Stereoselective synthesis of functionalised cycloalkene α-quaternary α-amino acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2003.10.013

A route for the preparation of unsaturated cyclic α-quaternary α-amino acid derivatives is described. Stepwise and stereocontrolled alkylations of the chiron (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine provided gem-disubstituted derivatives with an

Full text of DOI:10.1016/j.tetasy.2003.10.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 53–63
Stereoselective synthesis of functionalised cycloalkene
a-quaternary a-amino acid derivatives
Mioara Andrei and Kjell Undheim*
Department of Chemistry, University of Oslo, N-0315 Oslo, Norway
Received 14 August 2003; accepted 21 October 2003
Abstract—A route for the preparation of unsaturated cyclic a-quaternary a-amino acid derivatives is described. Stepwise and
stereocontrolled alkylations of the chiron (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine provided gem-disubstituted deriva-
tives with an alkene and an alkoxo substituent. The Wacker oxidation was compatible for chemoselective oxidation of the alkene
function. Formation of a methyl ketone or an aldehyde was substrate dependent. Spiroannulation in the dioxo substrates was
effected with caesium carbonate in acetonitrile by intramolecular aldol condensations. The regiochemistry was substrate dependent.
Cleavage of the heterospiranes under mild acidic conditions provided cyclic a-quaternary a-amino acid derivatives.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In the present work the target molecules were oxo-
functionalised cyclic a-quaternary a-amino acids shown
in the structures G, H and I in Scheme 1.
Cyclic a-quaternary a-amino acids are conformationally
constrained. When incorporated into peptidic material
the conformational freedom of the peptidic material will
be significantly affected. Hence the preparation and
studies of the bioproperties of this class of compounds
have attracted great attention.1;2 Our efforts to develop
methodologies for the construction of cyclic a-quater-
nary a-amino acids can be summarised as in Scheme 1.
2. Results and discussion
The chiron (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydro-
pyrazine was lithiated and alkylated to provide the
substrate 1.3c The aldols 2a and 2b were obtained in
reactions between the lithiated species of substrate 1
and acetaldehyde. The new stereogenic centre in the
heterocyclic 2-position was formed with high trans-
selectivity. The trans-product was isolated after chro-
matography. Low diastereoselectivity, ratio 4:1 for 2a
and 7:1 for 2b, was observed at the aldehyde carbon in
the aldol formation. The aldol isomers could be sepa-
rated by chromatography, but the configuration at the
alcohol carbon was not determined. The mixture was
used as a substrate for the subsequent oxidation by the
Dess–Martin procedure.6 The oxidation provided
the corresponding ketones in the range 70–80% yield.
The ketones 3a and 3b have the oxo group next to the
quaternary spirocentre. In a second series illustrated by
structures 3c and 3d, the oxo group has been moved one
carbon unit away from the spirocentre and is thus less
sterically shielded. Substrate 1 was used for their prep-
aration with racemic propylene oxide as the alkylating
reagent to provide the alcohols 2c and 2d. High trans-
diastereoselectivity was observed at the heterocyclic
Group A structures are available from ruthenium-
catalysed ring-closing metathesis (RCM) reactions on
appropriately substituted (2R)- or (2S)-2-isopropyl-3,6-
dimethoxy-2,5-dihydropyrazine as a chiron. The ring
sizes can be varied from five- to seven-membered rings
and the products are 1-aminocycloalkene-1-carboxylic
acids and hydroxylated analogues.3 Group B structures
in the same way are conjugated vinyl derivatives with
one of the double bonds exocyclic.3 The complementary
alkylidene derivatives C, D and E are available from
palladium-catalysed cycloisomerisation reactions.4 Oxo
derived analogues F are available by the RCM Ru(II)-
catalysed route.5
* Corresponding author. Tel.: +47-22-85-55-21; fax: +47-22-85-55-07;
e-mail: kjell.undheim@kjemi.uio.no
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.013

54
M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
Wacker oxidation was attempted and found to provide a
direct synthesis of methyl ketones. In the Wacker oxi-
dation, however, it is known that from some substrates
aldehydes may be formed alone or in mixture with the
methyl ketone. One reason for aldehyde formation may
be steric hindrance, which may affect the relative rate of
olefin oxidation.7 Coordination to heteroatoms may
also retard oxidation leading to a reversal of the regio-
chemistry in Wacker type oxidations.8
In the heterocyclic substrates 3b and 3d, which carry a
C4-olefin substituent, the Wacker oxidation in an
aqueous medium proceeded well with formation of the
methyl ketones 4b and 4d in high yields. Steric effects, or
perhaps heteroatom coordination effects, become more
important in the propene substrates 3a and 3c resulting
in coformation, or a dominating formation, of aldehyde.
With the acetyl substituent at the spirocentre 3a, the
ratio between aldehyde 4a and ketone 5a formation was
1:3. With an acetonyl substituent at the spirocentre 3c,
by far the major product was the aldehyde 4c (Scheme
3).
In Scheme 4 spiroannulation reactions are shown. In a
search for procedures to effect internal aldol condensa-
tions under mild alkaline conditions, the most satisfac-
tory results were obtained with caesium carbonate as
base.9 The aldol reactions were run in acetonitrile under
reflux conditions using 1–1.5 equiv of caesium carbon-
ate. The acetyl oxo group in the substrates 4a, 4b and 5a
is attached directly to a quaternary centre and is steri-
cally shielded. Enolate addition to this carbonyl group is
slower than enolate addition to the less shielded oxo
group in the other gem-substituent further away from
the quaternary centre. Enolisation of the acetyl methyl
group in substrate 4a therefore leads preferentially to
six-membered ring spiroannulation and formation of the
heterospirane 6. The acetonyl substrate 5a, as well as the
higher 2-butanoyl homologue 4b, react regioselectively
with formation of the five- and six-membered hetero-
spiranes 7a and 7b, respectively. In the acetonyl sub-
strates 4c and 4d, the carbonyl group is located one
carbon unit further away from the quaternary centre.
Enolisation can take place in either gem-dicarbonyl
substituent in the heterocycle. Competitive internal en-
olisations in the aldehyde 4c led to a mixture of the
isomeric five-membered spiroannulated structures 7c
and 8c, almost in ratio 1:1. Seven-membered ring for-
mation, after enolisation in the methyl group, was not
seen. A similar product ratio resulted in the cyclocon-
densation of the diketone 4d with formation of the iso-
meric heterospiranes 7d and 8d. Enolisation in the
methyl groups was not an important pathway for
product formation.
Scheme 1.
2-position. The trans-product was isolated after chro-
matography. The expected 1:1 ratio of epimeric isomers
at the alcohol carbon was observed. The subsequent
Dess–Martin oxidation proceeded well to provide the
desired ketones 3c and 3d (Scheme 2).
Mild acid hydrolysis using 0.1 M TFA in aqueous ace-
tonitrile was used to effect hydrolytic cleavage of the
pyrazine ring. The ketospirane substrates in Scheme 5
are pure diastereomers after chromatographic purifica-
tion procedures. Hydrolysis does not affect the a-qua-
ternary carbon in the new a-amino acid. Hence the
amino acid derivatives in Scheme 5 are assumed to be
pure enantiomers.
The oxo-alkylidene derivatives 3 were to be investigated
as substrates for introduction of a second oxo function
by the Wacker type oxidation procedure. Chemoselec-
tivity for oxidation of the carbon–carbon double bond
in the heterocyclic substrates 3 was essential. Therefore

M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
55
Scheme 2.
Scheme 3.
Acid hydrolysis next to the spirocentre was slow, and
the reaction was run at ambient temperature over 3 days
when TLC-monitoring showed the absence of the sub-
strate. Strongly acidic conditions during hydrolysis is to
be avoided since the reaction then proceeds via the
corresponding 2,5-diketopiperazine, which requires
forcing acidic conditions for further cleavage into its
amino acid components.10 Under mild acidic conditions,
cleavage takes another course providing the amino acid
components as esters, which can be readily separated.11
This reaction pathway, however, is sensitive to steric
interactions as is evident in the spiro substrates in
Scheme 5. The 1-oxospiranes 6a and 6b furnished the
corresponding cyclic amino acid esters 9a and 9b in
moderate yields. The 1-acetyl derivative 9c was cleaved
in a similar manner to the functionalised cyclic amino
ester 9c. The formyl spirane derivative 7c (Scheme 4)
was unstable under the reaction conditions and the
corresponding amino acid could not be prepared. The
spirane 7d provided the desired amino acid ester 11 in a
moderate yield together with the valine dipeptide 12 in
low yield. Formation of the latter is ascribed to initial
cleavage in the piperazine ring between the nitrogen
adjacent to the spirocentre and the corresponding enol
ether carbon. Cleavage of the second iminoether func-
tion would subsequently provide the peptide bond. The
same course of the reaction was seen with the hetero-
spirane 8d and formation of the cyclic amino ester 13
and the valine dipeptide 14.
3. Conclusions
We have developed a route for the preparation of
unsaturated cyclic a-quaternary a-amino acid deriva-
tives. Stepwise and stereocontrolled alkylations of the
chiron (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyra-
zine provided gem-disubstituted derivatives with an

56
M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
Scheme 4.
alkene and an ethanol or propanol substituent. The
epimeric alcohols were oxidised by the Dess–Martin
methodology to the corresponding acetyl or acetonyl
derivatives. The Wacker oxidation was compatible for
chemoselective oxidation of the alkene function. For-
mation of a methyl ketone or an aldehyde was substrate
dependent. The products were dioxo derivatives. Spiro-
annulation in the dioxo substrates was effected with
caesium carbonate in acetonitrile by intramolecular
aldol condensations. The regiochemistry was substrate
dependent. The heterospiranes were cleaved under mild
acidic conditions to cyclic a-quaternary a-amino acid
derivatives.
under electron-impact conditions (EI) were recorded at
70 eV ionising potential, methane was used for chemical
ionisation (CI). The spectra are presented as m=z (% rel
int.). IR spectra were measured on a Perkin–Elmer 1310
infrared spectrophotometer or a Nicolet Magna 550
spectrometer using attenuated total reflectance (ATR).
Dry THF was distilled from sodium and benzophenone
under argon. Dry dichloromethane was distilled from
calcium hydride under argon.
4.1. (20S,50R)-1-(2-Allyl-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-yl)ethanol 2a
A solution of (2S,5R)-2-allyl-2,5-dihydro-5-isopropyl-
3,6-dimethoxypyrazine 1a (2.00 g, 8.92 mmol) in THF
(30 mL) under argon was lithiated by the addition of
n-BuLi (6.13 mL, 9.81 mmol, 1.6 M in hexane) at )78 ꢁC.
The mixture was stirred at this temperature for 30 min
4. Experimental
1H NMR spectra were recorded in CDCl3 at 500, 300 or
200 MHz with Bruker DPX 500, DPX 300 or DPX 200.
The 13C spectra were recorded in CDCl3 at 125 MHz on
a Bruker DPX 500, at 75 MHz with DPX 300 and at
50 MHz on a Bruker DPX 200 instrument. NMR tech-
niques such as DEPT, COSY, HETCOR, COLOC, gs-
HMBC were used. Chemical shifts are reported in ppm
with residual CHCl3 (7.24 ppm) and CDCl3 (77 ppm) as
references. J values are given in hertz. Mass spectra
and
a solution of acetaldehyde (0.784 g, 1.0 mL,
17.84 mmol) in THF (15 mL) added dropwise. The re-
sultant mixture was stirred at )78 ꢁC for 1 h, allowed to
reach ambient temperature and the reaction terminated
by addition of phosphate buffer pH 7 (25 mL). The
mixture was extracted with diethyl ether (3 · 20 mL),
the extracts dried (MgSO4) and the solvent evaporated.

M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
57
Scheme 5.
The residual material was subjected to flash chromato-
graphy on silica gel using EtOAc/hexane 1:4. The product
was a colourless oil and consisted of two alcohol epimers
in the ratio 1:4; yield 1.800 g (75%). The epimer mixture
was used as such in the subsequent reaction. For ana-
lytical purposes the epimers were separated by repetition
of the chromatographic conditions as above.
CHOHCH3), 2.24–2.30 (1H, m, CH(CH3)2), 2.63–2.69
(3H, m, CH2CH@CH2 and CHOHCH3), 3.62 and 3.67
(6H, 2s, 2 · OCH3), 3.84–3.90 (2H, m, CHOHCH3 and
H-5), 4.90–5.01 (2H, m, CH@CH2), 5.47–5.62 (1H, m,
CH@CH2); dC (CDCl3) 17.6, 18.8 and 19.6 (CH(CH3)2
and CH3), 30.8 (CH(CH3)2), 41.4 (CH2CH@CH2), 52.1
and 52.5 (2 · OCH3), 60.9 (C-5), 65.1 (C-2), 71.8
(CHOH), 117.7 (CH@CH2), 134.5 (CH@CH2), 162.5
and 164.4 (2 · C@N); m=z (EI) 268 (Mþ, 1%), 224 (4),
223 (4), 207 (6), 182 (7), 181 (100), 179 (13), 167 (8), 166
(5), 141 (8), 45 (20), 43 (22).
Major epimer: Rf 0.24 (Found: C, 62.39; H, 8.85.
C14H24N2O3 requires C, 62.66; H, 9.01%); HRMS: M
268.1783; C14H24N2O3 requires 268.1787; mmax (film/
cmÀ1) 3416, 2971, 2945, 2872, 1694, 1670, 1432, 1289,
1237; dH (CDCl3) 0.63 and 1.05 (6H, 2d, J 6.8,
CH(CH3)2), 1.08 (3H, d, J 6.2, CHOHCH3), 2.07–2.10
4.2. (20S,50R)-1-[2-(3-Butenyl)-5-isopropyl-3,6-dimeth-
oxy-2,5-dihydropyrazin-2-yl]ethanol 2b
(1H, d,
J
8.9, CHOHCH3), 2.28–2.34 (1H, m,
CH(CH3)2), 2.35–2.41 (1H, m, CHHCH@CH2), 2.57–
2.64 (1H, m, CHHCH@CH2), 3.65 and 3.66 (6H, 2s,
2 · OCH3), 3.74–3.79 (1H, m, CHOHCH3), 3.86 (1H,
d, J 3.4, H-5), 4.92–5.03 (2H, m, CH@CH2), 5.50–5.6
(1H, m, CH@CH2); dC (CDCl3) 17.2, 17.6 and 19.6
(CH(CH3)2 and CH3), 30.5 (CH(CH3)2), 40.2
(CH2CH@CH2), 52.2 and 52.4 (2 · OCH3), 60.6 (C-5),
65.6 (C-2), 72.9 (CHOH), 117.7 (CH@CH2), 134.2
(CH@CH2), 162.4 and 163.6 (2 · C@N); m=z (EI) 268
(Mþ, 1%), 224 (19), 223 (10), 183 (7), 182 (11), 181 (100),
141 (14), 41 (8).
Compound 2b was prepared as above from (2S,5R)-2-
(3-butenyl)-2,5-dihydro-5-isopropyl-3,6-dimethoxypyr-
azine 1b4 (2.00 g, 8.40 mmol) in THF (30 mL) under
argon. Lithiation was effected with n-BuLi (5.77 mL,
9.24 mmol, 1.6 M in hexane) at )78 ꢁC. Dropwise addi-
tion of acetaldehyde (0.740 g, 0.94 mL, 16.80 mmol) in
THF (15 mL) gave the adduct. The crude product was
subjected to flash chromatography on silica gel using
EtOAc/hexane 1:4. The product was a colourless oil and
consisted of two alcohol epimers in the ratio 1:7; yield
1.720 g (73%). The epimer mixture was used as such in
the subsequent reaction. For analytical purposes the
epimers were separated by repetition of the chroma-
tography as above.
Minor epimer: Rf 0.33; HRMS:
M
268.1790;
C14H24N2O3 requires 268.1787; dH (CDCl3) 0.66 and
1.05 (6H, 2d, 6H, J 6.8, CH(CH3)2), 0.87 (3H, d, J 6.2,

58
M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
Major epimer: Rf 0.30 (Found: C, 63.46; H, 9.24.
C15H26N2O3 requires C, 63.80; H, 9.28%); HRMS:
[Mþ+H] 283.2015; C15H26N2O3+H requires 283.2021;
mmax (film/cmÀ1) 3460, 2971, 2943, 2871, 1694, 1641,
1462, 1436, 1241, 1197; dH (CDCl3) 0.65 (3H, d, J 6.7,
CH(CH3)2), 1.07 (6H, 2d, CH(CH3)2 and CHOHCH3),
1.66–1.92 (4H, m, 2 · CH2), 2.00 (1H, d, J 9.2,
CHOHCH3), 2.30–2.47 (1H, m, CH(CH3)2), 3.65 and
3.67 (6H, 2s, 2 · OCH3), 3.69–3.78 (1H, m, CHOHCH3),
3.88 (1H, d, J 3.4, H-5), 4.87–4.99 (2H, m, CH@CH2),
5.69–5.83 (1H, m, CH@CH2); dC (CDCl3) 17.0 and 19.5
(CH(CH3)2), 17.5 (CHOHCH3), 28.8 (CH2), 30.5
(CH(CH3)2), 34.6 (CH2), 52.2 and 52.3 (2 · OCH3), 60.6
(C-5), 65.3 (C-2), 73.0 (CHOH), 114.2 (CH@CH2),
138.7 (CH@CH2), 162.7 and 163.7 (2 · C@N); m=z (CI–
CH4) 283 (Mþ+H, 72%), 265 (15), 251 (8), 239 (30), 238
(31), 237 (100), 223 (18), 211 (27), 197 (23), 195 (99), 169
(25), 153 (5).
2 · CH@CH2); dC (CDCl3) 17.4, 17.6, 19.5 and 19.6
(2 · CH(CH3)2), 23.5 and 23.7 (2 · CHOHCH3), 30.6
and
31.0
(2 · CH(CH3)2),
42.2
and
46.1
(2 · CH2CH@CH2), 47.6 and 47.8 (2 · CH2CHOH),
52.2, 52.3, 52.4 and 52.8 (4 · OCH3), 60.1 and 60.9
(2 · C-5), 61.6 (2 · C-2), 64.6 and 65.5 (2 · CHOH),
117.9 and 118.0 (2 · CH@CH2), 133.7 and 134.1
(2 · CH@CH2), 163.1, 163.3, 163.6 and 164.3 (4 · C@N);
m=z (EI) 282 (Mþ, 1%), 241 (21), 209 (7), 198 (13), 197
(100), 181 (52), 155 (14).
4.4. (20S,50R)-1-[2-(3-Butenyl)-5-isopropyl-3,6-dimeth-
oxy-2,5-dihydropyrazin-2-yl]propan-2-ol 2d
Compound 2d was prepared as above from (2S,5R)-2-
(3-butenyl)-2,5-dihydro-5-isopropyl-3,6-dimethoxypyr-
azine 1b (2.00 g, 8.40 mmol) in THF (30 mL), under
argon, n-BuLi (5.77 mL, 9.24 mmol, 1.6 M in hexane)
and a solution of propylene oxide (0.803 g, 0.97 mL,
13.86 mmol) in THF (15 mL). The reaction product was
subjected to flash chromatography on silica gel using
EtOAc/hexane 3:7; Rf 0.32. The product consisted of
two alcohol epimers, in an inseparable mixture, in the
ratio 1:1; yield 1.720 g (62%). The epimer mixture was
used in the subsequent reaction. HRMS (electrospray):
[Mþ+H] 297.2180; C16H28N2O3+H requires 297.2172;
mmax (film/cmÀ1) 3383, 2969, 2944, 2871, 1694, 1654,
1642, 1460, 1437, 1381, 1230, 1198, 1144; dH (CDCl3)
0.64–0.69 (6H, 2d overlap, 2 · CH(CH3)2), 1.05–1.09
(9H, 3d overlap, 2 · CH(CH3)2 and CHOHCH3), 1.50–
2.08 (12H, m, 6 · CH2), 2.18–2.42 (2H, m,
2 · CH(CH3)2), 2.77 (1H, br s, OH), 3.63–3.71 (13H, 4s
and 1m, 4 · OCH3 and CHOHCH3), 3.89 (1H, d, J 3.4,
H-5), 3.95 (1H, d, J 3.4, H-5), 4.09–4.23 (1H, m,
CHOHCH3), 4.71 (1H, br s, OH), 4.87–4.94 (4H, m,
2 · CH@CH2), 5.69–5.80 (2H, m, 2 · CH@CH2); dC
(CDCl3) 17.1, 17.4 and 19.5, 19.6 (2 · CH(CH3)2), 23.6
and 23.6 (2 · CHOHCH3), 28.6 and 29.2 (2 · CH2), 30.5
and 30.9 (2 · CH(CH3)2), 36.5, 40.5, 48.3 and 48.4
(4 · CH2), 52.3 and 52.4 (4 · OCH3), 60.1 and 60.9
(2 · C-5), 60.3 (2 · C-2), 64.6 and 65.5 (2 · CHOH),
114.3 and 114.4 (2 · CH@CH2), 138.3 and 138.4
(2 · CH@CH2), 163.3, 163.6, 163.8 and 164.3 (4 · C@N);
m=z (CI–CH4) 297 (Mþ+H, 64%), 281 (8), 279 (6), 265
(17), 238 (8), 237 (56), 223 (11), 209 (7), 197 (13), 195
(100), 181 (16), 167 (6), 139 (7).
Minor epimer: Rf 0.22; dH (CDCl3) 0.65 and 1.05 (6H,
2d, J 6.8, CH(CH3)2), 0.85 (3H, d, J 6.2, CHOHCH3),
1.62–1.98 (4H, m, 2 · CH2), 2.26–2.37 (1H, m,
CH(CH3)2), 2.55 (1H, d, J 9.8, CHOHCH3), 3.61 and
3.65 (3H, 2s, 2 · OCH3), 3.79–3.87 (2H, m, CHOHCH3
and H-5), 4.84–4.95 (2H, m, CH@CH2), 5.67–5.78 (1H,
m, CH@CH2); dC (CDCl3) 17.2 and 19.5 (CH(CH3)2),
18.7 (CHOHCH3), 29.2 (CH2), 30.7 (CH(CH3)2), 35.6
(CH2), 52.1 and 52.5 (2 · OCH3), 60.8 (C-5), 64.9 (C-2),
72.3 (CHOH), 114.1 (CH@CH2), 138.5 (CH@CH2),
162.7 and 164.4 (2 · C@N).
4.3. (20S,50R)-1-(2-Allyl-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-yl)propan-2-ol 2c
A solution of (2S,5R)-2-allyl-2,5-dihydro-5-isopropyl-
3,6-dimethoxypyrazine 1b (1.5 g, 6.7 mmol) in THF
(30 mL) under argon, was lithiated by the addition of
n-BuLi (4.60 mL, 7.37 mmol, 1.6 M in hexane) at )78 ꢁC,
the mixture stirred at this temperature for 30 min and a
solution of propylene oxide (0.70 mL, 0.583 g,
10.05 mmol) in THF (15 mL) added dropwise. The re-
sultant mixture was stirred at )78 ꢁC for 1 h, allowed to
reach ambient temperature and the reaction terminated
by addition of phosphate buffer pH 7 (25 mL). The
mixture was extracted with diethyl ether (3 · 20 mL),
the extracts dried (MgSO4) and the solvent evaporated.
The crude product was purified by flash chromatography
on silica gel using EtOAc/hexane 3:7. The product was a
colourless oil consisting of the two alcohol epimers 1:1;
Rf 0.22; yield 1.228 g (65%) (Found: C, 63.56; H, 9.12.
C15H26N2O3 requires C, 63.80; H, 9.28%); HRMS: M
282.1944; C15H26N2O3 requires 282.1943; mmax (film/
cmÀ1) 3406, 2944, 2872, 1694, 1462, 1437, 1237; dH
(CDCl3) 0.63 and 1.02 (6H, 2d, J 6.8, CH(CH3)2), 0.67
and 1.10 (6H, 2d, J 6.8, CH(CH3)2), 1.12 and 1.15 (6H,
4.5. (20R,50R)-1-(2-Allyl-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-yl)ethanone 3a
A solution of (20S,50R)-1-(2-allyl-5-isopropyl-3,6-dimeth-
oxy-2,5-dihydropyrazin-2-yl)ethanol
2a
(0.850 g,
3.17 mmol) in dry dichloromethane (25 mL) was added
with stirring to a solution of the Dess–Martin reagent
(1.61 g, 3.8 mmol) in dry dichloromethane (20 mL) at
ambient temperature. The homogeneous reaction mix-
ture was diluted with diethyl ether (50 mL) after 1 h, and
the resulting suspension added to 1.3 M NaOH (30 mL).
The mixture was stirred for 10 min, the ether layer ex-
tracted with 1.3 M NaOH (25 mL) and water (25 mL).
The ether phase was dried (MgSO4), evaporated and
2d,
J
6.4, 2 · CHOHCH3), 1.55–2.07 (4H, m,
2 · CH2CHOH), 2.12–2.28 (2H, m, 2 · CH(CH3)2),
2.30–2.56 (4H, m, 2 · CH2CH@CH2), 2.90 (1H, br
s, CHOH), 3.60–3.64 (12H, 4s, 4 · OCH3), 3.79–3.95
(signals overlap, 3H, CHOHCH3 and 2 · H-5), 4.10–
4.25 (1H, m, CHOHCH3), 4.80 (1H, br s, CHOH), 4.92–
5.03 (4H, m, 2 · CH@CH2), 5.50–5.60 (2H, m,

M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
59
residual material subjected to flash chromatography on
silica gel using EtOAc/hexane 1:4; Rf 0.46. The product
was a colourless oil; yield 0.600 g (71%) (Found: C,
63.05; H, 8.12. C14H22N2O3 requires C, 63.13; H,
8.33%); HRMS: M 266.1620; C14H22N2O3 requires
266.1630; mmax (film/cmÀ1) 2970, 2945, 2871, 1716, 1694,
1670, 1437, 1245; dH (CDCl3) 0.65 and 1.08 (6H, 2d, J
6.8, CH(CH3)2), 2.03 (3H, s, COCH3), 2.31–2.36 (1H, m,
CH(CH3)2), 2.58–2.65 (1H, m, CHHCH@CH2), 2.74–
2.81 (1H, m, CHHCH@CH2), 3.64 and 3.68 (6H, 2s,
2 · OCH3), 3.98 (1H, d, J 3.4, H-5), 4.94–5.05 (2H, m,
CH@CH2), 5.48–5.60 (1H, m, CH@CH2); dC (CDCl3)
17.3 and 19.6 (CH(CH3)2), 25.1 (COCH3), 30.6
(CH(CH3)2), 39.4 (CH2CH@CH2), 52.7 and 52.8
(2 · OCH3), 60.6 (C-5), 71.3 (C-2), 118.3 (CH@CH2),
133.5 (CH@CH2), 159.8 and 164.2 (2 · C@N), 202.9
(CO); m=z (EI) 266 (Mþ, 1%), 223 (25), 182 (11), 181
(100), 68 (5), 43 (54).
64.29; H, 8.55. C15H24N2O3 requires C, 64.26; H,
8.63%); HRMS: M 280.1784; C15H24N2O3 requires
280.1787; mmax (film/cmÀ1) 2969, 2945, 2867, 1726, 1697,
1436, 1235; dH (CDCl3) 0.61 and 1.02 (6H, 2d, J 6.8,
CH(CH3)2), 1.96 (3H, s, COCH3), 2.21–2.30 (1H, m,
CH(CH3)2), 2.31–2.42 (2H, m, CH2CH@CH2), 2.68 and
2.79 (2H, 2d, J 15.6, CH2CO), 3.54 and 3.58 (6H, 2s,
2 · OCH3), 3.92 (1H, d, J 3.4, H-5), 4.92–4.98 (2H, m,
CH@CH2), 5.52–5.60 (1H, m, CH@CH2); dC (CDCl3)
17.6 and 19.7 (CH(CH3)2), 30.5 (COCH3), 31.4
(CH(CH3)2), 45.6 (CH2CH@CH2), 51.8 (CH2COCH3),
52.3 (2 · OCH3), 59.4 (C-2), 61.0 (C-5), 118.2
(CH@CH2), 133.7 (CH@CH2), 162.5 and 163.6
(2 · C@N), 206.2 (CO); m=z (EI) 280 (Mþ, 4%), 239 (33),
237 (7), 223 (6), 197 (100), 195 (12), 181 (6), 155 (6), 154
(9).
4.8. (20S,50R)-1-[2-(3-Butenyl)-5-isopropyl-3,6-dimeth-
oxy-2,5-dihydropyrazin-2-yl]propan-2-one 3d
4.6. (20R,50R)-1-[2-(3-Butenyl)-5-isopropyl-3,6-dimeth-
oxy-2,5-dihydropyrazin-2-yl]ethanone 3b
The reaction was carried out as above from (20S,50R)-1-
[2-(3-butenyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-
pyrazin-2-yl]propan-2-ol 2d (1.5 g, 5.06 mmol) and the
Dess–Martin reagent (2.58 g, 6.07 mmol). The product
was isolated after chromatography on silica gel using
EtOAc/hexane 1:4. The product thus obtained was a
colourless oil; yield 1.16 g (78%); Rf 0.29; HRMS (elec-
trospray): [Mþ+H] 295.2005; C16H26N2O3 (M+H) re-
quires 295.2016; mmax (film/cmÀ1) 2958, 2945, 2929, 2871,
1726, 1697, 1645, 1462, 1437, 1364, 1243, 1223, 1146; dH
(CDCl3) 0.65 and 1.07 (6H, 2d, J 6.8, CH(CH3)2), 1.63–
1.92 (4H, m, CH2CH2), 2.29–2.35 (1H, m, CH(CH3)2),
2.00 (3H, s, COCH3), 2.71 and 2.82 (2H, 2d, J 15.4,
CHHCO), 3.59 and 3.63 (6H, 2s, 2 · OCH3), 3.96 (1H,
d, J 3.4, H-5), 4.87–4.97 (2H, m, CH@CH2), 5.68–5.78
(1H, m, CH@CH2); dC (CDCl3) 17.3 and 19.6
(CH(CH3)2), 28.41 (CH2CH2), 30.3 (CH(CH3)2), 31.4
(COCH3), 39.9 (CH2CH2), 52.2 (CH2CO), 52.4
(2 · OCH3), 59.3 (C-2), 60.9 (C-5), 114.3 (CH@CH2),
138.3 (CH@CH2), 162.4 and 163.8 (2 · C@N), 206.09
(CO); m=z (CI–CH4) no molecular ion, 239 (18), 237
(100), 223 (7), 195 (71), 55 (3).
Compound 3b was prepared as above from (20S,50R)-
1-[2-(3-butenyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-
pyrazin-2-yl]ethanol 2b (1.500 g, 5.31 mmol) in dry
dichloromethane (25 mL) and the Dess–Martin reagent
(2.819 g, 6.64 mmol) in dry dichloromethane (20 mL) at
ambient temperature. The homogeneous reaction mix-
ture was diluted with diethyl ether (50 mL) and subse-
quently treated with 1.3 M NaOH (30 mL). The mixture
was stirred for 10 min, the ether layer extracted with
1.3 M NaOH (25 mL) and water (25 mL). The crude
product was purified by flash chromatography on silica
gel using EtOAc/hexane 1:4; Rf 0.46. The product was a
colourless oil; yield 1.200 g (81%); HRMS: [Mþ+H]
281.1854; C15H24N2O3+H requires 281.1865; mmax (film/
cmÀ1) 2971, 2961, 2946, 2872, 2846, 1728, 1686, 1641,
1438, 1383, 1246, 1146; dH (CDCl3) 0.68 and 1.09 (6H,
2d, J 6.7, CH(CH3)2), 1.66–1.99 (2H, m, CH2–CH2),
2.00–2.15 (2H, m, CH2–CH2), 2.05 (3H, s, COCH3),
2.28–2.41 (1H, m, CH(CH3)2), 3.67 and 3.69 (6H, 2s,
2 · OCH3), 3.98 (1H, d, J 3.4, H-5), 4.84–5.03 (2H, m,
CH@CH2), 5.68–5.88 (1H, m, CH@CH2); dC (CDCl3)
17.0 and 19.5 (CH(CH3)2), 25.1 (COCH3), 28.5 (CH2–
CH2), 30.6 (CH(CH3)2), 34.2 (CH2–CH2), 52.8
(2 · OCH3), 60.6 (C-5), 71.3 (C-2), 114.5 (CH@CH2),
138.3 (CH@CH2), 160.1 and 164.4 (2 · C@N), 203.12
(CO); m=z (CI–CH4) 281 (Mþ+H, 100%), 253 (9), 238
(13), 237 (56), 236 (12), 211 (14), 195 (28), 169 (6), 153
(3).
4.9. (20R,50R)-3-(2-Acetyl-5-isopropyl-3,6-dimethoxy-
2,5-dihydropyrazin-2-yl)propionaldehyde 4a
Palladium dichloride (0.066 g, 0.375 mmol) and cop-
per(I) chloride (0.371 g, 3.75 mmol) in water (2 mL) and
DMF (14 mL) were stirred together at room tempera-
ture for 1 h before (20R,50R)-1-(2-allyl-5-isopropyl-3,6-
dimethoxy-2,5-dihydropyrazin-2-yl)ethanone 3a (1.00 g,
3.75 mmol) was added. The black solution was stirred
under an oxygen atmosphere at room temperature and
the progress of the reaction monitored by TLC. The
reaction was essentially complete after 10 h. The result-
ing solution was poured into water (10 mL), extracted
with diethyl ether (3 · 20 mL) and the combined organic
extracts dried (MgSO4), and evaporated at reduced
pressure. The product was isolated after flash chroma-
tography on silica gel using EtOAc/hexane 1:5 and was a
colourless oil; yield 0.190 g (18%); Rf 0.20; HRMS: M
4.7. (20S,50R)-1-(2-Allyl-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-yl)propan-2-one 3c
Compound 3c was prepared as above from a solution of
(20S,50R)-1-(2-allyl-5-isopropyl-3,6-dimethoxy-2,5-dihy-
dropyrazin-2-yl)propan-2-ol 2c (0.600 g, 2.12 mmol) and
Dess–Martin reagent (1.030 g, 2.43 mmol). The product
was isolated after flash chromatography on silica gel
using EtOAc/hexane 1:4; Rf 0.30. The product was a
colourless oily material; yield 0.457 g (77%) (Found: C,

60
M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
282.1588; C14H22N2O4 requires 282.1579; mmax (film/
cmÀ1) 2960, 2873, 2789, 1725, 1690, 1670, 1461, 1439,
1354, 1311, 1247, 1184, 1145; dH (CDCl3) 0.68 and 1.07
(6H, 2d, J 6.8, CH(CH3)2), 2.00 (3H, s, CH3), 2.13–2.19
(1H, m, CHHCH2), 2.29–2.43 (4H, m, CHHCH2 and
CH(CH3)2), 3.64 (6H, s, 2 · OCH3), 3.98 (1H, d, J 3.4,
H-5), 9.67 (1H, t, J 1.7, CHO); dC (CDCl3) 16.9 and 19.5
(CH(CH3)2), 25.0 (COCH3), 28.1 (CH2), 30.78
(CH(CH3)2), 39.0 (CH2), 52.9 and 54.0 (2 · OCH3), 60.8
(C-5), 70.3 (C-2), 159.9 and 165.0 (2 · C@N), 202.1 and
202.4 (2 · CO); m=z (EI) 282 (Mþ, 2%), 255 (39), 240
(10), 239 (63), 213 (30), 198 (11), 197 (100), 195 (43), 182
(16), 167 (25), 153 (42).
(Mþ, 3%), 269 (63), 255 (39), 253 (32), 239 (40), 197
(100), 195 (24), 167 (18), 155 (24), 43 (69).
4.12. (20S,50R)-4-[5-Isopropyl-3,6-dimethoxy-2-(2-oxo-
propyl)-2,5-dihydropyrazin-2-yl]butan-2-one 4d
Compound 4d was prepared as above from (20S,50R)-1-
[2-(3-butenyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-
pyrazin-2-yl]propan-2-one 3d (1.00 g, 3.40 mmol),
palladium dichloride (0.060 g, 0.34 mmol) and copper(I)
chloride (0.337 g, 3.40 mmol). The product was a col-
ourless oil after flash chromatography using EtOAc/
hexane 1:4; yield 0.790 g (75%); Rf 0.18; HRMS:
[Mþ+H] 311.1970; C16H26N2O4+H requires 311.1970;
mmax (film/cmÀ1) 2959, 2946, 2871, 1719, 1694, 1462,
1437, 1357, 1308, 1243, 1200; dH (CDCl3) 0.65 and 1.05
(6H, 2d, J 6.8, CH(CH3)2), 1.83–2.08 (8H, m+2s,
CH2CH2 and 2 · COCH3), 2.11–2.35 (3H, m, CH2CH2
and CH(CH3)2), 2.68 and 2.81 (2H, 2d, J 15.5,
CHHCO), 3.54 and 3.59 (6H, 2s, 2 · OCH3), 3.96 (1H,
d, J 3.4, H-5); dC (CDCl3) 17.3 and 19.5 (CH(CH3)2),
29.8 (COCH3), 30.2 (CH(CH3)2), 31.4 (COCH3), 34.4
and 38.6 (CH2CH2), 51.8 (CH2CO), 52.2 and 52.3
(2 · OCH3), 58.5 (C-2), 60.9 (C-5), 162.1 and 164.1
(2 · C@N), 205.8 (CO), 208.07 (CO); m=z (CI–CH4) 311
(Mþ+H, 100%), 310 (8), 268 (7), 267 (28), 253 (23), 252
(9), 239 (7), 211 (5), 197 (9).
4.10. (20R,5R)-1-(2-Acetyl-5-isopropyl-3,6-dimethoxy-
2,5-dihydropyrazin-2-yl)butan-3-one 4b
Compound 4b was prepared as above from (20R,50R)-1-
[2-(3-butenyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-
pyrazin-2-yl]ethanone
3b
(1.150 g,
4.10 mmol),
palladium dichloride (0.072 g, 0.41 mmol) and copper(I)
chloride (0.406 g, 4.10 mmol). The product was a col-
ourless oil after flash chromatography on silica gel using
EtOAc/hexane 1:4; yield 1.00 g (83%); HRMS: [M+1]
297.1803; C15H24N2O4+1 requires 297.1814; mmax (film/
cmÀ1) 2961, 2948, 2873, 1720, 1689, 1461, 1438, 1366,
1247, 1202; dH (CDCl3) 0.68 and 1.06 (6H, 2d, J 6.8,
CH(CH3)2), 1.90–2.08 (1H, m, CHHCH2), 1.99 (3H, s,
COCH3), 2.06 (3H, s, COCH3), 2.11–2.41 (4H, m,
CHHCH2 and CH(CH3)2), 3.63 and 3.65 (6H, 2s,
2 · OCH3), 3.96 (1H, d, J 3.4, H-5); dC (CDCl3) 17.0 and
19.5 (CH(CH3)2), 25.1 (COCH3), 29.4 (COCH3), 29.8
(CH2), 30.8 (CH(CH3)2), 38.7 (CH2), 52.8 and 52.9
(2 · OCH3), 60.8 (C-5), 70.3 (C-2), 160.2 and 164.7
(2 · C@N), 202.69 (CO), 208.9 (CO); m=z (CI–CH4) 297
(Mþ+H, 100%), 255 (6), 254 (16), 253 (66), 227 (8), 211
(34), 197 (4), 153 (8).
4.13. (20R,50R)-1-(2-Acetyl-5-isopropyl-3,6-dimethoxy-
2,5-dihydropyrazin-2-yl)propan-2-one 5a
The diketone 5a was the second product eluted from the
flash chromatography column in the experiment de-
scribed for the preparation of propionaldehyde 4a (vide
supra); yield 0.581 g (55%) of an oily material; Rf 0.16;
HRMS: [Mþ+H] 283.1643; C14H22N2O4+H requires
283.1657; mmax (film/cmÀ1) 2960, 2947, 2872, 1722, 1691,
1666, 1462, 1437, 1356, 1300, 1249; dH (CDCl3) 0.72 and
1.08 (6H, 2d, J 6.7, CH(CH3)2), 2.02 and 2.05 (6H, 2s,
2 · COCH3), 2.28–2.40 (1H, m, CH(CH3)2), 3.03 (1H, d,
J 16.0, CHHCO), 3.18 (1H, d, J 16.0, CHHCO), 3.63
(6H, s, 2 · OCH3), 3.95 (1H, d, J 3.4, H-5); dC (CDCl3)
16.9 and 19.6 (CH(CH3)2), 24.9 (COCH3), 30.6
(CH(CH3)2), 31.2 (CH2COCH3), 48.3 (CH2), 52.9 and
53.1 (2 · OCH3), 60.91 (C-5), 69.7 (C-2), 159.2 and 165.0
(2 · C@N), 201.9 and 205.1 (2 · CO); m=z (CI–CH4) 283
(Mþ+H, 100%), 265 (3), 251 (6), 241 (12), 239 (33), 197
(41).
4.11. (20S,50R)-3-[5-Isopropyl-3,6-dimethoxy-2-(2-oxo-
propyl)-2,5-dihydropyrazin-2-yl]propionaldehyde 4c
Compound 4c was prepared as above from (20S,50R)-1-
(2-allyl-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-
2-yl)propan-2-one 3c (1.00 g, 3.57 mmol), palladium
dichloride (0.063 g, 0.357 mmol) and copper(I) chloride
(0.353 g, 3.57 mmol). The product was obtained as a
colourless oil after flash chromatography on silica gel
using EtOAc/hexane 1:4; yield 0.676 g (64%); Rf 0.11;
HRMS: M 296.1745; C15H24N2O4 requires 296.1736;
mmax (film/cmÀ1) 2959, 2946, 2871, 1724, 1697, 1472,
1437, 1364, 1308, 1242, 1201; dH (CDCl3) 0.66 and 1.07
(6H, 2d, J 6.8, CH(CH3)2), 1.97–2.09 (5H, m and 1s,
CH3 and CH2), 2.22–2.34 (3H, m, CH2 and CH(CH3)2),
2.72 and 2.84 (2H, 2d, J 15.9, CHHCOCH3), 3.56 and
3.62 (6H, 2s, 2 · OCH3), 3.99 (1H, d, J 3.4, H-5), 9.66
(1H, t, J 1.6, CHO); dC (CDCl3) 17.3 and 19.6
(CH(CH3)2), 30.3 (COCH3), 31.4 (CH(CH3)2), 33.1 and
38.9 (2 · CH2), 51.7 (CH2COCH3), 52.4 and 52.5
(2 · OCH3), 58.6 (C-2), 60.9 (C-5), 161.9 and 164.5
(2 · C@N), 201.9 (CHO), 205.7 (COCH3); m=z (EI) 296
4.14. (3R,6S)-3-Isopropyl-2,5-dimethoxy-1,4-diaza-
spiro[5.5]undeca-1,4,8-trien-7-one 6
Caesium carbonate (0.194 g, 0.59 mmol) was added
to a solution of (20R,50R)-3-(2-acetyl-5-isopropyl-3,6-
dimethoxy-2,5-dihydropyrazin-2-yl)propionaldehyde 4a
(0.150 g, 0.59 mmol) in acetonitrile (5 mL). The suspen-
sion was stirred under reflux. TLC monitoring showed
the reaction to be complete after 2 h. The mixture was
filtered through a short silica gel column, the filtrate
evaporated and the residual material subjected to flash

M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
61
chromatography on silica gel using EtOAc/hexane 3:7.
The product was a colourless oil; yield 0.073 g (47%); Rf
0.47.
(100), 209 (9), 207 (31), 196 (10), 154 (26), 153 (56),
123 (10), 82 (23).
The spectroscopic data were in agreement with the
spectroscopic data reported in the literature for this
compound.5b
4.17. (5R,8R)-8-Isopropyl-7,10-dimethoxy-3-methyl-
6,9-diazaspiro[4.5]deca-2,6,9-triene-2-carbaldehyde 7c
Compound 7c was obtained as above from (20S,50R)-
3-[5-isopropyl-3,6-dimethoxy-2-(2-oxo-propyl)-2,5-di-
hydropyrazin-2-yl]propionaldehyde
4c
(0.600 g,
4.15. (5R,8R)-8-Isopropyl-7,10-dimethoxy-3-methyl-
6,9-diazaspiro[4.5]deca-2,6,9-trien-1-one 7a
2.02 mmol) and caesium carbonate (0.666 g, 2.02 mmol).
The reaction was run under reflux for 2 h. The product
was isolated as a colourless oil after flash chromatog-
raphy on silica gel using EtOAc/hexane 3:7; yield 0.196 g
(35%); Rf 029; HRMS: M 278.1627; C15H22N2O3 re-
Caesium carbonate (0.575 g, 1.77 mmol) was added
to a solution of (20R,50R)-1-(acetyl-5-isopropyl-3,6-
dimethoxy-2,5-dihydropyrazin-2-yl)propan-2-one
5a
quires 278.1630; ½aꢀ )70.2 (c 1.00, CHCl3); mmax (film/
D
(0.500 g, 1.77 mmol) in acetonitrile (15 mL). The result-
ing suspension was stirred under reflux, and the progress
of the reaction monitored by TLC. The reaction was
complete after 2 h when the mixture was filtered through
a short silica gel column and the filtrate evaporated. The
product was isolated from the residual material after
flash chromatography on silica gel using EtOAc/hexane
3:7. The product was a colourless oil; yield 0.229 g
(49%); Rf 0.22; HRMS: M 264.1477; C14H20N2O3 re-
quires 264.1473; mmax (film/cmÀ1) 2959, 2947, 2871, 1721,
1693, 1672, 1635, 1437, 1300, 1288, 1238, 1198, 1144; dH
(CDCl3) 0.62 and 1.01 (6H, 2d, J 6.8, CH(CH3)2), 2.13
(3H, s, CH3), 2.20–2.26 (1H, m, CH(CH3)2), 2.53 (1H, d,
J 18.1, CHH), 2.98 (1H, d, J 18.1, CHH), 3.58 (6H, s,
2 · OCH3), 4.10 (1H, d, J 3.2, H-8), 5.92 (1H, s, CH); dC
(CDCl3) 16.3, 19.2 and 19.4 (CH3 and CH(CH3)2), 30.8
(CH(CH3)2), 48.3 (CH2), 52.6 (2 · OCH3), 60.9 (C-8),
66.5 (C-5), 127.6 (CH@), 160.3 and 164.8 (2 · C@N),
178.1 (C@), 204.2 (CO); m=z (EI) 264 (Mþ, 45%), 249
(11), 222 (27), 221 (100), 297 (14), 193 (21), 192 (43), 178
(8), 153 (11).
cmÀ1) 2959, 2946, 2872, 2844, 1690, 1667, 1644, 1438,
1382, 1349, 1305, 1238; dH (CDCl3) 0.65 and 1.01 (6H,
2d, J 6.8, CH(CH3)2), 1.12–2.23 (4H, m+1s, CH3 and
CH(CH3)2), 2.55–2.60 (2H, 2d, 2 · CHH), 2.99 (1H, d, J
16.2, CHH), 3.20 (1H, d, J 18.8, CHH), 3.58 and 3.63
(6H, 2s, 2 · OCH3), 3.95 (1H, d, J 3.4, H-8), 9.96 (1H, s,
CHO); dC (CDCl3) 14.5 (CH3), 17.3 and 19.7
(CH(CH3)2), 31.7 (CH(CH3)2), 47.0 (CH2), 52.7 and
53.0 (2 · OCH3), 56.1 (CH2), 60.9 (C-5), 61.6 (C-8),
135.9 (C-3), 159.5 (C-2), 162.5 and 165.2 (2 · C@N),
188.2 (CHO); m=z (EI) 278 (Mþ, 17%), 277 (12), 251
(31), 235 (73), 207 (13), 197 (100), 195 (15), 167 (17), 153
(24).
4.18. (5R,8R)-1-(8-Isopropyl-7,10-dimethoxy-3-methyl-
6,9-diazaspiro[4.5]deca-2,6,9-trien-2-yl)ethanone 7d
Compound 7d was prepared as above from (20S,5,R)-4-
[5-isopropyl-3,6-dimethoxy-2-(2-oxo-propyl)-2,5-dihy-
dropyrazin-2-yl]butan-2-one 4d (0.600 g, 1.93 mmol)
and caesium carbonate (0.945 g, 2.9 mmol). The reaction
mixture was heated under reflux for 4 h. The product
was isolated as a colourless oil after flash chromatog-
raphy on silica gel using EtOAc/hexane 3:7; yield
0.197 g (35%); Rf 0.36; HRMS: [Mþ+H] 293.1852;
4.16. (3R,6R)-3-Isopropyl-2,5-dimethoxy-9-methyl-
1,4-diazaspiro[5.5]undeca-1,4,8-trien-7-one 7b
Compound 7b was prepared as above from (20R,50R)-
1-(2-acetyl-5-isopropyl-3,6-dimethoxy-2,5-dihydropyr-
azin-2-yl)butan-3-one 4b (0.950 g, 3.2 mmol) and
caesium carbonate (1.043 g, 3.2 mmol) by heating under
reflux for 2 h. The product was a colourless oil after
flash chromatography on silica gel using EtOAc/hex-
ane 1:4; yield 0.560 g (63%); Rf 0.4; HRMS: M
C16H24N2O3+H requires 293.1865; ½aꢀ )57.3 (c 1.00,
D
CHCl3); mmax (film/cmÀ1) 2958, 2954, 2872, 2843, 1690,
1657, 1635, 1619, 1462, 1437, 1365, 1305, 1227, 1200; dH
(CDCl3) 0.67 and 1.03 (6H, 2d, J 6.8, CH(CH3)2), 2.09
(3H, s, CH3), 2.15–2.23 (4H, m and 1s, COCH3 and
CH(CH3)2), 2.51 (1H, d, J 17.8, CHH-4), 2.62 (1H, d, J
15.0, CHH-1), 3.13–3.19 (2H, 2d, CHH-4 and CHH-1),
3.60 and 3.66 (6H, 2s, 2 · OCH3), 3.96 (1H, d, J 3.4,
H-8); dC (CDCl3) 16.7 (CH3), 16.9 and 19.3 (CH(CH3)2),
30.4 (COCH3), 31.3 (CH(CH3)2), 50.2 (C-1), 52.4 and
52.6 (2s, 2 · OCH3), 56.2 (C-4), 60.2 (C-5), 61.1 (C-8),
133.1 (C-3), 150.9 (C-2), 161.8 and 165.0 (2 · C@N),
197.3 (CO); m=z (CI–CH4) 293 (Mþ+H, 61%), 292 (20),
265 (8), 250 (18), 249 (100), 207 (18), 192 (6).
278.1632; C15H22N2O3 requires 278.1630; ½aꢀ )23.6
D
(c 1.28, CHCl3); mmax (film/cmÀ1) 2957, 2946, 2871,
1697, 1677, 1636, 1461, 1436, 1381, 1241, 1214, 1200;
dH (CDCl3) 0.64 and 1.06 (6H, 2d, J 6.8, CH(CH3)2),
1.78–1.85 (1H, m, CHHCHH), 1.98 (3H, s, CH3),
2.13–2.22 (1H, m, CHHCHH), 2.25–2.30 (1H, m,
CH(CH3)2), 2.55–2.60 (1H, m, CHHCHH), 2.70–2.89
(1H, m, CHHCHH), 3.59 and 3.65 (6H, 2s, 2 · OCH3),
4.05 (1H, d, J 3.2, H-3), 5.85 (1H, s, C@CH); dC
(CDCl3) 16.6 and 19.3 (CH(CH3)2), 24.5 (CH3), 27.6
(CH2CH2), 30.6 (CH(CH3)2), 34.1 (CH2CH2), 52.4 and
52.5 (2s, 2 · OCH3), 60.7 (C-3), 63.9 (C-6), 124.3
(C@CH), 161.4 (C@N), 163.6 (C@CH), 164.3 (C@N),
193.6 (CO); m=z (EI) 278 (Mþ, 30%), 236 (21), 235
4.19. (5S,8R)-1-(8-Isopropyl-7,10-dimethoxy-6,9-diaza-
spiro[4.5]deca-1,6,9-trien-1-yl)ethanone 8c
The diketone 8c was the second product eluted from the
flash chromatography column in the experiment

62
M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
described for the preparation of the carbaldehyde 7c (vide
supra) The product was obtained as an oily material;
yield 0.235 g (42%); HRMS: M 278.1642; C15H22N2O3
169.0738; ½aꢀ +34.2 (c 0.77, CH2Cl2); mmax (film/cmÀ1
)
D
3368, 3306, 2959, 2923, 1744, 1705, 1621, 1435, 1255,
1204, 1149, 1067; dH (CDCl3) 1.96–2.04 (2H, br s, NH2),
2.06 (3H, s, CH3), 2.52 (1H, d, J 18.3, CHH), 3.09 (1H,
d, J 18.3, CHH), 3.69 (3H, s, CO2CH3), 5.95 (1H, s,
CH); dC (CDCl3) 19.5 (CH3), 47.2 (CH2), 52.9
(CO2CH3), 66.1 (C-1), 127.2 (CH@), 174.6 (CO2CH3),
178.3 (C@), 204.2 (CO); m=z (EI) 169 (Mþ, 10%), 154
(6), 149 (7), 126 (5), 111 (19), 110 (100), 82 (17).
requires 278.1630; ½aꢀ +30.7 (c 1.55, CHCl3); mmax (film/
D
cmÀ1) 2957, 2946, 2867, 1694, 1674, 1436, 1367, 1303,
1241, 1170; dH (CDCl3) 0.67 and 1.05 (6H, 2d, J 6.8,
CH(CH3)2), 1.93–2.01 (1H, m, CHHCH2), 2.22–2.35
(5H, m+1s, CH(CH3)2, CHHCH2 and COCH3), 2.55–
2.68 (2H, m, CHHCH2), 3.56 and 3.59 (6H, 2s,
2 · OCH3), 4.09 (1H, d, J 5.2, H-8), 6.89 (1H, t, J 3.4,
CH@); dC (CDCl3) 17.0 and 19.4 (CH(CH3)2), 27.1
(COCH3), 30.8 (CH(CH3)2), 31.5 and 39.9 (2 · CH2),
52.3 and 52.5 (2 · OCH3), 61.1 (C-8), 68.33 (C-5), 146.7
(C-1 and C-2), 163.3 (2 · C@N), 194.8 (COCH3); m/z
(EI) 278 (Mþ, 100%), 263 (61), 253 (18), 247 (23), 239
(99), 235 (91), 206 (57), 197 (60), 193 (21).
4.23. (1S)-1-Amino-4-methyl-2-oxo-cyclohex-3-ene-
carboxylic acid methyl ester 9b
The product 9b was a colourless oil; yield 0.054 g (59%).
Rf 0.26; HRMS: [Mþ+H] 184.0973; C9H13NO3+H re-
quires 184.0973; ½aꢀ )39.8 (c 1.28, CHCl3); mmax (film/
D
cmÀ1) 3383, 3314, 2954, 2925, 2851, 1735, 1670, 1633,
1435, 1381, 1247, 1172. dH (CDCl3) 1.94 (3H, s, CH3),
1.89–2.05 (3H, m, NH2 and CHHCH2), 2.35–2.49 (3H,
m, CHHCH2), 3.68 (3H, s, OCH3), 5.90 (1H, s, CH); dC
(CDCl3) 24.7 (CH3), 29.0 (CH2CH2), 33.9 (CH2CH2),
53.1 (OCH3), 63.7 (C-1), 125.0 (C@CH), 163.6 (C@CH),
173.6 (C@N), 193.6 (CO2Me), 195.3 (CO); m=z (CI–
CH4) 184 (Mþ+H, 100%), 167 (8), 166 (13), 135 (10), 124
(74), 96 (14), 82 (24).
4.20. (5S,8R)-1-(8-Isopropyl-7,10-dimethoxy-2-methyl-
6,9-diaza-spiro[4.5]deca-1,6,9-trien-1-yl)ethanone 8d
Compound 8d was the second product eluted from the
flash chromatography column in the reaction above
with 4d as substrate with formation of the methyl ketone
7d (vide supra); yield of colourless oily material 0.214 g
(38%); Rf
0.28; HRMS: [Mþ+H] 293.1863;
C16H24N2O3+H requires 293.1865; ½aꢀ )46.4 (c 1.00,
D
CHCl3); mmax (film/cmÀ1) 2959, 2945, 2871, 2843, 1686,
1619, 1461, 1435, 1358, 1305, 1285, 1241, 1097; dH
(CDCl3) 0.69 and 1.05 (6H, 2d, J 6.8, CH(CH3)2), 1.8–
1.95 (1H, m, CHHCH2), 2.02 (3H, s, CH3), 2.11 (3H, s,
COCH3), 2.12–2.30 (2H, m, CHHCH2 and CH(CH3)2),
2.52–2.7 (2H, m, CHHCH2), 3.57 and 3.62 (6H, 2s,
2 · OCH3), 4.04 (1H, d, J 3.4, H-8); dC (CDCl3) 17.2 and
19.4 (CH(CH3)2), 17.5 (CH3), 29.8 (COCH3), 31.2
(CH(CH3)2), 38.6 (C-3), 39.1 (C-4), 52.5 and 52.7
(2 · OCH3), 61.3 (C-8), 70.6 (C-5), 139.4 (C-2), 156.7
(C-1), 163.1 and 164.6 (2 · C@N), 197.2 (CO); m=z
(CI–CH4) 293 (Mþ+H, 100%), 292 (53), 277 (36), 261
(13), 250 (9), 249 (38), 220 (26), 207 (5), 197 (8).
4.24. (1S)-2-Acetyl-1-amino-cyclopent-2-enecarboxylic
acid methyl ester 9c
The product 9c was a colourless oil; yield 0.043 g
(47%). Rf 0.2; HRMS (electrospray): [Mþ+H] 184.0977;
C9H13NO3+H requires 184.0968; ½aꢀ +74.2 (c 1.00,
D
CH2Cl2); mmax (film/cmÀ1) 3367, 3302, 2953, 1735, 1674,
1651, 1593, 1437, 1378, 1276, 1258, 1178, 1086; dH
(CDCl3) 1.88–1.94 (1H, m, CHHCH2), 2.06 (2H, br s,
NH2), 2.24–2.31 (4H, m+1s, COCH3 and CHHCH2),
2.61–2.9 (2H, m, CHHCH2), 3.63 (3H, s, CO2CH3), 6.85
(1H, t, J 2.6, CH@); dC (CDCl3) 26.6 (COCH3),
31.5 and 38.3 (2 · CH2), 52.4 (CO2CH3), 68.4 (C-1),
147.0 (C-3), 147.4 (C-2), 176.7 (CO2CH3), 195.8
(COCH3); m=z (CI–CH4) 184 (Mþ+H, 7%), 135 (17),
124 (100), 72 (82).
4.21. Hydrolytic formation of cyclic a-amino acid esters
The bicyclic products 7a–d and 8c,d (0.50 mmol) were
separately stirred with trifluoroacetic acid (25 mL,
5.0 mmol, 0.2 M) in acetonitrile (25 mL) at ambient
temperature for 3 d. The solution was evaporated al-
most to dryness at reduced pressure, water (10 mL) and
dichloromethane (20 mL) were added and the aqueous
layer made alkaline (pH 10) by addition of concd aq
ammonia. The mixture was extracted with dichlorome-
thane (2 · 20 mL), the combined organic layers dried
(MgSO4), evaporated and the product isolated from the
residual material after flash chromatography on silica
gel using MeOH/CH2Cl2 1:20.
4.25. (1R)-3-Acetyl-1-amino-4-methylcyclopent-3-ene-
carboxylic acid methyl ester 11
The product 11 was a colourless oil; yield 0.057 g (58%).
Rf 0.23; HRMS: [Mþ+H] 198.1120; C10H15NO3+H re-
quires 198.1130; ½aꢀ +40.0 (c 1.00, CH2Cl2); mmax (film/
D
cmÀ1) 3368, 3301, 2954, 2923, 1732, 1678, 1650, 1631,
1617, 1434, 1361, 1221, 1064; dH (CDCl3) 1.82 (2H, br s,
NH2), 2.08 (3H, s, CH3), 2.22 (3H, s, COCH3), 2.40 (1H,
d, J 17.5, CHH-5), 2.61 (1H, d, J 14.7, CHH-2), 3.15–
3.26 (2H, 2d, CHH-5 and CHH-2), 3.70 (3H, s,
CO2CH3); dC (CDCl3) 16.7 (CH3), 30.3 (COCH3), 48.0
(C-2), 52.5 (CO2CH3), 53.7 (C-5), 61.0 (C-1), 132.9 (C-
4), 150.1 (C-3), 176.3 (CO2CH3), 196.9 (COCH3); m=z
(CI–CH4) 198 (Mþ+H, 9%), 181 (6), 154 (6), 149 (11),
139 (12), 138 (199), 96 (12), 95 (7), 94 (8).
4.22. (1S)-1-Amino-4-methyl-2-oxo-cyclopent-3-enecarb-
oxylic acid methyl ester 9a
Compound 9a was a colourless oil; yield 0.047 g (56%);
Rf 0.25; HRMS: M 169.0742; C8H11NO3 requires

M. Andrei, K. Undheim / Tetrahedron: Asymmetry 15 (2004) 53–63
63
4.26. (10R,2R)-2-[(3-Acetyl-1-amino-4-methylcyclopent-
3-enecarbonyl)amino]-3-methylbutyric acid methyl
ester 12
0.25; HRMS: [Mþ+H] 297.1808; C15H24N2O4+1 re-
quires 297.1814; ½aꢀ +52.8 (c 0.50, CH2Cl2); mmax (film/
D
cmÀ1) 3368, 2963, 2930, 2875, 1740, 1671, 1655, 1510,
1436, 1371, 1267, 1154; dH (CDCl3) 0.85–0.91 (6H, 2d,
CH(CH3)2), 1.75–1.81 (1H, m, CHHCH2), 2.02 (3H, s,
CH3), 2.03–2.30 (4H, m, CHHCH2, NH2 and
CH(CH3)2), 2.33 (3H, s, COCH3), 2.58–2.63 (2H, m,
CHHCH2), 3.72 (3H, s, CO2CH3), 3.73–3.49 (1H, dd, J
4.8, J 9.0, CHNH), 7.74 (1H, d, J 9.0, CHNH); dC
(CDCl3) 17.6 (CH3), 17.7 and 19.0 (CH(CH3)2), 30.8
(COCH3), 31.4 (CH(CH3)2), 35.8 (CH2CH2), 38.9
(CH2CH2), 52.1 (CO2CH3), 57.1 (NHCH), 72.8 (C-1),
141.5 (C-3), 154.3 (C-2), 172.3 (CONH), 174.3
(CO2CH3), 198.0 (COCH3); m=z (CI–CH4) 297 (17), 289
(10), 198 (6), 139 (10), 138 (100), 96 (10).
The dipeptide 12 was formed by partial hydrolysis in the
above reaction from the bicyclic substrate 7d, and was
the first product eluted from the flash chromatography
column in the above reaction. The dipeptide 11 thus
obtained was an oily material; yield 0.022 g (15%); Rf
0.33; HRMS: [Mþ+H] 297.1816; C15H24N2O4+H re-
quires 297.1814; ½aꢀ +41.3 (c 1.00, CH2Cl2); mmax (film/
D
cmÀ1) 3362, 2964, 2933, 2876, 1740, 1713, 1674, 1616,
1509, 1466, 1437, 1371, 1312, 12611211; dH (CDCl3)
0.88–0.93 (6H, 2d, CH(CH3)2), 1.80 (2H, br s, NH2),
2.08 (3H, s, CH3), 2.12–2.22 (4H, s+m, COCH3 and
CH(CH3)2), 2.29 (1H, d, J 18.4, CHH-5), 2.53 (1H, d, J
15.9, CHH-2), 3.31–3.47 (2H, 2d, CHH-5 and CHH-2),
3.70 (3H, s, CO2CH3), 4.44–4.49 (1H, dd, J 4.7, J 8.9,
CHNH), 8.10 (2H, d, J 8.9, NH); dC (CDCl3) 16.8
(CH3), 17.7 and 19.1 (CH(CH3)2), 30.3 (COCH3), 31.1
(CH(CH3)2), 49.3 (C-2), 52.0 (CO2CH3), 55.0 (C-5), 57.2
(NHCH), 61.9 (C-1), 132.6 (C-4), 150.7 (C-3), 172.4
(CONH), 175.7 (CO2CH3), 197.3 (COCH3); m/z (CI–
CH4) 297 (Mþ+H, 24%), 280 (25), 269 (8), 149 (11), 138
(100), 137 (17), 132 (12), 111 (8), 110 (29), 96 (14), 72 (8).
References and Notes
ꢀ
1. Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron: Asym-
metry 1998, 9, 3517–3599.
ꢀ
2. Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron: Asym-
metry 2000, 11, 645–732.
3. (a) Hammer, K.; Undheim, K. Tetrahedron 1997, 53,
10603–10614; (b) Hammer, K.; Undheim, K. Tetrahedron
1997, 53, 5925–5936; (c) Hammer, K.; Undheim, K.
Tetrahedron 1997, 53, 2309–2322; (d) Hammer, K.;
Undheim, K. Tetrahedron: Asymmetry 1998, 9, 2359–
2368.
4.27. (1S)-2-Acetyl-1-amino-3-methyl-cyclopent-2-ene-
carboxylic acid methyl ester 13
4. (a) Møller, B.; Undheim, K. Eur. J. Org. 2003, 332–336;
(b) Møller, B.; Undheim, K. Tetrahedron 1998, 54, 5789–
5804.
The product 13 was a colourless oil; yield 0.057 g (51%).
Rf 0.18; HRMS: [M+H] 198.1137; C10H15NO3+H re-
quires 198.1130; ½aꢀ +81.9 (c 0.76, CH2Cl2); mmax (film/
ꢀ
5. (a) Krikstolaityte, S.; Hammer, K.; Undheim, K. Tetra-
hedron Lett. 1998, 39, 7595–7598; (b) Krikstolaityte, S.;
D
cmÀ1) 3368, 3304, 2953, 1736, 1673, 1651, 1593, 1434,
1378, 1367, 1276, 1259, 1178, 1086; dH (CDCl3) 1.75–
1.81 (1H, m, CHHCH2), 2.07–2.18 (4H, m + s,
CHHCH2 and CH3), 2.20–2.41 (5H, br s + s, NH2 and
COCH3), 2.50–2.63 (1H, m, CHHCHH), 2.71–2.83 (1H,
m, CHHCHH), 3.65 (3H, s, CO2CH3); dC (CDCl3) 17.5
(CH3), 30.5 (COCH3), 36.2 (CH2CH2), 39.4 (CH2CH2),
52.4 (CO2CH3), 71.2 (C-1), 140.9 (C-3), 156.4 (C-2),
177.1 (CO2CH3), 196.9 (CO); m=z (CI–CH4) 198
(Mþ+H, 5%), 181 (5), 152 (9), 149 (22), 138 (100), 96
(18), 72 (9).
ꢀ
€
Hammer, K.; Romming, C.; Undheim, K. Synth. Com-
mun. 2002, 32, 571–580.
6. (a) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org.
Chem. 1999, 64, 4537–4538; (b) Dess, B. D.; Martin, J. C.
J. Org. Chem. 1983, 48, 4156–4158; (c) Ireland, R. E.; Liu,
L. J. Org. Chem. 1993, 58, 2899.
7. Tsuji, J. Synthesis 1984, 369–384.
8. (a) Lai, J.-y.; Shi, X.-x.; Dai, L.-x. J. Org. Chem. 1992, 57,
3485–3487; (b) Pellissier, H.; Michellys, P.-y.; Santelli, M.
Tetrahedron 1997, 53, 10733–10742; (c) Bose, A. K.;
Krishnan, L.; Wagle, D. R.; Manhas, M. S. Tetrahedron
Lett. 1986, 27, 5955–5958.
9. (a) Chapdelaine, D.; Belzile, J.; Deslongchamps, P. J. Org.
Chem. 2002, 67, 5672–5699; (b) Ruel, R.; Deslongchamps,
P. Can. J. Chem. 1992, 70, 1939–1949; (c) Leclaire, M.;
Levet, R.; Lallemand, J. Y. Synth. Commun. 1993, 23(13),
1923–1927.
4.28. (10S,2R)-2-[(2-Acetyl-1-amino-3-methylcyclopent-
2-enecarbonyl)amino]-3-methylbutyric acid methyl
ester 14
10. Bull, S. D.; Davies, S. G.; Epstein, S. W.; Leech, M. A.;
Ouzman, J. V. A. J. Chem. Soc., Perkin Trans. 1 1998,
2321–2330.
The dipeptide 14 was formed by partial hydrolysis in the
above reaction from the bicyclic substrate 8d, and was
the first product eluted from the flash chromatography
column in the above reaction. The dipeptide 13 thus
obtained was an oily material; yield 0.015 g (10%); Rf
€
11. (a) Schollkopf, U. Tetrahedron 1983, 39, 2085–2091; (b)
Beulshausen, T.; Groth, U.; Schollkopf, U. Liebigs Ann.
€
Chem. 1991, 1207–1209.