Optically active α-spirocyclopropyllactones and 3-aminopyrrolidones via stereoselective diazoalkane cycloaddition at α-alkylidenelactones

Article abstract of DOI:10.1055/s-1999-6065

1,3-Dipolar cycloaddition of diazoalkanes 2 to optically active α- alkylidenelactones 1 gives high yields of pyrazolines 3 and 4 in a stereoselective manner. These pyrazolines can further be transformed into α- spirocyclopropyllactones 5 and 6 by irradiation and into α-amino-α-(ω- hydroxyalkyl)-γ-butyrolactams 7 and 8 by reductive N-N bond cleavage.

Full text of DOI:10.1055/s-1999-6065

PAPER
965
Optically Active a-Spirocyclopropyllactones and 3-Aminopyrrolidones via
Stereoselective Diazoalkane Cycloaddition at a-Alkylidenelactones
Andreas Otto, Burkhard Ziemer, Jürgen Liebscher*
Institut für Chemie, Humboldt-Universität Berlin, Hessische Str. 1–2, D-10115 Berlin, Germany
Fax +49(39)20938907; E-mail: liebscher@chemie.hu-berlin.de
Received 20 November 1998; revised 3 February 1998
tive (for diastereomeric ratios see Table). With the excep-
tion of 3b the major diastereomer of 3 and 4 could be
separated in pure form by column chromatography. Ethyl
diazoacetate 2 (R2 = COOEt) was not reactive enough to
Abstract: 1,3-Dipolar cycloaddition of diazoalkanes 2 to optically
active a-alkylidenelactones 1 gives high yields of pyrazolines 3 and
4 in a stereoselective manner. These pyrazolines can further be
transformed into a-spirocyclopropyllactones 5 and 6 by irradiation
and into a-amino-a-(w-hydroxyalkyl)-g-butyrolactams 7 and 8 by undergo cycloadditions with a-alkylidenelactones 1 at
reductive N–N bond cleavage.
room temperatures but was found to react in refluxing tol-
uene after two days (Method D). These drastic conditions
caused elimination of N2 from the expected pyrazoline 3
(R2 = COOEt) giving rise to the formation of the corre-
sponding cyclopropane 5c. Remarkably, thermal condi-
tions were not appropriate for the N2-elimination from the
other pyrazolines 3 and 4 derived from diazomethane (R2
= H) in order to synthesize corresponding cyclopropanes
5 and 6 (R2 = H) since corresponding alkenes such as 9
were formed instead. On the other side UV-irradiation of
3 or 4 gave corresponding a-spirocyclopropyllactones 5
or 6 (R2 = H), respectively, in high yields (see Table).
These products were obtained as single stereoisomers if
pure precursors 3 or 4 were used (v.i.). A mixture of dias-
tereomeric pyrazolines 3b gave diastereomeric cyclopro-
panes 5b (separable by flash chromatography) in the same
ratio as started with (see Table).
Key words: diazoalkanes, cycloaddition, spirocyclopropanes, lac-
tones, a-amino acids, lactams
1,3-Dipolar cycloaddition of diazomethane to a-alkyl-
idene or d-lactones was repeatedly used as the first step in
the synthesis of a-spirocyclopropyl-g-butyrolactones in
particular in the naturally occurring a-methylidenelactone
series.1,2 The transformation of the 1-pyrazolines primari-
ly formed into the spirocyclopropyllactones by the loss of
nitrogen was achieved by irradiation with UV-light,
which is a general method for the synthesis of cyclopro-
panes.2 Some of such spirocyclopropyl compounds are in-
teresting as constraint derivatives of anticonvulsant and
convulsant a,a-dialkyl-g-butyrolactones.3 If additional
substituents were attached to a noncondensed a-alkyl-
idenelactone ring a stereoselective anti-addition of diazo-
methane was observed.4,5
Reductive N–N-bond cleavage of pyrazolines represents a
convenient pathway to 1,3-diamines.8,9 If an ester moiety
is attached to the pyrazoline ring the resulting diamines
can cyclize to corresponding lactams.10.11 Hydrogenation
of the a-spiropyrazolinyllactones 3 or 4 in the presence of
Raney Ni gave rise to the formation of a-amino-a-(w-hy-
droxyalkyl)-g-butyrolactams 7 or 8, respectively (see Ta-
ble). Obviously the 1,3-diamines 11 formed by reductive
N–N bond cleavage undergo a ring transformation reac-
tion by attack of the terminal amino group at the carbonyl
carbon. The N-benzyl groups of 8f survived the hydro-
genolytic conditions. The transformation of 1 to 7 or 8
represents a novel comparatively short access to a-amino-
a-(w-hydroxyalkyl)-g-butyrolactams. Hitherto such lac-
tams and corresponding open-chained a-amino-a-(w-hy-
droxyalkyl)carboxylic acid derivatives were only
accessible by multistep syntheses.12,13 These compounds
are of interest in the synthesis of dipeptide bioisosteres12
or as pharmacologically active lactam-conformationally
restricted amino acids,13 respectively.
We became interested if chiral substituents attached to the
exocyclic position of the C–C double bond of a-alkyl-
idene-g-lactones and d-lactones can also exert a stereodi-
recting effect onto the cycloaddition of diazoalkanes. The
expected optically active pyrazolines were promising can-
didates for new a-spirocyclopropyllactones by N2-elimi-
nation and for a novel access to a-amino-a-(w-
hydroxyalkyl)-g-butyrolactams by reductive N–N bond
cleavage.
a-Alkylidenelactones 16 derived from D- or L-glyceralde-
hyde or from L-alanine, i. e. with heteroatoms connected
to the stereogenic centre of R1, were used as enantiopure
starting materials. Reaction of 1 with diazomethane 2 (R2
= H) or trimethylsilyldiazomethane 2 (R2 = TMS) at room
temperature or at 0°C gave smooth 1,3-cycloaddition af-
fording high yields of 1-pyrazolines 3 and 4 (Methods A
and B). The dibenzylaminopropylidenebutyrolactone 1f
however required high pressure conditions to undergo a
All products 3, 4, 5, 6, 7, 8, 9 and 10 are new. Their struc-
ture was elucidated by X-ray crystal analyses (see Figures
1, 2, 3, 4) and spectroscopic data (see Table). As could be
seen from the X-ray crystal analysis of pyrazolines 3a and
4f (see Figures 1 and 2) the face selectivity of the cycload-
successful
cycloaddition
with
trimethylsilyldi-
azomethane. The TMS group was lost and a correspond-
ing 2-pyrazoline 10 was obtained. Silylpyrazolines are
known to lose the TMS group during chromatography on
silica gel.7 All cycloadditions of 2 to 1 were stereoselec-
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York

966
A. Otto et al.
PAPER
n
1
R1
R2
H
1
a
3
a
4
5
a
6
7
a
8
n
1
R1
R2
H
1
e
3
4
e
5
6
f
7
8
f
1
1
1
TMS
CO2Et
H
b
b
c
1
2
H
H
f
f
g
g
g
g
d
d
Scheme 1
dition is governed by the configuration at the substituent hydrazines6 and in the 1,3-dipolar addition of diazo-
R1. The same mode of asymmetric induction was ob- alkanes to acrylates14 with the same chiral substitutents R1
served in the stereoselective transformation of a-alkyl- attached to the ß-position as found in the lactones 1.This
idenelactones 1 into w-hydroxyalkylpyrazolidones with effect could be explained by Houks outside-crowded
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Optically Active a-Spirocyclopropyllactones and 3-Aminopyrrolidones
967
Table 1 Pyrazolines 3 and 4 and 10, a-Spirocyclopropyllactones 5 und 6, a-Amino-a-(w-hydroxyalkyl)-g-butyrolactams 7 and 8, and a-Aky-
lidenelactone 9
mp (°C)a
(Solvent)
[a]D
1H NMRa
(CDCl3)
d, J (Hz)
13C NMRa
(CDCl3)
d, J (Hz)
20a
Prod- Reaction
Yield
(%)
d. r.
uct
conditions
(c=1,
CHCl3)
3ab
16 h, 0°C,
Et2O,
5 eq. 2
91
85:15
117–118
(MeOH/
Et2O, 3:1)
–455.6
1.19 (s, 3 H, Me); 1.28 (s, 3 H, Me);
2.49 (ddd, 1 H, CH-CH2N, J = 8.6, 3.8, (CH2C); 38.5 (CHCH2N); 67.4
2.1); 2.61 (m, 2 H, CH2C); 3.49 (CH2O); 67.7 (CHCH2O); 72.7
24.6 (Me); 26.0 (Me); 29.4
(dd, 1 H, CHCH2O, J = 6.7, 4.6); 3.97 (CHO); 78.8 (CH2N); 95.8
(dd, 1 H, CHCH2O, J = 6.7, 4.6); 4.02 (CN); 109.7 (Me2C); 173.4
(m, 1 H, CHO); 4.82 (m, 2 H, CH2N); (C=O)
4.86 (m, 2 H, CH2O)
3b
3d
4 d, r. t.,
MePh,
1.5 eq. 2
74
92
88:12c
84:16
yellowish
oil
0.00 (s, 9 H, Me3Si); 1.06 (s, 3 H, Me); 0.00 (Me3Si); 27.0 (Me); 27.5
1.15 (s, 3 H, Me); 228 (m, 2 H, CH2C); (Me); 33.3 (CH2C); 42.5
2.34 (m, 1 H, CHCHSi); 3.23 (m, 1 H, (CHCHSi); 69.4 (CH2O); 69.8
CHCH2-O); 3.80 (m, 1 H, CHCH2O); (CHCH2O); 74.4 (CHO); 90.8
4.37 (m, 1 H, CHO); 4.61 (m, 2 H,
CH2O); 4.67 (m, 1 H, CHSi)
(CHSi); 98.1 (Cq-N); 111.4
(Cq Me2C); 176.0 (C=O)
2 d, 0°C,
Et2O,
3 eq. 2
124–125
(MeOH/
Et2O, 3:1))
–354.8
–424.2
1.38–1.51 (m, 10 H, 5x CH2); 2.49
24.1, 24.2, 25.3, 34.5, 36.1
(m, 1 H, CHCH2N), 2.62 (m, 2 H,
(5x CH2); 30.0 (CH2C); 38.7
CH2C); 3.48 (m, 1 H, CHCH2O); 3.98 (CHCH2N); 67.7 (CH2O); 67.8
(m, 1 H, CHCH2O); 4.00 (m, 1 H,
CHO); 4.55 (m, 2 H, CH2O); 4.62
(CHCH2O); 72.7 (CHO); 79.3
(CH2N); 96.3 (Cq-N); 110.7
(m, 2 H, CH2N); 4.81 (m, 1 H, CH2O); (Cq); 173.9 (C=O)
4.86 (m, 1 H, CH2N)
3g
16 h, 0°C,
Et2O,
5 eq. 2
62
82:18
125–126
(MeOH/
Et2O, 3:1)
1.21 (s, 3 H, Me); 1.29 (s, 3 H, Me), 2.09 21.4 (CH2C); 25.3 (Me); 26.0
(m, 2 H, CH2C); 2.24 (m, 1 H,
(Me); 26.6 (CH2CH2C); 41.1
CH2CH2C); 2.65 (m, 1 H, CH2CH2C); (CHCH2N); 68.5 (CHCH2O);
2.74 (m, 1 H, CHCH2N); 3.48 (m, 1 H, 70.6 (CH2O); 72.8 (CHO);
CHCH2O); 4.01 (m, 1 H, CHCH2O);
4.06 (m, 1 H, CHO); 4.45 (m, 1 H,
CH2O); 4.63 (dd, 1 H, J = 17.6, 8.4,
CH2N); 4.79 (m, 1 H, CH2O); 4.89 (m,
1 H, CH2N)
79.5 (CH2N); 96.4 (Cq-N);
110.2 (Cq); 168.6 (C=O)
4c
2 d ,-18°C - 89
r. t., Et2O,
3 eq. 2
86:14
102–103
(MeOH)
+304.1
2.22 (s, 1 H, OH); 2.37 (m, 2 H, CH2-C); 29.4 (CH2C); 38.9 (CHCH2N);
2.63 (m, 1 H, CHCH2N); 3.39 (m, 1 H, 62.6 (CH2OH); 67.9 (CH2O);
CH-O); 3.62 (m, 2 H, CH2OH); 4.31 (d, 71.6 (OCH2-arom.); 77.2
1 H, J = 11.8, O-CH2-arom.); 4.48 (m, 1 (CHO); 79.8 (CH2N); 96.3
H, CH2-O); 4.59 (d, 1 H, J = 11.8, O-
(CN); 127.4, 127.8, 128.3,
CH2-arom.); 4.72 (m, 1 H, CH2N); 4.80 128.9, 129.0 (CH-arom.);
(m, 1 H, CH2O); 4.89 (m, 1 H, CH2N); 138.1 (Cq-arom.); 174.7 (C=O)
7.11–7.27 (m, 5 H, CH-arom.);
4f
20 h, 0°C,
Et2O,
5 eq. 2
87
82:18
164–165
(MeOH/
Et2O, 1:2)
+152.3
0.94 (d, 3 H, J = 6.4, Me); 1.56 (m, 1 H, 11.5 (Me); 27.9 (CH2C); 41.6
CH2C); 1.99 (m, 1 H, CH2C); 2.43
(CHCH2N); 52.5 (CHMe);
(1H,CHCH3); 2.59 (m, 1 H, CHCH2N); 53.8 (2x PhCH2N);
3.21 (d, 2 H, J = 13.6, PhCH2N); 3.73 66.9 (CH2O); 82.3 (NCH2CH);
(d, 2 H, J = 13.6, PhCH2N); 4.00
92.9 (CqN); 127.4, 128.9,
(dd, 1 H, J = 18.3, 10.2, NCH2CH); 4.38 129.1 (CH-arom.); 139.6 (Cq-
(m, 1 H, CH2O); 4.59 (m, 1 H, CH2O); arom.); 174.8 (C=O)
5.07 (dd, 1 H, J = 18.3, 8.5, NCH2CH);
7.13–7.28 (m, 10 H, CH-arom.)
5ad
1 h, r. t.,
MeCN,
hn
95
>95:5
105–106
(MePh)
–74.1
1.01 (m, 1 H, CHCH2-C); 1.21
(s, 3 H, Me); 1.24 (m, 1 H, CHCH2C); 25.6 (CHC); 26.12 (Me); 26.8
1.28 (s, 3 H, Me); 1.53 (m, 1 H, CHC); (Me); 27.1 (CH2C); 66.5
18.5 (CHCH2C); 23.4 (Cq);
Method C
2.10 (m, 1 H, CH2C); 2.25 (m, 1 H,
(CH2O); 69.6 (CHCH2-O),
CH2C); 3.59 (dd, 1 H, J = 7.8, 6.2,
75.1 (CHO); 109.8 (Cq); 179.7
CHCH2O); 3.76 (dd, 1 H, J = 13.1, 6.1, (C=O)
CHO); 4.02 59 (dd, 1 H, J = 7.8, 6.2,
CHCH2O); 4.29 (m. 2 H, CH2O)
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York

968
A. Otto et al.
PAPER
Table 1 (continued)
mp (°C)a
(Solvent)
[a]D
1H NMRa
(CDCl3)
d, J (Hz)
13C NMRa
(CDCl3)
d, J (Hz)
20a
Prod- Reaction
Yield
(%)
d. r.
uct
conditions
(c=1,
CHCl3)
5be
2 h, r. t.,
MeCN,
hn
68
88:12
92–93
(MeOH/
Et2O, 1:3)
–43.9
0.00 (s, 9 H, MeSi); 0.36 (d, 1 H, J = 8.7, 0.0 (Me3Si); 22.0 (CH-Si);
CHSi); 1.25 (s, 3 H, Me); 1.29 26.9 (Me); 27.6 (Me); 29.2
(s, 3 H, Me); 1.59 (dd, 1 H, J = 8.7, 5.5, (CqCH2); 30.3 (CH2C); 32.5
CHCHSi); 2.00 (m, 1 H, CH2C); 2.39 (CHCHSi); 67.3 (CH2O); 70.7
(m, 1 H, CH2C); 3.60 (dd, 1 H, J = 8.0, (CHCH2O); 76.5 (CHO); 110.5
Method C
6.8, CHCH2O); 3.86 (q, 1 H, J = 6.1,
CHO); 4.06 (dd, 1 H, J = 8.0, 6.1,
CHCH2O); 4.29 (m, 2 H, CH2O);
(Cq); 180.0 (C=O)
5c
2 d, reflux, 70
MePh,
88:12
yellowish
oil
–56.5
1.19 (t, 3 H, J = 3.5, MeCH); 1.30
(s, 3 H, Me); 1.36 (s, 3 H, Me); 2.18
14.4 (MeCH2); 26.0 (Me); 26.7
(Me); 28.3 (CH2C); 30.4
1.5 eq. 2
(m, 1 H, CHC=O); 2.28 (m, 1 H, CH2C); (CHC=O); 30.6 (Cq-CH2) 31.8
Method D
2.31 (m, 1 H, CHCHC=O); 2.47
(m, 1 H, CH2C); 3.60 (m, 1 H,
CHCH2O); 3.71(m, 1 H, MeCH2O);
4.08 (m, 2 H, CH2O); 4.72 (m, 1 H,
CHO); 4.19 (m, 1 H, MeCH2O); 4.39
(m, 1 H, CHCH2O)
(CHCHC=O); 61.8 (CH2O);
66.5 (CHCH2O); 69.7
(MeCH2O); 72.3 (CHO); 110.2
(Cq); 167.7 (C=O); 175.3
(C=O)
5g
2 h, r. t.,
MeCN,
hn
89
>95:5
>95:5
>95:5
112–113
(MeOH/
Et2O, 1:2)
–49.7
–44.8
–19.0
1.02 (m, 2 H, CHCH2C); 1.12 (s, 3 H, 22.7 (CHCH2C); 23.3
Me); 1.19 (s, 3 H, Me); 1.37 (dd, 1 H, (CH2CH2C); 23.7 (CHCq);
J = 9.2, 4.0, CHCHC); 1.52 (m, 1 H,
26.2 (Me), 27.2 (Me); 30.3
Method C
CH2CH2C); 1.67 (m, 2 H, CH2CH2C); (CHCHC); 69.5 (CHCH2O);
1.80 (m, 1 H, CH2CH2C); 3.54 (m, 1 H, 70.4 (CH2O); 109.7 (Cq); 174.0
CHCH2O); 3.66 (dd, 1 H, J = 12.9, 6.3, (C=O)
CHO); 3.92 (m, 1 H, CHCH2O); 4.22
(m, 2 H, CH2O)
6f
1.3 h, r. t.,
MeCN,
hn
43
149–150
(MePh)
0.78 (m, 1 H, CHCH2C); 1.09 (d, 3 H, 15.2 (Me); 21.3 (CHCH2C);
J = 6.6, Me); 1.39 (m, 2 H, CHCH2C); 24.1 (CH2Cq); 26.1 (CH2C);
1.57 (m, 1 H, CHCH2); 1.72 (m, 1 H,
CH2CH2C); 1.91 (m, 1 H, CH2CH2C); 54.1 (2x CH2N); 66.4 (CH2O);
2.11 (m, 1 H, CHMe); 3.48 (d, 2 H, 127.2, 128.6, 129.0, (CH-
29.1 CHCH2); 53.3 (CHMe);
Method C
J = 13.7, CH2N); 3.71 (d, 2 H, J = 13.7, arom.); 140.5 (Cq-arom.);
CH2N); 4.22 (m, 2 H, CH2O) 7.11-7.29 180.1 (C=O)
(m, 10 H, CH-arom.)
7af
30 h, 50°C, 93
50 bar,
MeOH,
123–124
(MeOH)
1.29 (s, 3 H, Me); 1.36 (s, 3 H, Me);
1.62 (m, 1 H, CH2C); 1.90 (m, 1 H,
CH2C); 2.43 (dt, 1 H, J = 7.7, 4.4,
CHCH2N); 2.58 (s, 2 H, NH2); 3.43
(m, 2 H, CHCH2N); 3.59 (dd, 1 H,
J = 8.3, 6.8; CH2O); 3.76 (m, 1 H,
CH2OH); 3.88 (m, 1 H, CH2OH); 4.12
(dd, 1 H, J = 8.3, 6.8; CH2O);
24.9 (Me); 26.2 (Me); 39.3
(CH2C);
39.7 (CH2N); 45.1 (CHCH2N);
58.8 CH2OH); 59.7 (CqNH2);
67.8 (CH2O); 73.4 (CHO);
109.2 (Cq); 180.7 (C=O)
Raney Ni
2 (CHO); 6.62 (s, 1 H, NH)
7g
20 h, 50°C, 44
50 bar,
MeOH,
>95:5
129–130
(MeOH)
–23.9
1.25 (s, 3 H, Me); 1.32 (s, 3 H, Me);
1.59 (m, 2 H, CH2CH2OH); 1.61
(m, 2 H, CH2C); 2.34 (m, 1 H,
25.2 (Me), 26.6 (Me), 27.8
(CH2CH2OH); 36.4 (CH2C);
40.2 (CH2N); 44.2 (CHCH2N);
59.7 (CH2OH); 68.2
Raney Ni
CHCH2N); 2.65 (s, 2 H, NH2); 3.35
(m, 2 H, CH2N); 3.56 (m, 2 H, CH2OH); (CHCH2O); 74.1 (CHO); 109.5
3.63 (dd, 1 H, J = 13.9, 7.0, CH2O); 4.08 (Cq); 181.4 (C=O)
(dd, 1 H, J =8.3, 7.0, CH2O); 4.36
(m, 1 H, CHO); 6.6 (s, 1 H, NHC=O)
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Optically Active a-Spirocyclopropyllactones and 3-Aminopyrrolidones
969
Table 1 (continued)
mp (°C)a
(Solvent)
[a]D
1H NMRa
(CDCl3)
d, J (Hz)
13C NMRa
(CDCl3)
d, J (Hz)
20a
Prod- Reaction
Yield
(%)
d. r.
uct
conditions
(c=1,
CHCl3)
8f
20 h, 50°C, 85
50 bar,
MeOH,
>95:5
255–236
(MeOH)
+5.2
1.13 (d, 3 H, J = 6.3, Me); 1.63 (m, 1 H, 10.2 (Me), 40.3 (CH2C); 43.7
CH2C); 1.76 (m, 1 H, CH2C); 2.46 (m, 1 (CHCH2N); 43.8 (CHCH2N);
H, CHCH2); 2.80 (m, 1 H, CHCH2N); 52.8 (CHMe); 53.0 (CH2OH);
2.87 (m, 1 H, CHMe); 3.31 (d, 2 H, J = 57.4 (2x CH2N); 58.4 (CqNH2);
13.7, PhCH2N); 3.44 (d, 2 H, J = 13.7, 126.7, 128.2, 128.5 (CH-
Raney Ni
PhCH2N); 3.53 (m, 2 H, CHCH2N);
arom.); 140.1 (Cq-arom.);
3.68 (d, 2 H, J = 13.6, CH2OH); 4.47 (s, 179.5 (C=O)
1 H, OH); 7.19-7.31 (m, 10 H, CH-
arom.); 7.61 (s, 1 H, NH)
9
5 d, reflux, 81
MePh
>95:5g colourless
oil
+31.5
g 1.42 (s, 3 H, MeC); 1.34 (s, 3 H, MeC); 12.2 (Me-C=C); 25.33 (Me-C);
2.16 (t, 3 H, J = 2.2, MeC=C); 2.78 (m, 25.9 (MeC); 26.9 (CH2C); 64.4
1 H, CH2C); 2.97 (m, 1 H, CH2C); 3.58 (CH2O); 67.1 (CHCH2O); 77.0
(t, 1 H, J = 8.0, CHCH2O); 4.09 (t, 1 H, (CHO); 110.3 (Cq); 120.6
J = 8.0, CHCH2O); 4.24 (m, 2 H,
CH2O); 4.68 (t, 1 H, J = 7.1, CHO)
(Me-C=C); 149.1 (CH2C);
170.1 (C=O)
10
4 d, r. t.,
10kbar
CH2Cl2,
2 eq. 2
76
74:26
colourless
oil
+192.1
0.95 (d, 3 H, J = 6.6, Me); 1.76 (m, 1 H, 11.3 (Me); 30.1 (CH2C); 58.8
CH2C); 2.03 (m, 1 H, CH2C); 2.86 (CHMe); 54.1 (2 x CH2N);
(m, 1 H, CHCH3); 3.30 (d, 1 H, J = 13.7, 56.8 (CHC); 65.8 (CH2O); 69.8
CH2N); 3.61 (d, 1 H, J = 10.85, CHC); (CqN); 127.6, 128.8, 129.1
3.83 (d, 1 H, J = 13.7, CH2N); 4.14
(CH-arom.); 139.5 (Cq-arom.);
(m, 2 H, CH2O); 5.71 (s, 1 H, NH); 7.19 147.0 (CH=N); 177.3 (C=O)
(m, 1 H, CH=N); 7.15–7.26 (m, 10 H,
CH-arom.)
a Spectra of major isomers. If not otherwise mentioned major isomers could be obtained in d.r. >95:5 by flash chromatography
b IR (KBr) n = 1760 cm–1; MS / m/z (rel. intensity) 241 (M+1, 0.33), 101 (14), 43 (100).
c Diastereomers not separable by flash chromatography.
d IR (KBr) n = 1754 cm–1, MS / m/z (rel. intensity) 213 (M+1, 0.15), 197 (33), 155 (11), 137 (11), 126 (13), 91 (29), 43 (100).
e R1 and R2 trans according to 1H NMR20,21
.
f IR (KBr) n = 1685 cm–1, MS / m/z (rel. intensity) 245 (M-15, 0.98), 142 (9), 115 (22), 100 (28), 82 (21), 70 (26), 43 (100).
g Compound suffers partial epimerization after standing in solution and also as a solid.
model 15 and the antiperiplanar effect. 16,17 But these mod-
els were developed for 1,2-disubstituted alkenes. Thus we
determined the optimized structures of 1a (Figure 5) and
1f (Figure 6) by PM3-calculations. They allow to con-
clude the same preferred facial selectivity (see Figures 5
and 6) as found in the experiment. The ring contraction of
pyrazolines 3 and 4 to cyclopropanes 5 and 6 by N2-elim-
ination maintains the configuration as can be seen from X-
ray crystal analysis of 3a and 5a (see Figures 1 and 3).
Our results demonstrate that the 1,3-dipolar cycloaddition
of diazoalkanes 2 to a-alkylidenelactones 1 is stereoselec-
tive and opens an easy access to optically active spirocy-
clopropyllactones
hydroxyalkyl)-g-butyrolactams 7 and 8 by N2-elimination
or hydrogenation, respectively.
5
and
6
and a-amino-a-(w-
Figure 1. X-ray crystal analysis of pyrazoline 3a
1H NMR and 13C NMR spectra were recorded at 300 and 75.5 MHz,
respectively, with a BRUKER AC-300 with TMS as internal stan-
dard. Optical rotations were determined with a PERKIN ELMER
polarimeter 241. Mass spectra (HP 5995 A) were measured at 70eV.
An immersion reactor with Hg high-pressure lamp from HERAEUS
Noblelight (150 W) was used for photochemical elimination of N2.
Silica gel (0.04–0.063 mm, MERCK) was used for preparative col-
umn chromatography. If not otherwise mentioned, chemicals were
purchased from ALDRICH. a-Alkylidenelatones 1 were prepared
as reported.6
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York

970
A. Otto et al.
PAPER
Figure 5. Stereochemical mode of attack of diazomethane at a-alky-
lidenelactone 1a (geometry of 1a optimized by PM3)
Figure 2. X-ray crystal analysis of pyrazoline 4f
Figure 6. Stereochemical mode of attack of diazomethane at a-alky-
lidenelactone 1f (geometry of 1f optimized by PM3)
Figure 3. X-ray crystal analysis of a-spirocyclopropyllactone 5a
Spiropyrazolines 3 and 4 by Addition of Diazoalkanes 2 to
a-Alkylidenelactones 1; General Procedures Diazomethane18
1M solution of diazomethane in Et2O was produced from N-methyl-
N-nitroso-4-toluenesulfonamide (DIAZALDR) in the distillation set
”DIAZALD-Kit” (ALDRICH). The safety instructions should be
followed.18
Cycloaddition
Method A
The freshly prepared solution of diazomethane in Et2O (1M, for
quantities see Table) was added to a solution of the a-alkylidenelac-
tone 1 (1 mmol) in Et2O (5 mL) at –20 to 0°C under stirring. After
further stirring (for temperatures and times see Table) the solution
was concentrated with a rotatory evaporator and the residue was pu-
rified by flash chromatography (hexane/EtOAc for 3a, 3h, 4f, 1:1,
for 3d 6:4, for 4e 3:7) and eventually by recrystallisation (3a, 3d,
3d, 3g, 4f).
Method B
A solution of trimethylsilyldiazomethane in hexane (0.75 mL, 1.5
mmol, 2M) was added to a solution of a-alkylidenelactone 1 (1
mmol) in toluene (5 mL). After stirring at r.t. for 4 d the solvent was
removed under vacuum and the remaining crude product was puri-
fied by flash chromatography (hexane/EtOAc 7:3)
Figure 4. X-ray crystal analysis of a-amino-a-(3-hydroxypropyl)bu-
tyrolactam 8f
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Optically Active a-Spirocyclopropyllactones and 3-Aminopyrrolidones
971
2-Pyrazoline 10
had intensities larger than 2s(I). The structure was solved by direct
methods and refined by least squares procedure within the SHELX
A
solution trimethylsilyldiazomethane in hexane
(0.5 ml,
~1 mmol, 2M) was combined with a solution of a-alkylidenelactone
1f (160 mg, 0.5 mmol) in CH2Cl2 (2 mL) and put into a Teflon tube.
After sealing the tube was kept at 10 kbar at r.t. for 48 h. The solu-
tion was concentrated under vacuum and the remaining material
was purified by flash chromatography (hexane/EtOAc 6:4).
program system. The final residuals were wR2 (all) = 0.0753, R1 all) =
0.0357 and R1 (obs) = 0.0311. The maximum and minimum peaks in
the final difmap were 0.126 and –0.162 e/Å3, respectively.
Crystal Structure Determination for 5a (see Figure 3)19
Crystals were obtained by crystallisation from hot toluene. A co-
lourless crystal of 5a with the dimensions 0.64 x 0.40 x 0.40 mm3
was measured on a STOE Ipds diffractometer using MoKa radiation
(l = 0.71073 Å). Crystal data: C11H16O4, M = 212.24, orthorhombic
space group P 21, a = 8.5844 (9) Å, b = 10.8689 (13) Å, c = 10.272
(2) Å, V = 1069.7 (2) Å3, Z = 4, Dc = 1.318 g/cm3, F(000) = 456, m
(MoKa) = 0.100 mm–1. At 180 (2) K in the range of 2.6° < Q < 26.0°
6298 reflections were measured (R(sig) = 0.0463) of which 2106
were unique (R(int) = 0.0777) and 1915, flagged as observed, had in-
tensities larger than 2s(I). The structure was solved by direct meth-
ods and refined by least squares procedure within the SHELX
a-Alkylidenebutyrolactone 9
A solution of 1a (120 mg, 0.5 mmol) in toluene (5 mL) was refluxed
for 5 days. The solvent was removed under vacuum and the remain-
der was purified by flash chromatography (hexane/EtOAc 6:4).
a-Spirocyclopropyllactones 5 and 6
Method C; General Procedure
A solution of the spiropyrazoline 3 or 4 (1 mmol) in degassed
MeCN (110 mL) was irradiated with broad band-UV (250–400 nm,
the major absorption band of 3a was at 330 nm) for 1–2 h (TLC-
control, see Table). After the reaction was complete, the solvent was
removed under vacuum. The remaining products 5 or 6 were puri-
fied by flash chromatography (hexane/EtOAc).
program system. The final residuals were wR2 (all) = 0.0864, R1 all)
=
0.0376 and R1 (obs) = 0.0340. The maximum and minimum peaks in
the final difmap were 0.159 and –0.176 e/Å3, respectively.
Method D
Crystal Structure Determination for 8f (see Figure 4)19
Crystals were obtained by crystallisation from hot toluene. A co-
lourless crystal of 8f with the dimensions 1.52 x 1.14 x 0.38 mm3
was measured on a STOE Ipds diffractometer using MoKa radiation
(l = 0.71073 Å). Crystal data: C22H29N3O2, M = 367.48, monoclinic
space group P 21, a = 9.6670 (7) Å, b = 8.0517 (4) Å, c = 13.1515
(13) Å, b = 92.172 (7)°, V = 1022.92 (14) Å3, Z = 2, Dc = 1.193 g/
cm3, F(000) = 396, m (MoKa) = 0.077 mm–1. At 180 (2) K in the
range of 1.55° < Q < 26.02° 4616 reflections were measured (R(sig)
= 0.0457) of which 3986 were unique (R(int) = 0.0241) and 3986,
flagged as observed, had intensities larger than 2s(I). The structure
was solved by direct methods and refined by least squares proce-
dure within the SHELX program system. The final residuals were
wR2 (all) = 0.1220, R1 all) = 0.0468 and R1 (obs) = 0.0457. The maxi-
mum and minimum peaks in the final difmap were 0.285 and –0.264
e/Å3, respectively.
A solution of a-alkylidenelactone 1a (198 mg, 1 mmol) and ethyl
diazoacetate (150 mg, 1.5 mmol) in toluene (5 mL) was refluxed for
2 d. After removing the solvent under vacuum the crude product 5c
was purified by column chromatography (hexane/EtOAc 1:1).
a-Amino-a-(w-hydroxyalkyl)-g-butyrolactams 7 and 8 by
Hydrogenation of 3 or 4, General Procedure
NaOH (1.1 g) was added in small portions to a suspension of Ni/Al
alloy (0.7 g) in water (7 mL). The mixture was heated to 70°C for
30 min. After cooling to r.t. the Raney Ni was filtered off and
washed with H2O (3x10 mL) and anhyd MeOH (20 mL). This fresh-
ly prepared Raney Ni (about 100 mg), anhyd MeOH (10 mL) and
the pyrazoline 3 or 4 (1 mmol) was brought into an autoclave and
was stirred at 50°C at 50 bar for 20–30 h (see Table). After filtering
the resulting mixture through Celite and concentrating the filtrate
with a rotatory evaporator the remaining material was purified by
flash chromatography (CHCl3/MeOH 9:1).
Acknowledgement
Crystal Structure Determination for 3a (see Figure 1)19
We gratefully acknowledge financial support from Fonds der Che-
mischen Industrie. We thank Mrs. Dr. G. Kociok-Köhn, Institut für
Chemie, Humboldt-Universtät Berlin for providing X-ray crystal
analysis of compound 8f and Konrad-Zuse-Zentrum für Informati-
onstechnik (Dr. T. Steinke) for computating capacity.
Crystals were obtained by crystallisation from hot toluene. A co-
lourless crystal of 3a with the dimensions 0.80 x 0.80 x 0.28 mm3
was measured on a STOE Ipds diffractometer using MoKa radiation
(l = 0.71073 Å). Crystal data: C11H16N2O4, M = 240.3, monoclinic
space group P 21, a = 9.054 (2) Å, b = 6.4622 (9) Å, c = 10.272 (2)
Å, b = 99.08 (2)° V = 593.5 (2) Å3, Z = 2, Dc = 1.345 g/cm3, F(000)
= 256, m (MoKa) = 0.064 mm–1. At 295(2) K in the range of 2.3° <
Q < 24.2° 4377 reflections were measured (R(sig) = 0.0321) of which
1802 were unique (R(int) = 0.0709) and 1706, flagged as observed,
had intensities larger than 2s(I). The structure was solved by direct
methods and refined by least squares procedure within the SHELX
References
(1) for some examples see Deuel, P. G., Geissman, T. A. J. Am.
Chem. Soc. 1957, 79, 3778.
Ludwig, G.-W.; Jakupovic, J.; King, R. M.; Robinson, H.
Liebigs Ann. Chem. 1984, 22. Romo, J.; de Vivar, A. R.;
Nathan, P. J. Tetrahedron 1967, 29.
Appendino, G.; Gariboldi, P.; Calleri, M.; Chiari, G.; Viterho,
D. J. Chem. Soc., Perkin Trans. 1 1983, 2705.
Acton, N.; Karle, J. M.; Miller, R. E. J. Med. Chem. 1993, 36,
2552.
program system. The final residuals were wR2 (all) = 0.0788, R1 all)
=
0.0323 and R1 (obs) = 0.0296. The maximum and minimum peaks in
the final difmap were 0.129 and –0.129 e/Å3, respectively.
Crystal structure determination for 4f (see Figure 2)19
Crystals were obtained by crystallisation from hot toluene. A co-
lourless crystal of 5f with the dimensions 0.56 x 0.48 x 0.32 mm3
was measured on a STOE Ipds diffractometer using MoKa radiation
(l = 0.71073 Å). Crystal data: C22H25N3O2, M = 363.45, orthorhom-
bic space group P 21, a = 10.7649 (14) Å, b = 12.577 (2) Å, c =
14.273 (2) Å, V = 967.6 (4) Å3, Z = 4, Dc = 1.249 g/cm3, F(000) =
776, m (MoKa) = 0.202 mm–1. At 295 (2) K in the range of 2.2° < Q
< 26.2° 11902 reflections were measured (R(sig) = 0.031) of which
3798 were unique (R(int) = 0.0361) and 3455, flagged as observed,
(2) Bushby, R., J. Cyclopropanes in Houben Weyl, Ed. de
Meijere, A. Vol. E 17B, p. 2059, Thieme: Stuttgart, 1997.
(3) Peterson, E. M.; Xu, K.; Holland, K. D.; McKeon, A. C.;
Rothman, S. M.; Ferrendelli, J. A., Covey, D. F. J. Med.
Chem. 1994, 37, 275.
(4) Huneck, S.; Tonsberg, T.; Bohlmann, F. O. Phytochemistry
1986, 25, 453.
(5) Huneck, S. Takeda, R. Z. Naturforsch. 1992, 47b, 842.
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York

972
A. Otto et al.
PAPER
(6) Otto, A.; Ziemer, B.; Liebscher, J. Eur. J. Org. Chem. 1998,
2667; incorrect configurations were given for compounds 7c,
11a, 11g in this paper. The correct configurations are for
7c:1´R,E; for 11a: 4S, 5R, 4´S and for 11g: 4R, 5S, 1´R.
(7) Aoyyama, T.; Iwamoto, Y.; Nishigaki, S.; Shioisi, T. Chem.
Pharm. Bull. 1989, 37, 253.
(8) Carter, H. E.; van Abeele, F. R., Rothrock, K. W. J. Biol.
Chem. 1949, 178, 325.
(9) Wilkinson, S. J. Chem. Soc. 1951, 104.
(10) Sicher, J.; Rajsner, M.; Rudinger, J.; Eckstein, M., Sorm, F.
Collect. Czech. Chem. Commun. 1959, 24, 3719.
(11) Bartels, A.; Liebscher, J. Synth. Commun., in press.
(12) Acton, J. J. III; Jones, A. B. Tetrahedron Lett. 1996, 37, 4319.
(13) Okayama, T.; Seki, S,.; Ito, H.; Takeshima, T.; Hagiwara, M.;
Morikawa, T. Chem. Pharm. Bull. 1995, 43, 1683.
(14) Galley, G.; Pätzel, M.; Jones, P. G. Tetrahedron 1995, 51,
1631.
(16) Caramella, P. N.; Rondan, G.; Paddon-Row, M. N.; Houk, K.
N. J. Am.Chem. Soc. 1981, 103, 2438-2440.
(17) Mulzer, J.; Altenbach, H. J.; Braun, M.; Krohn, K.; Reissig, H.
U. Organic Synthesis Highlights, VCH, Weinheim, 1991, 4
and 247.
(18) de Boer, T. J.; Backer, H. J. Org. Synth. 1963, Coll. Vol. 4,
250.
(19) Full details have been deposited at: Fachinformationszentrum
Karlsruhe, Gesellschaft für wissenschaftlich-technische
Information mbH, 76344 Eggenstein-Leopoldshafen, whence
this material can be obtained on quoting a full literature
citation and the deposition number CSD 410652 (3a), CSD
410653 (4f), CSD 410654 (5a), and CSD 410655 (8f).
(20) Schaumann, E.; Friese, C.; Adiwidijaja, G. Tetrahedron Lett.
1989, 45, 3163.
(21) Zaitseva, G. S.; Lorberth, J. J. Organomet. Chem. 1996, 525,
175.
(15) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y. D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.;
Loncharich, R. J. Science 1986, 231, 1108.
Article Identifier:
1437-210X,E;1999,0,06,0965,0972,ftx,en;H10698SS.pdf
Synthesis 1999, No. 6, 965–972 ISSN 0039-7881 © Thieme Stuttgart · New York