Diastereoselective alkylation of a proline-derived bicyclic lactim ether

Article abstract of DOI:10.1002/hlca.200690181

N-Boc-protected L-proline (6) was converted into the bicyclic lactim ether (8aS)-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5) in four steps (Scheme 1). Deprotonation with LDA or LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis- and trans-9. The diastereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably cis-9, sterically more-demanding alkyl halides resulted in cisltrans mixtures. Electrophiles bearing a π-system favored the trans-products 9. Some isolated cis- and tranx-lactim ethers 9 were converted to the corresponding diketopiperazines cis- and trans-10 by acid hydrolysis. The structures and configurations of several compounds were confirmed by NMR and NOE experiments, as well as by X-ray crystallography (Figs. 1-4).

Full text of DOI:10.1002/hlca.200690181

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Helvetica Chimica Acta – Vol. 89 (2006)
Diastereoselective Alkylation of a Proline-Derived Bicyclic Lactim Ether
by Daniela Hendea, Sabine Laschat*, Angelika Baro, and Wolfgang Frey
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart
(fax: +49-(0)711-685-64285; e-mail: sabine.laschat@oc.uni-stuttgart.de)
Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday
N-Boc-protected L-proline (6) was converted into the bicyclic lactim ether (8aS)-6,7,8,8a-tetrahydro-
1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5) in four steps (Scheme 1). Deprotonation with LDA or
LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis-and trans-9. The dia-
stereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably
cis-9, sterically more-demanding alkyl halides resulted in cis/trans mixtures. Electrophiles bearing a p-
system favored the trans-products 9. Some isolated cis-and trans-lactim ethers 9 were converted to
the corresponding diketopiperazines cis-and trans-10 by acid hydrolysis. The structures and configura-
tions of several compounds were confirmed by NMR and NOE experiments, as well as by X-ray crystal-
lography (Figs. 1–4).
Introduction. – In contrast to the well-known ꢀSchçllkopf bislactim-ether methodꢁ
for the synthesis of a-amino acids [1–3], the alkylation of monolactim ethers has
been rarely reported in the literature [4–6]. Recently, we have published the prepara-
tion of tricyclic diketopiperazines with an annulated tetrahydroisoquinoline moiety via
diastereoselective alkylation of the corresponding monolactim ethers and subsequent
hydrolysis [7].
Several secondary metabolites of microorganisms with interesting biological prop-
erties such as deoxybrevianamide E (1) [8], tryprostatins A and B (2a,b) [9], spirotry-
prostatin A (3) [10], and fumitremorgin C (4) [11] contain a proline-derived diketopi-
perazine as part of their molecular skeleton. Furthermore, this type of compound has
been found in the bitter flavor of roasted coffee [12]. The diketopiperazine structural
motif in these natural products was prepared in most cases by cyclocondensation
[8–11][13][14]. However, we were interested to synthesize related proline-based dike-
topiperazines via alkylation of the bicyclic lactim ether 5, followed by acidic hydrolysis.
The results of our investigation are reported in this paper.
Results and Discussion. – The synthesis of the lactim ether 5 is outlined in Scheme 1.
N-Boc-protected L-proline (6) was converted quantitatively into the anhydride 7
[7][15], which was reacted with glycine methyl ester hydrochloride in the presence
of Et3N, and subsequently exposed to boiling H2O to afford the bicyclic diketopipera-
A
zine 8 in 87% yield over both steps [16]. Alternatively, compound 8 is accessible in 46%
yield according to the method by Viallefont and co-workers [17]. Upon treatment of 8
with Meerweinꢁs salt, the desired lactim ether 5 was obtained in 77% yield (67% total
yield over four steps).
ꢂ 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
1895
Scheme 1
An X-ray crystal-structure analysis of the diketopiperazine 8 revealed the presence
of H-bridges in the solid state (Fig. 1). The bond length of N(1)ꢀH was found to be 2.8
Š, with a bridge angle N(1)ꢀH···O(2) of 175.188.
Next, the alkylation of 5 with different electrophiles was investigated (Scheme 2,
Table 1). Since lithium diisopropylamide (LDA) and lithium hexamethyldisilazane
(LHMDS) were previously found to be most promising with regard to yield and diaster-
eoselectivity [7], both bases were tested in the deprotonation step. Treatment of the lac-
tim ether 5 with LDA, followed by addition of MeI and aqueous workup after 16 h,
gave the crude product 9a in an excellent diastereoisomeric ratio of cis/trans 98 :2
(96% diastereoisomeric excess). The mixture was separated by flash chromatography,

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Helvetica Chimica Acta – Vol. 89 (2006)
Fig. 1. X-Ray crystal structure of 8 (ORTEP representation)
which afforded the major diastereoisomer cis-9a in 94% yield (Table 1, Entry 1). Sim-
ilar results were obtained with LHMDS (Entry 2). The alkylation of 5 with EtI also
favored the formation of the corresponding cis-9b (Entry 3). However, for electrophiles
with either longer alkyl chains or bulkier alkyl groups, the diastereoselectivity
decreased remarkably (Entries 4–12). While BuI gave an equimolar mixture of cis-
and trans-9c (Entries 4 and 5), the i-Bu (9d) and i-Pr (9e) congeners were obtained
in cis/trans ratios of 29 :71 and 68 :32, respectively (Entries 6 and 10, resp.).
The situation changed remarkably, when electrophiles with additional p-systems
were applied (Entries 13–21). In these cases, a pronounced preference of the trans-
products (9f–9j) was observed. The best selectivity (cis/trans<1:99) was obtained
for the benzylated product 9h prepared with LHMDS as base (Entry 19). It should
be noted that, in some cases, the yields of the isolated products 9 considerably
decreased due to difficulties in chromatographic purification of the diastereoisomers.
Furthermore, the trans-diastereoisomers of both the prenyl- and 3-chlorobenzyl-substi-
tuted lactim ethers 9g and 9i turned out to be more prone to hydrolysis than their cis-
congeners. Upon prolonged chromatographic purification, the diketopiperazines trans-
10g and trans-10i were isolated rather than the corresponding trans-configured lactim
ethers. In contrast, the cis-lactim ethers cis-9g and cis-9i were readily obtained.
Finally, selected pure cis-and trans-lactim ethers 9 were treated with 1 equiv. of
TsOH at room temperature in CH2Cl2 to afford the corresponding diketopiperazines
cis-10 and trans-10 in good yields (Scheme 2, Table 2).
To confirm the preliminary stereochemical assignment of the lactim ethers 9 and of
the corresponding diketopiperazines 10, based on NMR and NOE experiments, cis-
10a,d,e,h derived from methyl L-alaninate (11a), L-leucinate (11b), L-valinate (11c),
and L-phenylalaninate (11d), were prepared, as outlined in Scheme 2. Following a pro-

Helvetica Chimica Acta – Vol. 89 (2006)
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Scheme 2
cedure by de Costa et al. [16], the L-proline derivative 6 was condensed with the amino
acid esters 11 in the presence of N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide
hydrochloride (EDC) and 1-hydroxy-1H-benzotriazole (HOBt) to afford intermediate
dipeptides, which were immediately cyclized to the cis-diketopiperazines cis-10.
The NMR data and optical-rotation values, together with an X-ray crystal structure
analysis (Fig. 2) of the methyl-substituted diketopiperazine cis-10a derived from L-ala-
nine, confirmed the cis assignment. Further support came from the X-ray crystal struc-
tures of the isobutyl-substituted diketopiperazines cis-10d and trans-10d (Fig. 3), iso-
lated via the alkylation route after chromatographic separation, as well as of the
prenyl-substituted diketopiperazine trans-10g (Fig. 4), obtained via hydrolysis on silica
gel.
Compounds 8 (Fig. 1) and 10 (Figs. 2–4) crystallized in chiral space groups as pure
enantiomers. In all cases, the determination of the absolute configuration by X-ray
analysis1) was not possible due to the lack of atoms with evident anomalous scattering
1
)
Crystallographic data for the structures have been deposited with the Cambridge Crystallographic
Data Centre, as CCDC-250728 (8), CCDC-605739 (cis-10a), CCDC-258427 (cis-10d), CCDC-
605738 (trans-10d), and CCDC-605740 (trans-10g). Copies of the data can be obtained, free of
charge, via www.ccdc.cam.ac.uk/data_request/cif.

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Helvetica Chimica Acta – Vol. 89 (2006)
Table 1. Alkylation of the Lactim Ether 5 to Compounds 9 under Various Conditions (see Scheme 2)
Entry
R
X
Base
Product
Conv. [%]a)
Yield [%]b)
cis/transa)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Me
Me
Et
Bu
I
I
I
I
I
I
Br
Br
Br
I
LDA
LHMDS
LDA
LDA
LHMDS
LDA
LDA
LHMDS
LDA
9a
9a
9b
9c
9c
9d
9d
9d
9e
9e
9e
9e
9f
9f
9f
9f
9g
9h
9h
9i
100
80
70
81
80
96
65
56
86
67
39
85
99
90
35
51
69
77
61
68
76
94
75
60
33c)
–
–
48
–
67
–
–
–
–
35c)
–
98 :2
95 :5
96 :4
50 :50
50 :50
29 :71
30 :70
40 :60
60 :40
68 :32
50 :50
50 :50
33 :67
33 :67
12 :88
30 :70
15 :85
4 :96
Bu
i-Bu
i-Bu
i-Bu
i-Pr
i-Pr
i-Pr
i-Pr
Allyl
Allyl
Allyl
Allyl
Prenyl
Bn
LDA
I
LHMDS
LHMDS
LDA
Br
Br
I
LDA
I
LHMDS
LHMDS
LDA
LDA
LHMDS
LDA
Br
Br
Br
Br
Br
Br
–
7d)
71
–
Bn
3-ClC
3-MeOC
<1:99
12 :88
12 :88
G
E
6d)
66
G
A
LDA
9j
a) Determined by capillary GC of the crude products. b) Isolated yield. c) Low yield mainly due to losses
during difficult chromatographic purification. d) Yield of minor cis-diastereoisomer; the trans-isomer was
hydrolyzed to the corresponding diketopiperazine 10 during chromatography (see Exper. Part).
Table 2. Hydrolysis of the Separated Lactim Ethers cis- and trans-9 to the Diketopiperazines cis- and trans-
10 (see Scheme 2)
Entry
Reactant
R
Product
Yield [%]
1
2
cis-9a
cis-9c
Me
Bu
cis-10a
cis-10c
81
81
3
4
5
6
7
8
9
10
trans-9c
cis-9d
trans-9d
trans-9e
cis-9e
cis-9f
trans-9f
trans-9h
Bu
trans-10c
cis-10d
trans-10d
trans-10e
cis-10e
cis-10f
trans-10f
trans-10h
quant.
quant.
quant.
94
quant.
70
i-Bu
i-Bu
i-Pr
i-Pr
Allyl
Allyl
Bn
60
83
parts (see crystal structure of 10d, Fig. 3,a). Nevertheless, the X-ray data unambigu-
ously confirmed the cis/trans-conformation of the diastereoisomers 10. In the solid
state, these compounds are stabilized by strong intermolecular H-bridges between
the NH donor and the carbonyl O-functions. This H-bridge is nearly linear, with the
exception of cis-10d, where the NꢀH···O bridge angle is 1458.

Helvetica Chimica Acta – Vol. 89 (2006)
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Fig. 2. X-Ray crystal structure of cis-10a (ORTEP representation)
Fig. 3. X-Ray crystal structures of a) cis-10d and b) trans-10d (ORTEP representations)

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Helvetica Chimica Acta – Vol. 89 (2006)
Fig. 4. X-Ray crystal structure of trans-10g (ORTEP representation)
A comparison of the NMR and optical-rotation data of the L-phenylalanine-derived
cis-10h ([a]2D5 =ꢀ165 (c=1.0, CH2Cl2)) and trans-10h ([a]2D5 =ꢀ14 (c=1.0, CH2Cl2)),
prepared via the benzylated lactim ether 9h, indicated correct assignment of the dia-
stereoisomers. At this point, it should be mentioned that the hydrolysis of 9 to 10 did
not affect the center of chirality at C(3). The isolated cis-and trans-lactim ethers 9
gave, in each case, a single diketopiperazine 10 with the same configuration at C(3)
and C(8), when treated with TsOH.
To check whether the observed diastereoselectivity in the alkylation step is due to
epimerization, the isolated Bn- and i-Pr-substituted lactim ethers cis-9e and trans-9h
were treated with LDA in THF at ꢀ788 for 4 h, followed by quenching with aqueous
NaHCO3 (Scheme 3). At given time intervals, aliquots were taken from the reaction
mixture and directly analyzed by capillary GC (for 9h) or by HPLC (for 9e). In the
case of trans-9h, a significant amount of the cis-congener was detected after 1 h (cis/
trans 38 :62), remaining nearly constant after 24 h. Thus, the excellent trans-selectivity
found in the alkylation step is probably due to kinetic control. In contrast, the i-Pr com-
pound cis-9e epimerized only to a small extent, resulting in a cis/trans ratio of 98 :2 after
24 h (Scheme 3).
From the results of the above alkylation reactions, the following mechanistic ration-
ale may be deduced. Assuming a Li-mediated attack of the electrophile, the four differ-
ent geometries A–D are conceivable. Small electrophiles such as MeI or EtI preferably
approach from the top (Si-face) of the carbanion (A), because attack from the bottom
face interferes with the lone pair at N(5). In the case of the bulkier i-Pr and i-Bn elec-
trophiles, two competing geometries are possible, which, however, suffer either from
steric hindrance between the alkyl moiety of the electrophile and the pyrrolidine
ring (B), or from lone pair repulsion between the leaving halogen and N(5) (C), in
accord with poor selectivities. For benzyl, allyl, and prenyl halides, which bear a p-sys-

Helvetica Chimica Acta – Vol. 89 (2006)
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Scheme 3
tem, a favorable p–p interaction between the electrophile and the carbanion is possible
in arrangement D [18].
Conclusions. – L-Proline provides a useful template for the diastereoselective alkyl-
ation of the bicyclic lactim ether 5 to afford products 9, which can be conveniently con-
verted to the corresponding diketopiperazines cis-and trans-10. This synthetic route
should allow a novel access to diketopiperazine alkaloids, and is currently under inves-
tigation.
Generous financial support by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen
Industrie, and the Ministerium für Wissenschaft, Forschung und Kunst des Landes Baden-Württemberg
is gratefully acknowledged. We would like to thank A. Hätzelt for initial experiments and helpful discus-
sions.

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Helvetica Chimica Acta – Vol. 89 (2006)
Experimental Part
General. Flash chromatography (FC): Merck silica gel 60 (0.040–0.60 mm), eluting with petroleum
ether (PE; b.p. 40–608)/AcOEt mixtures. Gas chromatography (GC): HP 6890 apparatus, with an Agilent
HP-5 column (30 m) and H2 as carrier gas. IR Spectra: in cmꢀ1. NMR Spectra: Bruker ARX-300 and
ARX-500; d in ppm, J in Hz. 13C-NMR Multiplicities were determined by DEPTexperiments. Mass Spec-
tra (MS): in m/z (rel. %).
(7aS)-Tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-1,3-dione (7) [15]. To a suspension of N-Boc-L-pro-
line (6; 10.9 g, 0.05 mol) in anh. CH2Cl2 (50 ml) was added dropwise PCl3 (8.20 g, 5.21 ml, 0.06 mol) at 08,
and the resulting mixture was stirred for 3 h at this temp. The solvent was removed under vacuum, and
the residue was washed with hexane (5”20 ml) and dried under high vacuum in a desiccator over P2O5 to
afford 7 (7.06 g) quantitatively. The product was used without further purification. Colorless solid. M.p.
50–528. 1H-NMR (300 MHz, (D6)DMSO): 1.90–2.34 (m, CH2(4), CH2(5)); 3.28–3.36 (m, HaꢀC(6));
3.72–3.81 (m, HbꢀC(6)); 4.33 (t, J=8.4, HꢀC(3)). 13C-NMR (75 MHz, DMSO): 23.1 (C(5)); 27.9
(C(4)); 45.1 (C(6)); 58.6 (C(3a)); 154.9 (C (1)); 170.4 (C(3)).
(8aS)-Hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (8) [7]. At ꢀ788, compound 7 (7.28 g, 0.051 mol)
was slowly added over 1–1.5 h to a cooled soln. of glycine methyl ester hydrochloride (8.8 g, 0.070 mol)
and Et
A
Cl2
A
filtered over Celite, and the filtrate was washed with CH2Cl2 (50 ml). The solvent was evaporated, and the
remaining yellowish oil was dissolved in H2O and heated at reflux for 24 h. The solvent was distilled off,
and the precipitate was purified by recrystallization from i-PrOH to afford 8 (6.8 g) in 87% yield. Color-
less crystals. M.p. 216–2178. [a]2D0 =ꢀ171 (c=2.0, CHCl3). IR (neat): 3161m, 2876m, 1674s, 1639vs, 1453s,
1293s, 1110m, 1103m, 778vs. 1H-NMR (500 MHz, CDCl3): 1.76–1.92 (m, HbꢀC(7)); 1.92–2.07 (m, Haꢀ
C(7), HbꢀC(8)); 2.26–2.36 (m, HaꢀC(8)); 3.45–3.62 (m, CH2(6)); 3.88 (dd, J=4.4, 16.4, HbꢀC(3)); 4.08
(d, J=15.6, HꢀC(8a), HaꢀC(3)); 6.89 (br. s, NH). 13C-NMR (125 MHz, CDCl3): 22.8 (C(7)); 28.8 (C(8));
45.7 (C(6)); 47.0 (C(3)); 58.9 (C(8a)); 163.9 (C(4)); 170.4 (C(1)). Anal. calc. for C7H10N2O2 (154.17): C
54.54, H 6.54, N 18.17; found: C 54.42, H 6.53, N 18.09.
(8aS)-6,7,8,8a-Tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5). A ground mixture of 8
(1.35 g, 8.75 mmol) and trimethyloxonium tetrafluoroborate (1.55g, 0.0105 mol) was suspended in anh.
CH2Cl2 (50 ml) and refluxed for 12 h. Then, further Me3
O+BFꢀ4 was added (0.809 g, 5.46 mmol), and
E
the suspension was stirred for a further 12 h. Under vigorous stirring, the mixture was slowly poured
into an ice-cold sat. NaHCO3 soln. (pH>8), the layers were separated, and the aq. layer was extracted
with CH2Cl2 (3”20 ml). The combined org. layers were dried (Na2SO4) and evaporated to afford 5 (1.13
g) in 77% yield. Colorless oil. [a]2D0 =ꢀ138 (c=1.0, CH2Cl2). IR (neat): 3455w, 2947m, 2847m, 1640vs,
1436s, 1315s, 1255s, 1019s, 748m. 1H-NMR (500 MHz, CDCl3): 1.76–1.93 (m, HaꢀC(8), HaꢀC(7));
2.02–2.08 (m, HbꢀC(7)); 2.30–2.34 (m, HbꢀC(8)); 3.40–3.50 (m, Haꢀ(6)); 3.65–3.70 (m, HbꢀC(6));
3.74 (s, MeO); 4.02–4.06 (m, HꢀC(8a)); 4.08 (dd, J=4.4, 19.5, HaꢀC(3)); 4.20 (d, J=17.9, HbꢀC(3)).
13C-NMR (125 MHz, CDCl3): 22.3 (C(7)); 29.4 (C(8)); 44.3 (C(3)); 52.7 (C(6)); 53.3 (MeO); 56.6
(C(8a)); 161.9 (C(4)); 166.4 (C(1)). HR-MS: 168.0902 (M+, C8
A
G
N
General Procedure (GP 1) for the Alkylation of the Lactim Ether 5. A soln. of 5 (100 mg, 0.594 mmol)
in THF (2 ml) was added dropwise to a cooled soln. of the respective base (0.630 mmol) in THF (3 ml) at
ꢀ788. LDA or LHMDS in THF were freshly prepared from BuLi and (i-Pr)
C
gradient from 80–1808 at 88 minꢀ1, then 180–2208 at 18 minꢀ1, then 220–3008 at 168 minꢀ1
(3S,8aS)-6,7,8,8a-Tetrahydro-1-methoxy-3-methylpyrrolo[1,2-a]pyrazin-4(3H)-one (cis-9a). Pre-
pared according to GP 1 with LDA, purified by FC (AcOEt/PE 3 :2). Yield: 102 mg (94%). Pale-yellow
oil. TLC (AcOEt/PE 4 :1): Rf 0.58. [a]2D5 =ꢀ48.7 (c=1.0, CH2Cl2). GC (PS086; gradient: 3 min at 1008,
100–1758 at 2.58 minꢀ1, 175–3008 at 208 minꢀ1): tR1.29 min (cis-9a), 1.85 min (trans-9a). IR (neat): 3246m,
1
2978m, 2948m, 2883w, 2198w, 1969w, 1637vs, 1436s. H-NMR (500 MHz, CDCl3): 1.38 (d, J=7.3, Me);

Helvetica Chimica Acta – Vol. 89 (2006)
1903
1.70–1.94 (m, HaꢀC(7), HaꢀC(8)); 2.00–2.08 (m, HbꢀC(7)); 2.26–2.34 (m, HbꢀC(8)); 3.40–4.48 (m,
HaꢀC(6)); 3.63–3.70 (m, HbꢀC(6)); 3.74 (s, MeO); 3.99–4.05 (m, HꢀC(8a)); 4.22 (dd, J=1.5, 7.2,
HꢀC(3)). 13C-NMR (125 MHz, CDCl3): 20.2 (Me); 22.5 (C(7)), 29.9 (C(8)); 44.8 (C(6)); 53.6 (MeO);
56.4 (C(8a)); 58.5 (C(3)); 161.1 (C(4)); 170.1 (C(1)). CI-MS (CH4): 183 (100, [M+H]+), 167 (2), 155
(11). HR-MS: 182.0155 (M+, C9
A
G
N
AHCTREUNG
low oil. GC: tR 11.67 min. [a]2D5 =ꢀ54 (c=1.0, CH2Cl2). IR (neat): 2996m, 1683vs, 1655vs, 1438s, 1321m,
1253s, 1130w, 1033w, 1004w, 808w. 1H-NMR (500 MHz, CDCl3): 0.96 (t, J=7.4, Me); 1.68–1.87 (m, Haꢀ
C(8), HaꢀC(7), CH2(1’)); 1.98–2.04 (m, HbꢀC(7)); 2.28 (quint., J=5.9, HbꢀC(8)); 3.34–3.45 (m, Haꢀ
C(6)); 3.65–3.71 (m, HbꢀC(6)); 3.73 (s, MeO); 3.98 (ddd, J=6.1, 7.3, 11.2, HꢀC(8a)); 4.12 (dt, J=5.9,
5.4, HꢀC(3)). 13C-NMR (125 MHz, CDCl3): 9.6 (C(2’)); 22.1 (C(1’)); 27.8 (C(7)); 29.7 (C(8)); 44.5
(C(6)); 53.3 (MeO); 56.5 (C(3)); 63.5 (C(8a)); 161.0 (C(4)); 169.4 (C(1)). EI-MS: 196 (6, M+), 181
(16, [MꢀMe]+), 168 (100, [MꢀEt]+), 153 (40), 139 (26), 126 (42), 112 (62), 96 (12), 83 (14), 70 (38),
60 (20). HR-MS: 196.1195 (M+, C10
A
G
N
3-Butyl-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (9c). Prepared according to
GP 1 with LDA. Purified by FC (AcOEt), which gave, in a first fraction (Rf 0.49), 22 mg (16.5%) of
cis-9c, and, in a second fraction (Rf 0.31), 23 mg (17%) of trans-9c.
Data of (3R,8aS)-Isomer (trans-9c). Pale-yellow oil. GC: tR 14.54 min. [a]2D0 =ꢀ61.3 (c=1.0,
1
CH2Cl2). IR (neat): 3232w, 2953m, 2871w, 1675vs, 1651vs, 1436s, 1323w, 1253w, 1013w, 742w. H-NMR
(300 MHz, CDCl3): 0.90 (t, J=6.6, Me(4’)); 1.26–1.45 (m, CH2(2’), CH2(3’)); 1.61–1.91 (m, CH2(7),
HaꢀC(8)); 1.98–2.07 (m, CH2(1’)); 2.25–2.33 (m, HbꢀC(8)); 3.39–3.47 (m, HaꢀC(6)); 3.64–3.71 (m,
HbꢀC(6)); 3.74 (s, MeO); 3.97–4.03 (m, HaꢀC(8)); 4.13–4.18 (m, HꢀC(3)). 13C-NMR (75 MHz,
CDCl3): 14.0 (C(4’)); 22.1 (C(3’)); 22.6 (C(7)); 27.7 (C(2’)); 29.7 (C(8)); 34.4 (C(1’)); 44.6 (C(6)); 53.3
(MeO); 56.4 (C(8a)); 62.5 (C(3)); 160.9 (C(4)); 169.6 (C(1)). HR-MS: 224.1525 (M+, C12
A
G
N
calc. 224.1525).
Data of (3S,8aS)-Isomer (cis-9c). Colorless solid. M.p. 46–488. GC: tR 14.48 min. [a]2D5 =ꢀ62.6
1
(c=1.0, CH2Cl2). IR (neat): 2951m, 2859w, 1653vs, 1431s, 1313m, 1255w, 1037m, 763w. H-NMR (300
MHz, CDCl3): 0.91 (t, J=6.7, Me); 1.30–1.44 (m, CH2(2’), CH2(3’)); 1.72–1.94 (m, CH2(7), HaꢀC(8));
1.94–2.10 (m, CH2(1’)); 2.20–2.34 (m, HbꢀC(8)); 3.39–3.49 (m, HaꢀC(6)); 3.57–3.69 (m, HbꢀC(6));
3.72 (s, MeO); 3.84–3.90 (m, HaꢀC(8)); 3.98–4.05 (m, HꢀC(3)). 13C-NMR (75 MHz, CDCl3): 14.0
(C(4’)); 20.0 (C(3’)); 22.6 (C(7)); 27.5 (C(2’)); 29.1 (C(8)); 31.8 (C(1’)); 44.1 (C(6)); 53.3 (MeO); 55.4
(C(8a)); 59.1 (C(3)); 165.8 (C(4)); 172.9 (C(1)). HR-MS: 224.1525 (M+, C12
A
G
N
6,7,8,8a-Tetrahydro-1-methoxy-3-(2-methylpropyl)pyrrolo[1,2-a]pyrazin-4(3H)-one (9d). Prepared
according to GP 1 with LDA. Purified by FC (AcOEt), which gave, in a first fraction, 29 mg (22%) of
cis-9d, and, in a second fraction, 35 mg (26%) of trans-9d.
Data of (3S,8aS)-Isomer (cis-9d). Pale-yellow oil. TLC (AcOEt/PE 1:1): Rf 0.35. GC: tR 13.71 min.
[a]2D5 =ꢀ59.7 (c=1.0, CH2Cl2). IR (neat): 2952s, 2869m, 1660vs, 1434s, 1333m, 1259s, 1038m, 798m. H-
1
NMR (300 MHz, CDCl3): 0.86 (d, J=6.4, Me); 0.90 (d, J=6.5, Me); 1.46–1.55 (m, HꢀC(2’));
1.72–1.80 (m, H2C(1’)); 1.83–1.88 (m, HaꢀC(7)); 1.91–2.02 (m, HbꢀC(7), HaꢀC(8)); 2.15–2.22 (m,
HbꢀC(8)); 3.33–3.40 (m, HaꢀC(6)); 3.47–3.57 (m, HbꢀC(6)); 3.65 (s, MeO); 3.80 (dt, J=4.1, 9.9, Hꢀ
C(8a)); 3.92–3.99 (m, HꢀC(3)). 13C-NMR (75 MHz, CDCl3): 20.6 (C(3’)); 21.7 (C(4’)); 22.5 (C(7));
23.8 (C(2’)); 28.0 (C(8)); 39.9 (C(1’)); 43.4 (C(6)); 52.2 (MeO); 55.8 (C(8a)); 57.1 (C(3)); 160.2
(C(4)); 168.5 (C(1)). HR-MS: 224.1525 (M+, C12
A
G
N
Data of (3R,8aS)-Isomer (trans-9d). Yellow oil. TLC (AcOEt/PE 1:1): Rf 0.23. GC: tR 13.88 min.
[a]2D5 =ꢀ56.5 (c=1.0, CH2Cl2). IR (neat): 2951m, 1679vs, 1654vs, 1435s, 1316m, 1252s, 1004m, 730w.
1H-NMR (500 MHz, CDCl3): 0.97 (d, J=3.4, Me); 0.98 (d, J=3.4, Me); 1.40–1.46 (m, HꢀC(2’));
1.54–1.59 (m, HaꢀC(1’)); 1.71–1.80 (m, HbꢀC(1’)); 1.81–1.91 (m, CH2(7)); 1.99–2.05 (m, HaꢀC(8));
2.27–2.32 (m, HbꢀC(8)); 3.04–3.45 (m, HaꢀC(6)); 3.63–3.69 (m, HbꢀC(6)); 3.73 (s, MeO); 4.00 (dd,
J=5.8, 9.7, HꢀC(8a)); 4.17–4.20 (m, HꢀC(3)). 13C-NMR (125 MHz, CDCl3): 22.1 (C(3’), C(4’)); 23.0
(C(7)); 24.7 (C(2’)); 29.5 (C(8)); 43.3 (C(1’)); 44.5 (C(6)); 53.2 (MeO); 56.1 (C(8a)); 60.8 (C(3));
160.9 (C(4)); 169.9 (C(1)). HR-MS: 224.1524 (M+, C12
A
G
N

1904
Helvetica Chimica Acta – Vol. 89 (2006)
6,7,8,8a-Tetrahydro-1-methoxy-3-(1-methylethyl)pyrrolo[1,2-a]pyrazin-4(3H)-one (9e). Prepared
according to GP 1 with LDA. Purified by FC (AcOEt), which gave, in a first fraction, 54 mg (43%) of
cis-9e, and, in a second fraction, 30 mg (24%) of trans-9e.
Data of (3S,8aS)-Isomer (cis-9e). Yellow oil. TLC (AcOEt/PE 2 :1): Rf 0.47. GC: tR 13.70 min.
[a]2D5 =ꢀ61.6 (c=1.0, CH2Cl2). IR (neat): 3233w, 2958m, 2872w, 1635vs, 1435s, 1328w, 1239w, 997w,
1
772w. H-NMR (500 MHz, CDCl3): 0.73 (d, J=6.6, Me); 1.12 (d, J=6.8, Me); 1.82–1.96 (m, HaꢀC(7),
HaꢀC(8)); 1.99–2.07 (m, HbꢀC(7)); 2.25–2.31 (m, HbꢀC(8)); 2.60 (ddd, J=13.5, 6.7, 2.8, HꢀC(1’));
3.39–3.44 (m, HaꢀC(6)); 3.62–3.68 (m, HbꢀC(6)); 3.74 (s, MeO); 3.79–3.81 (m, HꢀC(8a)); 3.95–4.01
(m, HꢀC(3)). 13C-NMR (125 MHz, CDCl3): 17.6 (C(3’)); 19.4 (C(2’)); 22.5 (C(7)); 29.4 (C(8)); 33.6
(C(1’)); 44.0 (C(6)); 53.0 (MeO); 56.6 (C(8a)); 64.5 (C(3)); 160.6 (C(4)); 168.5 (C(1)). EI-MS: 210
(10, M+), 168 (100, [MꢀC3H7]+), 140 (20), 112 (25), 70 (30). HR-MS: 210.1368 (M+, C11
A
G
G
calc. 210.1368).
Data of (3R,8aS)-Isomer (trans-9e). Yellow oil. TLC (AcOEt/PE 2 :1): Rf 0.35. GC: tR 13.86 min.
[a]2D5 =ꢀ22.6 (c=0.5, CH2Cl2). IR (neat): 3232w, 2961m, 2873w, 1646vs, 1440s, 1327w, 1251w, 1021w,
1
780w. H-NMR (500 MHz, CDCl3): 0.89 (d, J=6.8, Me); 1.00 (d, J=6.7, Me); 1.80–1.96 (m, CH2(7));
2.00–2.06 (m, HaꢀC(8)); 2.26–2.31 (m, HbꢀC(8)); 2.38–2.42 (m, HꢀC(1’)); 3.40–3.45 (m, HaꢀC(6));
3.49–3.54 (m, HbꢀC(6)); 3.75 (s, MeO); 3.79 (d, J=3.0, HꢀC(8a)); 4.03 (dd, J=1.8, 4.8, HꢀC(3)).
13C-NMR (125 MHz, CDCl3): 18.2 (C(2’)); 18.9 (C(3’)); 21.5 (C(7)); 28.9 (C(8)); 33.1 (C(1’)); 45.0
(C(6)); 53.2 (MeO); 57.6 (C(8a)); 58.3 (C(3)); 160.7 (C(4)); 169.0 (C(1)). EI-MS: 210 (10, M+), 168
(100, [MꢀC3H7]+), 154 (35), 140 (25), 112 (30), 70 (50). HR-MS: 210.1368 (M+, C11
A
G
G
210.1368).
6,7,8,8a-Tetrahydro-1-methoxy-3-(prop-2-en-1-yl)pyrrolo[1,2-a]pyrazin-4(3H)-one (9f). Prepared
according to GP 1 with LDA. Purified by FC (AcOEt/PE 5 :1), which gave, in a first fraction, 7 mg
(6%) of cis-9f, and, in a second fraction, 33 mg (29%) of trans-9f.
Data of (3S,8aS)-Isomer (cis-9f). Colorless oil. TLC (AcOEt/PE 1:1): Rf 0.56. GC: tR 14.83 min.
[a]2D0 =ꢀ15 (c=0.5, THF). IR (neat): 3231m, 2949m, 1638vs, 1432s, 1305m, 1177w, 996w, 917w. 1H-
NMR (500 MHz, CDCl3): 1.73–1.92 (m, HaꢀC(7), HaꢀC(8)); 1.97–2.06 (m, HbꢀC(7)); 2.23–2.30 (m,
HbꢀC(8)); 2.55–2.65 (m, HaꢀC(1’)); 2.75–2.85 (m, HbꢀC(1’)); 3.38–3.49 (m, HaꢀC(6)); 3.58–3.67
(m, HbꢀC(6)); 3.73 (s, MeO); 3.95–4.04 (m, HꢀC(8a), HꢀC(3)); 5.03–5.18 (m, CH2(3’)); 5.85–5.99
(m, HꢀC(2’)). 13C-NMR (125 MHz, CDCl3): 22.6 (C(7)); 29.2 (C(8)); 36.6 (C(1’)); 44.2 (C(6)); 53.3
(MeO); 56.9 (C(8a)); 60.0 (C(3)); 116.9 (C(3’)); 135.5 (C(2’)); 161.3 (C(4)); 168.2 (C(1)). EI-MS: 208
(100, M+), 193 (46, [MꢀCH3]+), 167 (25, [MꢀC3H7]+), 151 (12), 139 (60), 112 (35), 70 (40). HR-MS:
208.1211 (M+, C11
A
G
N
Data of (3R,8aS)-Isomer (trans-9f). Yellow oil. TLC (AcOEt/PE 1:1): Rf 0.34. GC: tR 15.08 min.
[a]2D5 =ꢀ17.4 (c=1.0, CH2Cl2). IR (neat): 3233m, 2947m, 2886w, 1637vs, 1433s, 1212m, 996m, 915m.
1H-NMR (500 MHz, CDCl3): 1.67–1.92 (m, HaꢀC(7), HaꢀC(8)); 1.97–2.09 (m, HbꢀC(7)); 2.21–2.31
(m, HbꢀC(8)); 2.51–2.65 (m, CH2(1’)); 3.38–3.46 (m, HaꢀC(6)), 3.57–3.69 (m, HbꢀC(6)); 3.74 (s,
MeO); 3.94–4.03 (m, HꢀC(8a)); 4.20–4.27 (m, HꢀC(3)); 5.02–5.18 (m, CH2(3’)); 5.71–5.98 (m, Hꢀ
C(2’)). 13C-NMR (125 MHz, CDCl3): 22.0 (C(7)); 29.0 (C(8)); 36.2 (C(1’)); 43.4 (C(6)); 53.3 (MeO);
57.1 (C(8a)); 61.8 (C(3)); 116.3 (C(3’)); 135.4 (C(2’)); 161.8 (C(4)); 168.5 (C(1)). EI-MS: 208 (100,
M+), 207 (15, [Mꢀ1]+), 193 (12, [MꢀCH3]+), 167 (35, [MꢀC3H7]+), 139 (60), 112 (20). HR-MS:
208.1211 (M+, C11
A
G
N
AHCTREUNG
10 mg (7%) of cis-9g, and, in a second fraction, a colorless solid, which turned out to be the diketopiper-
azine derivative of the second diastereoisomer (for anal. data, see the diketopiperazine section).
Data of (3S,8aS)-Isomer (cis-9g). Yellow oil. TLC (Et2O/MeOH 8 :1): Rf 0.44. GC: tR 15.82 min.
C
1
[a]2D5 =ꢀ19 (c=1.0, CH2Cl2). IR (neat): 3246m, 2970m, 1664vs, 1444s, 1305w, 1180w, 1117w, 801w. H-
NMR (300 MHz, CDCl3): 1.57 (s, Me); 1.66 (s, Me); 1.68–1.72 (m, HaꢀC(8)); 1.76–1.86 (m, Haꢀ
C(7)); 1.94–2.02 (m, HbꢀC(7)); 2.24 (q, J=6.0, HbꢀC(8)); 2.49 (t, J=6.8, CH2(1’)); 3.37–3.41 (m,
HaꢀC(6)); 3.63–3.68 (m, HbꢀC(6)); 3.71 (s, MeO); 3.88 (dd, J=5.9, 11.3, HaꢀC(8)); 4.03 (dt, J=1.5,
5.5, HꢀC(3)); 5.08–5.11 (m, HꢀC(2’)). 13C-NMR (125 MHz, CDCl3): 17.9 (C(3’)); 22.0 (C(7)); 26.0

Helvetica Chimica Acta – Vol. 89 (2006)
1905
(C(4’)); 29.7 (C(8)); 32.8 (C(1’)); 44.4 (C(6)); 53.3 (MeO); 56.7 (C(8a)); 62.5 (C(3)); 118.6 (C(2’)); 135.7
(C(3’)); 161.3 (C(4)); 169.2 (C(1)). EI-MS: 236 (22, M+), 168 (28, [MꢀC5H9]+), 70 (35). HR-MS:
236.1525 (M+, C13
A
G
N
(3R,8aS)-6,7,8,8a-Tetrahydro-1-methoxy-3-(phenylmethyl)pyrrolo[1,2-a]pyrazin-4(3H)-one (trans-
9h). Prepared according to GP 1 with LDA, and purified by FC (AcOEt/PE 1:20; Rf 0.3), which gave
109 mg (71%) of the title compound. Yellow oil. [a]2D0 =ꢀ31.1 (c=1.0, CH2Cl2). GC: 24.97 min (trans-
9h)2). IR (neat): 3438w, 3027w, 2945m, 1679s, 1639s, 1437m, 1318m, 1253m, 1027m, 700s. 1H-NMR
(500 MHz, CDCl3): 1.68–1.82 (m, HaꢀC(7), HaꢀC(8)); 1.86–2.02 (m, HbꢀC(7)); 2.18–2.36 (m, Hbꢀ
C(8)); 2.97 (dd, J=4.6, 13.3, CH2(1’)); 3.10–3.22 (m, HaꢀC(6)); 3.47–3.57 (m, HbꢀC(6)); 3.67 (s,
MeO); 3.90–3.97 (m, HꢀC(8a)); 4.05 (dd, J=1.6, 17.5, HꢀC(3)); 7.01–7.04 (m, 2 arom. H);
7.13–7.15 (m, 3 arom. H). 13C-NMR (125 MHz, CDCl3): 21.4 (C(7)); 29.0 (C(8)); 39.6 (C(1’)); 43.6
(C(6)); 53.1 (MeO); 55.6 (C(8a)); 62.8 (C(3)); 126.1, 126.6, 127.7, 128.0, 130.1, 136.4 (arom. C); 160.9
(C(4)); 167.0 (C(1)). EI-MS: 258 (30, M+), 167 (35, [MꢀC6H5CH2]+), 139 (20), 57 (100), 43 (70), 29
(30), 18 (50). HR-MS: 258.1369 (M+, C15
A
G
N
(3S,8aS)-3-[(3-Chlorophenyl)methyl]-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-
one (cis-9i). Prepared according to GP 1 with LDA. Purified by FC (AcOEt), which gave, in a first frac-
tion (Rf 0.31), 10.5 mg (6%) of cis-9i, and, in a second fraction (Rf 0.09), a colorless solid, which proved to
be the diketopiperazine derivative of the second diastereoisomer (for anal. data, see the diketopiperazine
section).
1
Data of cis-9i. Yellow oil. TLC (AcOEt): Rf 0.31. GC: tR 27.17 min. H-NMR (300 MHz, CDCl3):
1.21–1.32 (m, HaꢀC(8)); 1.74–1.81 (m, HaꢀC(7)); 1.86–1.93 (m, HbꢀC(7)); 2.08–2.14 (m, HbꢀC(8));
3.17 (dd, J=6.9, 13.4, HaꢀC(1’)); 3.30 (dd, J=4.3, 13.4, HbꢀC(1’)); 3.33–3.38 (m, HaꢀC(6));
3.58–3.64 (dt, J=8.6, 17.1, HbꢀC(6)); 3.72 (s, MeO); 3.87–3.91 (m, HꢀC(8a)); 4.19–4.22 (quint.,
J=4.0, HꢀC(3)); 7.15–7.17 (m, 3 arom. H); 7.31 (s, arom. H). 13C-NMR (75 MHz, CDCl3): 22.4
(C(8)); 29.0 (C(7)); 38.2 (C(1’)); 44.2 (C(6)); 53.3 (MeO); 56.9 (C(3)); 60.9 (C(8a)); 126.2, 128.5,
128.9, 130.4, 133.4, 140.9 (arom. C); 160.9 (C(4)); 167.7 (C(1)). EI-MS: 294 (32), 292 (98, M+), 167
(100), 139 (60), 112 (28), 70 (30), 43 (28), 28 (12). HR-MS: 292.0979 (M+, C15
A
G
N
6,7,8,8a-Tetrahydro-1-methoxy-3-[(3-methoxyphenyl)methyl]pyrrolo[1,2-a]pyrazin-4(3H)-one (9j).
Prepared with LDA, and purified by FC (AcOEt) to afford, in a first fraction (Rf 0.44), 13.4 mg (8%)
of cis-9j, and, in a second fraction (Rf 0.32), 99 mg (58%) of trans-9j.
Data of (3S,8aS)-Isomer (cis-9j). Pale yellow oil. GC: tR 29.17 min. [a]2D5 =ꢀ58.4 (c=1.0, CH2Cl2). IR
(neat): 3229m, 2947m, 1655vs, 1600m, 1488m, 1434vs, 1294w, 1259vs, 1153s, 1109w, 1040s, 870m, 776vs,
730vs, 697vs. 1H-NMR (300 MHz, CDCl3): 1.13–1.27 (m, HaꢀC(7)); 1.66–1.90 (m, HbꢀC(7), Haꢀ
C(8)); 2.02–2.11 (m, HbꢀC(8)); 3.17 (dd, J=7.0, 13.4, HaꢀC(6)); 3.28–3.36 (m, CH2(1’)); 3.58–3.69
(m, HbꢀC(6)); 3.72 (s, MeO); 3.77 (s, MeO); 3.82–3.89 (m, HꢀC(8a)); 4.20–4.25 (m, HꢀC(3));
6.70–6.74 (m, 1 arom. H); 6.84–6.87 (m, 2 arom. H); 7.11–7.17 (m, 1 arom. H). 13C-NMR (75 MHz,
CDCl3): 22.3 (C(8)), 28.9 (C(7)); 38.7 (C(1’)); 44.1 (C(6)); 53.1 (MeO); 55.1 (MeO); 56.8 (C(3)); 61.2
(C(8a)); 111.9, 115.5, 122.6, 128.6, 140.4, 159.1 (arom. C); 160.5 (C(4)); 167.9 (C(1)). CI-MS: 329 (1,
[M+C3H5]+), 317 (10, [M+C2H5]+), 289 (100, [M+H]+), 167 (15, [MꢀMeOC6H4CH2]+), 139 (15).
HR-MS: 288.1458 (M+, C16
A
G
N
Data of (3R,8aS)-Isomer (trans-9j). GC: tR 32.20 min. [a]2D0 =ꢀ21.9 (c=1.0, CH2Cl2). IR (neat):
1
2949m, 1650vs, 1600m, 1487w, 1436vs, 1320w, 1256vs, 1152s, 1039s, 868w, 776m, 729vs, 697vs. H-NMR
(300 MHz, CDCl3): 1.44–1.67 (m, CH2(7)); 1.83–1.92 (m, HaꢀC(8)); 1.98 (dd, J=5.1, 11.4, HbꢀC(8));
3.03 (dd, J=4.6, 13.2, HaꢀC(6)); 3.19–3.26 (m, CH2(1’)); 3.57–3.67 (m, HbꢀC(6)); 3.74 (s, MeO);
3.78 (s, MeO, HꢀC(8a)); 4.50 (dt, J=1.9, 4.7, HꢀC(3)); 6.65–6.71 (m, 2 arom. H); 6.76 (ddd, J=0.8,
2.6, 8.2, 1 arom. H); 7.12 (t, J=7.8, 1 arom. H). 13C-NMR (75 MHz, CDCl3): 21.6 (C(8)); 29.3 (C(7));
40.0 (C(1’)); 43.8 (C(6)); 53.3 (MeO); 55.2 (MeO); 55.9 (C(3)); 62.9 (C(8a)); 112.9, 115.1, 122.6, 128.9,
138.1, 159.3 (arom. C); 162.0 (C(4)); 167.9 (C(1)). EI-MS: 288 (68, M+), 167 (100, [MꢀMeOC6H4CH2]),
139 (18), 83 (12). HR-MS: 288.1458 (M+, C16
A
G
N
2
)
GC Retention time for cis-9h: tR 23.94 min.

1906
Helvetica Chimica Acta – Vol. 89 (2006)
General Procedure (GP 2) for the Hydrolysis of cis- and trans-9. A soln. of cis-or trans-9 (1 mmol) in
CH2Cl2 (10 ml) was treated with 4-methylbenzenesulfonic acid (TsOH·H2O; 190 mg, 1 mmol), and the
mixture was stirred at r.t. for 20 h. Then, a sat. aq. NaHCO3 soln. (20 ml) was added, and the mixture was
extracted with CH2Cl2 (5”100 ml). The combined org. layers were dried (MgSO4) and evaporated, and
the residue was purified by FC (SiO2; AcOEt) to afford the cis-or trans-diketopiperazines 10.
(3S,8aS)-Hexahydro-3-methylpyrrolo[1,2-a]pyrazine-1,4-dione (cis-10a) [19]. Prepared according to
GP 2. Yield: 136 mg (81%). Yellow oil. TLC (Et
2O/MeOH 4 :1): Rf 0.31. [a]2D5 =ꢀ84 (c=0.5, EtOH). IR
HR-MS: 168.0899 (M+, C8
A
G
A
2O/MeOH 8 :1): Rf 0.63. [a]2D5 =ꢀ58 (c=1.0,
CH2Cl2). IR (neat): 3228m, 2956m, 2870m, 1686vs, 1420s, 1297w, 1154w, 997w, 675w. 1H-NMR (500
MHz, CDCl3): 0.93 (t, J=7.0, Me(4’)); 1.33–1.48 (m, CH2(2’), CH2(3’)); 1.72–1.81 (m, HaꢀC(1’));
1.87–1.96 (m, HbꢀC(1’)); 1.99–2.13 (m, CH2(7), HaꢀC(8)); 2.32–2.37 (m, HbꢀC(8)); 3.51–3.56 (m,
HaꢀC(6)); 3.59–3.64 (m, HbꢀC(6)); 4.01–4.03 (m, HꢀC(8a)); 4.10 (t, J=7.5, HꢀC(3)); 7.25 (br. s,
NH). 13C-NMR (125 MHz, CDCl3): 13.9 (C(4’)); 22.5(C(3’)); 22.6 (C(7)); 27.3 (C(2’)); 28.2 (C(8));
29.6 (C(1’)); 45.3(C(6)); 55.4 (C(8a)); 59.0 (C(3)); 165.9 (C(1)); 170.7 (C(4)). HR-MS: 210.1368 (M+,
C
A
G
N
2O/MeOH 8 :1): Rf 0.59. [a]2D5 =ꢀ58 (c=1.0, CH2Cl2).
IR (neat): 3228m, 2956m, 2870m, 1686vs, 1420s, 1297w, 1154w, 997w, 675w. 1H-NMR (300 MHz,
CDCl3): 0.89 (t, J=7.0, Me(4’)); 1.27–1.47 (m, CH2(2’), CH2(3’)); 1.65–2.06 (m, CH2(1’), CH2(7), Haꢀ
C(8)); 2.34–2.44 (m, HbꢀC(8)); 3.47–3.54 (m, HaꢀC(6)); 3.60–3.69 (m, HbꢀC(6)); 3.88 (quint.,
J=4.8, HꢀC(3)); 4.06 (dd, J=6.4, 9.1, HꢀC(8a)); 7.13 (br. s, NH). 13C-NMR (75 MHz, CDCl3): 13.8
(C(4’)); 22.1 (C(3’)); 22.2 (C(7)); 27.4 (C(2’)); 29.0 (C(8)); 34.0 (C(1’)); 45.5 (C(6)); 58.0 (C(8a)); 58.1
(C(3)); 166.1 (C(1)); 169.5 (C(4)). HR-MS: 210.1368 (M+, C11
A
N2
A
cis-Hexahydro-3-(2-methylpropyl)pyrrolo[1,2-a]pyrazine-1,4-dione (cis-10d). Prepared according to
GP 2. Yield: 210 mg (quant.). Colorless crystals. M.p. 1658. TLC (Et2O/MeOH 8 :1): Rf 0.67.
U
[a]2D5 =ꢀ137.5 (c=0.4, CH2Cl2). IR (neat): 3221m, 2956m, 2871m, 1659vs, 1125s, 1302w, 1157w, 919w,
1
730w. H-NMR (500 MHz, CDCl3): 0.95 (d, J=6.5, Me); 1.00 (d, J=6.5, Me); 1.53 (ddd, J=5.0, 9.4,
14.4, HaꢀC(1’)); 1.71–1.82 (m, HꢀC(2’)); 1.87–1.95 (m, HaꢀC(7)); 1.99–2.08 (m, HbꢀC(7), Hbꢀ
C(1’)); 2.10–2.16 (m, HaꢀC(8)); 2.33–2.36 (m, HbꢀC(8)); 3.51–3.62 (m, CH2(6)); 4.01 (dd, J=3.4,
9.3, HꢀC(8a)); 4.12 (t, J=8.3, HꢀC(3)); 6.45 (br. s, NH). 13C-NMR (125 MHz, CDCl3): 21.3 (C(3’));
22.8 (C(7)); 23.3 (C(4’)); 24.6 (C(2’)); 28.1 (C(8)); 38.6 (C(1’)); 45.5 (C(6)); 53.4 (C(8a)); 59.0 (C(3));
166.3 (C(1)); 170.4 (C(4)). Anal. calc. for C11H18N2O2 (210.27): C 62.83, H 8.63, N 13.32; found: C
62.71, H 8.58, N 13.29. X-Ray data: C11H18N2O2, Mr 210.3, orthorhombic, space group P212121;
a=6.3429(4), b=9.466(3), c=19.5950(16) Š; a=b=g=908; V=1176.5(4) Š3, Z=4; Dc =1.187 g
cmꢀ3; crystal size 0.50”0.25”0.05 mm; 1592 reflections for q=4.51–67.888, 1434 unique reflections;
1434 reflection data (I>2s(I)), 141 parameters; R=0.0758, Rw=0.2069; residual electron density
ꢀ3
between 0.256 and ꢀ0.269 e Š
.
trans-Hexahydro-3-(2-methylpropyl)pyrrolo[1,2-a]pyrazine-1,4-dione (trans-10d). Prepared accord-
ing to GP 2. Yield: 210 mg (quant.). Colorless crystals. M.p. 150–1528. TLC (Et2O/MeOH 8 :1): Rf
AHCTREUNG
0.65. [a]2D5 =ꢀ93 (c=0.4, CH2Cl2). IR (neat): 3230m, 2955m, 2360m, 1649vs, 1433s, 1300m, 1144w,
918w, 729m. 1H-NMR (300 MHz, CDCl3): 0.95 (d, J=6.5, Me); 1.00 (d, J=6.5, Me); 1.62–1.68 (m,
HaꢀC(1’)); 1.70–1.96 (m, HꢀC(2’), CH2(7)); 1.97–2.07 (m, HbꢀC(1’), HaꢀC(8)); 2.36–2.43 (m, Hbꢀ
C(8)); 3.48–3.56 (m, HaꢀC(6)); 3.60–3.70 (m, HbꢀC(6)); 3.89–3.96 (m, HꢀC(3)); 4.06–4.11 (m, Hꢀ
C(8a)); 6.50 (br. s, NH). 13C-NMR (75 MHz, CDCl3): 21.4 (C(4’)); 22.2 (C(7)); 23.0 (C(3’)); 24.5
(C(2’)); 29.0 (C(8)); 42.6 (C(1’)); 45.6 (C(6)); 56.4 (C(8a)); 58.0 (C(3)); 166.3 (C(1)); 169.4 (C(4)).
Anal. calc. for C11H18N2O2 (210.27): C 62.83, H 8.63, N 13.32; found: C 62.62, H 8.54, N 13.18. X-Ray
data: C11H18N2O2, Mr 210.3, orthorhombic, space group P212121; a=6.303(2), b=8.0267(14),

Helvetica Chimica Acta – Vol. 89 (2006)
1907
c=23.146(4) Š; a=b=g=908; V=1171.0(5) Š3, Z=4; Dc =1.193 g cmꢀ3; crystal size 0.65”0.2”0.05
mm, 1103 reflections in the range q=3.82–62.508, 1103 unique reflections; 1103 reflection data
(I>2s(I)), 141 parameters; R=0.0775, Rw=0.2084; residual electron density between 0.217 and
ꢀ3
ꢀ0.218 e Š
.
cis-Hexahydro-3-(1-methylethyl)pyrrolo[1,2-a]pyrazine-1,4-dione (cis-10e) [20]. Prepared according
to GP 2. Yield: 195 mg (quant.). Colorless solid. M.p. 185–1878. TLC (CH2Cl2/MeOH 90 :9): Rf 0.6.
[a]2D5 =ꢀ146.6 (c=0.45, CH2Cl2). IR (neat): 3393s, 2255w, 2128w, 1657m, 1050s, 1023vs, 1003vs, 823m,
761m. 1H-NMR (500 MHz, (D6)DMSO): 0.85 (d, J=6.9, Me); 1.01 (d, J=7.2, Me); 1.75–1.89 (m,
CH2(7), HaꢀC(8)); 2.10–2.15 (m, HbꢀC(8)); 2.34 (dqq, J=7.2, 6.9, 2.5, HꢀC(1’)); 3.31–3.43 (m,
CH2(6)); 3.90–3.92 (br. s, HꢀC(3)); 4.10–4.13 (m, HꢀC(8a)); 7.97 (br. s, NH). 13C-NMR (125 MHz,
(D6)DMSO): 16.1 (C(2’)); 19.3 (C(3’)); 22.4 (C(7)); 28.4 (C(8)); 28.5 (C(1’)); 45.2 (C(6)); 58.8
(C(8a)); 60.4 (C(3)); 164.9 (C(1)); 170.1 (C(4)). HR-MS: 194.1212 (M+, C10
A
G
N
trans-Hexahydro-3-(1-methylethyl)pyrrolo[1,2-a]pyrazine-1,4-dione (trans-10e). Prepared according
to GP 2. Yield: 184 mg (94%). Colorless solid. M.p. 1508. TLC (CH2Cl2/MeOH 90 :9): Rf 0.56.
[a]2D5 =ꢀ20 (c=0.45, CH2Cl2). IR (neat): 3216m, 2962m, 1674s, 1648vs, 1447s, 1270m, 777s. 1H-NMR
(500 MHz, CDCl3): 0.88 (d, J=6.7, Me); 0.90 (d, J=6.8, Me); 1.69–1.80 (m, HaꢀC(7), HaꢀC(8));
1.83–1.88 (m, HbꢀC(7)); 2.00 (dqq, J=6.8, 6.8, 6.7, HꢀC(1’)); 2.12–2.16 (m, HbꢀC(8)); 3.30–3.35
(m, HaꢀC(6)); 3.38 (dd, J=4.2, 6.3, HꢀC(3)); 3.42–3.49 (m, HbꢀC(6)); 4.09 (dd, J=6.7, 9.7, Hꢀ
C(8a)); 8.45 (br. s, NH). 13C-NMR (125 MHz, CDCl3): 18.2 (C(2’)); 19.0 (C(3’)); 21.5 (C(7)); 28.9
(C(8)); 32.4 (C(1’)); 45.1 (C(6)); 57.6 (C(8a)); 62.6 (C(3)); 165.0 (C(1)); 169.0 (C(4)). HR-MS:
194.1212 (M+, C10
cis-Hexahydro-3-(prop-2-enyl)pyrrolo[1,2-a]pyrazine-1,4-dione (cis-10f). Prepared according to GP
2. Yield: 136 mg (70%). Yellow oil. TLC (Et
A
N2
A
2O/MeOH 8 :1): Rf 0.36. [a]2D5 =ꢀ89 (c=0.1, CH2Cl2). IR
(neat): 3202m, 2981w, 2880w, 1664vs, 1420s, 1336m, 1241w, 996w, 916m, 678w. 1H-NMR (300 MHz,
CDCl3): 1.86–1.97 (m, HaꢀC(7)); 1.98–2.17 (m, HbꢀC(7), HaꢀC(8)); 2.31–2.47 (m, HbꢀC(8), Haꢀ
C(1’)); 2.83–2.97 (m, HbꢀC(1’)); 3.51–3.67 (m, CH2(6)); 4.06 (dd, J=3.8, 9.3, HꢀC(3)); 4.13 (t,
J=7.4, HꢀC(8a)); 5.21–5.27 (m, CH2(3’)); 5.73–5.87 (m, HꢀC(2’)); 6.20 (br. s, NH). 13C-NMR (125
MHz, CDCl3): 22.6 (C(7)); 28.1 (C(8)); 34.7 (C(1’)); 45.3 (C(6)); 53.8 (C(3)); 59.1 (C(8a)); 120.0
(C(3’)); 133.0 (C(2’)); 165.0 (C(4)); 169.6 (C(1)). HR-MS: 194.1056 (M+, C10
trans-Hexahydro-3-(prop-2-enyl)pyrrolo[1,2-a]pyrazine-1,4-dione (trans-10f) [21]. Prepared accord-
ing to GP 2. Yield: 116 g (60%). Yellow oil. TLC (Et
A
G
N
U
CH2Cl2). IR (neat): 3220m, 2981w, 2881w, 1663vs, 1416s, 1305m, 1002m, 921m, 708w. 1H-NMR (500
MHz, CDCl3): 1.87–1.97 (m, HaꢀC(7)); 2.01–2.14 (m, HbꢀC(7), HaꢀC(8)); 2.34–2.46 (m, HbꢀC(8),
HaꢀC(1’)); 2.89–2.94 (m, HbꢀC(1’)); 3.53–3.64 (m, CH2(6)); 4.06 (dd, J=3.2, 8.8, HaꢀC(3)); 4.13 (t,
J=7.6, HꢀC(8a)); 5.22–5.26 (m, CH2(3’)); 5.76–5.84 (m, CH(2’)); 6.33 (br. s, NH). 13C-NMR (125
MHz, CDCl3): 22.5 (C(7)); 28.1 (C(8)); 34.6 (C(1’)); 45.3 (C(6)); 53.8 (C(3)); 59.0 (C(8a)); 119.9
(C(3’)); 133.0 (C(2’)); 165.0 (C(4)); 169.7 (C(1)). HR-MS: 194.1056 (M+, C10
(3R,8aS)-Hexahydro-3-(phenylmethyl)pyrrolo[1,2-a]pyrazine-1,4-dione
A
G
ACHTREUNG
according to GP 2. Yield: 203 mg (83%). Colorless oil. [a]2D5 =ꢀ14 (c=1.0, CH2Cl2). IR (neat): 3245m,
2928m, 1661vs, 1453s, 1307w, 1184w, 1107w, 703w. 1H-NMR (500 MHz, CDCl3): 1.64–1.74 (m, Haꢀ
C(7), HaꢀC(8)); 1.76–1.86 (m, HbꢀC(7)); 1.90–1.98 (m, HbꢀC(8)); 2.01–2.09 (m, HaꢀC(1’)); 2.20 (q,
J=5.9, HbꢀC(1’)); 3.00 (q, J=6.4, HꢀC(8a)); 3.10 (dd, J=6.7, 14.6, HꢀC(3)); 3.38–3.43 (m, Haꢀ
C(6)); 3.60–3.68 (m, HbꢀC(6)); 6.04 (br. s, NH); 7.20 (d, J=5.8, 2 arom. H); 7.26 (s, 1 arom. H); 7.30
(t, J=7.5, 2 arom. H). 13C-NMR (125 MHz, CDCl3): 21.7 (C(7)); 29.0 (C(8)); 40.7 (C(1’)); 45.2 (C(6));
57.8 (C(3)); 59.2 (C(8a)); 127.5, 128.9, 134.3 (arom. C); 162.5 (C(1)); 169.0 (C(4)). HR-MS: 244.1211
(M+, C14
trans-Hexahydro-3-(3-methylbut-2-enyl)pyrrolo[1,2-a]pyrazine-1,4-dione (trans-10g). Obtained dur-
O/MeOH 8 :1): Rf 0.28. GC: tR 19.80 min.
A
N2
A
ing FC of the diastereoisomeric mixture 9g on SiO2. TLC (Et2
ACHTREUNG
[a]2D5 =ꢀ2.7 (c=1.0, CH2Cl2). IR (neat): 3235m, 2927m, 1666vs, 1447s, 1304w, 1263w, 731m. H-NMR
(300 MHz, CDCl3): 1.64 (s, Me); 1.73 (s, Me); 1.84–2.09 (m, CH2(7), HaꢀC(8)); 2.37–2.44 (m, Hbꢀ
C(8)); 2.52 (t, J=6.9, CH2(1’)); 3.49–3.56 (m, HaꢀC(6)); 3.64–3.74 (m, HbꢀC(6)); 3.93 (td, J=3.9,
6.1, HꢀC(3)); 4.05 (dd, J=6.6, 9.6, HꢀC(8a)); 5.15 (m, HꢀC(2’)); 6.42 (br. s, NH). 13C-NMR (125
MHz, CDCl3): 17.9 (Me); 22.0 (C(7)); 26.0 (Me); 29.3 (C(8)); 33.0 (C(1’)); 45.5 (C(6)); 58.1 (C(3));
1

1908
Helvetica Chimica Acta – Vol. 89 (2006)
58.4 (C(8a)); 117.5 (C(3’)); 137.6 (C(2’)); 165.7 (C(1)); 169.3 (C(4)). EI-MS: 223 (45, M+), 154 (100,
[MꢀC5H9]+), 125 (16), 70 (100). HR-MS: 222.1352 (M+, C12
C
G
A
Š; a=b=g=908; V=1215.1(2) Š3, Z=4; Dc =1.215 g cmꢀ3; crystal size 0.5”0.3”0.3 mm, 2377 reflec-
tions in the range q=3.68–67.998, 1992 unique reflections; 1992 reflection data (I>2s(I)), 150 parame-
ꢀ3
ters; R=0.0821, Rw=0.1872; residual electron density between 0.267 and ꢀ0.238 e Š
.
3-[(3-Chlorophenyl)methyl]hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (trans-10i). Obtained during
FC of the diastereoisomeric mixture 9g on SiO2. M.p. 135–1378. TLC (AcOEt): Rf 0.09. GC: tR 29.95 min.
[a]2D5 =ꢀ20.6 (c=1.0, CH2Cl2). IR (neat): 3226m, 2954m, 1646vs, 1439vs, 1305s, 1089m, 919m, 727s. H-
1
NMR (500 MHz, CDCl3): 1.69–1.85 (m, HaꢀC(7), HbꢀC(8)); 1.94–2.00 (m, HbꢀC(7)); 2.19–2.24 (m,
HaꢀC(8)); 3.05–3.09 (m, CH2(1’)); 3.12 (dd, J=6.4, 13.6, HꢀC(8a)); 3.41–3.46 (m, HaꢀC(6)); 3.64
(dt, J=8.7, 12.0, HbꢀC(6)); 4.22–4.25 (m, HꢀC(3)); 7.12 (dt, J=1.1, 6.9, 1 arom. H)); 7.25 (d, J=6.7,
2 arom. H); 7.27–7.29 (m, 1 arom. H). 13C-NMR (125 MHz, CDCl3): 21.7 (C(7)); 29.0 (C(8)); 40.1
(C(1’)); 45.2 (C(6)); 57.8 (C(3)); 58.7 (C(8a)); 127.6, 128.1, 129.9, 130.0, 134.5, 137.6 (arom. C); 164.6
(C(4)); 169.4 (C(1)). Anal. calc. for C16H17ClN2O2 (292.10): C 60.33, H 5.42, Cl 12.72, N 10.05; found:
C 60.17, H 5.45, Cl 12.81, N 10.01.
Preparation of cis-10a,d,e,h from 6 and L-Amino Acid Esters 11. These compounds were prepared
according to the procedure described in [16].
Data of cis-10a. M.p. 173–1758. TLC (Et
A
(c=0.5, EtOH). IR (neat): 3228m, 1661vs, 1429m, 1302w, 1202w, 1159w, 1127w, 658w. H-NMR (500
MHz, CDCl3): 1.48 (d, J=6.8, Me); 1.86–1.95 (m, HaꢀC(7)); 1.99–2.06 (m, HbꢀC(7)); 2.07–2.15 (m,
HaꢀC(8)); 2.31–2.37 (m, HbꢀC(8)); 3.52–3.56 (m, HaꢀC(6)); 3.58–3.63 (m, HbꢀC(6)); 4.10–4.15 (m,
HaꢀC(3), HꢀC(8a)); 7.27 (br. s, NH). 13C-NMR (125 MHz, CDCl3): 15.9 (C(1’)); 22.8 (C(7)); 28.2
(C(8)); 45.4 (C(6)); 51.2 (C(3)); 59.3 (C(8a)); 166.6 (C(1)); 170.7 (C(4)). EI-MS: 169 (10, [M+1]+),
168 (62, M+), 125 (30), 112 (10), 97 (50), 70 (100), 55 (12). X-Ray data: C8H12N2O2, Mr 168.2; monoclinic,
space group P21; a=7.2825(13), b=6.5604(13), c=9.2844(13) Š; a=g=908, b=111.399(11)8;
V=412.99(12) Š3, Z=2; Dc =1.353 g cmꢀ3; crystal size 0.50”0.25”0.15 mm, 858 reflections in the
range q=2.36–24.998, 795 unique reflections; 795 reflection data (I>2s(I)), 158 parameters;
ꢀ3
R=0.0352, Rw=0.0719; residual electron density between 0.131 and ꢀ0.128 e Š
.
Data of cis-10d. M.p. 157–1598. TLC (Et
A
(neat): 3262m, 2952m, 2871w, 1669vs, 1634vs, 1432s, 1301m, 1180w, 1157w, 916m, 710w. H-NMR (500
MHz, CDCl3): 0.95 (d, J=6.5, Me); 1.00 (d, J=6.6, Me); 1.51 (ddd, J=4.9, 9.5, 14.3, HaꢀC(1’));
1.73–1.81 (m, HꢀC(2’)); 1.85–1.93 (m, HaꢀC(7)); 1.97–2.06 (m, HbꢀC(7), HbꢀC(1’)); 2.09–2.15 (m,
HaꢀC(8)); 2.23–2.36 (m, HbꢀC(8)); 3.45–3.61 (m, CH2(6)); 4.00 (dd, J=3.4, 9.4, HꢀC(8a)); 4.10 (t,
J=8.0, HꢀC(3)); 6.42 (br. s, NH). 13C-NMR (125 MHz, CDCl3): 21.3 (C(4’)); 22.8 (C(3’)); 24.6
(C(2’)); 28.1 (C(8)); 38.6 (C(1’)); 45.5 (C(6)); 53.4 (C(8a)); 58.9 (C(3)); 166.3 (C(1)); 170.5 (C(4)).
Data of cis-10e. M.p. 181–1838. TLC (Et
A
(c=0.45, CH2Cl2). IR (neat): 3210m, 2962m, 1672vs, 1428s, 1298m, 1180w, 1121w, 916m, 735w. 1H-
NMR (500 MHz, CDCl3): 0.91 (d, J=6.6, Me); 1.07 (d, J=7.6, Me); 1.86–1.96 (m, HaꢀC(7));
2.01–2.10 (m, HbꢀC(7), HaꢀC(8)); 2.36–2.41 (m, HbꢀC(8)); 2.64 (sept., J=6.9, HꢀC(1’)); 3.52–3.57
(m, HaꢀC(6)); 3.62–3.67 (m, HbꢀC(6)); 3.94 (s, HꢀC(3)); 4.08 (t, J=7.3, HꢀC(8a)); 5.96 (br. s, NH).
13C-NMR (125 MHz, CDCl3): 16.1 (C(2’)); 19.3 (C(3’)); 22.4 (C(7)); 28.3 (C(1’)); 28.5 (C(8)); 45.2
(C(6)); 58.8 (C(3)); 60.4 (C(8a)); 164.9 (C(1)); 167.0 (C(4)). EI-MS: 196 (5, M+), 154 (100,
[MꢀC3H7]+), 125 (35), 110 (10), 98 (12), 72 (32), 70 (98).
Data of cis-10h. TLC (Et
A
(neat): 3228m, 2881m, 1660vs, 1453s, 1421s, 1310w, 1204w, 1115w, 920w, 731m, 702m, 593w. 1H-NMR (500
MHz, CDCl3): 1.86–2.04 (m, HaꢀC(8), CH2(7)); 2.29–2.34 (m, HbꢀC(8)); 2.82 (dd, J=10.2, 14.5, Haꢀ
C(1’)); 3.53–3.67 (m, HbꢀC(1’), CH2(6)); 4.07 (t, J=7.9, HꢀC(3)); 4.29 (dd, J=3.2, 10.1, HꢀC(8a));
6.00 (br. s, NH); 7.23 (d, J=6.8, 2 H); 7.28 (dd, J=8.5, 14.8, 1 H); 7.34 (t, J=7.1, 2 H). 13C-NMR (125
MHz, CDCl3): 22.5 (C(7)); 28.3 (C(8)); 36.8 (C(1’)); 45.4 (C(6)); 56.2 (C(3)); 59.1 (C(8a)); 127.5 (C);
129.2 (2 C); 136.0 (C); 165.1 (C(1)); 169.4 (C(4)). EI-MS: 245 (12, [M+1]+), 244 (50, M+), 153 (10,
[MꢀC6H5CH2]+), 125 (100), 104 (12), 91 (70), 70 (60), 64.9 (20). Anal. calc. for C14H16N2O2 (244.12):
C 68.83, H 6.60, N 11.47; found: C 68.30, H 6.55, N 11.43.

Helvetica Chimica Acta – Vol. 89 (2006)
1909
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Received May 2, 2006