Asymmetric synthesis of α-allenylglycines

Article abstract of DOI:10.1002/ejoc.200900462

The coupling of the homocuprate of the bislactim ether of cyclo-(-L-Val-Gly-) (9) with primary propargyl halides produces the allenyl-substituted bislactim ethers 11 in a highly diastereoselective manner, whereas the alkylation of the lith-iated bislactim ether of cyclo-(-L-Val-Gly-) yields the proparg-yl-substituted bislactim ethers 12. Subsequent hydrolysis affords, after protection of the amino group, the methyl α- allenylglycinates 15, the α-allenylglycines 16, and the methyl α-propargylglycinates 17.

Full text of DOI:10.1002/ejoc.200900462

FULL PAPER
DOI: 10.1002/ejoc.200900462
Asymmetric Synthesis of α-Allenylglycines
Carmen Bucuroaia,[a] Ulrich Groth,*[a] Thomas Huhn,[a] and Michael Klinge[b]
Keywords: Asymmetric synthesis / Amino acids / Cuprates / Allenes / Alkynes
The coupling of the homocuprate of the bislactim ether of
cyclo-(- -Val-Gly-) (9) with primary propargyl halides pro-
duces the allenyl-substituted bislactim ethers 11 in a highly
affords, after protection of the amino group, the methyl α-
allenylglycinates 15, the α-allenylglycines 16, and the methyl
α-propargylglycinates 17.
L
diastereoselective manner, whereas the alkylation of the lith-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
iated bislactim ether of cyclo-(-L-Val-Gly-) yields the proparg- Germany, 2009)
yl-substituted bislactim ethers 12. Subsequent hydrolysis
give the Schiff base 4. This Schiff base tautomerizes either
with (path B) or without (path A) decarboxylation to afford
the imines 5 or 6. These imines act as Michael acceptors,
which undergo irreversible Michael addition with a nucleo-
philic part of the enzyme to give the “inhibited” enzymes 7
or 8.
I. Introduction
β,γ-Unsaturated α-amino acids such as vinylglycines 1
and alkynylglycines 2 have attracted considerable attention
because of their potential biological activity.[1,2] α-Allenylic
α-amino acids such as allenylglycines 3 are attractive candi-
dates for the specific inhibition of vitamin B6-linked (pyr-
idoxal-linked) enzyme systems;[3] α-allenyl DOPA, for ex-
ample, rapidly inactivates porcine kidney aromatic amino
acid decarboxylase.[4]
These kinds of unsaturated amino acids are challenging
target molecules in asymmetric synthesis because of their
known tendency towards racemization and their tauto-
merization to unstable α,β-dehydro amino acids.[5] Together
with a few methods for the synthesis of racemic α-alk-
ynylglycines[6,7] and α-allenylphenylalanines,[8] efficient
methods for the asymmetric construction of vinyl-[9–12] and
alkynylglycines[13–15] have already been developed, but
asymmetric syntheses for allenyl amino acids are still lack-
ing. While studying asymmetric syntheses of nonproteinog-
enic α-amino acids, we took special interest in α-allenyl
amino acids 3, because these amino acids have been recog-
nized as irreversible enzyme inhibitors.[16,17] In the pro-
posed mechanism (Scheme 1), an α-allenyl amino acid 3 re-
acts with the cofactor pyridoxalphosphate (Py-CHO) to
Scheme 1. Proposed mechanism of pyridoxal phosphate-dependent
decarboxylase inhibition by α-allenyl amino acids.
[a] Fachbereich Chemie und Konstanz Research School Chemical
Biology der Universität Konstanz, Fach 720,
Universitätsstr. 10, 78457 Konstanz, Germany
Fax: +49-7531-884155
Krantz and Castelhano[8] prepared α-allenyl-α-benzyl
amino acids by using oxazoles as intermediates; these
underwent Claisen rearrangements to afford allenyl-substi-
tuted oxazolones. A four-step hydrolysis gave the corre-
E-mail: Ulrich.Groth@uni-konstanz.de
[b] GIT Verlag GmbH & Co. KG,
64220 Darmstadt, Germany
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Bucuroaia, U. Groth, T. Huhn, M. Klinge
FULL PAPER
sponding α,α-disubstituted amino acids in about 70%
yields. However, this method seems to be limited to the syn-
thesis of racemic α-benzyl-α-allenylglycines, which obvi-
ously cannot act as suicide substrates as in path A because
a rearrangement to imine 5 is impossible. Utilizing an allen-
ylic N-benzoyl-protected amino acid ester, Casara et al.
were able to obtain racemic α-allenylic amino acids by a
cumbersome sequential five-step alkylation/deprotection se-
quence.[18] Kazmaier, employing a chelate-controlled ester
enolate Claisen rearrangement, succeeded in the synthesis
of α-H-allenyl amino acids.[19,20] With zinc(II) chloride as
chelating agent rearrangements of amino acid propargylic
esters proceeded in a highly diastereoselective fashion. In
1990, Doyle et al. reported on a synthesis of racemic N,N-
dimethyl-α-allenylglycine.[21] The key step of their synthesis
was a [2,3]-sigmatropic rearrangement of N,N-dimeth-
ylamino propyne.
Scheme 2. Reactions between the bislactim ether homocuprate and
different propargylic bromides.
Recently two different approaches towards enantiomer-
ically enriched α-allenylglycines and α-alkynylglycines uti-
lizing tin organyls have been published. Hamon et al. pre-
pared 2-allenylglycinates by treatment of allenyltriphenyl-
stannane with 8-phenylmenthyl N-Boc-2-bromoglycinate,
albeit in 53% yield and with ees of 86%.[22] Utilizing allen-
yltributylstannane, Akiyama et al. succeeded in the prepa-
ration of α-alkynylglycinates.[23] With catalytic amounts of
a copper-based Lewis acid in conjunction with chiral di-
phosphanes, treatment of an α-iminoglycinate gave the cor-
responding α-alkynylglycinates under optimized reaction
conditions in yields of up to 93% but with only 86% ees.
Both methods suffer from the limited availability of substi-
tuted allenyltin organyls and complicated starting material
preparation.
low reactivities of the acetates. Despite these results, reac-
tions between the bislactim ether homocuprate and the pro-
pargylic bromides 10 were investigated. The results are sum-
marized in Table 1. Treatment of the bislactim ether homo-
cuprate with primary propargylic bromides afforded the
dihydropyrazines 11 with excellent diastereoselectivities
(Ͼ 98% des). As byproducts (11–30%, Ͼ98% des) the dihy-
dropyrazines 12 were formed by a simple alkylation of the
homocuprate. The adduct 11a obtained from propargyl
bromide (10a) decomposed after chromatographic purifica-
tion within a few hours. With tertiary propargylic bromides
the corresponding dihydropyrazines 11 were obtained as the
only products with low to reasonable diastereoselectivities
(22–40% des). As would be expected, no SN2 alkylation of
the cuprate took place with tertiary propargylic bromides.
The yields are usually below 50% because only one equiva-
lent of the bislactim ether from its homocuprate is con-
sumed.
II. Results and Discussion
The strategy employed here for the synthesis of enantio-
merically pure α-H-allenyl amino acids is illustrated in
Scheme 2. Allenes were synthesized by Crabbé et al.,[24] who
treated propargylic acetates with homocuprates. The reac-
tion sequence starts with an attack of the homocuprate at
the triple bond to afford a copper-substituted allene, which
then yields the allene with reductive elimination of alk-
ylcopper.[25–27] We tried to apply this method for the synthe-
sis of bislactim ethers 11, which upon acidic hydrolysis
should give the allenylglycine methyl esters 15.
Because the synthetic value of alkyl, aryl, and alkenyl
homocuprates is well established, only a very few azaenol-
ate cuprates have been described.[28,29] The bislactim ether
homocuprate was generated from two equivalents of the lith-
iated bislactim ether of cyclo-(--Val-Gly-) (9) and one
equivalent of copper(I)bromide/dimethyl sulfide complex at
–30 °C. This homocuprate is fairly stable at temperatures
lower than –30 °C but decomposes rapidly at temperatures
Table 1. Allenyl- and propargyl-substituted dihydropyrazines 11
and 12.
10,11,12 R1
R2
11
12
yield [%] de [%]
yield [%] de [%]
a
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
H
Me
38
–
42
37
40
24
–
59
50
59
98
–
98
98
98
98
–
40
32
22
6
98
54 [a]
98
98
98
98
38 [a]
–
88
14
11
16
30
91
–
nBu
tBu
nHex
Ph
SiMe3
nBu
nHex Me
Ph Me
–
–
–
–
[a] These reactions were carried out with the lithiated bislactim
ether of cyclo-(--Val-Gly-).
The isomers 11a–e and 12a–e, as well as the dia-
higher than –20 °C, as judged by strongly diminished yields. stereomers of 11g–i, were easily separated by flash
Under similar reaction conditions, mixed organocuprates chromatography on silica gel, so the allenyl-substituted bis-
were not obtainable. The first experiments carried out with lactim ethers 11 can be obtained diastereomerically pure.
this cuprate and propargylic acetates failed because of the The configurations of compounds 11 and 12 were estab-
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Eur. J. Org. Chem. 2009, 3605–3612

Asymmetric Synthesis of α-Allenylglycines
lished through their 5J coupling constants. For trans-substi-
Hydrolysis of compounds 11 with TFA in THF (0.2 )
tuted dihydropyrazines 5J constants of about 3.0–3.5 Hz are followed by protection of the amino group with (Boc)2O/
5
typical, whereas for the corresponding cis isomers J con- triethylamine afforded, besides methyl N-Boc--valinate, the
stants of about 4.5–6.0 Hz were observed.
hitherto unknown N-Boc-protected methyl α-allenylglycin-
At this point it should be mentioned that α-propargylgly- ates 15. The crude methyl α-allenylglycinates, which were
cines are also obtainable by the bislactim ether method, be- obtained after hydrolysis, were protected as their N-Boc de-
cause the lithiated bislactim ether reacts with primary pro- rivatives because these compounds are more easily separa-
pargyl bromides in a SN2 fashion to yield the adducts 12a ble from methyl N-Boc--valinate by chromatography than
and 12f.
To our surprise the hydrolysis of the allenyl adducts 11
the free amino acid esters.
In a model experiment it was demonstrated that the
with HCl in THF/MeCN (0.1  up to 3 ) did not afford methyl α-allenylglycinates 15 can be hydrolyzed to the cor-
the α-allenyl amino acid esters 15. In these cases, the hydrol- responding α-allenylglycines. Therefore, the N-Boc-pro-
ysis occurred only at one of the two imino ether functions, tected methyl α-allenylglycinate 15d was treated with
yielding 1:1 mixtures of dipeptide esters 13 and 14 in almost 1.2 equiv. of lithium hydroxide in aqueous THF to afford,
quantitative yield.
after aqueous workup and chromatographic purification, a
56% yield of the N-Boc-protected α-allenylglycine 16d.
As mentioned earlier, the lithiated bislactim ether of cy-
clo-(--Val-Gly-) (9) can be alkylated with primary propar-
gyl bromides to afford the propargyl-substituted bislactim
ethers 12. Adducts 12a and 12f were isolated in 88 and 91%
yields with des of 54 and 38%, respectively. After chromato-
graphic separation of diastereomers the propargyl-substi-
tuted bislactim ethers 12a and 12f were obtained dia-
stereomerically pure. The configurations of the new ste-
5
reogenic centers were once again established through the J
coupling constants.
This result may be explained in terms of a nucleophilic
attack of the chloride at the methyl imino ether group of
the protonated bislactim ether.[30] Therefore, the hydrolysis
of the bislactim ethers 11 with trifluoroacetic acid (TFA)
was investigated. Unlike the chloride ion, the non-nucleo-
philic trifluoroacetate anion should not be able to cleave the
imino ether bond. The results are summarized in Table 2.
This low diastereoselectivity for the alkylation step is
somewhat surprising because the diastereoselectivity for the
alkylation of the lithiated bislactim ether of cyclo-(--Val-
Gly-) (9) usually varies between 75 and Ͼ95% de[31] Only
for the alkylation with the relatively small methyl iodide
and trimethylsilylmethyl iodide did the diastereoselectivity
drop down to 43 and ca. 60% de.[32]
Hydrolysis of the diastereomerically pure progargyl-sub-
stituted bislactim ethers 12 afforded, besides methyl -valin-
ate, the methyl α-propargylglycinates 17, which could usu-
ally be separated by bulb-to-bulb distillation (Table 3). Be-
cause methyl -propargylglycinate (17a) and methyl -valin-
ate are not easily separable by distillation, 17a can be pre-
pared more conveniently through its trimethylsilyl deriva-
tive 17b by simple desilylation.
Table 2. Methyl α-allenylglycinates 15.
11
15
R1
R2
Yield [%] Ee [%]
[α]2D0[a]
b
d
g
h
h
a
b
c
d
nBu
nHex
nBu
nHex
nHex
H
H
Me
Me
Me
60
83
68
77
89
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
–50.8
–28.4
–36.3
–24.2
+23.7[b]
ent-d
In this communication the asymmetric synthesis of enan-
tiomerically pure (R)-allenylglycines and (R)-propargylgly-
cines by use of the bislactim ether of cyclo-(--Val-Gly-) has
[a] c = 1.0, CHCl3. [b] Minor diastereomer (2S,5S)-11h was used to afford
(S)-15d.
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C. Bucuroaia, U. Groth, T. Huhn, M. Klinge
FULL PAPER
evaporation and the residue was purified by flash chromatography
on silica gel (70 g).
Table 3. Methyl α-propargyl glycinates 17.
Yield
[%]
12
17
R
H
ee [%]
[α]2D0
(2R,5S)-5-Isopropyl-3,6-dimethoxy-2-(propa-1,2-dienyl)-2,5-dihy-
dropyrazine (11a): Bislactim ether 9 (0.70 g, 3.8 mmol), copper(I)
bromide/dimethyl sulfide complex (0.39 g, 1.9 mmol), and propar-
gyl bromide 10a (0.45 g, 3.8 mmol) were used to obtain allenyl-
substituted bislactim ether 11a (0.32 g, 38%) and propargyl-substi-
tuted bislactim ether 12a (51 mg, 6%) after flash chromatography
with diethyl ether/petroleum ether (1:20).
a
f
f
a
b
ent-b
51
Ͼ95
Ͼ95
Ͼ95
+1.7[a]
SiMe3 83
SiMe3 78
–38.4[b]
+38.1[b],[c]
[a] c = 1.0, EtOH. [b] c = 1.0, CHCl3. [c] Minor diastereomer (2S,5S)-
12f was used to afford (S)-17b.
1
Compound 11a: Rf = 0.13; diastereomeric purity Ͼ98%. H NMR
been described. Likewise, (S)-α-allenylglycines can be ob-
tained by use of the bislactim ether of cyclo-(--Val-Gly-).
Both enantiomeric forms of the bislactim ether are com-
mercially available.[33] Through the use of enantiomerically
pure secondary propargyl bromides for this reaction en-
antio- and diastereomerically pure α-allenylglycines 3
should be obtainable.
(200 MHz, CDCl3): δ = 0.66, 1.03 [2ϫd, J = 6.8 Hz, 6 H, CH-
(CH3)2], 2.27 [dsp, J = 6.8 and 3.4 Hz, 1 H, CH(CH3)2], 3.69 (s, 6
3
5
5
H, OCH3), 3.92 (dd, J = J = 3.4 Hz, 1 H, 5-H), 4.55 (ddd, J1 =
5J2 = 5J3 = 3.4 Hz, 1 H, 2-H), 4.72–4.90 (m, 2 H, C=C=CH2), 5.32
(ddd, 3J = 4J1 = 4J2 = 6.6 Hz, 2 H, C=C=CH2–H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 16.55, 19.11 [CH(CH3)2], 31.46 [CH(CH3)2],
52.70, 52.81 (OCH3), 54.36, 60.52 (C-2,5), 77.91, 91.46 (C=C=C),
162.13, 164.70 (C=N), 208.47 (C=C=C) ppm. IR (neat): ν = 1960
˜
(C=C=C), 1690 (C=N) cm–1. MS: m/z (%) = 222 (31) [M]+, 183
(23), 179 (46), 141 (100).
Experimental Section
Compound 12a: Rf = 0.08; diastereomeric purity Ͼ98%; spectro-
General: Infrared (IR) spectra were obtained with a Perkin–El-
mer 298 spectrometer. NMR spectra were obtained with a Varian
XL 200 or VXR 200 spectrometer for 1H and 13C NMR spec-
troscopy. Chemical shifts are given in parts per million (δ) with
tetramethylsilane as an internal standard for 1H and 13C NMR
spectroscopy. A diastereomeric purity of Ͼ98% was assumed when
only the signals of one isomer were detectable in the 1H and 13C
NMR spectra or in the capillary GC. Optical rotations were mea-
sured with a Perkin–Elmer Mod. 141 polarimeter. TLC analyses
were performed on Polygram Sil G/UV254 silica gel plates. Silica
gel (0.030–0.060 mm) from Macherey & Nagel, Düren was used for
flash chromatography. Combustion analyses were carried out by
the microanalytical laboratory of the University of Konstanz. If
required, reactions were carried out under dry argon or nitrogen.
All reagents were purified and dried by standard protocols prior to
use. The bislactim ether 9 was purchased from Merck,[33] or pre-
pared according to ref.[34] The propargylic alcohols, necessary for
the preparation of the propargylic bromides 10, were prepared by
deprotonation of the corresponding alkynes either with ethylmag-
nesium bromide or with n-butyllithium and subsequent addition of
the corresponding aldehydes or ketones.[35] The transformation of
the propargylic alcohols into their bromides was carried out by
addition of phosphorus tribromide (0.35 equiv.) to ethereal solu-
tions of these alcohols and pyridine (0.2 equiv.) at –70 °C.[36]
scopic data see below.
(2R,5S)-2-(Hepta-1,2-dien-3-yl)-5-isopropyl-3,6-dimethoxy-2,5-di-
hydropyrazine (11b): Bislactim ether 9 (0.74 g, 4.0 mmol), copper(I)
bromide/dimethyl sulfide complex (0.41 g, 2.0 mmol), and propar-
gyl bromide 10b (0.70 g, 4.0 mmol) were used to obtain allenyl-
substituted bislactim ether 11b (0.47 g, 42%) and propargyl-substi-
tuted bislactim ether 12b (0.16 g, 14%) after flash chromatography
with diethyl ether/petroleum ether (1:50).
1
Compound 11b: Rf = 0.13; diastereomeric purity Ͼ98%. H NMR
(200 MHz, CDCl3): δ = 0.69, 1.07 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 0.88 [t, J = 7 Hz, 3 H, (CH2)3CH3], 1.32 [m, 4 H, (CH2)2-
CH3], 1.88 (m, 2 H, C=C=C–CH2), 2.31 [dsp, J = 7 and 3.5 Hz, 1
H, CH(CH3)2], 3.71 (s, 6 H, OCH3), 3.95 (dd, J = J = 3.5 Hz, 1
H, 5-H), 4.54 (dt, 4J = 1.3, 5J = 3.5 Hz, 1 H, 2-H), 4.81, 4.83 (2ϫt,
5J = 1.2 Hz, 2 H, C=C=CH2) ppm. 13C NMR (50 MHz, CDCl3):
δ = 13.97, 16.49, 19.20 [CH(CH3)2, (CH2)3CH3], 22.41, 27.70, 29.55
(CH2), 31.39 [CH(CH3)2], 52.67, 52.81 (OCH3), 59.18, 60.55 (C-
2,5), 77.64, 104.14 (C=C=C), 162.49, 164. 96 (C=N),
3
5
207.08 (C=C=C) ppm. IR (neat): ν = 1960 (C=C=C), 1690.
˜
(C=N) cm–1. MS: m/z (%) = 278 (20) [M]+, 263 (4), 235 (12), 183
(35), 141 (100). C16H26N2O2 (278.39): calcd. C 69.03, H 9.41; found
C 69.22, H 9.35.
1
Compound 12b: Rf = 0.09; diastereomeric purity Ͼ98%. H NMR
General Procedure for the Preparation of Allenyl-Substituted Bislac-
tim Ethers 11: n-Butyllithium (2.6 mL, 4.1 mmol of a 1.58  solu-
tion in hexane) was added dropwise at –70 °C to a solution of the
bislactim ether 9 (0.74 g, 4.0 mmol) in THF (10 mL) and stirring
was continued for 10 min. Separately, dimethyl sulfide was added at
room temp. to a suspension of copper(I) bromide/dimethyl sulfide
complex (0.41 g, 2.0 mmol) in THF (10 mL) until the copper(I)
bromide complex was completely dissolved (ca. 3–4 mL). The re-
sulting solution was cooled to –70 °C and the solution of the yellow
lithiated bislactim ether, prepared as described above, was added
by cannula at –70 °C. The resulting orange solution was stirred for
30 min at –30 °C. A solution of the propargyl bromide 10
(200 MHz, CDCl3): δ = 0.69, 1.06 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 0.89 [t, J = 7 Hz, 3 H, (CH2)3CH3], 1.38 [m, 4 H, (CH2)2-
CH3], 2.29 [dsp, J = 7 and 3.5 Hz, 1 H, CH(CH3)2], 2.68 (m, 4 H,
3
5
CH2-CϵC–CH2), 3.72 (s, 6 H, OCH3), 4.01 (dd, J = J = 3.5 Hz,
1 H, 5-H), 4.10 ppm (m, 1 H, 2-H). 13C NMR (50 MHz, CDCl3):
δ = 13.57, 16.56, 19.11 [CH(CH3)2, (CH2)3CH3], 18.38, 21.66,
25.37, 30.96 (CH2), 31.60 [CH(CH3)2], 52.49, 52.56 (OCH3), 54.82,
60.90 (C-2,5), 75.81, 82.23 (CϵC), 162.21, 164.71 ppm (C=N). IR
(neat): ν = 2220 (CϵC), 1690 (C=N) cm–1.
˜
(2R,5S)-2-(2,2-Dimethyl-3,4-pentadien-3-yl)-5-isopropyl-3,6-dimeth-
oxy-2,5-dihydropyrazine (11c): Bislactim ether 9 (0.74 g, 4.0 mmol),
(4.0 mmol) in THF (5 mL) was added at –70 °C and stirring was copper(I) bromide/dimethyl sulfide complex (0.41 g, 2.0 mmol),
continued for 12 h at –70 °C. Over 5 h the solution was allowed to
warm to room temp. The heterogeneous mixture was filtered
through silica gel (30 g) and the solid material was washed with
diethyl ether (300 mL). The filtrate was concentrated by rotary
and propargyl bromide 10c (0.70 g, 4.0 mmol) were used to obtain
allenyl-substituted bislactim ether 11c (0.41 g, 37%) and propargyl-
substituted bislactim ether 12c (0.12 g, 11%) after flash chromatog-
raphy with diethyl ether/petroleum ether (1:50).
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Asymmetric Synthesis of α-Allenylglycines
1
1
Compound 11c: Rf = 0.11; diastereomeric purity Ͼ98%. H NMR
(200 MHz, CDCl3): δ = 0.70, 1.08 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 1.19 [s, 9 H, C(CH3)3], 2.26 [dsp, J = 7 Hz and 3.5 Hz, 1
Compound 11e: Rf = 0.41; diastereomeric purity Ͼ98%. H NMR
(200 MHz, CDCl3): δ = 0.74, 1.06 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 2.32 [dsp, J = 7 and 3.5 Hz, 1 H, CH(CH3)2], 3.66, 3.68
3
5
H, CH(CH3)2], 3.67, 3.69 (2ϫs, 6 H, OCH3), 3.95 (dd, J = J = (2ϫs, 6 H, OCH3), 3.94 (dd, 3J = 5J = 3.5 Hz, 1 H, 5-H), 5.01 (m,
5
3.5 Hz, 1 H, 5-H), 4.57 (d, J = 3.5 Hz, 1 H, 2-H), 4.72 ppm (m,
1 H, 2-H), 5.13 (m, 2 H, C=C=CH2), 7.35 (m, 5H. C6H5) ppm.
2 H, C=C=CH2). 13C NMR (50 MHz, CDCl3): δ = 16.23, 19.00
13C NMR (50 MHz, CDCl3): δ = 16.57, 19.19 [CH(CH3)2], 31.42
[CH(CH3)2], 27.48 [C(CH3)3], 29.55 [C(CH3)3], 32.05 [CH(CH3)2], [CH(CH3)2], 52.56, 52.67 (OCH3), 57.52, 60.56 (C-2,5), 79.46,
52.44, 52.53 (OCH3), 54.38, 60.77 (C-2,5), 78.50, 104.33 (C=C=C), 106.54 (C=C=C), 126.78, 126.89, 128.21, 134.73 (C6H5), 162.27,
163.20, 164.03 (C=N), 207.19 ppm (C=C=C). IR (neat): ν = 1955 164.61 (C=N), 209.40 (C=C=C) ppm. IR (neat): ν = 1955
˜
˜
(C=C=C), 1690 (C=N) cm–1. MS: m/z (%) = 278 (6) [M]+, 263 (3), (C=C=C), 1690 (C=N) cm–1. MS: m/z (%) = 298 (40) [M]+, 283
235 (1), 183 (37), 141 (100). C16H26N2O2 (278.39): calcd. C 69.03,
H 8.41; found C 68.94, H 8.29.
(5), 198 (4), 183 (32), 141 (100), 115 (30). C18H22N2O2 (298.38):
calcd. C 72.46, H 7.43; found C 72.34, H 7.43.
1
1
Compound 12e: Rf = 0.31; diastereomeric purity Ͼ98%. H NMR
Compound 12c: Rf = 0.07; diastereomeric purity Ͼ98%. H NMR
(200 MHz, CDCl3): δ = 0.68, 1.07 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 2.30 [dsp, J = 7 and 3.5 Hz, 1 H, CH(CH3)2], 2.88, 2.99
(2ϫdd, AB part of ABX, JAB = 11.5, JAX = JBX = 4.5 Hz, 2 H,
CH2), 3.64 (s, 6 H, OCH3), 4.05 (dd, J = J = 3.5 Hz, 1 H, 5-H),
4.22 (ddd, X part of ABX, JAX = JBX = 4.5, J = 3.5 Hz, 1 H, 2-
(200 MHz, CDCl3): δ = 0.68, 1.05 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 1.13 [s, 9 H, C(CH3)3], 2.28 [dsp, J = 7 and 3.5 Hz, 1 H,
CH(CH3)2], 2.59, 2.73 (2ϫdd, AB part of ABX, JAB = 11, JAX
JBX = 4 Hz, 2 H, CH2), 3.71, 3.72 (2ϫs, 6 H, OCH3), 4.02 (dd, J
= J = 3.5 Hz, 1 H, 5-H), 4.11 ppm (ddd, X part of ABX, JAX
=
3
5
3
5
5
=
H), 7.27 (m, 5H. C6H5) ppm. 13C NMR (50 MHz, CDCl3): δ =
16.53, 19.12 [CH(CH3)2], 26.13 (CH2), 31.55 [CH(CH3)2], 52.56,
52.61 (OCH3), 54.66, 60.87 (C-2,5), 82.40, 86.16 (CϵC), 123.78,
127.62, 128.16, 131.57 (C6H5), 161.93, 164.84 (C=N) ppm. IR
JBX = 4, 5J = 3.5 Hz, 1 H, 2-H). 13C NMR (50 MHz, CDCl3): δ
= 16.56, 19.17 [CH(CH3)2], 25.38 (CH2), 27.25 [C(CH3)3], 31.18
[C(CH3)3], 31.56 [CH(CH3)2], 52.38, 52.45 (OCH3), 54.91, 60.95
(C-2,5), 74.31, 91.07 (CϵC), 162.09, 164.51 ppm (C=N). IR (neat):
(neat): ν = 2220 (CϵC), 1690 (C=N) cm–1.
ν = 2220 (CϵC), 1690 (C=N) cm–1.
˜
˜
(2R,5S)-5-Isopropyl-3,6-dimethoxy-2-(1-methylocta-2,3-dien-4-yl)-
2,5-dihydropyrazine (11g): Bislactim ether 9 (0.74 g, 4.0 mmol), cop-
per(I) bromide/dimethyl sulfide complex (0.41 g, 2.0 mmol), and
propargyl bromide 10g (0.81 g, 4.0 mmol) were used to obtain
(2R,5S)-11g (0.51 g, 42%) and (2S,5S)-11g (0.22 g, 18%) after flash
chromatography with diethyl ether/petroleum ether (1:10); the dia-
stereomeric ratio was 70:30, 40% de.
(2R,5S)-5-Isopropyl-3,6-dimethoxy-2-(nona-1,2-dien-3-yl)-2,5-dihy-
dropyrazine (11d): Bislactim ether 9 (0.74 g, 4.0 mmol), copper(I)
bromide/dimethyl sulfide complex (0.41 g, 2.0 mmol), and propar-
gyl bromide 10d (0.81 g, 4.0 mmol) were used to afford allenyl-sub-
stituted bislactim ether 11d (0.49 g, 40 %) and propargyl-substi-
tuted bislactim ether 12d (0.20 g, 16%) after flash chromatography
with diethyl ether/petroleum ether (1:20).
1
Compound (2R,5S)-11g: Rf = 0.50. H NMR (200 MHz, CDCl3): δ
1
Compound 11d: Rf = 0.38; diastereomeric purity Ͼ98%. H NMR
= 0.69, 1.08 [2ϫd, J = 7 Hz, 6 H, CH(CH3)2], 0.89 [t, J = 7 Hz, 3
H, (CH2)3CH3], 1.34 [m, 4 H, (CH2)2CH3], 1.65, 1.67 [2ϫs, 6 H,
C=C=C-(CH3)2], 1.98 (m, 2 H, C=C=C–CH2), 2.33 [dsp, J = 7 and
3.5 Hz, 1 H, CH(CH3)2], 3.70, 3.72 (2ϫs, 6 H, OCH3), 3.86 (dd,
(200 MHz, CDCl3): δ = 0.70, 1.09 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 0.88 [t, J = 7 Hz, 3 H, (CH2)5CH3], 1.35 [m, 8 H, (CH2)4-
CH3], 1.90 (m, 2 H, C=C=C–CH2), 2.34 [dsp, J = 7 and 3.5 Hz, 1
3
5
H, CH(CH3)2], 3.72 (s, 6 H, OCH3), 3.96 (dd, J = J = 3.5 Hz, 1
H, 5-H), 4.55 (dt, 5J1 = 3.5, 5J2 = 1.3 Hz, 1 H, 2-H), 4.84 ppm (dt,
5J1 = 3.8, 5J2 = 1.3 Hz, 2 H, C=C=CH2). 13C NMR (50 MHz,
CDCl3): δ = 14.10, 16.47, 19.17 [CH(CH3)2, (CH2)3CH3], 22.65,
27.31, 27.98, 29.01, 31.71 (CH2), 31.35 [CH(CH3)2], 52.60, 52.73
(OCH3), 59.13, 60.48 (C-2,5), 77.54, 104.08 (C=C=C), 162.29,
5
5
3J = J = 3.5 Hz, 1 H, 5-H), 4.27 (d, J = 3.5 Hz, 1 H, 2-H) ppm.
13C NMR (50 MHz, CDCl3): δ = 14.05, 16.42, 19.29 [CH-
(CH3)2, (CH2)3CH3], 20.44, 20.64 [C=C=C-(CH3)2], 22.29, 29.36,
29.82 (CH2), 30.88 [CH(CH3)2], 52.47, 52.62 (OCH3), 59.33, 60.08
(C-2,5), 98.28, 102.61 (C=C=C), 163.19, 164.61 (C=N), 199.52
(C=C=C) ppm. IR (neat): ν = 1960 (C=C=C), 1690 (C=N) cm–1.
˜
164.74 (C=N), 206.85 ppm (C=C=C). IR (neat): ν = 1960
˜
MS: m/z (%) = 306 (11) [M]+, 263 (5), 249 (3), 183 (13), 141 (100),
70 (72). C18H30N2O2 (306.45): calcd. C 70.55, H 9.87; found C
69.94, H 9.29.
(C=C=C), 1690 (C=N) cm–1. MS: m/z (%) = 306 (11) [M]+, 291
(5), 263 (33), 183 (41), 141 (100). C18H30N2O2 (306.45): calcd. C
70.55, H 9.87; found C 70.04, H 9.41.
1
Compound (2S,5S)-11g: Rf = 0.27. H NMR (200 MHz, CDCl3): δ
1
Compound 12d: Rf = 0.24; diastereomeric purity Ͼ98%. H NMR
= 0.79, 1.04 [2ϫd, J = 7 Hz, 6 H, CH(CH3)2], 0.90 [t, J = 8 Hz, 3
H, (CH2)3CH3], 1.35 [m, 4 H, (CH2)2CH3], 1.67, 1.68 [2ϫs, 6 H,
C=C=C-(CH3)2], 2.08 [m, 3 H, C=C=C–CH2, CH(CH3)2], 3.70,
3.71 (2ϫs, 6 H, OCH3), 3.85 (dd, 3J = 6, 5J = 4 Hz, 1 H, 5-H),
4.46 (d, 5J = 4 Hz, 1 H, 2-H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 14.08, 18.65, 19.97 [CH(CH3)2, (CH2)3CH3], 20.38, 20.50
[C=C=C-(CH3)2], 22.32, 29.91, 30.79 (CH2), 32.71 [CH(CH3)2],
52.32 (OCH3), 59.09, 61.49 (C-2,5), 98.25, 103.58 (C=C=C),
(200 MHz, CDCl3): δ = 0.71, 1.03 [2 ϫ d, J = 7 Hz, 6 H, CH-
(CH3)2], 0.87 [t, J = 7 Hz, 3 H, (CH2)5CH3], 1.35 [m, 8 H, (CH2)4-
CH3], 2.29 [dsp, J = 7 and 3.5 Hz, 1 H, CH(CH3)2], 2.69 (m, 4 H,
3
5
CH2-CϵC–CH2), 3.70, 3.71 (2ϫs, 6 H, OCH3), 4.02 (dd, J = J
= 3.5 Hz, 1 H, 5-H), 4.08 ppm (m, 1 H, 2-H). 13C NMR (50 MHz,
CDCl3): δ = 13.88, 16.84, 19.45 [CH(CH3)2, (CH2)3CH3], 18.35,
21.68, 25.36, 28.94, 29.72, 30.82 (CH2), 31.55 [CH(CH3)2], 52.41,
52.55 (OCH3), 54.70, 60.78 (C-2,5), 75.70, 82.11 (CϵC), 162.00,
162.85, 164.34 (C=N), 199.06 (C=C=C) ppm. IR (neat): ν = 2220
˜
164.39 (C=N) ppm. IR (neat): ν = 2220 (CϵC), 1690 (C=N) cm–1.
(CϵC), 1690 (C=N) cm–1.
˜
(2R,5S)-5-Isopropyl-3,6-dimethoxy-2-(1-phenylpropa-1,2-dien-1-yl)-
2,5-dihydropyrazine (11e): Bislactim ether 9 (0.74 g, 4.0 mmol), cop-
per(I) bromide/dimethyl sulfide complex (0.41 g, 2.0 mmol), and
propargyl bromide 10e (0.78 g, 4.0 mmol) were used to obtain al-
lenyl-substituted bislactim ether 11e (0.29 g, 24%) and propargyl-
substituted bislactim ether 12e (0.36 g, 30%) after flash chromatog-
raphy with diethyl ether/petroleum ether (1:5).
(2R,5S)-5-Isopropyl-3,6-dimethoxy-2-(1-methyldeca-2,3-dien-4-yl)-
2,5-dihydropyrazine (11h): Bislactim ether 9 (0.74 g, 4.0 mmol), cop-
per(I) bromide/dimethyl sulfide complex (0.41 g, 2.0 mmol), and
propargyl bromide 10h (0.92 g, 4.0 mmol) were used to obtain
(2R,5S)-11h (0.44 g, 33%) and (2S,5S)-11h (0.23 g, 17%) after flash
chromatography with diethyl ether/petroleum ether (1:20); the dia-
stereomeric ratio was 66:34, 32% de.
Eur. J. Org. Chem. 2009, 3605–3612
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3609

C. Bucuroaia, U. Groth, T. Huhn, M. Klinge
FULL PAPER
Compound (2R,5S)-11h: Rf = 0.28. H NMR (200 MHz, CDCl3): δ
= 0.68, 1.08 [2ϫd, J = 7 Hz, 6 H, CH(CH3)2], 0.88 [t, J = 8 Hz, 3
1
butyl dicarbonate [(Boc)2O, 0.65 g, 3.0 mmol] in dichloromethane
(5 mL) was added at room temp., and subsequently triethylamine
H, (CH2)5CH3], 1.33 [m, 8 H, (CH2)4CH3], 1.66, 1.68 [2ϫs, 6 H, (0.35 mL, 2.5 mmol) was added at –5 °C. After stirring at room
C=C=C-(CH3)2], 1.95 (m, 2 H, C=C=C–CH2), 2.31 [dsp, J = 7 and
3.5 Hz, 1 H, CH(CH3)2], 3.68, 3.70 (2ϫs, 6 H, OCH3), 3.82 (dd,
temp. for 12 h the reaction mixture was extracted with HCl (0.1 ,
20 mL). The aqueous layer was reextracted with dichloromethane
(20 mL), the combined organic layers were dried with MgSO4, and
the solvent was evaporated in vacuo. The residue – the crude methyl
5
5
3J = J = 3.5 Hz, 1 H, 5-H), 4.45 (d, J = 3.5 Hz, 1 H, 2-H) ppm.
13C NMR (50 MHz, CDCl3): δ = 14.14, 16.40, 19.29 (CH-
(CH3)2, (CH2)5CH3), 20.45, 20.65 [C=C=C-(CH3)2], 22.73, 27.61, tert-butyloxycarbonyl-α-allenyl glycinates 15 and methyl N-tert-bu-
28.93, 29.64, 31.87 (CH2), 30.86 [CH(CH3)2], 52.46, 52.60 (OCH3), tyloxycarbonyl--valinate – was purified by chromatography on sil-
59.35, 60.07 (C-2,5), 98.26, 102.64 (C=C=C), 163.17, 164.56
ica gel (70 g).
(C=N), 199.53 (C=C=C) ppm. IR (neat): ν = 1955 (C=C=C), 1690
˜
Methyl (2R)-3-Butyl-2-[(tert-butyloxycarbonyl)amino]penta-3,4-di-
enoate (15a): Compound 11b (0.28 g, 1.0 mmol) was used to obtain
15a (0.17 g, 60%) after flash chromatography with diethyl ether/
petroleum ether (1:5). Rf = 0.32. [α]2D0 = –50.8 (c = 1.0, CHCl3). 1H
NMR (200 MHz, CDCl3): δ = 0.87 [t, J = 7 Hz, 3 H, (CH2)3CH3],
1.28 [m, 4 H, (CH2)2CH3], 1.42 [s, 9 H, C(CH3)3], 2.02 (m, 2 H,
C=C=C–CH2), 3.71 (s, 3 H, OCH3), 4.64 (d, J = 8 Hz, 1 H, 2-H),
(C=N) cm–1. MS: m/z (%) = 334 (14) [M]+, 291 (16), 264 (7), 249
(12), 183 (46), 141 (100). C20H34N2O2 (334.50): calcd. C 71.81, H
10.24; found C 71.70, H 10.10.
1
Compound (2S,5S)-11h: Rf = 0.05. H NMR (200 MHz, CDCl3): δ
= 0.83, 1.04 [2ϫd, J = 7 Hz, 6 H, CH(CH3)2], 0.90 [t, J = 8 Hz, 3
H, (CH2)5CH3], 1.33 [m, 8 H, (CH2)4CH3], 1.63, 1.65 [2ϫs, 6 H,
C=C=C-(CH3)2], 2.07 [m, 3 H, C=C=C–CH2, CH(CH3)2], 3.69,
3.71 (2ϫs, 6 H, OCH3), 3.84 (dd, 3J = 6, 5J = 4 Hz, 1 H, 5-H),
4.50 (d, 5J = 4 Hz, 1 H, 2-H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 14.15, 18.66, 19.96 (CH(CH3)2, (CH2)5CH3), 20.38, 20.51
[C=C=C-(CH3)2], 22.74, 27.69, 28.95, 31.05, 31.90 (CH2), 32.73
[CH(CH3)2], 52.33 (OCH3), 59.08, 61.48 (C-2,5), 98.26, 103.61
(C=C=C), 162.86, 164.35 (C=N), 199.04 (C=C=C) ppm. IR (neat):
2
4.86, 4.91 (AB signal, JAB = 3 Hz, 2 H, C=C=CH2), 5.16 (brd, J
= 8 Hz, 1 H, NH) ppm. 13C NMR (50 MHz, CDCl3): δ = 13.99
[(CH2)3CH3], 22.51, 27.54, 30.92 (CH2), 28.20 [C(CH3)3], 52.30
(OCH3), 55.35 (C-2), 79.80, 101.92 (C=C=C), 79.98 [C(CH3)3],
155.03
[(CH3)3CO-C=O],
171.40
(COOCH3),
206.00
(C=C=C) ppm. IR (neat): ν = 3420–3200 (NH), 1960 (C=C=C),
˜
1740 (C=O) cm–1. MS: m/z (%) = 226 (1) [M – C4H9]+, 209 (1), 172
(12), 158 (2), 116 (21), 72 (28), 57 (100). C15H25NO4 (283.37): calcd.
C 63.56, H 8.89; found C 63.34, H 8.62.
ν = 2220 (CϵC), 1690 (C=N) cm–1.
˜
(2R,5S)-5-Isopropyl-3,6-dimethoxy-2-(3-methyl-1-phenylbuta-1,2-
dien-1-yl)-2,5-dihydropyrazine (11i): Bislactim ether
9 (0.74 g,
Methyl (2R)-2-[(tert-Butyloxycarbonyl)amino]-3-hexylpenta-3,4-di-
enoate (15b): Compound 11d (0.31 g, 1.0 mmol) was used to obtain
15b (0.26 g, 83%) after flash chromatography with diethyl ether/
petroleum ether (1:5). Rf = 0.45. [α]2D0 = –28.4 (c = 1.0, CHCl3). 1H
NMR (200 MHz, CDCl3): δ = 0.86 [t, J = 7 Hz, 3 H, (CH2)5CH3],
1.28 [m, 8 H, (CH2)4CH3], 1.44 [s, 9 H, C(CH3)3], 2.02 (m, 2 H,
C=C=C–CH2), 3.65 (s, 3 H, OCH3), 4.67 (d, J = 8.5 Hz, 1 H, 2-
H), 4.89, 4.94 (AB signal, 2JAB = 3 Hz, 2 H, C=C=CH2), 5.18 (brd,
J = 8.5 Hz, 1 H, NH) ppm. 13C NMR (50 MHz, CDCl3): δ = 13.97
[(CH2)5CH3], 22.51, 27.20, 28.72, 29.21, 31.53 (CH2), 28.21
[C(CH3)3], 52.24 (OCH3), 55.26 (C-2), 79.62, 101.89 (C=C=C),
79.93 [C(CH3)3], 154.99 [(CH3)3CO-C=O], 171.24 (COOCH3),
4.0 mmol), copper(I) bromide/dimethyl sulfide complex (0.41 g,
2.0 mmol), and propargyl bromide 10i (0.89 g, 4.0 mmol) were used
to obtain (2R,5S)-11i (0.47 g, 36%) and (2S,5S)-11i (0.30 g, 23%)
after flash chromatography with diethyl ether/petroleum ether
(1:20); the diastereomeric ratio was 61:39, 22% de.
1
Compound (2R,5S)-11i: Rf = 0.13. H NMR (200 MHz, CDCl3): δ
= 0.72, 1.09 [2ϫd, J = 7 Hz, 6 H, CH(CH3)2], 1.74, 1.77 [2ϫs, 6
H, C=C=C-(CH3)2], 2.35 [dsp, J = 7 and 3.5 Hz, 1 H, CH(CH3)2],
3
5
3.67, 3.68 (2ϫs, 6 H, OCH3), 3.88 (dd, J = J = 3.5 Hz, 1 H, 5-
5
H), 5.05 (d, J = 3.5 Hz, 1 H, 2-H), 7.32 (m, 5 H, C6H5) ppm. 13C
NMR (50 MHz, CDCl3): δ = 16.45 19.30 [CH(CH3)2], 19.80, 20.25
[C=C=C-(CH3)2], 30.91 [CH(CH3)2], 52.47, 52.59 (OCH3), 57.40,
60.11 (C-2,5), 100.79, 105.29 (C=C=C), 126.33, 126.90, 128.10,
136.66 (C6H5), 162.95, 164.23 (C=N), 202.17 (C=C=C) ppm. IR
205.16 (C=C=C) ppm. IR (neat): ν = 3420–3200 (NH), 1960
˜
(C=C=C), 1740 (C=O) cm–1. MS: m/z (%) = 255 (38) [M –
C4H8]+, 240 (5), 223 (21), 196 (43), 170 (54), 57 (100). C17H29NO4
(311.42): calcd. C 65.55, H 9.39; found C 65.17, H 9.07.
(neat): ν = 1955 (C=C=C), 1690 (C=N) cm–1. MS: m/z (%) = 326
˜
(27) [M]+, 311 (2), 183 (25), 141 (100), 128 (15). C20H26N2O2
(326.44): calcd. C 73.59, H 8.03; found C 73.62, H 8.11.
Methyl
(2R)-3-Butyl-2-[(tert-butyloxycarbonyl)amino]-5-methyl-
hexa-3,4-dienoate (15c): Compound 11g (0.31 g, 1.0 mmol) was
used to obtain 15c (0.21 g, 68%) after flash chromatography with
diethyl ether/petroleum ether (1:15). Rf = 0.17. [α]2D0 = –36.3 (c =
1
Compound (2S,5S)-11i: Rf = 0.38. H NMR (200 MHz, CDCl3): δ
= 0.82, 1.07 [2ϫd, J = 7 Hz, 6 H, CH(CH3)2], 1.71, 1.78 [2ϫs, 6
H, C=C=C-(CH3)2], 2.12 [dsp, J = 7 and 4 Hz, 1 H, CH(CH3)2],
3.66, 3.67 (2ϫs, 6 H, OCH3), 3.90 (dd, 3J = 4, 5J = 5 Hz, 1 H, 5-H),
5.12 (d, 5J = 5 Hz, 1 H, 2-H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 18.32, 19.88 [CH(CH3)2], 20.01, 20.03 [C=C=C-(CH3)2], 32.40
[CH(CH3)2], 52.29, 52.36 (OCH3), 57.26, 61.17 (C-2,5), 100.72
105.41 (C=C=C), 126.32, 126.86, 128.08, 137.25 (C6H5), 162.18,
1
1.0, CHCl3). H NMR (200 MHz, CDCl3): δ = 0.89 [t, J = 7 Hz;
3 H, (CH2)3CH3], 1.40 [m, 4 H, (CH2)2CH3], 1.45 [s, 9 H,
C(CH3)3], 1.68, 1.69 [2ϫs, 6 H, C=C=C(CH3)2], 2.03 (t, J = 7 Hz,
2 H, C=C=C–CH2), 3.71 (s, 3 H, OCH3), 4.61 (d, J = 8.5 Hz, 1 H,
2-H), 5.09 (brd, J = 8.5 Hz, 1 H, NH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 14.11 [(CH2)3CH3], 20.37, 20.51 [C=C=C(CH3)2],
22.55, 27.29, 30.99 (CH2), 28.29 [C(CH3)3], 52.10 (OCH3), 56.14
(C-2), 79.91 [C(CH3)3], 100.49, 100.69 (C=C=C), 155.39 [(CH3)3-
163.67 (C=N), 202.06 (C=C=C) ppm. IR (neat): ν = 2220 (CϵC),
˜
1690 (C=N) cm–1.
CO-C=O], 171.91 (COOCH ), 198.50 (C=C=C) ppm. IR (neat): ν
˜
3
General Procedure for Hydrolysis of Allenyl-Substituted Bislactim
Ethers 11 to Afford Methyl α-Allenyl-N-Boc-glycinates 15: Tri-
fluoroacetic acid (0.2 , 15 mL, 3.0 mmol) was added at 0 °C to a
stirred solution of the bislactim ether 11 (1.0 mmol) in THF
(10 mL) and stirring was continued at room temp. until the bislac-
tim ether 11 was no longer detectable by TLC analysis (22–36 h).
The reaction mixture was concentrated to dryness and the residue
was dissolved in dichloromethane (15 mL). A solution of di-tert-
= 3420–3200 (NH), 1960 (C=C=C), 1740 (C=O) cm–1. MS: m/z
(%) = 255 (19) [M – C4H8]+, 238 (5), 198 (14), 123 (31), 81 (52),
57 (100). C17H29NO4 (311.42): calcd. C 65.55, H 9.39; found C
65.23, H 9.02.
Methyl
(2R)-2-[(tert-Butyloxycarbonyl)amino]-3-hexyl-5-methyl-
3,4-hexadienoate (15d): Compound (2R,5S)-11h (0.33 g, 1.0 mmol)
was used to obtain (2R)-15d (0.26 g, 77%) after flash chromatog-
3610
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3605–3612

Asymmetric Synthesis of α-Allenylglycines
raphy with diethyl ether/petroleum ether (1:10). Rf = 0.17. [α]2D0
–24.2 (c = 1.0, CHCl3). H NMR (200 MHz, CDCl3): δ = 0.88 [t, to-bulb distillation; b.p. 70–80 °C/0.1 Torr; the diastereomeric ratio
J = 7 Hz, 3 H, (CH2)5CH3], 1.38 [m, 8 H, (CH2)4CH3], 1.45 [s, 9 was 77:23, 54% de. After chromatographic separation with diethyl
=
(1.43 g, 12 mmol) were used to obtain 12a (1.95 g, 88%) after bulb-
1
H, C(CH3)3], 1.68, 1.71 [2ϫs, 6 H, C=C=C(CH3)2], 2.02 (t, J =
7 Hz, 2 H, C=C=C–CH2), 3.70 (s, 3 H, OCH3), 4.61 (d, J = 8.5 Hz, 65%) and (2S,5S)-12a (0.41 g, 18%) were obtained as colorless oils
1 H, 2-H), 5.09 (brd, J = 8.5 Hz, 1 H, NH) ppm. 13C NMR
that crystallized upon refrigeration.
(50 MHz, CDCl3): 14.10 [(CH2)5CH3], 20.35, 20.52
ether/petroleum ether (1:8) the diastereomers (2R,5S)-12a (1.45 g,
δ
=
Compound (2R,5S)-12a: Rf
0.20; m.p. 38 °C. 1H NMR
=
[C=C=C(CH3)2], 22.68, 27.50, 28.77, 30.37, 31.77 (CH2), 28.34
[C(CH3)3], 52.13 (OCH3), 56.08 (C-2), 79.85 [C(CH3)3], 100.49,
100.76 (C=C=C), 155.21 [(CH3)3CO-C=O], 171.86 (COOCH3),
(200 MHz, CDCl3): δ = 0.66; 1.04 [2ϫd, J = 7 Hz, 6 H, CH-
4
(CH3)2], 1.87 (t, J = 2.5 Hz, 1 H, CϵC–H), 2.26 [dsp, J = 3,5 and
7 Hz, 1 H, CH(CH3)2], 2.58–2.82 (m, 2 H, CϵC–CH2), 3.69, 3.70
(2ϫs, 6 H, OCH3), 4.02 (dd, 3J = 5J = 3.5 Hz, 1 H, 5-H), 4.08 (dt,
3J = 2.5, 5J = 3.5 Hz, 1 H, 2-H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 16.48, 19.09 [CH(CH3)2], 25.01 (CϵC–CH2), 31.56 [CH-
(CH3)2], 52.41, 52.47 (OCH3), 54.39 (C-5), 60.89 (C-2), 70.14
(CϵC–H), 80.46 (CϵC–H), 161.79, 164.70 (C=N) ppm. IR (neat):
198.40 (C=C=C) ppm. IR (neat): ν = 3420–3200 (NH), 1960
˜
(C=C=C), 1740 (C=O) cm–1. MS: m/z (%) = 283 (11) [M –
C4H8]+, 268 (5), 250 (18), 225 (18), 57 (100). C19H33NO4 (339.47):
calcd. C 67.21, H 9.81; found C 66.96, H 9.64.
Methyl
(2S)-2-[(tert-Butyloxycarbonyl)amino]-3-hexyl-5-methyl-
ν = 3290 (CϵC–H), 2100 (CϵC), 1690 (C=N) cm–1. MS: m/z (%)
˜
hexa-3,4-dienoate (15d): Compound (2S,5S)-11h (0.33 g, 1.0 mmol)
was used to obtain (2S)-15d (0.30 g, 89%) after flash chromatog-
= 222 (8) [M]+, 183 (70) [M – C3H3]+, 141 (100) [M – C3H3
–
C3H6]+. C12H18N2O2 (222.29): calcd. C 64.84, H 8.16; found C
64.55, H 8.19.
raphy with diethyl ether/petroleum ether (1:10). Rf = 0.18. [α]2D0
=
+23.7 (c = 1.0, CHCl3); Spectroscopic data were identical with
those obtained for (2R)-15d.
Compound (2S,5S)-12a: Rf = 0.17; m.p. 32 °C. 1H NMR (200 MHz,
CDCl3): δ = 0.72, 1.06 [2ϫd, J = 7 Hz, 6 H, CH(CH3)2], 1.92 (t,
4J = 2.5 Hz, 1 H, CϵC–H) 2.24 [dsp, J = 3.5 and 7 Hz, 1 H,
CH(CH3)2], 2.48–2.82 (m, 2 H, CϵC–CH2), 3.63, 3.66 (2ϫs, 6 H,
(2R)-2-[(tert-Butyloxycarbonyl)amino]-3-hexyl-5-methylhexa-3,4-di-
enoic Acid (16d): Lithium hydroxide monohydrate (30 mg,
0.71 mmol) was added at 0 °C to a stirred solution of (2R)-15d
(200 mg, 0.59 mmol) in THF (15 mL) and H2O (5 mL) and stirring
was continued at room temp. for 48 h. The solvent was evaporated
in vacuo to dryness and the residue was dissolved in phosphate
buffer solution (20 mL, pH 7) and dichloromethane (20 mL). The
aqueous layer was extracted with dichloromethane (2ϫ20 mL), the
combined organic layers were dried with MgSO4, and the solvent
was removed in vacuo. The residue was purified by chromatography
on silica gel (70 g) with diethyl ether/petroleum ether (1:1) to yield
α-allenylglycine 16d (106 mg, 56%). Rf = 0.30. [α]2D0 = –34.6 (c =
3
5
3
OCH3), 3.88 (dd, J = 3.5, J = 4.5 Hz, 1 H, 5-H), 4.10 (dt, J =
2.5, 5J = 4.5 Hz, 1 H, 2-H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 17.41, 19.67 [CH(CH3)2], 25.11 (CϵC–CH2), 30.85 [CH(CH3)2],
52.42, 52.47 (OCH3), 54.52 (C-5), 60.83 (C-2), 70.13 (CϵC–H),
81.23 (CϵC–H), 161.40, 163.97 (C=N) ppm. IR (neat): ν = 3295
˜
(CϵC–H), 2100 (CϵC), 1685 (C=N) cm–1. C12H18N2O2 (222.29):
calcd. C 64.84, H 8.16; found C 65.00, H 7.99.
5-Isopropyl-3,6-dimethoxy-2-(trimethylsilyl)propargyl-2,5-dihydro-
pyrazine (12f): Bislactim ether 9 (1.84 g, 10 mmol), and propargyl
bromide 10f (2.30 g, 12 mmol) were used to obtain 12f (2.68 g,
91%) after bulb-to-bulb distillation; b.p. 100–110 °C/0.1 Torr. Ratio
of diastereomers = 69:31, 38% de. After chromatographic separa-
tion with diethyl ether/petroleum ether (1:8) the diastereomers
(2R,5S)-12f (1.65 g, 56%) and (2S,5S)-12f (0.76 g, 26%) were ob-
tained as pale yellow oils.
1
1.0, CHCl3). H NMR (200 MHz, CDCl3): δ = 0.88 [t, J = 7 Hz,
3 H, (CH2)5CH3], 1.32 [m, 8 H, (CH2)4CH3], 1.45 [s, 9 H,
C(CH3)3], 1.69, 1.70 [2ϫs, 6 H, C=C=C(CH3)2], 2.07 (t, J =
7.5 Hz, 2 H, C=C=C–CH2), 4.59 (d, J = 8 Hz, 1 H, 2-H), 5.09
(brd, J = 8 Hz, 1 H, NH), 9.30 (broad, 1 H, COOH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 14.09 [(CH2)5CH3], 20.16, 20.53
[C=C=C(CH3)2], 22.67, 27.46, 28.77, 30.42, 31.78 (CH2), 28.32
[C(CH3)3], 55.87 (C-2), 80.09 [C(CH3)3], 100.27, 101.46 (C=C=C),
155.27 [(CH3)3CO-C=O], 176.73 (COOH), 198.49 (C=C=C) ppm.
1
Compound (2R,5S)-12f: Rf = 0.29. H NMR (200 MHz, CDCl3): δ
= 0.08 [s, 9 H, Si(CH3)3], 0.67 and 1.04 [2ϫd, J = 7 Hz, 6 H,
CH(CH3)2], 2.26 {dsp, J = 3.3 and 7 Hz, 1 H, [CH(CH3)2]}, 2.65,
2.76 (AB part of ABX, JAB = 16.9, JAX = 4.6, JBX = 4.4 Hz, 2 H,
CϵC–CH2), 3.69, 3.70 (2ϫs, 6 H, OCH3), 3.98 (dd, 3J = 5J =
IR (neat): ν = 3400–3200 (OH, NH), 1955 (C=C=C) cm–1. MS:
˜
m/z (%) = 269 (9) [M – C4H8]+, 252 (5), 225 (6), 208 (32), 110 (33),
57 (39), 41 (100). C18H31NO4 (325.45): calcd. C 66.41, H 9.61;
found C 66.05, H 9.83.
5
3.3 Hz, 1 H, 5-H), 4.09 (X part of ABX, JAX = 4.6, JBX = 4.4, J
= 3.3 Hz, 1 H, 2-H) ppm. 13C NMR (50 MHz, CDCl3): δ = –0.34
[Si(CH3)3], 16.23, 18.92 [CH(CH3)2], 26.12 (CH2), 31.52 [CH-
(CH3)2], 52.07, 52.14 (OCH3), 54.37 (C-5), 60.67 (C-2), 86.23
(CϵC-Si) 103.15 (CϵC-Si), 161.52, 164.42 (C=N) ppm. IR (neat):
General Procedure for Preparation of Propargyl-Substituted Bislac-
tim Ethers 12: n-Butyllithium (7.0 mL, 11 mmol of a 1.58  solu-
tion in hexane) was added dropwise at –70 °C to a solution of bi-
slactim ether 9 (1.84 g, 10 mmol) in THF (25 mL) and stirring was
continued for 10 min. A solution of the propargyl bromide 10
(12 mmol) in THF (10 mL) was added at –70 °C and stirring was
continued for 4 h at –70 °C. The solution was allowed to warm to
room temp. over 1 h, the solvent was removed in vacuo, and the
residue was dissolved in diethyl ether (50 mL) and H2O (50 mL).
The layers were separated and the aqueous layer was extracted with
diethyl ether (2ϫ30 mL). The combined organic layers were dried
with MgSO4, the diethyl ether was removed in vacuo, and the resi-
due was purified by bulb-to-bulb distillation. The diastereomers
(2R,5S)-12 and (2S,5S)-12 were separated by flash chromatography
on silica gel.
ν = 2160 (CϵC–Si), 1690 (C=N) cm–1. C H N O Si (294.47):
˜
15 26
2
2
calcd. C 61.18, H 8.90; found C 61.15, H 8.89.
1
Compound (2S,5S)-12f: Rf = 0.22. H NMR (200 MHz, CDCl3): δ
= 0.09 [s, 9 H, Si(CH3)3], 0.67, 1.07 [2ϫd, J = 7 Hz, 6 H, CH-
(CH3)2], 2.25 [dsp, J = 3.9 and 7 Hz, 1 H, CH(CH3)2], 2.67, 2.80
(AB part of ABX, JAB = 16.1, JAX = 6.1, JBX = 4.9 Hz, 2 H, CϵC–
CH2), 3.67, 3.68 (2ϫs, 6 H, OCH3), 3.89 (dd, 3J = 3.9, 5J = 5.7 Hz,
1 H, 5-H), 4.10 (X part of ABX, JAX = 6.1, JBX = 4.9, 5J = 5.7 Hz,
1 H, 2-H) ppm. 13C NMR (50 MHz, CDCl3): δ = –0.08 [Si-
(CH3)3], 17.78, 19.63 [CH(CH3)2], 26.21 (CH2), 30.99 [CH(CH3)2],
52.36, 52.41 (OCH3), 54.39 (C-5), 60.74 (C-2), 86.41 (CϵC-Si),
103.61 (CϵC-Si), 161.48, 163.86 (C=N) ppm. IR (neat): ν = 2160
˜
5-Isopropyl-3,6-dimethoxy-2-propargyl-2,5-dihydropyrazine (12a): (CϵC–Si), 1690 (C=N) cm–1. C15H26N2O2Si (294.47): calcd. C
Bislactim ether 9 (1.84 g, 10 mmol) and propargyl bromide 10a 61.18, H 8.90; found C 61.07, H 8.82.
Eur. J. Org. Chem. 2009, 3605–3612
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3611

C. Bucuroaia, U. Groth, T. Huhn, M. Klinge
FULL PAPER
[5] P. Friis, P. Helboe, P. O. Larsen, Acta Chem. Scand., Ser. B
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[9] U. Schöllkopf, U. Groth, Angew. Chem. 1981, 93, 1022–1023.
[10] U. Groth, U. Schöllkopf, Y.-C. Chiang, Synthesis 1982, 864–
866.
General Procedure for Hydrolysis of Propargyl-Substituted Bislac-
tim Ethers 12 to Afford Methyl α-Propargylglycinates 17: Trifluoro-
acetic acid (0.2 , 75 mL, 15 mmol) was added at 0 °C to a stirred
solution of the bislactim ether 12 (5 mmol) in THF (30 mL) and
stirring was continued at room temp. until the bislactim ether 12
was no longer detectable by TLC analysis (8 –12 h). Most of the
solvent was removed in vacuo and the remaining aqueous solution
(≈10 mL) was diluted with dichloromethane (50 mL). Conc. aque-
ous ammonia was added until pH 10, the layers were separated,
and the aqueous layer was extracted with dichloromethane
(2ϫ20 mL). The combined organic layers were dried with MgSO4,
and the solvent was evaporated in vacuo (0 °C/20 Torr). Methyl -
valinate was removed by bulb-to-bulb distillation (50 °C/10 Torr)
and the residue – the crude methyl α-propargylglycinate 17 – was
purified by bulb-to-bulb distillation.
[11] U. Schöllkopf, J. Nozulak, U. Groth, Tetrahedron 1984, 40,
1409–1417.
[12] For a review for the asymmetric synthesis of vinylglycines, see:
R. M. Williams, Synthesis of Optically Active α-Amino Acids,
Pergamon Press, Oxford, 1989.
[13] W. Karnbrock, H.-J. Musiol, L. Moroder, Tetrahedron 1995,
51, 1187–1196.
Methyl (R)-α-Propargylglycinate (17a): Compound 12a (1.10 g,
5 mmol) was used to obtain 17a (0.32 g, 51%) after bulb-to-bulb
distillation. In order to obtain analytically pure 17a the bulb-to-
[14] S. Rødbotten, T. Benneche, K. Undheim, Acta Chem. Scand.
1997, 51, 873–880.
[15] U. Schöllkopf, U. Groth, C. Deng, Angew. Chem. 1981, 93,
bulb distillation was repeated twice; b.p. 80–85 °C/10 Torr. [α]2D0
=
793–795.
1
1.7 (c = 1.0, EtOH). H NMR (200 MHz, CDCl3): δ = 1.73 (s, 2
[16] G. C. Barrett (Ed.), Chemistry and Biochemistry of the Amino
Acids, Chapman and Hall, London, 1985.
4
4
H, NH2), 2.04 (t, J = 3 Hz, 1 H, CϵC–H), 2.59 (dd, J = 6, J =
3 Hz, 2 H, CH2CϵC–H), 3.60 (t, J = 6 Hz, 1 H, α-H), 3.72 (s, 3 [17] A. Hoffmann-Röder, N. Krause, Angew. Chem. Int. Ed. 2004,
43, 1196–1216.
H, OCH ) ppm. IR (neat): ν = 3400–3200 (NH and CϵC–H),
˜
3
2
2100 (CϵC), 1730 (C=O) cm–1. C6H9NO2 (127.14): calcd. C 56.68,
[18] P. Casara, K. Jund, P. Bey, Tetrahedron Lett. 1984, 25, 1891–
1894.
H 7.13; found C 56.67, H 7.18.
[19] U. Kazmaier, C. H. Goerbitz, Synthesis 1996, 1489–1493.
[20] U. Kazmaier, Liebigs Annalen/Recueil 1997, 1997, 285–295.
[21] M. P. Doyle, V. Bagheri, E. E. Claxton, J. Chem. Soc., Chem.
Commun. 1990, 46–48.
[22] D. P. G. Hamon, R. A. Massy-Westropp, P. Razzino, Tetrahe-
dron 1995, 51, 4183–4194.
[23] H. Kagoshima, T. Uzawa, T. Akiyama, Chem. Lett. 2002, 298–
299.
[24] J. L. Luche, E. Barreiro, J. M. Dollat, P. Crabbe, Tetrahedron
Lett. 1975, 16, 4615–4618.
[25] Organometallic Derivatives of Allenes and Ketenes, J.-L. Mo-
reau, in The Chemistry of Ketenes, Allenes, and Related Com-
pounds (Ed.: S. Patai), Wiley-VCH, New York, 1980, vol. 1,
p. 363–413.
[26] H. Yamamoto, in Comprehensive Organic Synthesis (Eds.:
B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1992, Vol. 2,
pp. 81–98.
Methyl (R)-α-(Trimethylsilyl)propargylglycinate (17b): Compound
(2R,5S)-12f (1.47 g, 5 mmol) was used to obtain (R)-17b (0.83 g,
83%) after bulb-to-bulb distillation; b.p. 115–120 °C/10 Torr. [α]2D0
1
= –38.4 (c = 1.0, CHCl3). H NMR (200 MHz, CDCl3): δ = 0.12
[s, 9 H, Si(CH3)3], 1.69 (s, 2 H, NH2), 2.57, 2.68 (AB part of ABX,
JAB = 16.9, JAX = 6.5, JBX = 6.4 Hz, 2 H, CϵC–CH2), 3.59 (X
part of ABX, JAX = 6.5, JBX = 6.4 Hz, 1 H, α-H), 3.72 (s, 3 H,
OCH3) ppm. 13C NMR (50 MHz, CDCl3): δ = –0.12 [Si(CH3)3],
26.31 (CH2), 52.07 (C-2), 53.22 (OCH3), 87.89 (CϵC–Si), 101.68
(CϵC-Si), 174.09 (COOCH ) ppm. IR (neat): ν = 3400–3200
˜
3
(NH2), 2160 (CϵC–Si), 1730 (C=O) cm–1. MS: m/z (%) = 199 (1)
[M]+, 184 (3) [M – CH3]+, 140 (56) [M – COOCH3]+, 73 (100)
[Si(CH3)3]. C9H17NO2Si (199.32): calcd. C 54.21, H 8.60; found C
54.36, H 8.55.
[27] Synthesis and Reaction of Allenylmetal Compounds, J. A. Mar-
shall, B. W. Gung, M. L. Grachan, in: Modern Allene Chemis-
try (Eds.: N. Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim,
Germany, 2004, pp. 493–592.
[28] E. J. Corey, D. Enders, Chem. Ber. 1978, 111, 1362–1383.
[29] K. Yamamoto, M. Iijima, Y. Ogimura, Tetrahedron Lett. 1982,
23, 3711–3714.
Methyl (S)-α-(Trimethylsilyl)propargylglycinate (ent-17b): Com-
pound (2S,5S)-12f (0.59 g, 2 mmol) was used to obtain (S)-17b
(0.31 g, 78%) after bulb-to-bulb distillation; b.p. 115–120 °C/
10 Torr. [α]2D0 = +38.1 (c = 1.0, CHCl3); spectroscopic data identical
with those obtained for (2R)-17b.
[30] T. Beulshausen, U. Groth, U. Schöllkopf, Liebigs Ann. Chem.
1991, 1991, 1207–1209.
Acknowledgments
[31] U. Schöllkopf, Tetrahedron 1983, 39, 2085–2091.
[32] U. Groth, Ph.D. Thesis, University of Göttingen, 1982.
[33] cyclo-(--Val-Gly-) [(2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-iso-
propylpyrazin] and its enatiomeric form are available from
Merck International (http://www.merck-chemicals.com).
[34] C. Bucuroaia, planned Ph.D. Thesis, University of Konstanz.
[35] L. Brandsma, H. D. Verkruijsse, Synthesis of Acetylenes, All-
enes and Cumulenes, A Laboratory Manual, Elsevier, Amster-
dam, 1981.
C.B. thanks the Herbert Quandt Foundation for a fellowship. The
authors are grateful to BASF AG and to Wacker AG for providing
valuable starting materials.
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Received: April 28, 2009
Published Online: June 16, 2009
3612
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3605–3612