Stereoselective synthesis of β-branched phenylalanine derivatives via chelate-claisen rearrangement

Article abstract of DOI:10.1055/s-0028-1088121

Ester enolate Claisen rearrangement of chelated N-protected chiral amino acid cinnamyl esters results in the formation of substituted phenylalanine derivatives with unsaturated side chains in good yields and with a high degree of chirality transfer. Georg

Full text of DOI:10.1055/s-0028-1088121

PAPER
1725
Stereoselective Synthesis of b-Branched Phenylalanine Derivatives via
Chelate-Claisen Rearrangement
Stereoselective
S
h
b
r
-Branc
h
i
edPhen
s
ylalanine
t
Deriva
i
tives an Quirin, Uli Kazmaier*
Institut für Organische Chemie, Universität des Saarlandes, Geb. C4.2, 66123 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 20 November 2008; revised 9 January 2009
rangement using chelated ester enolates.11 Because of the
fixed enolate geometry, due to chelation, and the preferred
chair-like transition state the rearrangement proceeds with
a high degree of diastereoselectivity. By using amino acid
esters of chiral allylic alcohols, optically active amino
acids can be obtained with excellent 1,3-chirality trans-
fer.12
Abstract: Ester enolate Claisen rearrangement of chelated N-pro-
tected chiral amino acid cinnamyl esters results in the formation of
substituted phenylalanine derivatives with unsaturated side chains
in good yields and with a high degree of chirality transfer.
Key words: amino acids, chelates, esters, rearrangements, stereo-
selective synthesis
Herein we report on an application of the chelate enolate
Claisen rearrangement towards the synthesis of b-alkylat-
ed phenylalanines, which are interesting candidates for
the modification of natural products such as bottromycin.
In human metabolism peptides fulfill important functions
as neurotransmitters or substrates for enzymes, which
makes them interesting lead structures for the develop-
ment of peptide based drugs. Nevertheless their use is re-
stricted, because of their polarity the resorption is often
bad. Further more fast elimination via the liver or kidneys
can also be a problem, and finally peptides underlie meta-
bolic degradation in the gastrointestinal tract and are not
stable. Hence different precautions have to be taken to
avoid these disadvantages. One possibility is the introduc-
tion of amino acids with unnatural side chains into pep-
tides.1 For example, the incorporation of b-branches
increases the stability against enzymymatic degradation.2
b-Alkylated amino acids are also found widespread in na-
ture, for example in bottromycin, which contains nearly
exclusively branched amino acids.3 Therefore, these un-
usual amino acids are interesting building blocks for pep-
tidomimetics, and not surprisingly, a wide range of
different protocols for their stereoselective synthesis has
been developed in the last decades.4
These phenylalanine analogues are easily accessible from
substituted cinnamyl alcohols 1, which can be obtained
enantiomerically pure from the racemate (see experimen-
tal) via enzymatic kinetic resolution using Novozyme
435® (Table 1).13 In the presence of vinyl acetate the R-
configured acetates were formed and the desired S-config-
ured allylic alcohols remained in high optical purity.
Table 1 Enzymatic Kinetic Resolution with Novozyme 435®
OH
R1
OH
R1
OAc
Novozyme
(10 equiv)
Ar
Ar
24 h
1a–g
(S)-1a–g
Entry Substrate Ar
R1
Me
Et
Product Yield (%) ee (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Ph
Ph
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
(S)-1g
49
42
46
49
47
44
44
98
>99
>99
>99
99
Our group is also involved in the synthesis of unnatural
amino acids, especially those with functionalized side
chains, using chelated amino acid ester enolates. These
chelated enolates can then be utilized for various reac-
tions, for example, Michael additions,5 aldol reactions,6 or
palladium-7 and rhodium-catalyzed allylic alkylations,8
which all allow the stereoselective introduction of b-sub-
stituents.
4-MeOC6H4 Me
naphthyl Me
4-MeC6H4 Me
4-BrC6H4
4-BrC6H4
Me
Et
99
a
1g
–
Especially for the introduction of g,d-unsaturated side
chains the Claisen rearrangement is a very suitable meth-
od. In 1975 Steglich9 reported the first rearrangement of
allylic amino acid esters via oxazoles and Bartlett10 was
successful in Ireland–Claisen rearrangement using the
same intermediates a few years later. In the 1990s we de-
veloped a new protocol for the ester enolate Claisen rear-
a No separation of the enantiomers was accomplished, neither by GC
nor by HPLC.
In the next step the allylic alcohols (S)-1a–g were coupled
with either Boc-protected glycine or alanine under
Steglich’s conditions14 to provide the chiral allylic amino
acid esters (S)-2a–h. The esters were subsequently sub-
jected to the chelate ester enolate Claisen rearrangement.
Deprotonation at –78 °C with LDA in the presence of
ZnCl2 resulted in the formation of chelated metal enolates,
SYNTHESIS 2009, No. 10, pp 1725–1731
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0028-1088121; Art ID: T20208SS
© Georg Thieme Verlag Stuttgart · New York

1726
C. Quirin, U. Kazmaier
PAPER
Table 2 DCC-Coupling and Claisen Rearrangement Products
R1
Ar
1. LDA (3.0 equiv)
ZnCl2 (1.2 equiv)
THF
R2
DCC
R1
Ar
OH
R1
R2
DMAP
R2
+
Et2O
0 °C to r.t.
BocHN
COOH
O
2. K2CO3 (1.2 equiv)
MeI (3.0 equiv)
DMF
Ar
BocHN
BocHN
COOMe
R2 = H, Me
(S)-1a–g
O
(S)-2a–h
(S,S)-3a–h
Entry
Alcohol Amino acid
Ester
Ar
Ph
Ph
Ph
R1
R2
Yield (%)
99
Product
(S,S)-3a
(S,S)-3b
(S,S)-3c
(S,S)-3d
(S,S)-3e
(S,S)-3f
(S,S)-3g
(S,S)-3h
Yield (%)
ee (%) ds (%)
1
2
3
4
5
6
7
8
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
(S)-1g
BocGlyOH
BocAlaOH
BocAlaOH
BocGlyOH
BocGlyOH
BocGlyOH
BocAlaOH
BocAlaOH
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-2f
(S)-2g
(S)-2h
Me
H
84
87
88
69
79
84
83
89
>99
>99
>99
>99
>99
98
>99
>99
>99
97
Me Me 96
Et
Me 96
4-MeOC6H4
2-naphthyl
4-MeC6H4
4-BrC6H4
4-BrC6H4
Me
Me
Me
H
H
H
97
93
94
99
>99
98
Me Me 99
Et Me 90
>99
97
>99
which undergo Claisen rearrangement upon warming to In conclusion, starting from the chiral allylic alcohols (S)-
room temperature and afford the g,d-unsaturated amino 1a–g we could synthesize a variety of optically active g,d-
acid esters (S,S)-3a–h in good yields and excellent diaste- unsaturated amino acids (S,S)-3a–h. With lactone (S,S)-5
reo- and enantioselectivities (Table 2).12 The alanine de- and iodolactone (S,S,R,S)-6 derivatives with constrained
rived allyl esters provide directly the corresponding a- side chains were also accessible.
alkylated amino acids.15
Finally we chose (S,S)-3b as an example to build up some
other interesting derivatives. Ozonolysis of the double
bond side chain and reductive workup with PPh3 yielded
aldehyde (S,S)-4 in 89%. Reduction of this aldehyde with
NaBH4 gave the five-membered lactone (S,S)-5 directly in
87% yield from the in situ developing alcohol. Of course
lactone formation also took place if NaBH4 was used as
All reactions were carried out in oven-dried glassware (100 °C) un-
der argon. All solvents were dried before use. THF was distilled
from LiAlH4. The products were purified by flash chromatography
on silica gel. TLC: commercially precoated Polygram® SIL-G/UV
254 plates. Visualization was accomplished with UV-light, I2, or
KMnO4 solution. Melting points are uncorrected. 1H and 13C NMR
were recorded on a Bruker DRX-500 spectrometer using CDCl3 as
solvent. Selected signals in the NMR spectra for the minor isomers
reducing reagent in the ozonolysis but the overall yield for are extracted from the spectra of the isomeric mixture. Enantio- and
diastereomeric excesses were determined on an analytical HPLC
using a Trentec Reprosil-100 Chiral-NR 8 mm column or a Chiracel
(S,S)-5 was higher with aldehyde (S,S)-4 as isolated inter-
mediate. Furthermore (S,S)-3b underwent an iodolacton-
OD-H column and a Shimadzu UV detector. As references, the ra-
ization on saponification of the methyl ester resulting in
cemic amino acids were obtained via rearrangement of the racemic
the iodolactone (S,S,R,S)-6 in 74% yield and 88% ds
allylic esters, which allows the differentiation between enantiomers
and diastereomers. Optical rotations were measured on a Perkin-
(Scheme 1).16
Elmer polarimeter PE 241. High-resolution mass spectra were re-
corded on a Finnigan MAT 95 (CI) mass spectrometer. Elemental
analyses were carried out at the department of chemistry, University
of Saarbrücken.
O
Ph
Ph
NaBH4
87%
1. O3
2. Ph3P
O
Compounds 1a and 1b were prepared via Grignard reaction from
cinnamyl aldehyde. Compounds 1c–f were prepared by carbonyl
olefination of the p-substituted benzaldehyde derivatives using the
Horner17 or Wittig reagent derived from chloroacetone, and subse-
quent Luche reduction.18 Compound 1g was obtained from p-bro-
mobenzaldehyde by Knoevenagel reaction and conversion of the
resulting cinnamyl acid to the corresponding a,b-unsaturated ethyl
ketone,19 which was finally reduced by the Luche protocol.
BocHN
COOMe
89%
BocHN
Ph
(S,S)-4
O
(S,S)-5
I
BocHN
COOMe
Ph
(S,S)-3
1. NaOH
2. I2, Et3N
I+
O–
O
Ph
BocHN
74%
O
(S,S,R,S)-6
Enzymatic Kinetic Resolution with Novozyme 435® of 1a–g;
General Procedure I
The racemic allylic alcohol 1 (1.0 equiv) was dissolved in vinyl
acetate (10 equiv) and Novozyme 435® (5 weight%) was added. Af-
ter shaking for 24 h, the enzyme was filtered off and washed with
BocHN
O
Scheme 1 Derivatization of rearrangement product (S,S)-3
Synthesis 2009, No. 10, 1725–1731 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of b-Branched Phenylalanine Derivatives
1727
Et2O (3 × 20 mL).The solvent was removed by rotary evaporation
and the enantiopure alcohol was separated from the corresponding
acetate by column chromatography (silica gel, hexanes–EtOAc).
After the addition of DMAP (0.2 equiv), the solution was cooled to
0 °C and DCC (1.2 equiv) was added in one portion. The mixture
was allowed to stir and warmed overnight up to r.t. The precipitated
DCU was filtered through a pad of Celite, washed with Et2O (50
mL) and the combined organic layers were concentrated in vacuo.
The crude product was purified by column chromatography (silica
gel, hexanes–EtOAc) to afford the allylic amino acid ester.
(S,E)-4-Phenylbut-3-en-2-ol [(S)-1a]20
Yield: 49%; 98% ee; white solid; mp <30 °C; Rf = 0.41 (hexanes–
EtOAc, 1:1); ee was determined by HPLC (Chiracel OD-H,
hexanes–i-PrOH, 90:10, flow 1 mL/min): tR (R)-1a = 8.26 min, tR
(S)-1a = 12.48 min; [a]D20 –27.0 (c = 1.0, CHCl3).
(S,E)-4-Phenylbut-3-en-2-yl 2-(tert-Butoxycarbonylamino)ace-
tate [(S)-2a]
(S,E)-1-Phenylpent-1-en-3-ol [(S)-1b]21
Yield: 42%; 99% ee; colorless oil; ee was determined by HPLC
(Chiracel OD-H, hexanes–i-PrOH, 90:10, flow 1 mL/min): tR (R)-
1b = 7.01 min, tR (S)-1b = 10.20 min; [a]D20 –4.5 (c = 1.0, CHCl3).
From BocGlyOH (1.72 g, 9.82 mmol), allylic alcohol (S)-1a (1.46
g, 9.82 mmol), DMAP (0.24 g, 1.96 mmol), and DCC (2.43 g, 11.8
mmol), the allylic ester (S)-2a (3.00 g, 9.82 mmol, ~100%, 98% ee)
was obtained as a white solid; mp 87 °C; ee was determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 97:3, flow
(S,E)-1-(4-Methoxyphenyl)pent-1-en-3-ol [(S)-1c]22
Yield: 46%, >99% ee; white solid; mp 81 °C; ee was determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 97:3, flow
2 mL/min): tR (R)-1c = 8.54 min, tR (S)-1c = 8.96 min; [a]D20 –38.5
(c = 1.0, CHCl3).
1 mL/min): tR (R)-2a = 17.81 min, tR (S)-2a = 20.28 min; [a]D
–53.8 (c = 1.0, CHCl3).
20
1H NMR (500 MHz, CDCl3): d = 1.36 (d, 3J = 6.5 Hz, 3 H), 1.38 (s,
9 H), 3.82 (dd, 2J = 18.3 Hz, 3J = 5.2 Hz, 1 H), 3.88 (dd, 2J = 18.3
Hz, 3J = 5.5 Hz, 1 H), 4.94 (br s, 1 H), 5.52 (dq, 3J = 6.5, 6.5 Hz, 1
H), 6.10 (dd, 3J = 16.0 Hz, 3J = 6.9 Hz, 1 H), 6.54 (d, 3J = 16.0 Hz,
1 H), 7.18 (m, 1 H), 7.24 (m, 2 H), 7.30 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 20.3 (q), 28.3 (q), 42.7 (t), 72.3
(d), 79.9 (s), 126.6 (d), 128.0 (s), 128.1 (d), 128.6 (d), 132.2 (d),
136.1 (s), 155.7 (s), 169.6 (s).
(S,E)-4-(Naphthalen-2-yl)but-3-en-2-ol [(S)-1d]
Yield: 49%, >99% ee; white solid; mp 85 °C; ee was determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow
2 mL/min): tR (R)-1d = 22.51, tR (S)-1d = 23.52 min; [a]D20 –26.1
(c = 1.0, CHCl3).
HRMS (CI): m/z calcd for C17H24NO4 [M + H]+: 306.1705; found:
306.1690.
3
1H NMR (400 MHz, CDCl3): d = 1.40 (d, J = 6.4 Hz, 3 H), 1.67
(br s, 1 H), 4.54 (ddq, 3J = 6.4, 6.4 Hz, 3J = 1.1 Hz, 1 H), 6.38 (dd,
3J = 15.9 Hz, 3J = 6.4 Hz, 1 H), 6.72 (d, 3J = 15.9 Hz, 1 H), 7.44
(m, 2 H), 7.58 (dd, 3J = 8.6 Hz, 4J = 1.7 Hz, 1 H), 7.71 (br s, 1 H),
7.78 (m, 3 H).
Anal. Calcd for C17H23NO4 (305.37): C, 66.86; H, 7.59; N, 4.59.
Found: C, 66.75; H, 7.44; N, 4.25.
13C NMR (100 MHz, CDCl3): d = 23.5 (q), 69.0 (d), 123.5 (d), 125.9
(d), 126.3 (d), 126.4 (d), 127.6 (d), 127.9 (d), 128.2 (d), 129.5 (d),
133.0 (s), 133.6, 133.9 (s, d), 134.1 (s).
HRMS (CI): m/z calcd for C14H14O [M]+: 198.1045; found:
198.1002.
(S)-[(S,E)-4-Phenylbut-3-en-2-yl] 2-(tert-Butoxycarbonylami-
no)propanoate [(S)-2b]
From BocAlaOH (1.78 g, 9.39 mmol), allylic alcohol (S)-1a (1.40
g, 9.39 mmol), DMAP (0.23 g, 1.88 mmol), and DCC (2.33 g, 11.3
mmol), the ester (S)-2b (2.88 g, 9.03 mmol, 96%, >99% ee) was ob-
tained as a white solid; mp 80–82 °C; ee was determined by HPLC
(Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 90:10, flow 1 mL/
min): tR (S)-2b = 19.07 min; [a]D20 –95.3 (c = 1.0, CHCl3).
(S,E)-1-p-Tolylpent-1-en-3-ol [(S)-1e]23
Yield: 47%; 99% ee; colorless oil; ee was determined by HPLC
(Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow 2 mL/
min): tR (R)-1e = 16.54 min, tR (S)-1e = 17.89 min; [a]D20 –22.8
(c = 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.31 (d, 3J = 7.2 Hz, 3 H), 1.37
3
(m, 12 H), 4.24 (m, 1 H), 4.98 (d, J = 5.0 Hz, 1 H), 5.49 (ddq,
3J = 6.5, 6.5 Hz, 4J = 0.9 Hz, 1 H), 6.10 (dd, 3J = 15.9 Hz, 3J = 6.8
Hz, 1 H), 6.54 (d, 3J = 15.9 Hz, 1 H), 7.18 (m, 1 H), 7.24 (m, 2 H),
7.30 (m, 2 H).
(S,E)-4-(4-Bromophenyl)but-3-en-2-ol [(S)-1f]23
13C NMR (125 MHz, CDCl3): d = 18.7 (q), 20.4 (q), 28.3 (q), 49.4
(d), 72.1 (d), 79.8 (s), 126.6 (d), 128.0 (d), 128.2 (d), 128.6 (d),
132.0 (d), 136.2 (s), 155.1 (s), 172.6 (s).
HRMS (CI): m/z calcd for C18H26NO4 [M + H]+: 320.1862; found:
320.1837.
Yield: 44%, 99% ee; white solid; mp 62 °C; ee was determined after
derivatization to the appropriate acetate using Ac2O by GC (Chira-
sil-Dex CB, T0 [3 min] = 80 °C, 2 °C/min to T = 200 °C [20 min],
injector = 250 °C, detector = 275 °C): tR (S)-1f = 47.12 min, tR (R)-
1f = 48.00 min; [a]D20 –25.5 (c = 1.0, CHCl3).
Anal. Calcd for C18H25NO4 (319.40): C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.82; H, 7.80; N, 4.39.
(S,E)-1-(4-Bromophenyl)pent-1-en-3-ol [(S)-1g]
Yield: 44%; 99% ee; colorless oil; [a]D20 –4.5 (c = 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.95 (t, 3J = 7.5 Hz, 3 H), 1.58 (br
s, 1 H) 1.64 (m, 2 H), 4.19 (ddt, 3J = 6.5, 6.5 Hz, 3J = 1.0 Hz, 1 H),
6.19 (dd, 3J = 15.9 Hz, 3J = 6.6 Hz, 1 H), 6.50 (d, 3J = 15.9 Hz, 1
H), 7.22 (m, 2 H), 7.41 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 9.7 (q), 30.2 (t), 74.2 (d), 121.3
(s), 128.0 (d), 129.1 (d), 131.7 (d), 133.1 (d), 135.7 (s).
(S)-[(S,E)-1-Phenylpent-1-en-3-yl] 2-(tert-Butoxycarbonylami-
no)propanoate [(S)-2c]
From BocAlaOH (0.85 g, 4.50 mmol), allylic alcohol (S)-1b (0.73
g, 4.50 mmol), DMAP (0.11 g, 0.90 mmol) and DCC (1.11 g, 5.40
mmol) allylic ester (S)-2c (1.45 g, 4.34 mmol, 96%, >99% ee) was
obtained as a waxy solid; ee was determined by HPLC (Reprosil
100 Chiral-NR 8 mm, hexanes–i-PrOH, 97:3, flow 1 mL/min): tR
(S)-2 = 40.20 min; [a]D20 –73.0 (c = 1.0, CHCl3).
HRMS (CI): m/z calcd for C11H13BrO [M]+: 240.0150; found:
240.0159.
1H NMR (500 MHz, CDCl3): d = 0.93 (t, 3J = 7.4 Hz, 3 H), 1.37
(d, 3J = 7.2 Hz, 3 H), 1.42 (s, 9 H), 1.75 (m, 2 H), 4.32 (m, 1 H),
5.03 (br s, 1 H), 5.35 (m, 1 H), 6.09 (dd, 3J = 15.9 Hz, 3J = 7.4 Hz,
1 H), 6.59 (d, 3J = 15.9 Hz, 1 H), 7.23 (m, 1 H), 7.30 (m, 2 H), 7.35
(m, 2 H).
DCC-Coupling Reactions with Boc-Protected Glycine or
Alanine; General Procedure II
The enantiopure alcohol (S)-1 (1.0 equiv) was dissolved together
with BocGlyOH or BocAlaOH (1.0 equiv) in Et2O (15 mL/mmol).
Synthesis 2009, No. 10, 1725–1731 © Thieme Stuttgart · New York

1728
C. Quirin, U. Kazmaier
PAPER
13C NMR (125 MHz, CDCl3): d = 9.5 (q), 18.7 (q), 27.6 (t), 28.3 (q),
49.4 (d), 77.1 (d), 79.7 (s), 126.6 (d), 126.9 (d), 128.0 (d), 128.6 (d),
133.0 (d), 136.3 (s), 155.1 (s), 172.7 (s).
13C NMR (100 MHz, CDCl3): d = 20.4 (q), 21.2 (q), 28.3 (q), 42.7
(t), 72.5 (d,), 79.9 (s), 126.5 (d), 127.0 (d), 129.3 (d), 132.1 (d),
133.3 (s), 137.9 (s), 155.6 (s), 169.6 (s).
HRMS (CI): m/z calcd for C19H27NO4 [M]+: 333.1940; found:
HRMS (CI): m/z calcd for C18H25NO4 [M]+: 319.1784; found:
333.1934.
319.1781.
(S,E)-4-(4-Methoxyphenyl)but-3-en-2-yl 2-(tert-Butoxycarbon-
ylamino)acetate [(S)-2d]
(S)-[(S,E)-4-(4-Bromophenyl)but-3-en-2-yl] 2-(tert-Butoxycar-
bonylamino)propanoate [(S)-2g]
From BocGlyOH (182 mg, 1.04 mmol), allylic alcohol (S)-1c (185
mg, 1.04 mmol), DMAP (25.7 mg, 0.21 mmol), and DCC (258 mg,
1.25 mmol), the ester (S)-2d (340 mg, 1.01 mmol, 97%, >99% ee)
was obtained as a colorless oil; ee was determined by HPLC
(Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 97:3, flow 1 mL/
min): tR (S)-2d = 36.24 min; [a]D20 –2.0 (c = 1.0, CHCl3).
From BocAlaOH (369 mg, 1.95 mmol), allylic alcohol (S)-1f (443
mg, 1.95 mmol), DMAP (47.6 mg, 0.39 mmol), and DCC (483 mg,
2.34 mmol), the ester (S)-2g (750 mg, 1.95 mmol, 100%, >99% ee)
was obtained as a white solid; mp 51 °C; ee was determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 90:10,
20
flow 1 mL/min): tR (S)-2g = 16.03 min; [a]D –76.7 (c = 1.0,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.40 (d, 3J = 6.5 Hz, 3 H), 1.43 (s,
9 H), 3.79 (s, 3 H), 3.87 (dd, 2J = 18.6 Hz, 3J = 5.6 Hz, 1 H), 3.93
1H NMR (500 MHz, CDCl3): d = 1.36 (d, 3J = 7.2 Hz, 3 H), 1.41
(d, 3J = 6.6 Hz, 3 H), 1.42 (s, 9 H), 4.29 (m, 1 H), 5.01 (d, 3J = 5.4
Hz, 1 H), 5.51 (ddq, 3J = 6.4, 6.4 Hz, 4J = 0.6 Hz, 1 H), 6.13 (dd,
2
(dd, J = 18.4 Hz, 3J = 5.7 Hz, 1 H), 4.99 (br s, 1 H), 5.55 (dq,
3
3J = 6.6, 6.6 Hz, 1 H), 6.01 (dd, J = 15.9 Hz, 3J = 7.1 Hz, 1 H),
6.54 (d, 3J = 15.9 Hz, 1 H), 6.83 (m, 2 H), 7.29 (m, 2 H).
3J = 15.9 Hz, J = 6.7 Hz, 1 H), 6.52 (d, 3J = 15.9 Hz, 1 H), 7.21
3
(m, 2 H), 7.41 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 20.4 (q), 28.3 (q), 42.7 (t), 55.3
(q), 72.6 (d), 79.9 (s), 114.0 (d), 125.8 (d), 127.8 (d), 128.8 (s),
131.9 (d), 155.7 (s), 159.6 (s), 169.7 (s).
HRMS (CI): m/z calcd for C18H25NO5 [M]+: 335.1733; found:
335.1711.
13C NMR (125 MHz, CDCl3): d = 18.6 (q), 20.3 (q), 28.3 (q), 49.4
(d), 71.9 (d), 79.8 (s), 121.8 (s), 128.1 (d), 129.0 (d), 130.7 (d),
131.7 (d), 135.1 (s), 155.1 (s), 172.6 (s).
HRMS (CI): m/z calcd for C18H25BrNO4 [M + H]+: 398.0967;
found: 398.0920.
Anal. Calcd for C18H25NO5 (335.40): C, 64.46; H, 7.51; N, 4.18.
Found: C, 64.35; H, 7.49; N, 4.25.
Anal. Calcd for C18H24BrNO4 (398.30): C, 54.28; H, 6.07; N, 3.52.
Found: C, 54.62; H, 6.05; N, 3.77.
(S,E)-4-(Naphthalen-2-yl)but-3-en-2-yl 2-(tert-Butoxycarbonyl-
amino)acetate [(S)-2e]
(S)-[(S,E)-1-(4-Bromophenyl)pent-1-en-3-yl] 2-(tert-Butoxycar-
bonylamino)propanoate [(S)-2h]
From BocGlyOH (180 mg, 1.03 mmol), allylic alcohol (S)-1d (188
mg, 1.03 mmol), DMAP (25.7 mg, 0.21 mmol), and DCC (256 mg,
1.24 mmol), the ester (S)-2e (325 mg, 0.96 mmol, 93%, >99% ee)
was obtained as a white solid; mp 82 °C; ee was determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 90:10,
BocAlaOH (329 mg, 1.74 mmol), allylic alcohol (S)-1g (420 mg,
1.74 mmol), DMAP (42.6 mg, 0.35 mmol), and DCC (431 mg, 2.09
mmol) yielded (S)-2h (643 mg, 1.56 mmol, 90%, 99% ee) as a col-
orless solid; mp 62 °C; ee was determined by HPLC (Reprosil 100
Chiral-NR 8 mm, hexanes–i-PrOH, 97:3, flow 1 mL/min): tR (R)-
20
flow 1 mL/min): tR (S)-2e = 51.92 min; [a]D –111.6 (c = 1.0,
20
CHCl3).
2h = 20.15 min, tR (S)-2h = 20.79 min; [a]D –75.6 (c = 1.0,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 9 H), 1.46 (d, 3J = 6.5 Hz,
3 H), 3.90 (dd, 2J = 18.5 Hz, 3J = 5.5 Hz, 1 H), 3.96 (dd, 2J = 18.5
Hz, 3J = 5.8 Hz, 1 H), 5.01 (br s, 1 H), 5.63 (dq, 3J = 6.5, 6.5 Hz, 1
H), 6.28 (dd, 3J = 15.9 Hz, 3J = 6.9 Hz, 1 H), 6.76 (d, 3J = 15.9 Hz,
1 H), 7.44 (m, 2 H), 7.56 (dd, 3J = 8.6 Hz, 4J = 1.7 Hz, 1 H), 7.72
(br s, 1 H), 7.78 (m, 3 H).
1H NMR (500 MHz, CDCl3): d = 0.93 (t, 3J = 7.4 Hz, 3 H), 1.37 (d,
3J = 7.2 Hz, 3 H), 1.42 (s, 9 H), 1.74 (m, 2 H), 4.31 (m, 1 H), 5.02
3
(d, 3J = 4.9 Hz, 1 H), 5.33 (dt, J = 6.6, 6.6 Hz, 1 H), 6.07 (dd,
3J = 15.9 Hz, 3J = 7.2 Hz, 1 H), 6.52 (d, 3J = 15.9 Hz, 1 H), 7.21
(m, 2 H), 7.41 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 20.4 (q), 28.3 (q), 42.7 (t), 72.4
(d), 79.9 (s), 123.4 (d), 126.1 (d), 126.3 (d), 126.9 (d), 127.6 (d),
128.0 (d), 128.2 (d), 128.4 (d), 132.2 (s), 133.2 (s), 133.5 (d, s),
155.7 (s), 169.7 (s).
13C NMR (125 MHz, CDCl3): d = 9.5 (q), 18.7 (q), 27.5 (t), 28.3 (q),
49.4 (d), 76.8 (d), 79.8 (s), 121.8 (s), 127.8 (d), 128.1 (d), 131.7 (2
d), 135.2 (d), 155.1 (s), 172.2 (s).
Anal. Calcd for C19H26BrNO4 (412.32): C, 55.35; H, 6.36; N, 3.40.
Found: C, 55.39; H, 6.21; N, 3.78.
HRMS (CI): m/z calcd for C21H25NO4 [M]+: 355.1784; found:
355.1767.
Chelate Ester Enolate Claisen Rearrangement of Allylic Esters
(S)-2a–h; General Procedure III
(S,E)-4-p-Tolylbut-3-en-2-yl 2-(tert-Butoxycarbonylamino)ace-
tate [(S)-2f]
A stirred solution of the allylic ester (S)-2 (1.0 equiv) and ZnCl2 (1.2
equiv) in anhyd THF (5 mL/mmol) was cooled to –78 °C. A freshly
prepared LDA solution (3.0 equiv) in anhyd THF (0.9 mL/mmol)
was also cooled to –78 °C and added dropwise to the solution of the
allylic ester via transfer cannula. The solution was allowed to warm
overnight up to r.t.. The mixture was diluted with Et2O (50 mL) and
quenched with aq 1 M KHSO4 (20 mL). The aqueous layer was ex-
tracted with Et2O (3 × 15 mL) and the combined organic layers were
dried (Na2SO4). The solvent was removed in vacuo, the residue dis-
solved in anhyd DMF (5 mL/mmol), and K2CO3 (1.2 equiv) was
added. The suspension was cooled to 0 °C and MeI (3.0 equiv) was
added dropwise. The reaction mixture was stirred at r.t. for 5 h, di-
luted with EtOAc (30 mL), and washed with H2O (3 × 15 mL). The
organic layer was dried (Na2SO4), the solvent removed in vacuo,
BocGlyOH (178 mg, 1.10 mmol), allylic alcohol (S)-1e (193 mg,
1.10 mmol), DMAP (26.9 mg, 0.22 mmol), and DCC (270 mg, 1.31
mmol) yielded (S)-2f (295 mg, 0.92 mmol, 94%, >99% ee) as a
white solid; mp 67 °C; ee was determined by HPLC (Reprosil 100
Chiral-NR 8 mm, hexanes–i-PrOH, 90:10, flow 1 mL/min): tR
(S)-2f = 34.14 min; [a]D20 –143.5 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.50 (d, 3J = 6.5 Hz, 3 H), 1.52 (s,
9 H), 2.40 (s, 3 H), 3.95 (dd, 2J = 18.4 Hz, 3J = 5.4 Hz, 1 H), 4.02
2
(dd, J = 18.3 Hz, 3J = 5.6 Hz, 1 H), 5.09 (br s, 1 H), 2.64 (dq,
3J = 3J = 6.5 Hz, 1 H), 6.18 (dd, 3J = 15.9 Hz, 3J = 7.0 Hz, 1 H),
6.65 (d, 3J = 15.9 Hz, 1 H), 7.19 (m, 2 H), 7.34 (m, 2 H).
Synthesis 2009, No. 10, 1725–1731 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of b-Branched Phenylalanine Derivatives
1729
and the crude product was purified by column chromatography (sil-
ica gel, hexanes–EtOAc).
13C NMR (125 MHz, CDCl3): d = 13.6 (q), 20.1 (q), 25.6 (t), 28.3
(q), 51.9 (q), 56.6 (s), 62.5 (d), 79.7 (s), 125.8 (d), 127.4 (d), 128.5
(d), 129.0 (d), 136.9 (d), 139.1 (s), 154.6 (s), 173.4 (s).
(2S,3S,E)-Methyl 2-(tert-Butoxycarbonylamino)-3-phenylhex-
4-enoate [(S,S)-3a]
HRMS (CI): m/z calcd for C20H29NO4 [M]+: 347.2097; found:
347.2091.
According to general procedure III, allylic ester (S)-2a (400 mg,
1.31 mmol), ZnCl2 (214 mg, 1.57 mmol), DIPA (398 mg, 3.93
mmol), n-BuLi (2.46 mL, 3.93 mmol, 1.6 M in hexanes), K2CO3
(218 mg, 1.57 mmol), and MeI (558 mg, 3.93 mmol) reacted to give
(S,S)-3a (349 mg, 1.10 mmol, 84%, >99% ds, >99% ee); white sol-
id; mp 67–68 °C; diastereo- and enantioselectivities were deter-
mined by HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–
i-PrOH, 99:1, flow 2 mL/min): tR (S,S)-3a = 8.49 min; [a]D20 +64.7
(c = 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.35 (s, 9 H), 1.66 (dd, 3J = 6.2
Hz, 4J = 1.2 Hz, 3 H), 3.63 (s, 3 H), 3.66 (m, 1 H), 4.57 (m, 1 H),
4.79 (d, 3J = 8.0 Hz, 1 H), 5.57 (dq, 3J = 15.0 Hz, 3J = 6.3 Hz, 1
H), 5.68 (ddq, 3J = 15.2 Hz, 3J = 8.6 Hz, 4J = 1.5 Hz, 1 H), 7.16
(m, 2 H), 7.21 (m, 1 H), 7.29 (m, 2 H).
Anal. Calcd for C20H29NO4 (347.45): C, 69.14; H, 8.41; N, 4.03.
Found: C, 68.79; H, 8.23; N, 3.98.
(2S,3S,E)-Methyl 2-(tert-Butoxycarbonylamino)-3-(4-methoxy-
phenyl)hex-4-enoate [(S,S)-3d]
According to general procedure III, allylic ester (S)-2d (250 mg,
0.75 mmol), ZnCl2 (121 mg, 0.89 mmol), DIPA (226 mg, 2.24
mmol), n-BuLi (1.40 mL, 2.24 mmol, 1.6 M in hexanes), K2CO3
(122 mg, 0.89 mmol), and MeI (318 mg, 2.24 mmol) reacted to give
(S,S)-3d (181 mg, 0.52 mmol, 69%, 97% ds, >99% ee); white solid;
mp 54 °C; diastereo- and enantioselectivities were determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow
2 mL/min): tR (S,R)-3d = 12.96 min, tR (S,S)-3d = 16.50 min;
[a]D20 +79.8 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.36 (s, 9 H), 1.66 (m, 3 H), 3.62
(m, 4 H), 3.76 (s, 3 H), 4.51 (m, 1 H), 4.78 (d, 3J = 8.5 Hz, 1 H),
5.55 (dq, 3J = 15.2 Hz, 3J = 6.1 Hz, 1 H), 5.65 (ddq, 3J = 15.2 Hz,
3J = 8.4 Hz, 4J = 1.3 Hz, 1 H), 6.83 (m, 2 H), 7.07 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 18.0 (q), 28.2 (q), 51.6 (d), 51.8
(q), 57.9 (d), 79.9 (s), 127.1 (d), 128.0 (d), 128.5 (d), 128.6 (d),
129.0 (d), 139.7 (s), 155.2 (s), 172.2 (s).
HRMS (CI): m/z calcd for C18H26NO4 [M + H]+: 320.1862; found:
320.1845.
13C NMR (100 MHz, CDCl3): d = 18.0 (q), 28.2 (q), 50.6 (d), 51.8
(q), 55.2 (q), 58.0 (d), 79.9 (s), 114.1 (d), 128.2 (d), 128.9 (d), 129.3
(d), 131.6 (s), 155.2 (s), 158.6 (s), 172.3 (s).
Anal. Calcd for C18H25NO4 (319.40): C, 67.69; H, 7.89; N, 4.39.
Found: C, 68.08; H, 7.78; N, 4.00.
HRMS (CI): m/z calcd for C19H28NO5 [M + H]+: 350.1967; found:
350.1977.
(2S,3S,E)-Methyl 2-(tert-Butoxycarbonylamino)-2-methyl-3-
phenylhex-4-enoate [(S,S)-3b]
Anal. Calcd for C19H27NO5 (349.43): C, 65.31; H, 7.79; N, 4.01.
Found: C, 65.28; H, 7.72; N, 3.67.
According to general procedure III, allylic ester (S)-2b (1.42 g, 4.45
mmol), ZnCl2 (0.73 g, 5.34 mmol), DIPA (1.36 g, 13.4 mmol), n-
BuLi (8.38 mL, 13.4 mmol, 1.6 M in hexanes), K2CO3 (0.74 g, 5.34
mmol), and MeI (1.90 g, 13.4 mmol) reacted to give (S,S)-3b (1.29
g, 3.88 mmol, 87%, >99% ds, >99% ee); white solid; mp 104–
105 °C; diastereo- and enantioselectivities were determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow
2 mL/min): tR (S,S)-3b = 4.86 min; [a]D20 +15.6 (c = 1.0, CHCl3).
(2S,3S,E)-Methyl 2-(tert-Butoxycarbonylamino)-3-(naphtha-
len-2-yl)hex-4-enoate [(S,S)-3e]
According to general procedure III, allylic ester (S)-2e (250 mg,
0.74 mmol), ZnCl2 (120 mg, 0.88 mmol), DIPA (224 mg, 2.21
mmol), n-BuLi (1.38 mL, 2.21 mmol, 1.6 M in hexanes), K2CO3
(122 mg, 0.88 mmol), and MeI (314 mg, 2.21 mmol) reacted to give
(S,S)-3e (206 mg, 0.58 mmol, 79%, 99% ds, >99% ee); white solid;
mp 93 °C; diastereo- and enantioselectivities were determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow
2 mL/min): tR (S,R)-3e = 18.21 min; tR (S,S)-3e = 23.37 min;
[a]D20 +113.4 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.32 (s, 9 H), 1.69 (d, 3J = 6.3 Hz,
3 H), 3.64 (s, 3 H), 3.83 (m, 1 H), 4.66 (m, 1 H), 4.84 (d, 3J = 8.2
Hz, 1 H), 5.63 (m, 1 H), 5.77 (dd, 3J = 15.2 Hz, 3J = 8.6 Hz, 1 H),
7.32 (d, 3J = 8.4 Hz, 1 H), 7.45 (m, 2 H), 7.62 (br s, 1 H), 7.79 (m,
3 H).
1H NMR (500 MHz, CDCl3): d = 1.34 (s, 9 H), 1.47 (s, 3 H), 1.63
3
4
(dd, J = 6.5 Hz, J = 1.0 Hz, 3 H), 3.55 (m, 1 H), 3.58 (s, 3 H),
4.94 (br s, 1 H), 5.50 (m, 1 H), 5.79 (m, 1 H), 7.10 (m, 2 H,), 7.19
(m, 1 H), 7.25 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 18.1 (q), 20.2 (q), 28.3 (q), 52.0
(q), 56.8 (s), 62.5 (d), 79.7 (s), 127.4 (d), 128.0 (d), 128.5 (d), 129.0
(d), 129.9 (d), 139.1 (s), 154.6 (s), 173.5 (s).
HRMS (CI): m/z calcd for C19H28NO4 [M + H]+: 334.2018; found:
334.2041.
Anal. Calcd for C19H27NO4 (333.43): C, 68.44; H, 8.16; N, 4.20.
Found: C, 68.38; H, 8.00; N, 3.89.
13C NMR (100 MHz, CDCl3): d = 18.0 (q), 28.1 (q), 51.7 (d), 51.9
(q), 57.8 (d), 80.0 (s), 125.8 (d), 125.9 (d), 126.2 (d), 126.8 (d),
127.6, 127.7 (3 d), 128.4 (d), 128.9 (d), 132.6 (s), 133.4 (s), 137.1
(s), 155.2 (s), 172.3 (s).
(2S,3S,E)-Methyl 2-(tert-Butoxycarbonylamino)-2-methyl-3-
phenylhept-4-enoate [(S,S)-3c]
According to general procedure III, allylic ester (S)-2c (500 mg,
1.50 mmol), ZnCl2 (245 mg, 1.80 mmol), DIPA (455 mg, 4.50
mmol), n-BuLi (2.81 mL, 3.93 mmol, 1.6 M in hexanes), K2CO3
(249 mg, 1.80 mmol), and MeI (639 mg, 4.50 mmol) reacted to give
(S,S)-3c (457 mg, 1.32 mmol, 88%, >99% ds, >99% ee white solid;
mp 51 °C; diastereo- and enantioselectivities were determined by
HPLC (Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow
2 mL/min): tR (S,S)-3c = 5.24 min; [a]D20 +12.1 (c = 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.90 (t, 3J = 7.4 Hz, 3 H), 1.33 (s,
9 H), 1.47 (s, 3 H), 1.98 (m, 2 H), 3.54 (m, 1 H), 3.58 (s, 3 H), 4.94
(br s, 1 H), 5.52 (dt, 3J = 15.0 Hz, 3J = 6.4 Hz, 1 H), 5.76 (m, 1 H),
7.11 (m, 2 H), 7.19 (m, 1 H), 7.26 (m, 2 H).
HRMS (CI): m/z calcd for C22H28NO4 [M + H]+: 370.2018; found:
370.1998.
Anal. Calcd for C22H27NO4 (369.46): C, 71.52; H, 7.37; N, 3.79.
Found: C, 71.19; H, 7.41; N, 3.44.
(2S,3S,E)-Methyl 2-(tert-Butoxycarbonylamino)-3-p-tolylhex-4-
enoate [(S,S)-3f]
According to general procedure III, allylic ester (S)-2f (250 mg,
0.78 mmol), ZnCl2 (128 mg, 0.94 mmol), DIPA (238 mg, 2.35
mmol), n-BuLi (1.47 mL, 2.35 mmol, 1.6 M in hexanes), K2CO3
(130 mg, 0.94 mmol), and MeI (334 mg, 2.35 mmol) reacted to give
(S,S)-3f (219 mg, 0.66 mmol, 84%, >99% ds, 98% ee); colorless oil;
Synthesis 2009, No. 10, 1725–1731 © Thieme Stuttgart · New York

1730
C. Quirin, U. Kazmaier
PAPER
diastereo- and enantioselectivities were determined by HPLC (Re-
prosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow 2 mL/
min): tR (R,R)-3f = 7.63 min; tR (S,S)-3f = 8.69 min; [a]D20 +57.5
(c = 1.0, CHCl3).
(2S,3S)-Methyl 2-(tert-Butoxycarbonylamino)-2-methyl-4-oxo-
3-phenylbutanoate [(S,S)-4]
Amino acid derivative (S,S)-3b (250 mg, 0.75 mmol) was dissolved
in anhyd CH2Cl2 (20 mL) and cooled to –78 °C. Ozone was bubbled
through the solution until a blue color remained and excess of ozone
was removed by bubbling N2 through the solution. Then PPh3 (216
mg, 0.82 mmol) was added and the mixture was allowed to warm
overnight up to r.t. The solvent was removed in vacuo and the resi-
due was purified by column chromatography (silica gel, hexanes–
EtOAc, 8:2) to yield aldehyde (S,S)-4 (222 mg, 0.67 mmol, 89%,
>99% ds, >99% ee) as a white solid; mp 102 °C; diastereo- and
enantioselectivities were determined by HPLC (Reprosil 100
Chiral-NR 8 mm, hexanes–i-PrOH, 97:3, flow 1 mL/min): tR
(S,S)-4 = 14.84 min; [a]D20 –67.6 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.35 (s, 9 H), 1.65 (d, 3J = 6.2 Hz,
3 H), 2.29 (s, 3 H), 3.63 (m, 4 H), 4.53 (m, 1 H), 4.78 (d, 3J = 8.4
3
3
Hz, 1 H), 5.56 (dq, J = 15.1 Hz, J = 6.1 Hz, 1 H), 5.66 (ddq,
3J = 15.1 Hz, 3J = 8.5 Hz, 4J = 1.3 Hz, 1 H), 7.04 (m, 2 H), 7.10
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 18.0 (q), 21.0 (q), 28.2 (q), 51.0
(d), 51.8 (q), 57.9 (d), 79.9 (s), 127.8 (d), 128.2 (d), 129.2 (d), 129.4
(d), 136.5 (s), 136.7 (s), 155.2 (s), 172.3 (s).
HRMS (CI): m/z calcd for C19H28NO4 [M + H]+: 334.2018; found:
334.2013.
1H NMR (400 MHz, CDCl3): d = 1.43 (s, 9 H), 1.56 (s, 3 H), 3.73
(s, 3 H), 4.54 (br s, 1 H), 5.02 (br s, 1 H), 7.18 (m, 2 H), 7.32 (m, 3
H).
Anal. Calcd for C19H27NO4 (333.43): C, 68.44; H, 8.16; N, 4.20.
Found: C, 68.23; H, 8.42; N, 4.30.
13C NMR (100 MHz, CDCl3): d = 21.0 (q), 28.2 (q), 52.8 (q), 60.9,
61.4 (s, d), 80.2 (s), 128.1 (d), 128.5 (d), 130.8 (d), 132.3 (s), 154.2
(s), 173.3 (s), 198.4 (d).
HRMS (CI): m/z calcd for C17H23NO5 [M]+: 321.1576; found:
321.1582.
(2S,3S,E)-Methyl 3-(4-Bromophenyl)-2-(tert-butoxycarbonyl-
amino)-2-methylhex-4-enoate [(S,S)-3g]
According to general procedure III, allylic ester (S)-2g (350 mg,
0.91 mmol), ZnCl2 (149 mg, 1.09 mmol), DIPA (276 mg, 2.73
mmol), n-BuLi (1.71 mL, 2.73 mmol, 1.6 M in hexanes), K2CO3
(151 mg, 1.09 mmol), and MeI (387 mg, 2.73 mmol) reacted to give
(S,S)-3g (301 mg, 0.73 mmol; 83%, 98% ds, >99% ee) as a colorless
oil; diastereo- and enantioselectivities were determined by HPLC
(Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow 2 mL/
min): tR (S,R)-3g = 4.27 min; tR (S,S)-3g = 5.52 min; [a]D20 +38.5
(c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.39 (s, 9 H), 1.51 (s, 3 H), 1.68
(dd, 3J = 6.5 Hz, 4J = 1.5 Hz, 3 H), 3.62 (m, 4 H), 4.99 (br s, 1 H),
5.55 (dq, 3J = 15.0 Hz, 3J = 6.4 Hz, 1 H), 5.79 (m, 1 H), 7.01 (m, 2
H), 7.42 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 18.1 (q), 20.5 (q), 28.3 (q), 52.1
(q), 56.0 (q), 62.3 (d), 79.9 (s), 121.3 (s), 127.5 (d), 130.4 (d), 130.6
(d), 131.6 (d), 138.4 (s), 154.5 (s), 173.3 (s).
HRMS (CI): m/z calcd for C19H27BrNO4 [M + H]+: 412.1123;
found: 412.1123.
tert-Butyl (3S,4S)-3-Methyl-2-oxo-4-phenyltetrahydrofuran-3-
ylcarbamate [(S,S)-5]
Aldehyde (S,S)-4 (150 mg, 0.47 mmol) was dissolved in trifluoro-
ethanol (5 mL) and after cooling to 0 °C, NaBH4 (17.7 mg, 0.47
mmol) was added. The cooling bath was removed and the mixture
allowed to stir at r.t. for 1 h. The solution was diluted with Et2O (30
mL), quenched with aq 1 M KHSO4 (10 mL), and the aqueous layer
was extracted with Et2O (3 × 15 mL). The combined organic layers
were dried (Na2SO4), the solvent was removed in vacuo, and the
residue was purified by column chromatography (silica gel, hex-
anes–EtOAc, 7:3) to yield lactone (S,S)-5 (119 mg, 0.41 mmol,
87%, >99% ds, >99% ee) as a white solid; mp 145 °C; diastereo-
and enantioselectivities were determined by HPLC (Reprosil 100
Chiral-NR 8 mm, hexanes–i-PrOH, 97:3, flow 1 mL/min): tR
(S,S)-5 = 23.38 min; [a]D20 –60.0 (c = 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.99 (s, 3 H), 1.48 (s, 9 H), 4.49
(dd, 3J = 10.7 Hz, 3J = 7.9 Hz, 1 H), 4.61 (m, 2 H), 4.74 (br s, 1 H),
7.16 (m, 2 H), 7.34 (m, 3 H).
Anal. Calcd for C19H26BrNO4 (412.32): C, 55.35; H, 6.36; N, 3.40.
Found: C, 55.67; H, 6.33; N, 3.38.
13C NMR (100 MHz, CDCl3): d = 18.4 (q), 28.3 (q), 45.7 (d), 59.3
(s), 67.0 (t), 80.9 (s), 127.9 (d), 128.1 (d), 128.8 (d), 134.2 (s), 176.3
(s); the signals for Boc(C=O) are missing because of low intensity.
HRMS (CI): m/z calcd for C16H21NO4 [M]+: 291.1471; found:
291.1458.
(2S,3S,E)-Methyl 3-(4-Bromophenyl)-2-(tert-butoxycarbonyl-
amino)-2-methylhept-4-enoate [(S,S)-3h]
According to general procedure III, allylic ester (S)-2h (350 mg,
0.85 mmol), ZnCl2 (139 mg, 1.02 mmol), DIPA (258 mg, 2.55
mmol), n-BuLi (1.59 mL, 2.55 mmol, 1.6 M in hexanes), K2CO3
(143 mg, 1.02 mmol), and MeI (362 mg, 2.55 mmol) reacted to give
(S,S)-3h (323 mg, 0.76 mmol, 89%, >99% ds, 97% ee); colorless
oil; diastereo- and enantioselectivities were determined by HPLC
(Reprosil 100 Chiral-NR 8 mm, hexanes–i-PrOH, 99:1, flow 2 mL/
min): tR (R,R)-3h = 4.17 min; tR (S,S)-3h = 4.91 min; [a]D20 +39.2
(c = 1.0, CHCl3).
Anal. Calcd for C16H21NO4 (291.35): C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.69; H, 7.16; N, 4.91.
tert-Butyl (3S,4S,5R)-5-[(S)-1-Iodoethyl]-3-methyl-2-oxo-4-phe-
nyltetrahydrofuran-3-ylcarbamate [(S,S,R,S)-6]
Amino acid derivative (S,S)-3b (147 mg, 0.44 mmol) was dissolved
in 1,4-dioxane (2.5 mL) and aq 1 M NaOH (0.53 mL) was added.
After stirring overnight, the mixture was heated up to 40 °C to com-
plete the saponification. The solution was concentrated in vacuo
and the residue dissolved in H2O (20 mL). After washing with Et2O
(3 × 10 mL), the aqueous layer was acidified with aq 1 M KHSO4
to pH 2 and extracted with EtOAc (3 × 10 mL). The combined or-
ganic layers were dried (Na2SO4) and the solvent removed in vacuo.
The residue was dissolved in THF (5 mL), Et3N (67 mL, 0.48 mmol)
was added and the solution cooled to 0 °C. After the addition of I2
(135 mg, 0.53 mmol), the cooling bath was removed and the solu-
tion was allowed to stir at r.t. overnight. The mixture was diluted
with Et2O (15 mL) and washed several times with a 5% Na2S2O3 so-
lution to remove the excess of I2. The ethereal layer was dried
1H NMR (400 MHz, CDCl3): d = 0.95 (t, 3J = 7.5 Hz, 3 H), 1.39 (s,
9 H), 1.51 (s, 3 H), 2.03 (m, 2 H), 3.60 (m, 1 H), 3.63 (s, 3 H), 4.98
3
4
(br s, 1 H), 5.57 (dt, J = 15.1 Hz, J = 6.4 Hz, 1 H), 5.75 (ddt,
3J = 14.9 Hz, 3J = 9.6 Hz, 4J = 1.2 Hz, 1 H), 7.02 (m, 2 H), 7.42
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.5 (q), 20.4 (q), 25.6 (t), 28.3
(q), 52.0 (q), 55.9 (q), 62.4 (d), 79.9 (s), 121.3 (s), 125.4 (d), 130.7
(d), 131.6 (d), 137.4 (d), 138.4 (s), 154.5 (s), 173.3 (s).
HRMS (CI): m/z calcd for C20H29BrNO4 [M + H]+: 426.1280;
found: 426.1253.
Anal. Calcd for C20H28BrNO4 (426.35): C, 56.34; H, 6.62; N, 3.29.
Found: C, 56.42; H, 6.44; N, 3.29.
Synthesis 2009, No. 10, 1725–1731 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of b-Branched Phenylalanine Derivatives
1731
(Na2SO4) and the solvent evaporated in vacuo. After column chro-
matography (silica gel, hexanes–EtOAc, 7:3), the iodolactone
(S,S,R,S)-6 (145 mg, 0.33 mmol, 74%, 88% ds, >99% ee) was ob-
tained as a white solid; mp 162–164 °C (dec.); diastereo- and enan-
tioselectivities were determined by HPLC (Reprosil 100 Chiral-NR
8 mm, hexanes–i-PrOH, 97:3, flow 1 mL/min): tR (S,S,R,S)-6 = 7.66
min, tR (S,S,S,R)-6 = 16.41 min; [a]D20 –49.2 (c = 1.0, CHCl3).
2003, 115, 4426. (h) Maruoka, K.; Ooi, T. Chem. Rev. 2003,
103, 3013. (i) Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.
Chem. Rev. 2004, 104, 5823. (j) Ager, D. J.; Laneman, S. A.
In Asymmetric Catalysis on Industrial Scale; Blaser, H. U.;
Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004, 259.
(k) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(5) (a) Mendler, B.; Kazmaier, U. Org. Lett. 2005, 7, 1715.
(b) Mendler, B.; Kazmaier, U.; Huch, V.; Veith, M. Org.
Lett. 2005, 7, 2643. (c) Schmidt, C.; Kazmaier, U. Eur. J.
Org. Chem. 2008, 887.
(6) (a) Kazmaier, U.; Grandel, R. Synlett 1995, 945.
(b) Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997, 38,
8009. (c) Kummeter, M.; Kazmaier, U. Eur. J. Org. Chem.
2003, 3325.
(7) (a) Kazmaier, U.; Zumpe, F. L. Eur. J. Org. Chem. 2001,
4067. (b) Weiss, T. D.; Helmchen, G.; Kazmaier, U. Chem.
Commun. 2002, 1270. (c) Kazmaier, U.; Lindner, T. Angew.
Chem. Int. Ed. 2005, 44, 3303; Angew. Chem. 2005, 117,
3368. (d) Kazmaier, U.; Stolz, D.; Krämer, K.; Zumpe, F.
Chem. Eur. J. 2008, 14, 1322.
(8) (a) Kazmaier, U.; Stolz, D. Angew. Chem. Int. Ed. 2006, 45,
3072; Angew. Chem. 2006, 118, 3143. (b) Stolz, D.;
Kazmaier, U. Synthesis 2008, 2288.
HRMS (CI): m/z calcd for C18H25I NO4 [M + H]+: 446.0828; found:
446.0736.
Anal. Calcd for C18H24INO4 (445.30): C, 48.55; H, 5.43; N, 3.15.
Found: C, 48.70; H, 5.37; N, 3.29.
Major Diastereomer (S,S,R,S)-6
1H NMR (400 MHz, CDCl3): d = 1.13 (s, 3 H), 1.48 (s, 9 H), 2.06
(d, 3J = 6.7 Hz, 1 H), 3.74 (m, 1 H), 4.26 (d, 3J10,7 = 4.3 Hz, 1 H),
4.72 (br s, 1 H), 5.09 (dd, 3J = 11.4 Hz, 3J = 4.7 Hz, 1 H), 7.16 (m,
2 H), 7.30 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 19.8 (q), 22.7 (d), 25.5 (q), 28.3
(q), 56.6 (d), 63.5 (q), 85.5 (d), 128.1 (d), 128.7 (d), 128.8 (s), 129.9
(d), 154.3 (s); the signals for Boc [C(CH3)3] and lactone (C=O) are
missing because of low intensity.
(9) (a) Kübel, B.; Höfle, G.; Steglich, W. Angew. Chem., Int. Ed.
1975, 14, 58; Angew. Chem. 1975, 87, 64. (b) Engel, N.;
Kübel, B.; Steglich, W. Angew. Chem., Int. Ed. 1977, 16,
394; Angew. Chem. 1977, 89, 408.
(10) (a) Bartlett, P. A.; Barstow, J. F. Tetrahedron Lett. 1982, 23,
623. (b) Bartlett, P. A.; Barstow, J. F. J. Org. Chem. 1982,
47, 3933.
Minor Diastereomer (S,S,S,R)-6
1H NMR (400 MHz, CDCl3): d (selected signals) = 1.00 (s, 3 H),
1.55 (s, 9 H), 1.99 (d, 3J = 6.9 Hz, 1 H), 4.18 (d, 3J = 10.4 Hz, 1 H),
4.68 (br s, 1 H), 4.94 (dd, 3J = 10.3 Hz, 3J = 5.3 Hz, 1 H), 7.36 (m,
3 H).
13C NMR: Signals of the minor diastereomer could not be detected.
(11) For reviews, see: (a) Kazmaier, U. Amino Acids 1996, 11,
283. (b) Kazmaier, U. Liebigs Ann./Recl. 1997, 285.
(c) Kazmaier, U.; Maier, S.; Zumpe, F. L. Synlett 2000,
1523.
(12) (a) Kazmaier, U.; Schneider, C. Synlett 1996, 975.
(b) Kazmaier, U.; Schneider, C. Tetrahedron Lett. 1998, 39,
817. (c) Schneider, C.; Kazmaier, U. Synthesis 1998, 1321.
(13) Faber, K.; Riva, S. Synthesis 1992, 895.
(14) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17,
522; Angew. Chem. 1978, 90, 556.
(15) (a) Kazmaier, U. J. Org. Chem. 1996, 61, 3694.
(b) Kazmaier, U.; Maier, S. Tetrahedron 1996, 52, 941.
(16) (a) Mues, H.; Kazmaier, U. Synlett 2000, 1004. (b) Mues,
H.; Kazmaier, U. Synthesis 2001, 487.
(17) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 2931.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft (Ka
880/8) as well as the Fonds der Chemischen Industrie is gratefully
acknowledged.
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Synthesis 2009, No. 10, 1725–1731 © Thieme Stuttgart · New York