexane/EtOH 8:2; 0.5 mL/min), and comparison with
Wipf, P. In Comprehensive Organic Synthesis, Vol 5; Trost, B.
M.; Fleming, I.; Paquette, L. A., Eds.; Pergamon: Oxford, 1991;
p 827.
Altenbach H. In Organic Synthesis Highlights; Mulzer, J.; Al-
tenbach, H.-J.; Braun, M.; Krohn, K.; Reissig H.-U., Eds.;
VCH: Weinheim, 1991; pp 111, 116.
Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17.
Frauenrath, H. In Houben-Weyl, 4th ed., Vol. E21; Helmchen,
G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme:
Stuttgart, 1996; p 3301 and references cited therein.
(9) Kazmaier, U. Angew. Chem. 1994, 106, 1046; Angew. Chem.,
Int. Ed. Engl. 1994, 33, 998.
(10) Review: Kazmaier, U. Liebigs Ann. Chem./Recl. 1997, 285.
(11) Kazmaier, U.; Krebs, A. Angew. Chem. 1995, 107, 2213;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2012.
samples obtained from (S)-Asp and (R/S)-Asp (tR(S): 20.27 min; tR(R)
:
22.95 min), determined the configuration of the rearrangement prod-
uct to be (R).
Krebs, A.; Kazmaier, U. Tetrahedron Lett. 1996, 37, 7945.
(12) Kazmaier, U.; Schneider, C. Synlett 1996, 975.
(13) Schneider, C.; Kazmaier, U. Synthesis 1998, 1314.
(14) Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556; Angew.
Chem., Int. Ed. Engl. 1978, 17, 522.
(15) Because the chiral center of the amino acid is destroyed during
enolate formation, racemic amino acids were used.
(16) Kazmaier, U.; Maier, S. J. Chem. Soc., Chem. Comm. 1995,
1991.
We thank Prof. Dr. G. Helmchen for his generous support of this
work. Financial support by the Deutsche Forschungsgemeinschaft as
well as the Fonds der Chemischen Industrie is gratefully acknowl-
edged.
Kazmaier, U.; Maier, S. Tetrahedron 1996, 52, 941.
Schoemaker, H. E. Acta. Chem. Scand. 1996, 50, 225.
Wirth, T. Angew. Chem. 1997, 109, 235; Angew. Chem., Int. Ed.
Engl. 1997, 36, 225 and references cited therein.
(17) For analytical purposes a mixture of stereoisomers was obtained
by rearrangement of the corresponding esters of racemic or epi-
meric allylic alcohols.
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