Synthesis of optically active C-allylglycine derivatives and conversion into isoquinolones

Article abstract of DOI:10.1055/s-2002-19804

C-Allylglycyl amides can be efficiently synthesized via an auxiliary controlled diastereoselective aza-Claisen rearrangement. The stereodirecting unit is placed on an auxiliary derived from commercially available (S)-proline. After N-allylation, the obtained optically active allylamines were reacted with various N-protected glycyl fluorides to give the (2R)-C-allylglycyl amides in good yields. The diastereoselectivity of the asymmetric allylation varied between 1:1 and > 1:15 depending on the N-protective group, the auxiliary, and the reaction temperature. Likewise, the C-allylglycine derivatives can be used as monomers in peptide synthesis to synthesize (R)-proline derivatives or chiral isoquinolones; the latter should serve as building blocks in the total syntheses of alkaloids.

Full text of DOI:10.1055/s-2002-19804

242
PAPER
Synthesis of Optically Active C-Allylglycine Derivatives and Conversion into
Isoquinolones
Synthesisof
Optic
o
allyActive
C
n
-Allylglycin
g
e
Derivatives Zhang, Udo Nubbemeyer*
Institut für Chemie - Organische Chemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855163; E-mail: udonubb@chemie.fu-berlin.de
Received 16 July 2001; revised 29 October 2001
Abstract: C-Allylglycyl amides can be efficiently synthesized via
an auxiliary controlled diastereoselective aza-Claisen rearrange-
ment. The stereodirecting unit is placed on an auxiliary derived
from commercially available (S)-proline. After N-allylation, the ob-
tained optically active allylamines were reacted with various N-pro-
tected glycyl fluorides to give the (2R)-C-allylglycyl amides in
good yields. The diastereoselectivity of the asymmetric allylation
varied between 1:1 and >1:15 depending on the N-protective group,
the auxiliary, and the reaction temperature. Likewise, the C-allyl-
glycine derivatives can be used as monomers in peptide synthesis to
synthesize (R)-proline derivatives or chiral isoquinolones; the latter
should serve as building blocks in the total syntheses of alkaloids.
Key words: chiral auxiliaries, amino acids, isoquinolone, allyla-
tions, aza-Claisen rearrangement, stereoselective synthesis
Figure 1 Literature syntheses of C-allylglycine derivatives
Optically active C-allylglycine derivatives serve as versa-
tile building blocks in organic synthesis. On one hand, the
amino acid has been introduced into an oligopeptide chain
to allow further transformation with the electron rich dou-
ble bond,1 on the other hand, this non-natural amino acid
is used as a chiral starting material to construct a range of
more complicated amino acids and alkaloids.2 Although
commercially available (C-allylglycine derivatives), the
high price prevents the use of the material in bulk quanti-
ties. Thus, a range of synthetic approaches, have been de-
veloped to obtain optically active C-allylglycine
derivatives. The synthetic strategies can be subdivided
into electrophilic amination of ester or amide enolates,3
nucleophilic substitutions of -halogen carboxylic acids
by amine reagents,4 allylation of glycine enolates with al-
lyl halides,5 allylation of iminium salts with allyl metal
compounds,6 and rearrangements7 (Figure 1). Generally,
the optical activity of the allylglycine has been introduced
by means of a chiral auxiliary.4–7 Here, we report on a
strategy using an auxiliary-controlled zwitterionic aza-
Claisen rearrangement as the key step to generate various
N-substituted or N-protected C-allylglycyl amides.
allylprolinol10 formed was finally protected as a TBDMS-
ether 211 and as a benzyl ether 3,12 using standard reaction
conditions (Scheme 1).
Scheme 1 Synthesis of optically active N-allylpyrrolidines
Reagents and Conditions: a) allyl bromide, K2CO3, DMF, r.t., 16 h,
89%; b) DIBAL-H, THF, 0 °C, 3 h, 81%; c) TBDMSCl, imidazole,
DMAP (cat.), THF, r.t., 3 h, 98% ( 2) or NaH, THF, then BnBr, 0 °C
to r.t., 20 h 84% ( 3)
The N-functionalized glycine derivatives 5 were generat-
ed via a four-step sequence. After treatment of 2-aminoac-
etaldehyde diethylacetal with ethyl bromoacetate, the
resultant 2-amino ester 413 was protected as t-butylcar-
bamate (a), benzylcarbamate (b) and benzylamine (c),14
in high yields, using standard procedures (Scheme 2).
Then, the ester was cleaved with aqueous sodium hydrox-
ide and lithium chloride to generate the carboxylic acids
5a–c.15 Finally, the activation was carried out with cyanu-
ric fluoride to synthesize the acyl fluorides 6a–c
(Scheme 2) in >90% as described later, for N-phthaloylg-
lycine (6d >90% yield), azido acetic acid ( 6e >90% yield)
and N-Boc-glycine (6f >90% yield).16 Generally, the flu-
orides prepared were used as crude compounds, no exten-
Our initial investigations started from N-allylproline me-
thyl ester (1), which was obtained from proline methyl es-
ter hydrochloride by treatment with allyl bromide in DMF
in the presence of a base.8 With the intention to test the
stereodirecting properties of some prolinol derivatives,
the ester 1 was reduced with DIBAL-H,9 the N-
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
1437-210X,E;2002,0,02,0242,0252,ftx,en;T06901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of Optically Active C-Allylglycine Derivatives
243
Scheme 2 Synthesis of N-protected glycyl fluorides
Reagents and Conditions: a) Et3N, Et2O, 0 °C, 24 h; b) Boc2O, then
aq NaOH, LiCl, 80 °C, then aq KHSO4, 62% (5a); CbzCl, Et3N, then
aq NaOH, LiCl, then aq KHSO4, 63% (5b); BnCl, then aq NaOH,
LiCl, then aq KHSO4, 65% (5c); c) (CNF)3, pyridine, CH2Cl2, r.t., 1–
3 h
sive purification was necessary to get satisfactory reactive
material.
The first series of zwitterionic aza-Claisen rearrange-
ments was run with N-allylproline methyl ester (1) as the
chiral C-3 fragment.17 The allylamine 1 was treated with
freshly prepared phthaloylglycyl fluoride (6d). In the
presence of Me3Al in a suspension of K2CO3 in anhydrous
CH2Cl2 at 0 °C, the -N-phthalimidopent-4-enoic acid
amides 7d/8d were obtained in 74% yield (Scheme 3).
The determination of the diastereoselectivity of the
present reactions turned out to be difficult. The 1H NMR
as well as 13C NMR spectra were always characterized by
a double set of peaks because of the non-symmetric amide
subunit. The partial double bond between carboxyl C and
N affected the coexistence of an E- and a Z- form with di-
astereomeric properties. These two conformers were
found in varying concentrations depending on the config-
urations of the stereogenic centers and the substitution
pattern of the molecules. In our hands coalescence could
not be achieved even by heating to about 120 °C. In the
case of the N-phthalimido amides 7d/8d the NMR spectra
proved the unselective generation of the material: three or
four sets of peaks indicated the coexistence of two diaste-
reomers 7d and 8d (each adopting two conformers),
which could be separated by means of preparative HPLC
or column chromatography. The rearrangement of azi-
doacetyl fluoride 6e with allylamine 1 gave a higher selec-
tivity during the formation of the amides 7e/8e (up to 77%
yield). Running the reaction at 20 °C, a 1:4 mixture of two
diastereomers 7e/8e was obtained (Scheme 3). By de-
creasing the temperature to about 0 °C the ratio increased
to 1:7, at –20 °C the ratio of the -azidoamides 7e/8e in-
creased again to about 1:9.5. In contrast, the most bulky
glycyl fluoride derivative 6a with an acceptor protected
nitrogen center was found to react highly diastereoselec-
tively. The amides 7a/8a were obtained in >73% yield (for
detailed data see Table). The N-Boc amides 7a/8a were
found to be unstable under the workup conditions. The N-
Boc group was completely removed passing the reaction
mixture through a short silica gel column. The in situ
formed secondary amine underwent immediate cycliza-
Scheme 3 Synthesis of C-allylglycyl amides: proline methyl ester
auxiliary
Reagents and Conditions: a) K2CO3, AlMe3, CH2Cl2, –20 °C, 0 °C or
r.t. (7/8a: 73%, 1:15; b: 74%; d: 74%, 1/1; e: 77%, 1:4–9.5). b) 6 N
aq HCl, reflux, 20 h, 52% (13:14 = 1:1); c) Cy2BH, CH2Cl2, 0 °C to
r.t., then NH4Cl, MeOH, 68% (11/12 = 1: 4–9.5); d) MeOH, SiO2, r.t.,
73% (9/10 = 1:15)
tion with the methyl ester of the auxiliary group generat-
ing the bicyclic piperazinediones 9 and 10 in 73% overall
yield (Scheme 3), the ratio of the diastereomers 9/10 was
determined to be about 1:15 according to HPLC and
NMR-analyses. The NOE analysis of the major product
proved undoubtedly the R configuration of the new stereo-
genic center in the allylglycine subunit while the minor
compound was shown to be S-configured (Figure 2).18
Figure 2 NOE data and structure determination of bicyclic com-
pounds 11 and 12
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244
N. Zhang, U. Nubbemeyer
PAPER
With the intention to check the stereochemical outcome of lished in the literature proved the R-configuration of the
the azidoacetyl fluoride 6e rearrangement the mixture of predominantly formed allylglycine function in the course
diastereomers 7e/8e was subjected to the reductive alkyla- of the rearrangement.
tion conditions developed by Evans and Sabol.19 The un-
saturated amide was treated with freshly prepared
dicyclohexylborane to achieve a smooth hydroboration of
the olefin for the initial step. The so formed trialkylborane
underwent an immediate cyclization with the nucleophilic
center of the azide. After elimination of N2 and ring con-
traction a new proline unit was formed, which underwent
a final intramolecular amination of the auxiliary ester
Aspiring more selective rearrangements and milder cleav-
age conditions we investigated the N-allylprolinol reac-
tants 2 and 3. The treatment of 2 with azidoacetyl fluoride
6e under standard conditions led to the formation of the -
azidoamides 15e/16e in 77% yield22 (Scheme 4). NMR
analyses proved the diastereoselective formation of a sin-
gle amide diastereomer (16e). As expected, the reaction of
the N-Boc protected glycine derivative 6a gave the -ami-
nopent-4-enoic acid amide 16a in high yield as a single di-
astereomer, but again, the Boc-group was found to be
unstable under the workup conditions. Hence, the rear-
rangement with N-Boc-glycyl fluoride 6f gave only poor
function to build up the tricyclic piperazinediones 11 and
12 in about 68% yield.20 The mixture of tricyclic products
contained one major meso species 12 originating from the
(R)-allylglycine subunit in amide 8e and the minor C-2
symmetric diastereomer 11 originating from the (S)- con-
results (6% yield of 15f/16f). In contrast, subjecting the
figured diastereomer 7e. Always, the major compound
more stable Cbz-protected acid fluoride 6b to the allyla-
was characterized by a specific rotation [ ]D20 0 (12) and
tion reaction with amine 3, the corresponding amide 16b
a minor compound with [ ]D20 +130 (11), proving, that
could be isolated in 75% yield as a single diastereomer.
the major reaction pathway generated predominantly the
Disappointingly, the rearrangement with the N-benzylgly-
(2R)-2-aminopentenoic acid fragment in 8e (Scheme 3).
cyl fluoride 6c gave no corresponding -aminopentenoic
acid amides 15c/16c. Some degradation product could be
isolated limiting the rearrangement to acceptor substituted
First attempts to remove the chiral auxiliary had to be con-
ducted under harsh conditions. The -azidoamides 7e/8e
were heated with 6 N HCl in methanol to give the -azi-
glycine fragments (Table).
dolactones 13 and 14 in 52% yield as a mixture of cis-13
Due to the fact, that the Boc group and the silyl ether of
amide were partly removed under non-neutral workup
conditions, a complete cleavage could be achieved upon
treating the crude material with SOCl2 in EtOH to give the
amino alcohol 19 (R1 = H). Several attempts to achieve a
chemoselective deprotection of the nitrogen in presence
of a silyl ether failed. Thus, we were forced to reintroduce
and trans-14 diastereomers, the ratio was about 1.2:1.21
Obviously, the cleavage of the auxiliary was accompanied
by the electrophilic regioselective addition of the carbox-
ylic acid function at the double bond, the diastereoselec-
tivity of this final step was low. Again, by comparison of
the spectral data of the trans-lactone 14 with that pub-
Table Synthesis of C-Allylglycyl Amides
Entry
Substituents
R1
Reactants
Amine
Temp
(°C)
Products
No
R2
R3
Fluoride
6a
Yield (%) Ratio
1
2
–
Boc
CH2CH(OEt)2
1
1
1
1
1
2
2
2
2
2
3
20
0
7/8
7/8
73a
74
77
77
77
51b
75
0
1:15
1:1
–
Pht
N2
N2
N2
6d
3
–
6e
20
0
7/8
1:4
4
–
6e
7/8
1:7
5
–
6e
–20
0
7/8
1:9.5
1:15
1:15
–
6
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
Bn
Boc
Cbz
Bn
CH2CH(OEt)2
CH2CH(OEt)2
CH2CH(OEt)2
6a
15/16
15/16
15/16
15/16
15/16
17/18
7
6b
0
8
6c
0
9
N2
6e
0
77
6
1:15
–
10
11
Boc
Boc
H
6f
0
d
CH2CH(OEt)2
6a
–
47c
1:15
a Yield determined after cyclization: 9 and 10.
b Yield determined over four steps: 21.
c Yield determined after cyclization: 23.
d See experimental.
Synthesis 2002, No. 2, 242–252 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of Optically Active C-Allylglycine Derivatives
245
the OTBDMS group subjecting the amino alcohol 19 to
standard silylation conditions (R1 = TBDMS).12 The so
obtained secondary amine was then benzylated with o-
bromomethylpiperonyl bromide in the presence of K2CO3
in acetonitrile to give the piperonylamine 21, from 2 and
6 in an overall yield of about 51% over four steps23
(Scheme 4). A final ring closure gave the optically active
isoquinolone derivative 23 under mild conditions as fol-
lows.24 The o-bromobenzylamine in 21 was treated with
BuLi in THF at –78 °C inducing the bromine–lithium ex-
change. This in situ formed aryllithium species attacked
the amide function resulting in the formation of the ketone
23, after removal of the auxiliary during the course of the
workup neither tertiary alcohol (alkylation of the ketone)
nor further side products were detected. The strong basic
conditions raised the question concerning the optical puri-
ty of the product 23. Analyzing the material by means of
chiral HPLC and 1H NMR shift experiments [Eu(tfc)3], re-
spectively, a single compound was found. The racemiza-
tion of the isoquinolone 23 and the reactant amide 16a
(diastereomers, conversion of the mixture into 23) could
be enforced by initial treatment with a strong base and a
consecutive re-protonation. Analyzing the so obtained ra-
Scheme 4 Synthesis of C-allylglycyl amides: prolinol auxiliaries,
synthesis of the isoquinolone
Reagents and Conditions: a) K2CO3, AlMe3, CH2Cl2, –20 °C, 0 °C or
r.t. (15a/16a: 75% (crude material); 1:15; b: 75%, 1:15; c: 0%, e:
77%, 1:15; f: 6%). 17a/18a: 75% (crude material), 1:15; b) 1. SOCl2,
EtOH, r.t., 2. TBDMSCl, imidazole, THF, r.t., c) ArCH2Br, K2CO3,
1
cemic material by means of chiral HPLC and H NMR
shift experiments [Eu(tfc)3], respectively, two compounds
were found proving the formation of optically pure mate-
rial under the course of the rearrangement and the final
ring closure (23).25 An analogous sequence allowed us to
avoid the use of the unstable silyl ether 19. The reaction
of allyl amine 3 and glycyl fluoride 6a gave the amides
17a/18a, the N-Boc group were completely removed by
treating with thionyl chloride and ethanol to give 20
(R1 = Bn). After benzylation with bromomethylpiperonyl
bromide generating 22, the final ring closure was
achieved by subjecting the crude material to halide–metal
exchange conditions. The yield of so obtained isoquinolo-
ne 23 was 47% over 4 steps avoiding all extensive inter-
mediate purification (Scheme 4). Again, this isoquinolone
was found to be optically pure (HPLC, 1H NMR).
MeCN, 80 °C, 51% 21 from 2 and 6a (16a
19
21, 4 steps,
R1 = H, TBDMS); d) BuLi, THF, –78 °C, 81%; 47% from 3 and 6a
(18a 20 22 23, 4 steps, R1 = Bn).
equatorial arrangement of the allyl side chain and the sub-
stituent of the chiral center) forming the syn-adduct of the
ketene equivalent. At ambient temperature, the flipping of
the nitrogen should not be suppressed. Consequently, less
bulky, reactive ketene fragments and auxiliaries bearing
stereogenic centers with less bulky substituents also allow
addition starting from the conformation B resulting in the
anti-adducts (Figure 3). However, the so generated zwit-
terion must be characterized by a defined Z-enolate geom-
etry of the amide subunit as is known for all related
systems.29 Finally, the acylammo-nium enolate undergoes
the 3,3 sigmatropic process. The charge neutralization
serves as a highly efficient driving force. Consistent with
well known acyclic Claisen rearrangements, the highly or-
dered transition state should have adopted a chair-like ar-
rangement to minimize repulsive 1,3 interactions. The
small CH2 part of the proline ring should have been placed
in an axial position and the bulky chain branched function
bearing the stereogenic center in the equatorial position.30
In combination with a Z-enolate structure the configura-
tion of the nascent stereogenic center must be R originat-
ing from the syn-adduct and S resulting from the anti-
analog. The diastereoselectivity of the auxiliary induced
acylation directly determines the stereochemical outcome
of the process. Expecting selective reactions with highly
reactive small glycyl fluorides 6e, the use of bulky auxil-
iaries (TBDMS-prolinol, 2) was mandatory, the rear-
Analyzing the stereochemical outcome of the C-allylgly-
cine derivatives 7/8 and 15–18 originating from the zwit-
terionic aza-Claisen rearrangement, three aspects have to
be considered: 1) the enolate geometry, 2) the transition
state conformation (simple diastereoselectivity, internal
asymmetric induction), and 3) the auxiliary-induced se-
lectivity.26,27
Considering the pathway of the process starting from the
allylamines 1–3 and the acyl fluorides 6, the first step was
thought to be the addition of a ketene equivalent at the nu-
cleophilic nitrogen to generate the hypothetical intermedi-
ate zwitterion.28 In this special case, such addition led to
the construction of a stereogenic ammonium center (syn
or anti with respect o the adjacent C-center). The diastere-
oselectivity of the process depends on the efficiency of the
auxiliary. Generally, a tertiary amine should suffer from a
fast nitrogen inversion A B (Figure 3), but here, the sub-
stitution pattern of the pyrrolidine should decelerate the
rate. The conformation A should predominate, (quasi-
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246
N. Zhang, U. Nubbemeyer
PAPER
rangement of less reactive bulky glycine derivatives 6a, and N-protective groups were used. The configuration of
6b can involve the small proline methyl ester substituent the newly formed stereogenic center was found to be R by
like 1 to achieve satisfactory results.31
analyzing the major product by NOE methods. The re-
moval of the auxiliary could be conducted by acidic cleav-
age as well as by a reaction with organolithium
compounds. A smooth cyclization to give optically active
isoquinolone 23 was observed by subjecting a suitable
functionalized N-benzylglycyl amide to halogen–metal
exchange conditions. Such isoquinolone derivatives
should be ideal precursors for the total syntheses of alka-
loids.32
Overall, the so obtained optically active C-allylglycine
derivatives should serve as versatile intermediates in ami-
no acid, peptide, pharmaceutical, and natural product syn-
theses. Further investigations concerning scope and
limitations of the auxiliary controlled aza-Claisen rear-
rangement as a chiral allylation reaction and the use of the
products in total syntheses are in progress.
For general experimental data, see Ref.33 The 1H NMR, 1H NMR-
COSY spectra and of 1, 3, 7d/8d, 10, 16b, and 21 were recorded on
a 500 MHz spectrometer.
(S)-N-Allylproline Methyl Ester (1)
For synthesis, data, and [ ]D, see Ref.8a
Proline methyl ester hydrochloride (900 mg, 5.4 mmol) in DMF (80
mL) was subsequently treated with solid K2CO3 (4 g) and allyl bro-
mide (0.56 mL, 6.48 mmol). The mixture was stirred overnight at
20 °C, then H2O (50 mL) was added. The aqueous layer was extract-
ed with Et2O (4 20 mL), the combined organic layers were dried
(MgSO4) and concentrated to give the crude product 1. Purification
by Kugelrohr distillation (140 °C/0.01 mm Hg) gave 818 mg (89%)
of 1 as a clear oil.
(S)-N-Allylprolinol
For synthesis, data and [ ]D, see Ref.10
Allylproline methyl ester 1 (1.57 g, 9.28 mmol) in anhyd THF (30
mL) was treated dropwise with DIBAL-H (17 mL, 20.4 mmol, 1.2
M in toluene) at 0 °C. After stirring for 3 h at 0 °C, the reaction was
quenched with MeOH (5 mL), and after a further 10 min of vigorous
stirring, aq sat. NaHCO3 (10 mL) and 30% aq sodium potassium tar-
trate (15 mL) were added. The aqueous layer was extracted with
Et2O (5 20 mL), the organic layers were dried (MgSO4) and con-
centrated to give 1.06 g (81%) of N-allylprolinol, which was used
without further purification.
Figure 3 Stereochemistry of the C-allylation: working hypothesis
In conclusion, the main reaction path could be described
as the syn-acylation of the allylamine conformation A, the
formation of the Z-enolate, and the forming of a chair-like
transition state to generate the (2R)-C-allylglycine deriva-
tives 8, 16, and 18. Obviously this hypothesis presents a
Claisen rearrangement proceeding with the well-known
1,3 chirality transfer, shifting the chiral information via
the heteroatom containing fragment.
(S)-N-Allyl-2-tert-butyldimethylsilyloxymethylpyrrolidine (2)
Prolinol (1 g, 7.08 mmol), imidazole (1 g, 14.7 mmol), and DMAP
(10 mg) in anhyd THF (50 mL) were treated with TBDMSCl (1.7 g,
11.3 mmol) at 0 °C. After 3 h of stirring at 20 °C (TLC control), the
mixture was quenched with H2O (20 mL). The aqueous layer was
extracted with Et2O (4 10 mL) and the combined organic layers
were dried (MgSO4). After removal of the solvent, the crude mate-
rial was purified by Kugelrohr distillation (85 °C/0.01 mm Hg),
gave 1.77 g (98%) of 2 as a colorless oil; [ ]D20 –50.1 (c 1.2,
CHCl3).
An efficient sequence to synthesize optically active C-al-
lylglycine derivatives has been developed starting from
chiral N-allylproline derivatives 1–3 and glycyl fluorides
6. The zwitterionic aza-Claisen rearrangement served as
the key step to introduce the stereogenic center with mod-
erate to high auxiliary induced diastereoselectivity to give
the , -unsaturated amides 7/8, 16, and 18 in >70% yield.
The results with N-glycine substituents were variable, at
least one electron acceptor was found to be necessary to
achieve a smooth reaction. The diastereoselectivity ob-
served increased when more bulky auxiliary substituents
IR (CHCl3): 3019, 2956, 2857, 2805 (CH2), 1471, 1463 (CH2) cm–1.
1H NMR (CDCl3, 500 MHz): = 0.0 (s, 6 H, Si(CH3)2), 0.85 (s, 9
H, (CH3)3C), 1.49–1.75 (m, 3 H, CH2CH2), 1.75–1.92 (m, 1 H,
CH2CH2), 2.20 (dd, 1 H, J = 8.8, 8.3 Hz, CH2CHHN), 2.55 (m, 1 H,
NCHCH2O), 2.88–3.05 (m, 2 H, CH2CHHN, NCH2CH=CH2), 3.40
(dd, 1 H, J = 9.8, 7.3 Hz, CH2O), 3.50 (dd, 1 H, J = 13.7, 5.9 Hz,
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Synthesis of Optically Active C-Allylglycine Derivatives
247
NCHHCH=CH2), 3.65 (dd, 1 H, J = 10.3, 5.4 Hz, CH2O), 5.04 (dd,
1 H, J = 10.3, 1.5 Hz, CH=CHH), 5.12 (dd, 1 H, J = 16.1, 1.5 Hz,
CH=CHH), 5.85 (dddd, 1 H, J = 16.9, 10.3, 7.4, 5.9 Hz, CH=CH2).
5a
IR (CHCl3): 3019, 2980, 2933 (CH2), 1731 (CO), 1697 (CON)
cm–1.
13C NMR (68 MHz, CDCl3): = –5.4 (Si(CH3)2), 18.2 ((CH3)3C),
22.8 (CH2), 25.8 ((CH3)3C), 28.3 (CH2), 54.6 (NCH2CH=CH2),
58.6 (CH2CH2N), 64.7 (NCHCH2O), 66.9 (CH2O), 116.5
(CH=CH2), 136.3 (CH=CH2).
Yield: 1.84 g (62%); clear oil.
1H NMR (270 MHz, CDCl3): = 1.15 (2 t, 6 H, J = 7.4 Hz,
CH3CH2O), 1.40 (2 s, 9 H, (CH3)3C), 3.30 (2 d, 2 H, J = 5.2 Hz,
NCH2CH(OEt)2), 3.45 (m, 2 H, CH3CH2O), 3.55 (m, 2 H,
CH3CH2O), 4.0 (2 s, 2 H, NCH2CO2H), 4.50 (2 t, 1 H, J = 5.2 Hz,
CH(OEt)2), 10.95 (br s, 1 H, CO2H).
MS (EI, 80 eV, 30 °C): m/z (%) = 255 (31, [M]+), 240 (33, [M –
CH3]+), 198 (59, [M – C4H9]+).
HRMS: m/z [M+] calcd for C14H29NOSi, 255.20184; found,
255.20433.
13C NMR (68 MHz, CDCl3): = 15.1 (CH3CH2O); 28.0, 28.2
((CH3)3C), 49.7, 50.7 (NCH2CO2H), 50.8, 51.1 (NCH2CH(OEt)2),
63.1, 63.4 (CH3CH2O), 80.7 ((CH3)3C), 101.8, 102.1 (CH(OEt)2),
155.2, 155.5 (NCO), 175.1 (CO2H).
(S)-N-Allyl-2-benzyloxymethylpyrrolidine (3)
NaH (255 mg, 10.6 mmol) was suspended in anhyd THF (30 mL)
and cooled to 0 °C. Prolinol (1 g, 7.08 mmol) in anhyd THF (10 mL)
was added and the deprotonation was completed within 1 h at 0 °C.
Then, benzyl bromide (1.3 g, 7.6 mmol) in anhyd THF (10 mL) was
added and the mixture was stirred overnight at 20 °C. The mixture
was quenched with H2O (10 mL), the aqueous layer was extracted
with Et2O (3 10 mL), the organic layers were dried (MgSO4), and
the solvent was evaporated. The crude material was purified by co-
lumn chromatography (hexane–EtOAc, 5:1) and gave 1.38 g (84%)
of 3 as a yellow oil; [ ]D20 –68.5 (c 1.4, CHCl3).
MS (neg. FAB): m/z (%) = 291 (17, [M]+), 290 (100, [M – H]+).
5b
Yield: 2.05 g (63%); clear oil.
IR (CHCl3): 3019, 2979, 2930, 2883 (CH), 1728 (CO), 1697 (CON)
cm–1.
1H NMR (270 MHz, CDCl3): = 1.15 (m, 6 H, 2 CH3CH2O),
3.35–3.75 (m, 6 H, 2 CH3CH2O, NCH2CH(OEt)2), 4.15 (2 s, 2
H, NCH2CO2H), 4.50 (2 t, 1 H, J = 5.2 Hz, CH(OEt)2), 5.14 (2
s, CH2Ph), 7.24–7.36 (m, 5 H, C6H5), 9.9 (br s, 1 H, CO2H).
IR (CHCl3): 3068, 3015, 2970, 2914, 2872, 2803 (CH2), 1732, 1643
(CH=CH), 1496, 1454 (CH2) cm–1.
13C NMR (68 MHz, CDCl3):
= 15.1 (CH3CH2O), 50.1
1H NMR (CDCl3, 270 MHz): = 1.49–1.75 (m, 3 H, CH2CH2),
1.75–1.92 (m, 1 H, CH2CH2), 2.21 (ddd, 1 H, J = 8.9, 8.1, 1.5 Hz,
CH2CHHN), 2.65 (m, 1 H, NCHCH2O), 2.92 (dd, 1 H, J = 13.2, 8.1
Hz, NCHHCH=CH2), 3.06 (ddd, 1 H, J = 9.6, 6.6, 2.9 Hz,
CH2CHHN), 3.36 (dd, 1 H, J = 6.6, 5.9 Hz, CH2O), 3.50 (dd, 1 H,
J = 9.6, 5.1 Hz, CH2O), 3.56 (dd, 1 H, J = 5.9, 1,5 Hz, NCH-
HCH=CH2), 4.42 (s, 2 H, PhCH2), 5.06 (dd, 1 H, J = 10.3 Hz, 1.5
Hz, CH=CHH), 5.12 (dd, 1 H, J = 16.1, 1.5 Hz, CH=CHH), 5.85
(dddd, 1 H J = 16.9, 10.3, 7.4, 5.9 Hz, CH=CH2), 7.15–7.26 (m, 5
H, C6H5).
13C NMR (68 MHz, CDCl3): = 22.8 (CH2), 28.6 (CH2), 54.4
(NCH2CH=CH2), 58.3 (CH2CH2N), 62.7 (CHCH2O), 73.2 (CH2O),
73.7 (PhCH2), 116.6 (CH=CH2), 136.2 (CH=CH2), 127.4, 127.5,
128.0, 128.2, 138.4 (C6H5).
(NCH2CH(OEt)2) 51.0, 51.4 (NCH2CO2H), 63.2, 63.5 (CH3CH2O),
67.6, 67.8 (CH2Ph), 101.7, 102.0 (CH(OEt)2), 126.9, 127.6, 127.9,
128.0, 128.1, 128.4, 128.5, 136.1 (C6H5), 156.1, 156.3 (NCO) 174.6
(CO2H).
MS (pos. FAB): m/z (%) = 348 (1.0, [M+ + Na]+), 326 (1.04, [M +
H]+), 280 (18, [M – CHO2]+), 236 (15, [M – C7H7]+), 103 (35,
[C5H11O2]+), 91 (100, [C7H7]+).
N-Benzyl-N-(2,2-diethoxyethyl)amino Acetic Acid (5c)
Ester 4 (10 mmol) was prepared as described above. Benzyl chlo-
ride (10 mmol) in anhyd Et2O (20 mL) was added and the mixture
was stirred at 20 °C for a further 24 h. Then, H2O (50 mL) was add-
ed and the aqueous phase was extracted with Et2O (4 30 mL). The
combined organic layers were dried (MgSO4) and concentrated to
give the crude -amino ester, which was purified by column chro-
matography on silica gel (hexane–EtOAc, 3:1) and gave 2.01 g
(65%) of 5c as a pale yellow oil. Cleavage as described above,
workup: extraction with CH2Cl2 (5 50 mL) gave 1.7 g (93%) of 5c
as a pale yellow oil.
MS (EI, 80 eV, 30 °C): m/z (%) = 231 (12, [M]+), 110 (100, [M –
C8H9O]+), 91 (77, [C7H7]+).
HRMS: m/z [M+] calcd C15H21NO, 231.16231; found, 231.16482.
N-tert-Butyloxycarbonyl-N-(2,2-diethoxyethyl)aminoacetic
Acid (5a) and N-Benzyloxycarbonyl-N-(2,2-diethoxyethyl)-
aminoacetic Acid (5b)
1H NMR (270 MHz, CDCl3): = 1.20 (m, 9 H, 2 CH3CH2O,
CH3CH2OCO), 2.86 (d, 2 H, J = 5.9 Hz, NCH2CH(OEt)2), 3.43–
3.56 (m, 4 H, NCH2CO, CH3CH2O), 3.57–3.67 (m, 2 H,
CH3CH2O), 3.86 (s, 2 H, CH2Ph), 4.13 (q, 2 H, J = 7.4 Hz,
CH3CH2OCO), 4.54 (t, J = 5.2 Hz, CH(OEt)2), 7.15–7.37 (m, 5 H,
C6H5).
13C NMR (68 MHz, CDCl3): = 14.2 (CH3CH2OCO), 15.2
(CH3CH2O), 55.0 (NCH2CH(OEt)2), 56.1 (CH3CH2OCO), 59.0
(NCH2CO), 60.0 (CH2Ph), 62.0 (CH3CH2O), 102.5 (CH(OEt)2),
127.0, 128.1, 128.8, 139.1 (C6H5), 171.7 (COO).
Aminoacetaldehyde diethyl acetal (1.33 g, 10 mmol) and Et3N (1.01
g, 1.4 mL, 10 mmol) in anhyd Et2O (100 mL) were cooled to 0 °C.
Ethyl bromoacetate (1.67 g, 1.11 mL, 10 mmol) in anhyd Et2O (50
mL) was added slowly and the mixture was stirred overnight at
0 °C. Di-tert-butyl dicarbonate or benzyloxycarbonyl chloride (10
mmol) in anhyd Et2O (20 mL) was added and the mixture was
stirred at r.t. for 5 h. 1 N HCl (50 mL) was added to the mixture and
the aqueous layer was extracted with Et2O (4 40 mL). The com-
bined organic layers were dried (MgSO4) and the solvent was re-
moved to give the crude protected -amino esters. The crude
protected -amino ester was treated with 1 N NaOH (100 mL) and
LiCl (0.5 g, 11.8 mmol). After stirring at 80 °C for 3 h and at 20 °C
for 1 h, aq sat. KHSO4 was added until the solution had a pH of 4–
5. The aqueous solution was extracted with Et2O (4 50 mL) and
the organic layers were dried (MgSO4). After removal of the sol-
vent, the carboxylic acids 5a and 5b were isolated pure enough for
further transformations.
Carboxylic Acid Fluorides; General Procedure
The amino acid (500 mg) in anhyd CH2Cl2 (70 mL) at 0 °C was
treated with pyridine (0.6 equiv) and cyanuric fluoride (0.6 equiv)
with stirring. The mixture was stirred at 0 °C for about 1.5 h (TLC
monitoring: 0.5 mL sample of the reaction mixture was quenched
with MeOH and detected on a TLC plate with hexane–EtOAc 1:1).
The reaction was stopped by quenching with ice-water (50 mL).
The aqueous phase was extracted with CH2Cl2 (3 20 mL), the
combined organic phases were dried (MgSO4), and concentrated to
Synthesis 2002, No. 2, 242–252 ISSN 0039-7881 © Thieme Stuttgart · New York

248
N. Zhang, U. Nubbemeyer
PAPER
give the amino acid fluoride, which was immediately used without
any further purification.
The mixture was stirred at 0 °C until no reactant remained accord-
ing TLC control. Then, MeOH (10 mL) was added dropwise and
stirring was continued for a further 30 min at 20 °C. The polar side
products and salts were filtered off by passing the mixture through
a short silica gel column. The filtrate was concentrated and crude
material was purified by column chromatography and HPLC (if
necessary).
N-tert-Butyloxycarbonyl-N-(2,2-diethoxyethyl)aminoacetic
Acid Fluoride (6a)
From acid 5a (500 mg, 1.72 mmol) following the general procedure
gave 468 mg (93%) of 6a as a pale yellow oil.
1H NMR (270 MHz, CDCl3): = 1.12 (m, 6 H, 2 CH3CH2O), 1.40
(2 s, 9 H, (CH3)3C), 3.30 (2 d, 2 H, J = 5.2 Hz, NCH2CH(OEt)2),
3.36–3.49 (m, 2 H, CH3CH2O), 3.56–3.67 (m, 2 H, CH3CH2O), 4.13
(2 d, 2 H, J = 3.7 Hz, NCH2COF), 4.42 (2 t, 1 H, J = 5.2 Hz,
CH(OEt)2).
13C NMR (68 MHz, CDCl3): = 15.1 (CH3CH2O), 27.9, 28.1
(CH3)3C), 47.6, 48.2, 48.6, 49.3 (NCH2COF), 50.6, 51.0
(NCH2CH(OEt)2), 63.1, 63.4 (CH3CH2O), 81.1, 81.2 ((CH3)3C)
102.0, 102.1 (CH(OEt)2), 154.4, 154.9 (NCO), 157.1, 163.1 (COF).
(S/R)-2-Phthaloylamidopent-4-enoic Acid [(2S)-Methoxycar-
bonylpyrrolidinyl]amide (7d/8d)
From N-allylproline methyl ester (1; 270 mg, 1.6 mmol) and azi-
doacetyl fluoride 6d (660 mg, 3.61 mmol) following the standard
procedure. Reaction temperature 0 °C, reaction time 16 h. Purifica-
tion and separation of the diastereomers via column chromatogra-
phy (hexane–EtOAc, 1:1); gave 420 mg (74%) of 7d/8d (1:1) as a
yellow oil.
Diastereomer 1
[ ]D20 –104.7 (c 1.1, CHCl3).
N-Benzyloxycarbonyl-N-(2,2-diethoxyethyl)aminoacetic Acid
Fluoride (6b)
From acid 5b (500 mg, 1.54 mmol) following the standard proce-
dure gave 448 mg (89%) of 6b as a pale yellow oil.
IR (CHCl3): 3020, 2982, 2956 (CH2), 1743 (CO), 1714 (CONCO),
1658 (CON), 1420, 1338 (CH2) cm–1.
1H NMR (CDCl3, 270 MHz): = 1.85–2.11 (m, 4 H, CH2CH2), 2.85
(ddd, 1 H, J = 14.7, 5.2, 5.2 Hz, CH2=CHCHH), 3.09 (ddd, 1 H,
J = 14.7, 9.6, 9.6 Hz, CH2=CHCHH), 3.30 (m, 1 H, CHHN), 3.60–
3.72 (m, 4 H, CHHN, OCH3), 4.45 (dd, 1 H, J = 8.1, 3.0 Hz,
CHCOO), 4.85 (dd, 1 H, J = 10.3, 4.4 Hz, CH2=CHCH2CH),4.96
(d, 1 H, J = 10.3 Hz, CHH=CH), 5.01 (d, 1 H, J = 16.9 Hz,
CHH=CH), 5.74 (dddd, 1 H, J = 16.9, 10.3, 7.3, 5.9 Hz, CH2=CH).
13C NMR (68 MHz, CDCl3): = 24.8 (CH2CH2), 28.6 (CH2CH2),
32.9 (CH2=CHCH2), 46.8 (CH2N), 52.2 (NCHCOO), 52.2
(CH2=CHCH2CH), 59.3 (CO2CH3), 118.6 (CH2=CH), 123.5, 131.4,
134.2 (Ar), 133.4 (CH2=CH), 167.0, 167.5 (CON), 172.4 (COO).
1H NMR (270 MHz, CDCl3): = 1.23 (2 t, 6 H, J = 7.4 Hz,
CH3CH2O), 3.34–3.74 (m, 6 H, 2 CH3CH2O, NCH2CH(OEt)2),
4.23 (d, 1 H, J = 3.7 Hz, NCH2COF), 4.26 (d, 1 H, J = 4.4 Hz,
NCH2COF), 4.48 (2 t, 1 H, J = 5.2 Hz, CH(OEt)2), 5.14 (2 s, 2
H, CH2Ph), 7.26–7.35 (m, 5 H, C6H5).
13C NMR (68 MHz, CDCl3): = 15.1 (CH3CH2O), 47.9, 48.1, 48.9,
49.1 (NCH2COF), 50.9, 51.3 (CH2CH(OEt)2), 63.2, 63.4
(CH3CH2O) 68.0 (CH2Ph), 101.8, 101.9 (CH(OEt)2), 127.9, 128.0,
128.2, 128.3, 128.5, 128.6, 128.7, 135.8, 135.9 (C6H5), 155.4, 155.8
(NCO), 157.6, 162.9 (COF).
N-Benzyl-N-(2,2-diethoxyethyl)aminoacetic Acid Fluoride (6c)
From acid 5c (500 mg, 1.78 mmol) following the standard proce-
dure gave 423 mg (84%) of 6c as a pale yellow oil.
Diastereomer 2
[ ]D20 +22.4 (c 4.3, CHCl3).
IR (film): 2980, 2953, 2879 (CH2), 1775 (CO), 1716 (CONCO),
1660 (CON), 1468, 1434 (CH2) cm–1.
1H NMR (270 MHz, CDCl3): = 1.15 (t, 6 H, J = 7.4 Hz, 2
CH3CH2O), 2.93 (dd, 2 H, J = 5.2, 1.5 Hz, NCH2CH(OEt)2), 3.44
(q, 2 H, J = 7.4 Hz, CH3CH2O), 3.61 (q, 2 H, J = 7.4 Hz,
CH3CH2O), 3.67 (d, 2 H, J = 2.9 Hz, NCH2COF), 3.90 (d, 2 H,
J = 1.5 Hz, CH2Ph), 4.53 [t, 1 H, J = 5.2 Hz, NCH2CH(OEt)2], 7.30
(m, 5 H, C6H5).
13C NMR (68 MHz, CDCl3): = 15.1 (CH3CH2O), 52.2, 53.1
(NCH2COF), 55.8 (NCH2CH(OEt)2), 58.9 (CH2Ph), 62.3
(CH3CH2O), 102.2 (NCH2CH(OEt)2), 127.5, 128.4, 128.8, 137.8
(C6H5), 158.4, 164.0 (COF).
1H NMR (CDCl3, 270 MHz): = 1.72–2.08 (m, 3 H, CH2CH2),
2.10–2.27 (m, 1 H, CH2CH2), 2.82 (m, 1 H, CH2=CHCHH), 3.03
(m, 1 H, CH2=CHCHH), 3.33 (dd, 1 H, J = 15.4, 7.4 Hz, CH2N),
3.55 (m, 1 H, CH2N), 3.63 (s, 3 H, CO2CH3), 4.48 (m, 1 H,
CHCOO), 4.97 (m, 3 H, CH2=CHCH2CH, CH2=CH), 5.70 (m, 1 H,
CH2=CH).
13C NMR (68 MHz, CDCl3): = 25.2 (CH2CH2), 28.6 (CH2CH2),
32.9 (CH2=CHCH2), 46.9 (CH2N), 51.7 (NCHCOO), 52.1
(CH2=CHCH2CH), 59.5 (CO2CH3), 118.8 (CH2=CH), 123.5, 131.4,
134.1 (Ar), 133.4 (CH2=CH), 166.8, 167.2 (CON), 172.4 (COO).
N-tert-Butyloxycarbonylaminoacetic Acid Fluoride (6f)
For previous preparation see Ref.16c
MS (EI, 80 eV, 100 °C): m/z (%) = 356 (25, [M]+, 297 (14, [M –
C2H3O2]+), 228 (9, [M –C6H10NO2]+), 200 (100, [M – C6H10NO2 –
CO]+).
From acid 5f (500 mg, 2.86 mmol) following the general procedure
gave 460 mg (91%) of 6f as a pale yellow oil.
1H NMR (270 MHz, CDCl3): = 1.40 (s, 9 H, (CH3)3C), 3.98 (m, 2
H, NCH2COF), 5.45 (br s, 1 H, NH).
HRMS: m/z [M+] calcd for C19H20N2O5, 356.13722; found,
356.13556.
13C NMR (68 MHz, CDCl3): = 28.0 ((CH3)3C), 40.0, 41.1
(NCH2COF), 80.6 ((CH3)3C), 155.7 (NCO), 158.4, 163.8 (COF).
For 6d and 6e, see Ref.16a
(S and R)-2-Azidopent-4-enoic Acid [(2S)-Methoxycarbonyl-
pyrrolidinyl]amide (7e/8e)
Reaction with N-allylproline methyl ester 1 (440 mg, 2.6 mmol) and
azidoacetyl fluoride 6e (618 mg, 6 mmol) following the general pro-
cedure. Reaction temperature 20 °C, 0 °C, –20 °C, reaction time 3
h. Purification via column chromatography (hexane–EtOAc, 2:1)
gave 505 mg (77%, 2.0 mmol) of 7e/8e as a yellow oil. Ratio: 1:4
(20 °C), 1:7 (0 °C, 1:9.5 (–20 °C). Diastereomers not separated.
Data of 8e: [ ]D20 –159.2 (c 1.3, CHCl3).
Zwitterionic Aza-Claisen Rearrangement; C-Allylation of Gly-
cyl Fluorides 6; General Procedure
Under Ar, N-allylpyrrolidine 1–3 (2.6 mmol) and Na2CO3 (2.3 g,
21.7 mmol) in anhyd CH2Cl2 (5 mL) were treated with freshly pre-
pared glycyl fluoride 6 (6 mmol) in anhyd CH2Cl2 (5 mL) at 0 °C.
Then AlMe3 (1.33 mL, 2.66 mmol, 2 M in heptane) was injected
slowly. A gas was evolved and the mixture darkened to light brown.
IR (film): 3079, 2980, 2954, 2882 (CH2CH2), 2103 (N3), 1746
(CO), 1653 (CON), 1436 (CH2) cm–1.
Synthesis 2002, No. 2, 242–252 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active C-Allylglycine Derivatives
249
1H NMR (CDCl3, 270 MHz): = 1.70–2.00 (m, 3 H, CH2CH2),
2.01–2.22 (m, 1 H, CH2CH2), 2.50 (m, 2 H, CH2CH=CH2), 3.35–
3.79 (m, 6 H, CH2CH2N, NCHCOO, CO2CH3), 4.40 (2 dd, 1 H,
J = 7.3, 3.9 Hz, N3CH), 5.14 (dd, J = 10.3, 1.0 Hz, CH=CHH), 5.22
(dd, 1 H, J = 17.1, 1.5 Hz, CH=CHH), 5.80 (dddd, 1 H, J = 17.1,
10.3, 6.8, 6.8 Hz, CH=CH2).
HRMS: m/z [M+] calcd for C16H26N2O4, 310.18925; found,
310.18777.
(3S,6S)-1,6-3,4-Bis(propylidene)-1,4-piperazine-2,5-dione (11)
and (3R,6S)-1,6-3,4-Bis(propylidene)-1,4-piperazine-2,5-dione
(12)
A solution of BH3 SMe2 (197 mg, 2.6 mmol) in anhyd CH2Cl2 (5
mL) was cooled to 0 °C under Ar. Cyclohexene (428 mg, 5.2 mmol)
was added over a period of 5 min by means of a syringe. After stir-
ring at 0 °C for 3 h, -azido amide 7e/8e (220 mg, 0.87 mmol) in
anhyd CH2Cl2 (5 mL) was added. The cooling bath was removed
and the reaction mixture was stirred overnight at 20 °C, the color of
the mixture turned to bright yellow. The reacion was quenched with
sat. aq NH4Cl (10 mL). After stirring for 30 min, sat. aq NaHCO3 (5
mL) was added and the mixture was stirred for further 1 h. Then, the
aqueous layer was extracted with CH2Cl2 (5 15 mL), the com-
bined organic layers were dried (MgSO4), and concentrated to give
crude product which was purified by column chromatography
(EtOAc) and gave115 mg (68%) of 11/12 as a white solid material.
Ratio of diastereomers, 1:4 (20 °C), 1:7 (0 °C, 1:9.5 (–20 °C) de-
pending on the reaction temperature of the allylation step (7e/8e).
The spectral data obtained were identical with those published in
the literature.20
13C NMR (68 MHz, CDCl3): = 22.0, 24.4 (CH2CH2), 28.6, 30.9
(CH2CH2), 34.3, 34.5 (CH2CH=CH2), 46.4, 46.6 (CH2CH2N), 51.9,
52.4 (CO2CH3), 58.7 (NCHCOO), 59.2 (N3CH), 118.2, 118.6
(CH=CH2), 132.3, 132.6 (CH=CH2), 167.5 (CON), 171.7, 171.9
(COO).
MS (EI, 80 eV, 110 °C): m/z (%) = 252 (5.2, [M]+), 210 (8.3, [M –
C2H3O]+), 193 (5.8, [M – C2H3O2]+), 165 (3.4, [M – N2]+).
HRMS: m/z [M+] calcd for C11H16N4O3, 252.1222; found,
252.1236.
(3S,6S) 6-Allyl-1-(2,2-diethoxyethyl)-3,4-propylidene-1,4-pipe-
razine-2,5-dione (9) and (3S,6R) 6-Allyl-1-(2,2-diethoxyethyl)-
3,4-propylidene-1,4-piperazine-2,5-dione (10)
From N-allylproline methyl ester (1; 120 mg, 0.71 mmol) and Boc-
glycyl fluoride 6a (250 mg, 0.85 mmol) following the general pro-
cedure. Reaction temperature, 0 °C reaction time, 16 h. During
workup, the Boc-group was completely removed to generate the
piperazinedione. Purification via column chromatography (EtOAc)
gave 160 mg (73%) of 9/10 as a yellow oil. (Ratio 9:10 = 1:>15).
Separation via preparative HPLC: Nucleosil 50-5, 4 250; 20%
propan-2-ol–hexane, 2 mL/min, 140 bar; t9 = 7.58 min, t10 = 7.16
min.
(3R,5S) 3-Azido-5-methyl-2(3H)-furanone (13) and (3R,5R) 3-
Azido-5-methyl-2-(3H)-fura-none (14)
-Azidoamide 7/8e (140 mg, 0.55 mmol) was heated in 6 N aq HCl
(5 mL) for 20 h. After cooling to 20 °C, the mixture was extracted
with Et2O (3 10 mL), the organic layers were dried (MgSO4), and
the solvent was removed. Purification and separation of the diaste-
reomers via column chromatography (hexane–EtOAc, 4:1) afford-
ed 20 mg (26%) of lactone 13 and 21 mg (27%) of lactone 14 as
clear oils.
9 (Minor Diastereomer)
1H NMR (CDCl3, 270 MHz): = 1.02 (t, 3 H, J = 7.4 Hz, CH3),
1.10 (t, 3 H, J = 7.4 Hz, CH3), 1.75–1.92 (m, 3 H, CH2CH2), 2.28
(m, 1 H, CH2CH2), 2.68 (m, 1 H, CH2=CHCHH), 2.85 (m, 1 H,
CH2=CHCHH), 2.90 (dd, 1 H, J = 14.0, 7.4 Hz, NCH2CH(OEt)2),
3.27–3.68 (m, 6 H, 2 CH3CH2, CH2NCO), 3.90 (m, 1 H, NCH-
CO), 4.11 (m, 1 H, CH2N), 4.28 (m, 1 H, NCHCH2CH=CH2), 4.55
(dd, 1 H, J = 6.6, 2.9 Hz, CH2CH(OEt)2), 4.97 (m, 2 H, CH2=CH),
5.45 (dddd, 1 H, J = 16.9, 10.3, 7.4, 7.4 Hz, CH2=CH).
13C NMR (68 MHz, CDCl3): = 15.1 (CH3CH2O), 21.7 (CH2CH2),
29.6 (CH2CH2), 33.4 (CH2=CHCH2), 44.8 (NCH2CH2), 45.3
(NCH2CH(OEt)2), 58.7 (NCHCO), 60.5 (NCHCH2CH=CH2), 63.1
(CH3CH2O), 64.2 (CH3CH2O), 100.4 (CH2CH(OEt)2), 119.4
(CH2=CH), 131.9 (CH2=CH), 164.1, 167.3 (CON).
cis-Lactone 13
[ ]D20 +143.8 (c 0.3, CHCl3).
IR (CHCl3): 3022, 2986, 2936 (CH), 2127 (N3), 1790 (CO) cm–1.
1H NMR (CDCl3, 270 MHz): = 1.45 (d, 3 H, J = 5.9 Hz, CH3),
1.74 (ddd, 1 H, J = 12.5, 11.0, 9.6 Hz, CH2), 2.66 (ddd, 1 H,
J = 13.2, 8.8, 5.9 Hz, CH2), 4.33 (dd, 1 H, J = 11.0, 8.8 Hz, CHN3),
4.53 (ddt, 1 H, J = 11.0, 5.9, 5.9 Hz, CHO).
13C NMR (68 MHz, CDCl3): = 20.8 (CH3), 36.5 (CH2), 58.1
(HN3), 74.3 (CHO), 172.9 (COO).
MS (EI, 80 eV, 30 °C): m/z (%) = 141 (8.5, [M]+), 126 (3.2, [M –
10 (Major Diastereomer)
[ ]D20 –48.3 (c 1.2, CHCl3).
IR (film): 2975, 2884 (CH2), 1666 (CON), 1454 (CH2) cm–1.
CH3]+), 113 (3.6, [M – N2]+).
HRMS: m/z [M+] calcd for C5H7N3O2, 141.05383; found,
141.05621.
1H NMR (CDCl3, 500 MHz): = 1.02 (t, 3 H, J = 7.4 Hz, CH3),
1.10 (t, 3 H, J = 7.4 Hz, CH3), 1.75–1.92 (m, 3 H, CH2CH2), 2.28
(m, 1 H, CH2CH2), 2.49 (m, 2 H, CH2=CHCH2), 2.85 (dd, 1 H,
J = 14.0, 7.4 Hz, NCHHCH(OEt)2), 3.27–3.68 (m, 6 H, 2
CH3CH2, CH2NCO), 3.82 (dd, 1 H, J = 14.0, 3.7 Hz, NCH-
HCH(OEt)2), 4.01 (dd, 1 H, J = 7.8, 6.6 Hz, COCHN), 4.12 (t, 1 H,
J = 5.9 Hz, NCHCH2CH=CH2), 4.49 (dd, 1 H, J = 7.4, 3.7 Hz,
CH2CH(OEt)2), 5.01(d, 1 H, J = 9.7 Hz, CHH=CH), 5.06 (dd, 1 H,
J = 16.9, 1.5 Hz, CHH=CH), 5.68 (dddd, 1 H, J = 16.9, 10.3, 7.4
Hz, 7.4 Hz, CH2=CH).
13C NMR (68 MHz, CDCl3): = 15.1 (CH3CH2O), 22.2 (CH2CH2),
29.4 (CH2CH2), 35.9 (CH2=CHCH2), 45.2 (NCH2CH2), 48.3
(NCH2CH(OEt)2), 58.3 (NCHCO), 63.1 (CH3CH2O), 63.8
(NCHCH2CH=CH2), 64.2 (CH3CH2O), 100.6 (CH2CH(OEt)2),
119.9 (CH2=CH), 131.8 (CH2=CH), 165.2, 167.7 (CON).
The spectral data of trans-lactone 14 were identical with those pub-
lished in the literature.21
(2R)-2-(N-Benzyloxycarbonyl)-N-(2,2-diethoxyethyl)amino)-
pent-4-enoic Acid [(2S)-tert-Butyldimethylsilyloxymethyl-
pyrrolidinyl]amide (16b)
From N-allylprolinol silyl ether 2 (800 mg, 3.14 mmol) and N-Cbz-
glycyl fluoride 6b (1.2 g, 3.67 mmol) following the general proce-
dure. Reaction temperature 0 °C, reaction time 16 h. Purification via
column chromatography (EtOAc), gave 1.32 g (75%) of 16b as a
colorless oil; [ ]D20 +2.4 (c 1.8, CHCl3). No diastereomer (2S)-15b
was detected.
IR (film): 3068, 3032 (C6H5), 2955, 2929, 2857 (CH2), 1701
(OCON), 1648 (CON), 1442, 1404 (CH2) cm–1.
1H NMR (CDCl3, 500 MHz): = 0.00 (s, 6 H, Si(CH3)2), 0.84 (s, 9
MS (EI, 80 eV, 90 °C): m/z (%) = 310 (1.4, [M]+), 269 (6.5, [M –
H, SiC(CH3)3), 1.10 (m, 6 H, 2
CH3CH2O), 1.80 (m, 4 H,
C3H5]+), 265 (18, [M – C2H5O]+).
CH2CH2), 2.50 (m, 2 H, CH2=CHCH2), 3.06–3.73 (m, 10 H, 2
Synthesis 2002, No. 2, 242–252 ISSN 0039-7881 © Thieme Stuttgart · New York

250
N. Zhang, U. Nubbemeyer
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CH3CH2O, CH2O, CbzNCH2CH, NCH2CH2), 4.08 (m, 1 H,
NCHCHO2), 4.58 (m, 1 H, CH(OEt)2), 4.88–5.23 (m, 5 H,
CH2=CH, CH2=CHCH2CH, PhCH2), 5.70 (m, 1 H, CH2=CH), 7.30
(m, 5 H, C6H5).
13C NMR (68 MHz, CDCl3): = –5.5 (SiCH3), 15.1 (CH3CH2O),
18.0 (SiC(CH3)3), 24.0, 24.2 (CH2CH2), 25.7 (SiC(CH3)3), 26.5,
26.9 (CH2CH2), 34.4, 34.6 (CH2=CHCH2), 46.1, 46.4 (NCH2CH2),
47.1, 47.4 (NCH2CH(OEt)2), 56.9, 57.3 (CHCH2O), 58.7
(NCHCH2O), 62.2, 62.3 (CH2=CHCH2CHN), 62.4, 62.6
(CH3CH2O), 67.5, 67.6 (PhCH2), 100.0, 101.0 (CH(OEt)2), 117.1,
117.3 (CH2=CH), 127.9, 128.0, 128.2, 128.3, 128.5, 134.0, 136.2
(C6H5), 134.5, 134.8 (CH2=CH), 156.6 (BnOCON), 168.5 (CON).
MS (EI, 80 eV, 125 °C): m/z (%) = 562 (1.6, [M]+), 547 (1.4, [M –
CH3]+), 533 (11, [M – C2H5]+), 505 (20, [M – C4H9]+), 103 (100,
[CH(OEt)2]+), 91 (55, [C7H7]+).
HRMS: m/z [M+] calcd C30H50N2O6Si, 562.34381; found,
562.34576.
(20 mL) was added and the aqueous layer was extracted with Et2O
(4 10 mL). After drying (MgSO4) the solvent was removed and
the crude benzyl ether was purified via column chromatography
(hexane–EtOAc, 7:1); gave 896 mg (51%) of 20 as a yellow oil;
[ ]D20 –13.5 (c 0.9, CHCl3).
IR (CHCl3): 3011, 2977, 2952, 2930, 2885, 2853 (CH), 1632
(CON) cm–1.
1H NMR (CDCl3, 500 MHz): = 0.00 (s, 6 H, SiCH3), 0.84 (s, 9 H,
SiC(CH3)3), 1.15 (2 t, 6 H, J = 7.4 Hz, CH3CH2O), 1.70–1.98 (m, 4
H, CH2CH2), 2.40 (ddd, 1 H, J = 14.0, 7.4, 6.6 Hz, CH2=CHCH2),
2.55 (ddd, 1 H, J = 14.0, 7.4, 6.6 Hz, CH2=CHCH2), 2.88 (dd, 2 H,
J = 14.0, 5.2 Hz, NCH2CH(OEt)2), 3.17 (m, 1 H, NCH2CH2), 3.31–
3.70 (m, 8 H, NCH2CH2, NCHCH2CH=CH2, CH3CH2O, CH2O),
3.79 (d, 1 H, J = 14.8 Hz, ArCH2), 3.93 (d, 1 H, J = 15.4 Hz,
ArCH2), 4.13 (m, 1 H, NCHCH2O), 4.31 (t, 1 H, J = 5.2 Hz,
CH(OEt)2), 4.97 (d, 1 H, J = 10.3 Hz, CH2 = CH), 5.05 (d, 1 H,
J = 16.9 Hz, CH2 = CH), 5.75 (dddd, 1 H, J = 16.9, 10.3, 7.4, 6.6
Hz, CH2=CH), 5.91 (s, 2 H, OCH2O), 6.90 (s, 1 H, Ar), 7.05 (s, 1 H,
Ar).
13C NMR (68 MHz, CDCl3): = –5.4 (SiCH3), 15.2 (CH3CH2O),
18.0 (SiC(CH3)3), 24.3 (CH2CH), 25.7 (SiC(CH3)3), 26.8
(CH2CH2), 31.7 (CH2=CHCH2), 46.8 (NCH2CH2), 54.5
(NCH2CH(OEt)2), 55.3 (CHCH2O), 58.3 (NCHCH2O), 61.9
(CH2=CHCH2CHN), 62.1 (ArCH2), 62.4, 62.6 (CH3CH2O), 101.4
(CH(OEt)2), 103.0 (OCH2O), 116.7 (CH2=CH), 110.2, 112.2,
113.8, 132.8, 146.9, 147.2 (Ar), 135.4 (CH2=CH), 170.7 (CON).
(2R)-2-(tert-Butyloxycarbonylamino)pent-4-enoic Acid [(2S)-
tert-Butyldimethylsilyloxymethylpyrrolidinyl]amide (16f)
From N-allylprolinol silyl ether 2 (500 mg, 1.96 mmol) and N-Boc-
glycyl fluoride 6f (630 mg, 3.58 mmol) following the standard pro-
cedure. Reaction temperature 0 °C, reaction time 16 h. Purification
via column chromatography (EtOAc) gave 73 mg (6%) of 16f as a
yellow oil; [ ]D20 –40.8 (c 0.6, CHCl3).
IR (CHCl3): 3291 (NH), 2929, 2955, 2883 (CH2), 1711 (OCON),
1640 (CON), 1435 (CH2) cm–1.
MS (EI, 80 eV, 160 °C): m/z (%) = 640 (3.6, [M]+), 539 (22, [M –
C5H11O2]+), 400 (83, [M – C12H24NO2Si]+), 103 (100, [C5H11O2]+).
1H NMR (CDCl3, 270 MHz): = 0.01 (s, 6 H, SiCH3), 0.90 (s, 9 H,
SiC(CH3)3), 1.40 (s, 9 H, OC(CH3)3), 1.80–2.10 (m, 4 H, CH2CH2),
2.35 (m, 2 H, CH2=CHCH2), 3.43 (m, 1 H, CHHN), 3.52–3.78 (m,
3 H, CHHN, CH2O), 4.10 (br s, NH), 4.45 (dd, 1 H, J = 14.7, 6.6 Hz,
NCHCH2O), 5.05 (d, 1 H, J = 10.3 Hz, CHH=CH), 5.10 (d, 1 H,
J = 16.9 Hz, CHH=CH), 5.33 (dd, 1 H, J = 18.4, 8.8 Hz, NCHCO),
5.71 (dddd, 1 H J = 16.9, 10.3, 7.4, 6.6 Hz, CH2=CH).
13C NMR (68 MHz, CDCl3): = –5.5 (SiCH3), 18.1 (SiC(CH3)3),
23.9, 24.3 (CH2CH2), 25.8 (SiC(CH3)3), 26.6, 26.9 (CH2CH2), 27.9,
28.2 (OC(CH3)3), 37.4, 37.5 (CH2=CHCH2), 47.2, 47.4 (CH2N),
51.5, 51.7 (NCHCO), 58.4, 58.5 (CHCH2O), 62.3, 62.5
(NCHCH2O), 79.3 (OC(CH3)3), 118.2 (CH2=CH), 132.8, 132.9
(CH2=CH), 169.9 (CON).
HRMS: m/z [M+] calcd for C30H49BrN2O6Si 640.25432; found,
640.25744.
(3R)-3-Allyl-N-(2,2-diethoxyethyl)-6,7-methylenedioxy-1,2,3,4-
tetrahydro-4-isoquinolone (23)
From amine 2 and amides 16a, 21 (R1 = TBDMS): Under argon, N-
piperonylprolinol silyl ether 21 (550 mg, 0.86 mmol, R1 = TBDMS)
in anhyd THF (20 mL) was cooled to –78 °C. BuLi (650 L, 1.04
mmol, 1.6 M in hexane) was injected dropwise. The temperature
was raised to –40 °C and the mixture was stirred under these condi-
tions for a further 3 h (TLC-monitoring). Sat. aq NH4Cl (10 mL)
was added to the mixture and the aqueous layer was extracted with
Et2O (4 10 mL), and the combined organic layers were dried
(MgSO4). After removal of the solvent, the crude material was pu-
rified by column chromatography (hexane–EtOAc, 5:1) gave 242
mg (81%) of 23 as a yellow oil.
MS (EI, 80 eV, 100 °C): m/z (%) = 412 (1.5, [M]+), 355 (30, [M –
C4H9]+), 299 (57, [M – C4H9 – C4H8]+).
HRMS: m/z [M+] calcd for C21H40N2O4Si, 412.27573; found,
Reaction via Amine 3 and Amides 18a, 22 (R1 = Bn): From N-allyl-
prolinol benzyl ether 2 (650 mg, 2.81 mmol) and N-Boc-glycyl flu-
oride 6a (1.0 g, 3.41 mmol) following the standard procedure.
Reaction time, 16 h at 0 °C. Complete removal of the Boc-group
412.27682.
(2R)-2-[N-(2-Bromo-4,5-methylenedioxyphenyl)methyl]-N-
(2,2-diethoxyethyl)aminopent-4-enoic Acid [(2S)-tert-
Butyldimethylsilyloxymethyl-pyrrolidinyl)]amide (20)
(
20) and benzylation of the amine ( 22) as described for benzy-
From N-allylprolinol silyl ether 2 (700 mg, 2.74 mmol) and N-Boc-
glycyl fluoride 6a (965 mg, 3.29 mmol) following the standard pro-
cedure. Reaction temperature 0 °C, reaction time 16 h. The majority
of the Boc-protective group had been removed during the course of
the workup. To a solution of the crude amide 16a in EtOH (10 mL)
cooled to 0 °C was added SOCl2 (5 mL) and the mixture was stirred
at 20 °C for 16 h. Aq NaHCO3 (20 mL) was added, then the mixture
was extracted with CH2Cl2. The combined organic layers were dried
(MgSO4) and the solvent was evaporated to give the crude amide 19
(R1 = H). The O-TBDMS group was reintroduced (R1 = TBDMS)
following the procedure as described for the silyl ether 2. Imidazole
(380 mg, 5.59 mmol), DMAP (10 mg), TBDMSCl (650 mg, 4.33
mmol), anhyd CH2Cl2 (30 mL), reaction time 16 h. Benzylation: the
crude silylether and K2CO3 (3 g, 21.7 mmol) in anhyd MeCN (20
mL) was treated with 2-bromopiperonyl bromide (1 g, 3.4 mmol).
The mixture was refluxed overnight. After cooling to 20 °C, H2O
lamine 21 skipping the silylation step. Bromine–metal exchange
and cyclization following the procedure of 22 described above, re-
action temperature –50 °C; yield: 460 mg (47%); yellow oil;
[ ]D20 –6.2 (c = 1.4, CHCl3).
IR (CHCl3): 3017, 2978, 2899 (CH), 1673 (CO) cm–1.
1H NMR (CDCl3, 270 MHz): = 1.10 (2 t, 6 H, J = 7.4 Hz,
CH3CH2O), 2.45 (ddd, 2 H, J = 14.0, 7.4, 6.6 Hz, CH2=CHCH2),
2.73 (dd, 2 H, J = 14.0, 5.2 Hz, NCH2CH(OEt)2), 3.35–3.43 (m, 3
H, CH3CH2O, NCHCO), 3.51–3.64 (m, 2 H, CH3CH2O), 3.86 (d, 1
H, J = 16.9 Hz, ArCH2), 4.18 (d, 1 H, J = 16.9 Hz, ArCH2), 4.48 (t,
1 H, J = 5.2 Hz, CH(OEt)2), 4.99 (d, 1 H, J = 10.3 Hz, CH2=CH),
5.03 (dd, 1 H, J = 16.9, 2.2 Hz, CH2=CH), 5.82 (dddd, 1 H, J = 16.9,
10.3, 7.4, 6.6 Hz, CH2=CH), 5.94 (s, 2 H, OCH2O), 6.53 (s, 1 H, Ar),
7.35 (s, 1 H, Ar).
Synthesis 2002, No. 2, 242–252 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active C-Allylglycine Derivatives
251
13C NMR (68 MHz, CDCl3):
= 15.2 (CH3CH2O), 31.8
(6) (a) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.;
(CH2=CHCH2), 50.7 (CH2CH(OEt)2), 56.2 (NCHCO), 62.1, 62.2
(CH3CH2O), 68.4 (NCH2Ar), 101.5 (CH(OEt)2), 102.4 (OCH2O),
105.7, 125.0, 125.0, 137.7, 147.2, 152.2 (Ar), 116.7 (CH2=CH),
135.0 (CH2=CH), 195.1 (CO).
Hazell, R. G.; Joergensen, K. A. J. Org. Chem. 1999, 64,
4844. (b) Yamamoto, Y.; Onuki, S.; Yumoto, M.; Asao, N.
Heterocycles 1998, 47, 765. (c) Kardassis, G.; Brungs, P.;
Steckhan, E. Tetrahedron 1998, 54, 3471. (d) Loh, T.-P.;
Ho, D. S.-C.; Xu, K.-C.; Sim, K.-Y. Tetrahedron Lett. 1997,
38, 865. (e) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett.
1996, 37, 5273. (f) Hanessian, S.; Yang, R.-Y. Tetrahedron
Lett. 1996, 37, 8997. (g) Kurokawa, N.; Ohfune, Y.
Tetrahedron 1993, 49, 6195. (h) Yamamoto, Y.; Ito, W.
Tetrahedron 1988, 44, 5415.
MS (EI, 80 eV, 130 °C): m/z (%) = 347 (0.23, [M]+), 306 (100, [M
– C3H5]+), 103 (75, [C5H11O2]+).
HRMS: m/z calcd for [M – C3H5]+, 306.13414; found, 306.13733.
Acknowledgement
(7) (a) Kazmaier, U.; Maier, S. J. Org. Chem. 1999, 64, 4574.
(b) Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed. Engl.
1995, 34, 2012; Angew. Chem. 1995, 107, 2213.
(8) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993, 58,
7216. (b) Sandrine, L.-A.; Savignac, M.; Dupuis, C.; Genet,
J. P. Bull. Soc. Chim. Fr. 1995, 132, 1157.
We thank the DFG the FCI and the Schering AG for support of this
research.
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(25) Chiral HPLC analyses were run using triacetyl cellulose
(Merck), Chirobiotic-V and Chirobiotic-T columns (Baker).
Flow rates: 1–2 mL/min, eluents: MeOH, EtOH, i-PrOH and
Synthesis 2002, No. 2, 242–252 ISSN 0039-7881 © Thieme Stuttgart · New York

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N. Zhang, U. Nubbemeyer
PAPER
varying mixtures of alcohol–hexanes. For chiral 1H NMR
shift experiments Eu(tfc)3 (tris-[3-(trifluoromethylhydroxy-
methylene)-(+)-camphorato]europium) was used. Ana-
lyzing the singlet at = 7.35, different downfield shifts were
found for the enantiomers.
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