Stereoselective diazoalkane cycloadditions to chiral 5-alkylidene-1,3- dioxan-4-ones and 3-benzylidene-β-lactones

Article abstract of DOI:10.1055/s-1998-2195

Stereoselective 1,3-dipolar cycloaddition of diazoalkanes to (E)-5- alkylidene-1,3-dioxan-4-ones 1 and the (Z)-isomers (Z)-I afforded spiropyrazolines 3 and 10, respectively. The optically active 2-benzylidene- 3-methyl-β-lactone (8) was synthesized from the corresponding 5-benzylidene- 1,3-dioxan-4-one 1f by hydrolysis and recyclization and added diazomethane with opposite stereodifferentiation. Photochemical elimination of nitrogen from spiropyrazolines 3 gave enantiomerically pure spirocyclopropanes 12 that could be further transformed to cyclopropanecarboxylic acids 13 and derivatives 14.

Full text of DOI:10.1055/s-1998-2195

SYNTHESIS
November 1998
1645
Stereoselective Diazoalkane Cycloadditions to Chiral 5-Alkylidene-1,3-dioxan-4-ones
and 3-Benzylidene-â-lactones
Annett Bartels,a Peter G. Jones,b Jürgen Liebschera*
a
Institut für Chemie, Humboldt-Universität Berlin, Hessische Str. 1–2, D-10115 Berlin, Germany
Fax +49(30)20938907; E-mail: liebscher@chemie.hu-berlin.de
b
Institut für Anorganische und Analytische Chemie, Technische Universität Braunschweig, Postfach 3329, D-38023 Braunschweig, Germany
Received 5 December 1997; revised 4 May 1998
Dedicated to Professor Dieter Seebach
Abstract: Stereoselective 1,3-dipolar cycloaddition of diazoal-
kanes to (E)-5-alkylidene-1,3-dioxan-4-ones 1 and the (Z)-iso-
mers (Z)-1 afforded spiropyrazolines 3 and 10, respectively. The
optically active 2-benzylidene-3-methyl-β-lactone (8) was synthe-
sized from the corresponding 5-benzylidene-1,3-dioxan-4-one 1f
by hydrolysis and recyclization and added diazomethane with
opposite stereodifferentiation. Photochemical elimination of nitro-
gen from spiropyrazolines 3 gave enantiomerically pure spirocy-
clopropanes 12 that could be further transformed to
cyclopropanecarboxylic acids 13 and derivatives 14.
Key words: diazoalkanes, 5-alkylidene-1,3-dioxan-4-ones, cyclo-
addition reactions, spiropyrazolines, spirocyclopropanes
Recently, the cycloaddition of diazomethane to 5-alkyl-
idene-1,3-dioxan-4-ones 1, derivatives of the naturally
Figure. X-Ray Crystal Analysis of the Pyrazoline 10b
occurring polyhydroxybutyrates (PHB), was reported in a
short communication.1 Spiropyrazolines 3 were obtained
with complete stereoselectivity, which could then lose N2
affording spirocyclopropanes 12 or 5-alkylidene-1,3-di-
oxan-4-ones 15 by irradiation or thermolysis, respective-
ly. In addition to detailed investigations and extension of
these reactions to substituted diazoalkanes 2 (R3 ≠ H) and
chemical transformations of the spirocyclopropanes 12,
we report here the possibility of changing the stereochem-
istry of the diazomethane cycloaddition (α versus β-at-
tack) by the application of a corresponding 3-alkylidene-
β-lactone 8. The addition of diazomethane to (E)-5-alkyl-
idene-1,3-dioxan-4-ones 1 gave β-products 3 (Scheme 1
and Table 1) with high stereoselectivity.1 The same holds
true for the addition of diazomethane to the (Z)-5-alkyl-
idene-1,3-dioxan-4-one (Z)-1a (R1 = Me, R2= t-Bu) af-
fording the diastereomer 10a (Scheme 2 and Table 1). In
the case of the less reactive 5-arylidene-1,3-dioxanones 1
and (Z)-1 (R1=Ph, 3-MeOC6H4) long reaction times were
necessary (1 week) and mixtures of the diastereomeric
spiropyrazolines 3 and 4 or 10 and 11 were obtained
(Schemes 1 and 2), that could be separated by chromatog-
raphy affording at least the major isomer in analytically
pure state (Table 1). The configuration and constitution of
the pyrazolines 3, 4, 10 and 11 were elucidated by NMR
spectroscopy (NOE-investigations included), and in some
cases by their transformation to cyclopropanes 12 (vide
infra). In addition, the structure of the cycloadduct 10b
was proved by X-ray crystal analysis ( Figure).
in reactions with the ethylidene compound 1a. Whereas
diazoethane gave comparable results to diazomethane, re-
actions with trimethylsilyldiazomethane and ethyl diazo-
acetate proved more difficult to realize. Finally, high pres-
sure conditions (10 kbar) or heating in benzene at 80oC
afforded complete cycloadditions (Table 1) to the corre-
sponding 1-pyrazolines 3 or 2-pyrazoline 6a, respective-
ly. The stereoselectivity was somewhat lower in these cas-
es.
Since most of the spiropyrazolines 3 were obtained in
high yields and in enantiomerically pure form, it was
worthwhile utilizing them as precursors for new optically
active cyclopropanecarboxylic acid derivatives. Attempts
to eliminate N2 by treatment with various metal salts such
•
as CuCl, CuCl2 H2O, Pd(OAc)2 or Ce(NH4)2(NO3)6 left 3
unchanged. Thermal elimination of N2 from 1-pyrazolines
3 by heating in xylene to 130°C for 5 hours gave 5-alkyl-
idene-1,3-dioxan-4-ones 15 (by 1,2 H-shift) in high
yields, rather than the expected cyclopropanes.1 These
hitherto unknown products were formally derived from
the aldol reaction of 1,3-dioxan-4-one with the corre-
sponding ketone, but have not been synthesized in this
way.3 The envisaged transformation of pyrazolines 3 to
spirocyclopropanes 12 could finally be achieved in high
yields and excellent stereoselectivity by irradiation (330
nm).1 Time-dependent absorption of the irradiation mix-
ture of 3a showed an isosbestic point. The configuration
of the products 12 could be proved by NOE-experiments
showing a positive NOE between the H-atom at position
6 of the dioxane ring and the methyl substituent (R1 = Me)
In order to check the scope of the dipolar cycloaddition of
diazoalkanes to 5-alkylidene-1,3-dioxan-4-ones 1, diazo-
ethane (R3 = Me), trimethylsilyldiazomethane (R3
=
TMS) and ethyl diazoacetate (R3 = CO2Et) were included

SYNTHESIS
Papers
1646
Reagents and conditions: a: Et2O, 0°C, 0°C to r.t., 20 h (R3 = H, Me) or benzene, reflux (R3 = TMS); b: NaOEt/EtOH, r.t., 12 h; c: 3 N HCl/
THF, r.t.; d: CH2Cl2, 10 kbar, 3 d; e: MesCl/CH2Cl2/NaHCO3, 1 h, 0°C, 3 h, r.t.; f: Et2O, 0°C to r.t., 20 h
Scheme 1
in the cyclopropane ring of compounds 12a and 12c de-
t-Bu
rived from pyrazoline 3a and 3c. Since no signs of
CH2N2
O
O
epimerization were observed during the photochemical
transformation of spiropyrazolines 3 into spirocyclopro-
panes, a concerted mechanism is likely4 rather than a
two-step reaction. The spirocyclopropanes 12 can fur-
ther be transformed to enantiopure cyclopropanecarbox-
ylic acids or esters 13 by nucleophilic opening of the di-
oxanone ring by sodium hydroxide or, more efficiently
by sodium alkoxides. Such hydroxyethylcyclopropane-
carboxylates can serve as precursors in Mitsunobu reac-
tion to enantiopure β-amino ester derivatives 14 in the
cyclopropane series (Scheme 4); as an example, ester
13d affords 14a.
Et2O, 0o - r.t., 20h
O
R1
(Z)-1
t-Bu
t-Bu
O
N
O
O
N
O
+
O
O
R1
R1
H
H
N
N
10
11
Scheme 2

SYNTHESIS
November 1998
1647
figurations at the pyrazoline ring of the spiro-β-lactone 9
are opposite to those of the spiro-1,3-dioxanone 3i. The
absolute stereochemistry could be determined by the de-
gradation of the O-heterocycle of 9, or of the correspond-
ing spirodioxanone 3i, in the presence of sodium ethoxide.
This degradation comprises nucleophilic attack at the lac-
tone C-atom, retro-aldol reaction splitting of the hydroxy-
ethyl moiety (presumably as acetaldehyde) and, in the
case of the dioxanone 3i, elimination of pivalaldehyde. In
this way two enantiomers (R)-5 and (S)-5 are formed from
9 or 3i, respectively. The cleavage is accompanied by
some racemization, as seen from the optical rotation,
which is lower in the latter case.
The change in stereodifferentiation of the cycloaddition of
diazomethane to the ylidene-dioxanones 1 as compared to
the ylidene-β-lactone 8 can be understood by conforma-
tional analysis. A half-chair conformation keeping the 6-H
atom in an axial position, was deduced from NOE-in-
vestigations of a 2,6-dimethyl-5-methylidenedioxanone2
and from energy minimization (PM3) of (E)-1f (see
Scheme 3). This conformation with the methyl substituent
in an equatorial position , however, suffers from un-
favourable 1,3-allylic strain, which could be reduced by
adopting a half-boat conformation (Scheme 3). In the
former conformation the axial H-atom at position 6 ham-
pers an attack from the bottom face. Thus, diazomethane
preferably approaches the dioxanone from the top-face.
The same directing effect would be exerted in the half-
boat conformation where the bottom face is a concave
side of a concave/convex-shaped molecule (Scheme 3).
The ylidene-β-lactone 8 must exist in a ‘square’ shape
(Scheme 3). The 4-methyl group and the 4-H-atom are
Scheme 3
Having established the synthetic utility of the spiropyra-
zolines 3, we further approached spiropyrazolines in the
β-lactone series, e.g. 8, as synthetic equivalents of 1.
Thus, the 5-benzylidene-1,3-dioxan-4-one 1f was hydrol-
ysed to the corresponding (R)-α-(1-hydroxyethyl)cin-
namic acid (7), which could be cyclodehydrated to the
benzylidene-β-lactone 8 with mesyl chloride in the pres-
ence of NaHCO3. Enantiopure ylidene-β-lactones are
rare.5, 6 The only access reported is based on the separa-
tion of a racemate by Diels–Alder cycloaddition, separa-
tion of the resulting diastereomers and retro Diels–Alder
reaction.6 In the racemic methylidene-β-lactone series,
the dipolar cycloaddition of diphenyldiazomethane was
reported,7 but it was not possible to investigate the stereo-
selectivity. The benzylidene-β-lactone 8 determines the
stereochemical outcome of the cycloaddition. Reaction
with diazomethane to 8 affords a quantitative yield of a
single stereoisomer. The short reaction time of 12 hours,
compared with 7 days in the analogous cycloaddition to
the 5-benzylidene-1,3-dioxan-4-one 1f (see above), dem-
onstrates the higher reactivity of the ylidene-β-lactone 8
as compared to the corresponding dioxanones 1. The con-
Reagents and conditions: a: hν/benzene; b: 10% aq HCl/THF, r.t.,
20 h (R4 = H) or NaOMe/MeOH, 0°C to r.t., 12 h (R4 = Me) or
K2CO3/EtOH, r.t. 20 h (R4 = Et); c: DEAD/Ph3P/Phthalimide/THF,
20 h; d: 130°C, 5 h
Scheme 4

SYNTHESIS
Papers
Table 1. Spiropyrazolines 3, 4, 6, 10, and 11 Prepared
1648
Prod- R1
uct
R2
R3
Yield
(%)/
mp
dr
[α]
1H NMR (CDCl3/TMS),
δ, J (Hz)
13C NMR (CDCl3/TMS)
δ
20
546
(°C)a
(c in
Method
g/100 mL
CHCl3
3a
Me
Me
t-Bu
H
99/A
oil
oil
>95:5
–277.0
(1)b
0.93 (d, J = 7.4, 3 H, 1'-CH3), 13.4 (1'-CH3), 16.1 (6-CH3),
0.99 (s, 9 H, t-C4H9), 1.09 (d, J 23.8
[C(CH3)3],
32.1
= 6.4, 3 H, 6-CH3), 2.74 (qd, 1J [C(CH3)3], 35.4 (CH-1'),
2
= 9.0, J = 7.3, 1 H, CH-pyra- 74.4 (CH-6), 85.9 (CH2),
zole), 4.11 and 4.93 (ABX, JAB 97.0 (C-5), 109.2 (CH-2),
= 18.0, JAX = 9.1, JBX = 6.9, 2 167.5 (C=O)
H, CH2-pyrazole), 4.13 (m, 1 H,
6-H), 5.10 (s, 1 H, 2-H)
3b
c-Hex
H
98/A
>95:5
–201.5
(2.5)
0.92 (d, J = 7.5, 1'-CH3), 1.07– 13.4 (1'-CH3), 16.1 (6-CH3),
1.14 (m, 8 H, 5 H-c-Hex, 6- 25.4 (CH2-c-Hex), 26.2
CH3), 1.63–1.89 (m, 6 H, c- (CH2-c-Hex), 26.3 (CH2-c-
1
2
Hex), 2.73 (qd, J = 7.3, J = Hex), 32.0 (CH-1'), 42.2
9.0, 1'-H), 4.10 and 4.92 (ABX, (CH-c-Hex), 74.4 (CH-6),
JAB = 17.9, JAX = 6.9, JBX
=
86.0 (CH2-pyrazole), 97.2
9.1, 2 H, CH2-pyrazole), 4.11 (C-5), 106.8 (CH-2), 167.4
(m, 1 H, 6-H), 5.25 (d, J = 4.5, (C=O)
1 H, 2-H)
3c
Me
t-Bu
Me
97/B
113–124 90:10
–127.2
(1.2)
0.97 (m, 6 H, 6-CH3 and 1'-
11.1 (1'-CH3), 15.6 (6-CH3),
CH3), 0.99 (s, 9 H, t-C4H9), 17.2 (CH3-pyrazole), 23.8
1.54 (d, J = 7.0, 3 H, CH3-pyra- [C(CH3)3], 35.4 [C(CH3)3],
1
2
zole), 2.30 (dq, J = 9.3, J = 39.0 (CH-1'), 74.3 (CH-6),
1
7.4, 1 H, 1'-H), 3.94 (dq, J = 92.6 (CH-N), 98.3 (C-5),
9.3, 2J = 7.0, 1 H, CH-pyrazo- 109.3 (CH-2), 167.8 (C=O)
le), 4.05 (q, J = 6.4, 1 H, 6-H),
5.11 (s, 1 H, 2-H)
3d
3e
Me
Et
t-Bu
t-Bu
TMS 99/D
94/C
120–123 89:11
83:17
–
3.73 (d, J = 8.7, 1 H, CHSi), –2.9 [(CH3)3Si], 13.5 (1'-
0.10 [m, 9 H, (CH3)3Si], 0.94 CH3), 15.6 (6-CH3), 23.8
(m, 15 H, t-C4H9, 6-CH3, 1'- [C(CH3)3], 33.8 [(CH3)3C],
CH3), 2.69 (qd, Jd = 8.5, Jq = 35.4 (CH-1'), 74.5 (CH-6),
7.4, 1 H, 1'-H), 3.94 (q, J = 6.3, 93.4 (CH-Si), 96.9 (C-5),
1 H, 6-H), 5.05 (s, 1 H, 2-H)
109.0 (CH-2), 168.4 (C=O)
H
H
H
98/A
97/A
99/A
123.5–125 >95:5
100–111 >95:5
120–125 >95:5
–327.3 (2) 0.90 (t, J = 7.3, 3 H, 2'-CH3), 14.0 (2'-CH3), 15.8 (6-CH3),
1.00 (s, 9 H, t-C4H9), 1.01 (d, J 21.1 (1'-CH2), 23.8
= 6.6, 3 H, 6-CH3), 1.10–1.42 [C(CH3)3], 35.4 [C(CH3)3],
(m, 2 H, 1'-CH2), 2.54–2.65 39.6 (CH-1'), 74.2 (CH-6),
(m, 1 H, CH-pyrazole), 4.02 83.7 (CH2-pyrazole), 96.7
and 4.93 (ABX, JAB = 18.0, (C-5), 109.2 (CH-2), 167.8
J
AX = 8.3, JBX = 9.3, 2 H, CH2- (C=O)
pyrazole), 4.12 (q, J = 6.6, 1 H,
6-H), 5.12 (s, 1 H, 2-H)
3f
i-Pr
t-Bu
–99.6 (2.1) 0.91 [m, 9 H, CH(CH3)2, 6- 15.7
(6-CH3),
23.6
CH3], 1.00 (s, 9 H, t-C4H9), [CH(CH3)2], 23.8 [C(CH3)3],
1.49 (m, 1 H, 1'-CH), 2.55 23.9 [CH(CH3)2], 26.4
(pseudo-q, J = 9.5, 1 H, CH- [CH(CH3)2], 35.5 [C(CH3)3],
pyrazole), 3.83 and 4.88 45.6 (CH-1'), 73.6 (CH-6),
(ABX, JAB = 17.9, JAX = 9.3, 81.5 (CH2-pyrazole), 95.2
JBX = 11.2, 2 H, CH2-pyrazo- (C-5), 109.3 (CH-2), 167.9
le), 4.12 (q, J = 6.4, 1 H, 6-H), (C=O)
5.15 (s, 1 H, 2-H)
3g
i-Pr
c-Hex
–167.0
(1.2)
0.89–1.99 (m, 8 H, 6-CH3 and 15.7 (6-CH3), 22.7, 23.6
5 H of c-Hex), 1.20 (d, J = 8.2, [CH(CH3)2], 25.5 (CH2),
6 H; 2 × CH3), 1.45 (m, 1 H, 26.1 (CH2), 26.2 (CH2), 26.3
CHMe2), 1.63–1.93 (m, 6 H, c- (CH2), 26.5 [CH(CH3)2],
Hex), 2.60 (pseudo-q, J = 11.2, 42.3 (CH-c-Hex), 45.5 (CH-
1 H, 1'H), 4.13 (q, J = 6.4, 1 H, 1'), 73.8 (CH-6), 81.5 (CH2-
6-H), 3.84 and 4.90 (ABX, JAB pyrazole), 95.5 (C-5), 107.0
= 17.9, JAX = 9.3, JBX = 11.2, 2 (CH-2), 167.7 (C=O)
H, CH2-pyrazole), 5.31 (s, 1 H,
2-H)

SYNTHESIS
November 1998
1649
Table 1. (continued)
Prod- R1
uct
R2
R3
Yield
(%)/
mp
dr
[α]
1H NMR (CDCl3/TMS),
δ, J (Hz)
13C NMR (CDCl3/TMS)
δ
20
546
(°C)a
(c in
Method
g/100 mL
CHCl3
3h
i-Pr
t-Bu
Me
50/B
oil
>95:5
–
0.95 [m, 9 H, 6-CH3 and 15.7 (1'-CH3), 19.8 (CH3-py-
(Rf 0.4)
CH(CH3)2], 1.0 (s, 9 H, t- razole), 22.0 [CH(CH3)2],
C4H9), 1.48 (m, 1 H, 2'-CH), 23.8
[C(CH3)2],
27.9
1.59 (d, J = 6.9, 3 H, CH3-pyra- [CH(CH3)2], 34.5 [C(CH3)3],
zole), 2.10 (m, 1 H, 1'-H), 4.05 52.4 (CH-1'), 73.8 (CH-6),
(q, J = 7.1, 1 H, 6-H), 4.10 (dq, 88.9 (CH-N), 96.9 (C-5),
1J = 9.5, 2J = 7.2, 1 H, CH-py- 109.4 (CH-2), 167.5 (C=O)
razole), 5.12 (s, 1 H, 2-H)
3i
Ph
t-Bu
H
H
53c/A
120–125 ≈50:50
Et2O/
pentane
–230.0 (1)
0.86 (d, J = 6.4, 3 H, 6-CH3), 15.6
(6-CH3),
23.8
(>95:5)d
1.00 (s, 9 H, t-C4H9), 3.73 (q, J [C(CH3)3], 35.4 [C(CH3)3],
= 6.4, 1 H, 6-H), 3.98 (dd, 1J = 44.5 (CH-1'), 74.9 (CH-6),
6.3, 2J = 8.9, 1 H, CH-pyrazo- 82.5 (CH2-pyrazole), 98.4
le), 4.94 and 5.10 (ABX, JAB
=
(C-5), 109.2 (CH-2), 128.0,
18.0, JAX = 8.9; JBX = 6.3, 2 H, 128.4, 129.1 (CHarom), 135.3
CH2-pyrazole), 5.00 (s, 1 H, 2- (Carom), 167.1 (C=O)
H), 6.99–7.31 (m, 5 H, C6H5)
3j
3-MeO- t-Bu
48/Ae
115–120 48:52
–202.0 (1) 0.86 (d, J = 6.4, 3 H, 6-CH3), 14.5
(6-CH3),
22.6
C6H4
0.96 (s, 9 H, t-C4H9), 3.11 (s, 3 [(CH3)3C], 34.2 [C(CH3)3],
H, OCH3), 3.75 (q, J = 6.4, 1 H, 43.3 (CH-1'), 54.1 (OCH3),
6-H), 3.98 (m, 1 H, CH-pyra- 73.6 (CH-6), 81.2 (CH2-py-
zole), 4.96 (s, 1 H, 2-H), 4.90 razole), 97.1 (C-5), 107.9 (C-
and 4.99 (ABX, 1J = 6.2, 2J = 5), 107.9 (CH-2), 111.5,
3
8.9, J = 27.0, 1 H, CH2-pyra- 113.5, 119.3, 129.0 (CHarom),
zole), 6.48 (m, 2 H, C6H5), 6.75 135.7, 158.8 (Carom), 165.9
(m, 1 H, C6H5), 7.20 (m, 1 H, (C=O)
(C6H5))
4i
4j
Ph
t-Bu
H
H
44/Af
118–125 ≈50:50
189.0 (1)
0.74 (d, J = 6.5, 6-CH3), 0.95 18.3
(6-CH3),
24.2
(>95:5)d
(s, 9 H, t-C4H9), 3.86 (dd, 1J = [C(CH3)]3, 35.3 [C(CH3)3],
7.4, 2J = 2.2, 1 H, CH-pyrazo- 45.0 (CH-1'), 73.5 (CH-6),
le), 4.95 (q, J = 6.5, 1 H, 6-H), 86.1 (CH2-pyrazole), 100.0
4.70–4.98 (m, 2 H, CH2-pyra- (C-5), 107.0 (CH-2), 128.4,
zole), 5.97 (s, 1 H, 2-H), 6.80– 129.3 (CHarom), 138.1 (Carom),
7.33 (m, 5 H, C6H5)
166.0 (C=O)
3-MeO- t-Bu
C6H4
29/Ag
120–122 52:48
(>95:5)d
+343.0 (1)
0.78 (d, J = 6.4, 6-CH3), 0.95 17.5
(6-CH3),
22.8
(s, 9 H, t-C4H9), 3.68 (s, 3 H, [C(CH3)3], 34.0 [C(CH3)3],
OCH3), 3.67–3.75 (m, 1 H, 43.5 (CH-1'), 54.2 (OCH3),
CH-pyrazole), 4.73 (q, J = 6.4, 72.0 (CH-6), 84.9 (CH2-py-
1 H, 6-H), 4.75–4.95 (m, 2 H, razole), 100.0 (C-5), 105.5
CH2-pyrazole), 6.00 (s, 1 H, 2- (CH-2), 111.8, 113.0, 119.3,
H), 6.34 (m, 2 H, C6H5), 7.08 129.0 (CHarom), 138.5, 158.8
(m, 1 H, (C6H5)), 7.19 (m, 1 H, (Carom), 164.5 (C=O)
C6H5)
6a
Me
Me
t-Bu
t-Bu
CO2 97/D
Et
oil
89:11
0.89 (s, 9 H, t-C4H9), 1.20 (d, J 10.8 (CH3CH2), 14.1 (1'-
= 6.3, 3 H, 6-CH3), 1.23–1.29 CH3), 16.6 (6-CH3), 23.6
(m, 6 H, 1'-CH3, CH3CH2), 4.01 [C(CH3)3], 35.1 [(CH3)3C],
(q, J = 7.5, 1 H, 1'-H), 4.11 (q, J 44.5 (CH-1'), 61.2 (OCH2),
= 6.4, 1 H, 6-H), 4.21 (q, J = 5.8, 73.2 (CH-6), 74.4 (C-5),
2 H, OCH2), 4.94 (s, 1 H, 2-H), 107.5 (CH-2), 145.3 (C=N),
6.65 (s, 1 H, NH)
161.5 (C=O), 169.3 (C=O)
10a
H
73/A
120–130 >95:5
–332.1
(1)b
0.98 (s, 9 H, t-C4H9), 1.10 (d, J 11.7 (1'-CH3), 14.2 (6-CH3),
= 6.9, 3 H, 1'-CH3), 1.20 (d, J = 23.8 [C(CH3)3], 34.5 (CH-1),
6.5,3 H, 6-CH3), 1.89 (m, 1 H, 35.5 [C(CH3)3], 76.9 (CH-6),
1'-H), 3.94 (q, J = 6.5, 1 H, 6- 82.5 (CH2-pyrazole), 97.7
H), 4.04 and 4.85 (ABX, JAB
=
(C-5), 109.3 (CH-2), 163.6
17.1, JAX = 8.6, JBX 10.4, 2 H, (C=O)
CH2-pyrazole), 5.03 (s, 1 H, 2-
H)

SYNTHESIS
Papers
Table 1. (continued)
1650
Prod- R1
uct
R2
R3
H
Yield
(%)/
Method
mp
dr
[α]
1H NMR (CDCl3/TMS),
δ, J (Hz)
13C NMR (CDCl3/TMS)
δ
20
546
(°C)a
(c in
g/100 mL
CHCl3
10b
Ph
t-Bu
80d/A
80/A
Ah
180–181 80:20
–312.0
0.89 (s, 9 H, t-C4H9), 1.42 (d, J 18.3
(6-CH3),
23.9
(>95:5)d (0.5)
= 6.6, 3 H, 6-CH3), 3.02 (dd, 1J [C(CH3)3], 35.0 [C(CH3)3],
= 8.8, 2J = 12.0, 1 H, 1'-H), 44.6 (CH-1'), 73.1 (CH-6),
4.26 (q, J = 6.2, 1 H, 6-H), 4.63 85.7 (CH2-pyrazole), 100.8
(s, 1 H, 2-H), 4.78 and 5.16 (C-5), 106.7 (CH-2), 127.9,
(ABX, JAB = 17.1, JAX = 8.6, 128.1, 128.9 (CHarom), 137.8
JBX = 11.2, 2 H, CH2-pyrazo- (Carom), 165.6 (C=O)
le), 7.20–7.21 (m, 5 H, C6H5)
10c 4-MeO- t-Bu
H
H
120–122 90:10
–424.6
0.86 (s, 9 H, t-C4H9), 1.37 (d, 14.9
(6-CH3),
23.9
C6H4
(>95:5)d (0.65)
J = 6.6, 6-CH3), 3.00 (m, 1 H, [C(CH3)3], 35.7 [C(CH3)3],
CH-pyrazole), 3.71 (s, 3 H, 47.3 (CH-1'), 55.7 (OCH3),
OCH3), 4.21 (q, J = 6.6, 6-H), 77.4 (CH-6) 81.1 (CH2-pyra-
4.63 (s, 1 H, 2 H), 4.78–5.10 zole), 98.4 (C-5), 109.3 (CH-
(m, 2 H, CH2-pyrazole), 6.74 2), 113.7, 115.1, 121.5,
(m, 3 H, C6H5), 7.18 (m, 1 H, 130.3 (CHarom), 134.9, 160.3
C6H5)
(Carom), 163.7 (C=O)
11b
Ph
t-Bu
–
20:80
–
–
15.1 (6-CH3),
24.0
[C(CH3)3], 35.5 [C(CH3)3],
43.0 (CH-1'), 75.2 (CH-6),
84.3 (CH2-pyrazole), 98.5
(C-5); 111.2 (CH-2), 128.6,
128.9, 129.2 (CHarom), 134.3
(Carom), 163.9 (C=O)i
a Compounds melt with decomposition and formation of a gas.
f Together with 53% 3i.
b [α]2D0
g Together with 48% 3j.
c Together with 44% 4i.
d After chromatography.
e Together with 29% 4j.
h Could not be isolated in pure state.
i Obtained from a diastereomeric mixture of 10b and 11b.
(2S,5R)-(E)-2-Cyclohexyl-5-ethylidene-6-methyl-1,3-dioxan-4-one
(1b): colorless oil; yield: 33%; Rf 0.45 (hexane/Et2O, 5:1).
1H NMR (CDCl3): δ = 0.97–1.18 (m, 6 H, 3 CH2 c-hex), 1.25 (d, J =
6.4 Hz, 3 H, 6-CH3), 1.27–1.76 (m, 5 H, 2 CH2 c-hex, 2-CH), 1.71 (d,
J = 7.4 Hz, 3 H, 1'-CH3), 3.35 (q, J = 7.0 Hz, 1 H, 6-H), 4.78 (d, J =
5.2 Hz, 1 H, 2-H), 6.71 (q, J = 7.4 Hz, 1 H, 1'-H).
symmetrically placed on each side of the ring. Thus, the
larger methyl group hampers the attack from the β-face.
These experiments show the possibility in principle of di-
recting the cycloaddition of diazomethane either to the β-
or to the α-face, depending on the type of 2-ylidene-3-
hydroxybutyric acid derivative 1 or 8 used in the cycload-
dition with diazomethane. Since 1 and 8 are synthetically
equivalent, the products 12, 13 and 14 obtained from 1 via
3 should be available with the opposite configuration in
the cyclopropane ring starting from the β-lactone 8 via 9.
13C NMR (CDCl3): δ =14.3 (CH3), 20.6 (CH3), 25.4 (CH2), 26.1
(CH2), 26.4 (CH2), 41.2 (CH), 71.5 (CH-6), 102.6 (CH-2), 131.6
(C-5), 138.4 (CH-1’), 166.4 (C=O).
(2S,5R)-(E)-2-Cyclohexyl-5-Isobutylidene-6-methyl-1,3-dioxan-4-
one (1e): colorless oil; yield: 37%; Rf 0.5 (hexane/Et2O, 5:1); [α]546
102.4 (c = 1.9, CHCl3).
1H NMR and 13C NMR spectra were recorded at 300 and 75.5 MHz,
respectively on a Bruker AC-300 with TMS as internal standard. Di-
astereomeric ratios were determined by NMR and in part by analytical
HPLC (Kontron Instruments) on RP 18 (Licrosphere, Hewlett-Pack-
ard; d = 4.5 mm, l = 20 cm, MeCN; 1 mL / min). Optical rotation was
determined with a Perkin-Elmer polarimeter 241 at 20°C. MS (HP
5995 A) and HRMS (MAT 711, Varian) were measured at 70eV. For
preparative column chromatography, silica gel (0.04–0.063 mm,
Merck) was used. An immersion reactor with Hg high-pressure lamp
from Heraeus Noblelight (150 W) was used for photochemical elimi-
nation of N2.
1H NMR (CDCl3): δ = 0.98 [dd, 6 H, CH(CH3)2], 1.02–1.29 (m, 6 H, 3 ×
CH2-cyclohexyl), 1.31 (d, J = 6.4 Hz, 3 H, 6-CH3), 1.49–1.81 (m, 5 H,
2 × CH2-cyclohexyl, CH), 2.43–2.49 (m, 1 H, CH), 4.80 (m, 1 H, 6-H),
4.83 (d, J = 5.2 Hz, 1 H, 2-H), 6.46 (d, J = 11.3 Hz, 1 H, 1'-H).
13C NMR (CDCl3): δ = 21.4 and 22.0 [CH(CH3)2], 22.1 (6-CH3), 25.5
(2 × CH2), 26.2 (CH2), 26.4 (CH2), 26.5 (CH2), 27.8 (CH-2'), 41.3 (=CH),
71.5 (CH-6), 102.7 (CH-2), 128.1 (C-6), 149.8 (CH-1’), 166.9 (C=O).
Spiropyrazolines 3, 4, 6, 10 and 11 by Addition of Diazoalkanes to
5-Alkylidene-1,3-dioxanones 1 and (Z)-1; General Procedures:
a) Diazomethane
A 1 M solution of CH2N2 in Et2O was prepared from N-methyl-N-
nitroso-4-toluenesulfonamide (Diazald®) in the distillation set “Diaz-
ald-Kit” (Aldrich).
Starting materials 1 were obtained in a known way starting from (R)-
polyhydroxybutyrate (donated from Zeneca Biopolymers), depoly-
merization,8 establishment of the dioxanone ring9 and final two-step
aldol condensation.3 For analytical data of new compounds 1b and 1e,
see below. Diazomethane was generated from a mixture of Diazald
(Aldrich), EtOH, KOH and Et2O by distillation.10
b) Diazoethane
A 40% aq KOH (9 mL) was immersed in Et2O (30 mL). At 0°C N-
ethyl-N-nitrosourea11 (3.5 g, 30 mmol) was added in small portions

SYNTHESIS
November 1998
1651
Table 2. Spirocyclopropanes 12, Cyclopropanecarboxylic Acids 13 and Esters 14 Prepared
Product
R1
R2
R3
R4
Yield
(%)
[a]546 (c in
g/100 mL
CHCl3)
1H NMR (CDCl3/TMS)
δ, J (Hz)
13C NMR (CDCl3/TMS) δ
12a
Me
t-Bu
H
–
99
98
+ 67.1 (2.25)
0.63 and 1.73 (ABX, JAB = 4.9, 13.3 (CH3-c-Pr), 18.9 (CH2-c-
Ax = 6.7, JBx = 9.3, 2H, Pr), 0.95 Pr), 21.6 (6-CH3), 23.8 (CH-c-
(s, 9H, t-C4H9), 1.10 (d, J = 6.4, Pr, 24.0 [C(CH3)3], 28.2 (C-5),
3H, 1-CH3), 1.18 (d, J = 6.3, 3H, 34.7 [(CH3)3C], 70.8 (CH-6),
6-CH3), 1.48 (m, 1H, CH-c-Pr), 105.7 (CH-2), 173.6 (C=O)
4.00 (q, J = 6.3, 1H, 6-H), 4.92
J
(s, 1H, 2-H)
12b
Me
c-Hex
H
–
+ 83.7 (1.78)
0.55 (dd, 1J = 4.9, 2J = 6.7, 1H, 13.2(CH3), 18.7 (CH2-c-Pr),
CH2-c-Pr), 1.07 (d, J = 6.4, 3H, 21.6 (CH3), 23.8 (CH-c-Pr),
CH3), 1.15 (d, J = 6.3, 3H, 6- 25.5 (CH2), 25.6 (CH2), 26.2
CH3), 1.10–1.22 (m, 5H, CH2-c- (CH2), 26.5 (CH2), 28.3 (C-5),
Hex), 1.40–1.81 (m, 7H, 5H- 41.6 (CH-c-Hex), 70.8 (CH-6),
CH2-c-Hex, 1H-CH-c-Hex, 1H- 103.2 (CH-2), 173.2 (C=O)
CH2-c-Pr), 3.97 (q, J = 6.3, 1H,
6-H), 5.04 (d, J = 5.0, 1H, 2-H)
12c
12d
12e
Me
Me
Et
t-Bu
t-Bu
t-Bu
Me
TMS
H
–
–
–
98
42
99
–
0.90 (s, 9H, t-C4H9), 0.96 (m, 12.6 (CH3), 13.0 (CH3), 21.1 (6-
1H, c-Pr), 1.10 (d, J = 6.4, 3H, CH3), 23.9 [C(CH3)3], 27.1
CH3-c-Pr), 1.16 (d, J = 6.3, 3H, (CH-c-Pr), 9.6 (CH-c-Pr), 32.2
6-CH3), 1.33 (d, J = 6.3, 1H, H- (C–5), 34.6 [(CH3)3C], 71.8
c-Pr), 1.41 (m, 1H, H-c-Pr), 3.88 (CH-6), 105.4 (CH-2), 172.0
(q, J = 6.3, 1H, 6-H), 4.89 (s, (C=O)
1H, 2-H)
+ 114.8 (0.5)
0.07 [s, 9H, Si(CH3)3], 0.89 (m, –0.43 [Si(CH3)3], 15.3 (CH3-c-
1H, CHSi), 0.94 (s, 9H, t-C4H9), Pr), 20.0 (CHSi), 22.2 (6-CH3),
1.20 (d, J = 6.2, 3H, 6-CH3), 24.0 [C(CH3)3], 27.6 (CH-c-Pr),
1.22 (d, J = 5.4, 3H, CH3-c-Pr), 33.8 (C), 34.4 (C), 71.1 (CH-6),
1.31 (m, 1H, CH-c-Pr), 3.90 (q, 104.6 (CH-2), 173.4 (C=O)
J = 6.3, 1H, 6-H), 4.90 (s, 1H,
2-H)
+ 109.2
(1.64)
0.60 and 1.67 (ABX, JAB = 5.0, 13.7 (CH3), 17.8 (CH2-c-Pr),
JAx = 9.4, JBx = 6.2, 2H-c-Pr), 21.6 (6-CH3), 21.7 (CH2), 23.9
0.92 (s, 9H, t-C4 H9), 1.00 (pseu- [C(CH3)3], 28.5 (C-5), 31.5
do-t, J = 7.0, 2H, CH2), 1.15 (d, (CH-c-Pr), 34.7 [(CH3)3C], 70.9
J = 6.3, 3H, 6-CH3), 1.28–1.35 (CH-6), 105.6 (CH-2), 173.6
(m, 4H, CH3, CH-c-Pr), 3.97 (q, (C=O)
J = 6.3, 1H, 6-H), 4.90 (s, 1H,
2-H)
12f
i-Pr
t-Bu
t-Bu
H
H
–
–
99
77
+ 80.7 (1)
0.62 and 1.65 (ABX, JAB = 5.0, 17.5 (CH2-c-Pr), 21.8 (6-CH3),
JAx = 7.7, JBx = 4.9, 2H-c-Pr), 22.3 [(CH3)2], 23.8 [C(CH3)3],
0.92 (s, 9H, t-C4H9), 1.00 (d, J = 27.8 [(CH3)2CH], 29.0 C-5, 34.6
3.1, 6H, CH(CH3)2], 1.15 (d, J = [(CH3)3C], 37.8 (CH-c-Pr), 70.7
6.2, 3H, 6-CH3), 1.32 (m, 1H, (CH-6), 105.4 (CH-2), 173.4
CH), 1.51 (m, 1H, CH), 4.02 (q, (C=O)
J = 6.2, 1H, 6-CH), 4.97 (s, 1H,
2-CH)
12g
Ph
+ 13.5 (2)
0.88 (d, J = 6.3, 3H, 6-CH3), 15.5 (CH2), 20.4 (6-CH3), 23.9
0.93 (s, 9H, t-C4H9), 1.48 and [C(CH3)3], 30.6 (C-5), 32.9
1.98 (ABX, JAB = 5.5, JAx = 9.4, (CH-c-Pr), 34.8 [(CH3)3C], 71.1
JBx = 7.2, 2H, CH2-c-Pr), 2.85 (CH-6), 106.4 (CH-2), 127.5,
(dd, JAX = 9.0, JBX = 7.2, CH-c- 128.7, 129.2 (CHarom), 134.5
Pr), 3.65 (q, J = 6.3, 1H, 6-H), (Caron), 172.6 (C=O)
4.90 (s, 1H, 2-H), 7.15–7.29 (m,
5H, (C6H5)

SYNTHESIS
Papers
Table 2. (continued)
1652
Product
R1
R2
R3
H
R4
H
Yield
(%)
[a]546 (c in
g/100 mL
CHCl3)
1H NMR (CDCl3/TMS)
δ, J (Hz)
13C NMR (CDCl3/TMS) δ
13a
Ph
t-Bua
66
–39.0 (2)
1.17 and 1.83 (ABX, JAB = 5.1, 16.9 (CH2), 21.1 (CH3), 33.9
Ax = 7.2, JBx = 9.1, 2H, CH2-c- (CHPh), 34.2 (C-1), 67.4
J
Pr), 1.35 (d, J = 6.6, 3H, CH3), (CHO), 127.4, 128.4, 129.6
2.97 (m, 2H, CHO, CHPh), (CHarom), 135.4 (Carom), 178.7
7.23–7.33 (m, 5H, C6H5)
(C=O)
13b
13c
Me
Ph
c-Hexa
t-Bua
H
H
H
40
+ 6.1 (1)
0.41 (dd, 1J = 3.5, 2J = 6.0, 1H,
H-c-Pr), 1.26 (d, J = 5.8, 3H, 2- (CH3), 32.1 (C–1), 68.0 (CHO),
CH3), 1.43 (d, J = 6.5, 3H, CH3), 180.4 (C=O)
1.53–1.58 (m, 2H, H-c-Pr, 2-H),
13.3 (2-CH3), 21.1 CH2), 21.2
3.42 (m 1H, CHO)
Me 73
–64.0 (3.9)
1.11 and 1.74 (ABX, JAB = 5.0, 16.9 (CH2), 21.4 (1'-CH3), 33.0
JAx = 7.3, JBx = 9.0, 2 x 1H-c- (2-CH), 34.4 (C-1), 67.6 (CH-
Pr), 1.34 (d, J = 6.6, 3H, CH3), 1), 126.1, 128.6, 128.7 (CHarom),
2.90 (m, 1H, 2-H), 3.02 (m, 1H, 135.8 (Carom), 174.5 (C=O)
1´-H), 3.75 (s, 3H, CH3O),
7.23–7.34 (m, 5H, C6H5)
13d
Et
t-Bua
H
Et
75
-
0.29 (dd, 1J = 5.5, 2J = 3.51H, H-
c-Pr), 1.01 (t, J = 7.2, 3H, CH3),
1.19 (t, J = 7.1, 3H, CH3), 1.35
(d, J = 6.5, 3H, CH3), 1.36 (m,
2H, 2-CH2), 1.41 (m, 1H, 2-H),
1.62 (m, 1H, H-c-Pr), 3.28 (q, J
= 6.4, 1H, CHO), 3.44 (br, 1H,
OH), 4.07 (dq, 1J = 7.2, 2J = 4.8,
2H, CH2-O)
–
14a
Et
–
H
Et
50b
–20.3 (2.25)
0.54 (dd, J = 4.7, 6.6, 1H, H-c- 13.9 (CH3), 14.1 (CH3), 17.8
Pr), 1.01 (t, J = 7.2, 3H, CH3), (CH3N), 18.6 (CH2), 21.6
1.21 (t, J = 7.1, 3H, CH3), 1.25– (CH2), 30.3 (CH-2), 31.1 (C-1),
1.42 (m, 3H, 2-CH2, 2-H), 1.68 49.2 (CHN), 60.7 (CH2O), 123.1
(m, 1H, H-c-Pr), 1.73 (d, J = 7.3, (2 × CHarom), 131.9 (Carom),
3H, 1'-CH3), 4.02 (q, J = 7.3, 1H, 133.8
(2 × CHarom),
168.4
1'-CH3), 4.02 (q, J = 7.3, 1H, 1'- (2 × C=O), 173.2 (C=O)
H), 4.10 (q, J = 7.0, 2H, CH2O,
7.62 (d, J = 3.1, 1H, C6H5), 7.72
(d, J = 3.1, 1H, C6H5, Ph), 7.73
(d, J = 3.1, 1H, C6H5)
a Substituent R2 refers to the precursor 12.
b After chromatography.
with stirring. After 30 min of stirring at 0°C the yellow Et2O phase of
diazoethane (about 0.5 M) was separated.
was either recrystallized from Et2O/pentane (3c, solid ) or purified by
column chromatography on silica gel with hexane/Et2O (1:1) (3h, oil;
Rf 0.4).
c) Cycloaddition
Method C: A solution of 2 M trimethylsilyldiazomethane in hexane
(0.5 mL, 1 mmol, Aldrich) was mixed with a solution of 1a (100 mg,
0.5 mmol) in benzene (20 mL). The mixture was refluxed till the re-
action was complete (TLC monitoring) and the solvent was removed
under vacuum. The remaining crude product (dr 83:17) was purified
by column chromatography on silica gel (hexane/Et2O, Rf 0.6) and
finally by recrystallization from Et2O affording 3d as colourless crys-
tals.
Method D: A mixture of the 1a (100 mg, 0.5 mmol), 2 M solution of
trimethylsilyldiazomethane in hexane (0.5 mL, ≈ 1 mmol) and
CH2Cl2 (5 mL) was transferred to a Teflon tube. The sealed tube was
kept in a high pressure set at 10 kbar at r.t. for 24 h. The resulting
mixture was evaporated and purified by column chromatography on
silica gel (hexane/Et2O, 6:1). The resulting colourless oily 3d crystal-
lized in the refrigerator after some time.
Method A: A 10-fold excess of a freshly prepared solution of CH2N2
in Et2O (about 1 M) was added to a cooled solution (–20 to 0°C) of 1
(1 mmol) in Et2O (10 mL). The reaction mixture was allowed to warm
up to r.t. overnight. The resulting solution was evaporated (rotary
evaporator) and the remaining solid material was recrystallized from
Et2O. Oily products were purified by column chromatography on sil-
ica gel (hexane/Et2O, 1:1). For 1f, 1g, (Z)-1f or (Z)-1g the mixture was
kept at r.t. for 7 d. The solid product obtained after evaporation of the
solvent was separated by column chromatography on silica gel elut-
ing 4 and 11 with hexane/Et2O (6:1) and afterwards 3 and 10 with
hexane/Et2O (1: 1) as eluents.
Method B: A freshly prepared ≈0.5 M solution of diazoethane in Et2O
(6 mL, 3 mmol for compound 3c; 5 mL, 2.5 mmol for 3h) was added
to an ice-cold solution of 1 (150 mg, 0.8 mmol for 1a; 90 mg, 0.4
mmol for 1d) in Et2O (5 mL). The mixture was allowed to warm up
to r.t. overnight. The solvent was removed and the remaining product
Method E: A solution of 1a (320 mg, 1.6 mmol) and ethyl diazoace-
tate (190 mg, 1.9 mmol) in CH2Cl2 (5 mL) was placed in a sealed

SYNTHESIS
November 1998
1653
Teflon tube and kept under 14 kbar at r.t. for 3 d. The resulting mix-
ture was concentrated at 60°C under vacuum and the yellow oil ob-
tained was purified by filtration on silica gel (hexane/Et2O, 6:1) (dr
89:11). Final column chromatography on silica gel (hexane/Et2O,
6:1) afforded the pure diastereomer 6a.
X-Ray Crystal Structure Analysis of Pyrazoline 10b:
Crystal data: C17H22N2O3, Mr = 302.37, monoclinic, C2, a =
1993.8(5), b = 614.6(2), c = 1348.7(3) pm, β = 102.35(2)°, V = 1.6144
nm3, Z = 4, Dx = 1.244 Mg m–3, F(000) = 648, λ(Mo Kα) = 71.073
pm, µ = 0.09 mm–1, T = –100°C.
Data collection and reduction: Irregular colourless prism 1.0 × 0.25
× 0.2 mm, Siemens P4 diffractometer, 2661 intensities to 2θmax 55°,
2002 independent. Structure solution: direct methods.
(3R)-(E)-2-Benzylidene-3-methyl-â-lactone (8):
A 3 M aq HCl (≈3 mL) solution was added to a solution of 1f (1.88 g,
7.22 mmol) in THF (20 mL). The mixture was stirred at r.t. until the
reaction was complete (TLC). The solution was extracted with Et2O
(5 × 10 mL). The combined Et2O phases were extracted with satd aq
NaHCO3 solution and brine. The organic phase was dried (Na2SO4)
and evaporated using a rotatory evaporator. The remaining β-hydroxy
acid 7 (1.08 g, 78% yield) was dissolved in CH2Cl2 (20 mL) without
prior purification. Methanesulfonyl chloride (3 mL, 39 mmol) and
Na2CO3 (3 g) were added at 0°C under stirring. The mixture was
stirred at 0°C for 1 h and at r.t. for 3 h. After complete reaction (TLC)
Na2CO3 was filtered off. The organic phase was washed with satd aq
NaHCO3 solution (3 × 10 mL) and with brine (10 mL). After drying
(Na2SO4) the solution was concentrated at r.t. under vacuum. Column
chromatography on silica gel (hexane/Et2O, 2:1) yielded 490 mg
(39%) of 8 as colourless crystalline solid: mp 62–63°C (Et2O); [α]D
+ 26.8 (c = 1, CHCl3).
Structure refinement: anisotropic on F2 (program SHELXL-93, G.M.
Sheldrick, University of Göttingen); H atoms with riding model or
rigid methyl groups; wR(F2) 0.112 (all refl.), R(F) 0.046 (F > 4σ(F))
for 203 parameters and 206 restraints (to light atom U components);
max. ∆ρ 315 e nm–3, S = 0.98. The absolute configuration was based
on the known configuration at C2 and C3. Full details have been de-
posited at Fachinformationszentrum Karlsruhe, Gesellschaft für wis-
senschaftlich-technische Information mbH, 76344 Eggenstein-Le-
opoldshafen and can be obtained by quoting a full literature citation
and the deposition number CSD 408033.
Spirocyclopropanes 12 by N2-Elimination from Pyrazolines 3;
General Procedure:
A solution of the spiropyrazoline 3 (0.5 mmol) in degassed benzene
(200 mL) was irradiated at 330 nm for 3–12 h (TLC-control). After
the reaction was complete, the solvent was removed under vacuum.
In most cases products 12 remained as colorless oils in analytically
pure form. In some cases further column chromatography was neces-
sary (12a: hexane/Et2O, 7:1; Rf 0.5; 12e: hexane/Et2O, 10:1; Rf 0.85)
(Table 2).
1H NMR (CDCl3): δ = 1.60 (d, J = 6.2 Hz, 3 H, CH3), 5.42 (q, J = 6.2
Hz, 1 H, CH), 7.04 (s, 1 H, 1'-H), 7.26–7.39 (m, 5 H, C6H5).
13C NMR (CDCl3): δ = 17.8 (CH3), 76.4 (CH), 129.2, 129.8 (CHarom),
130.0 (CH-1'), 130.6 (CHarom), 132.1 (C-3), 137.2 (Carom), 164.6
(C=O).
IR (KBr): ν = 3426, 1799, 1691, 1450, 1261, 1136, 1116, 808, 771,
691 cm–1.
Cyclopropanecarboxylic Acids 13 (R4 = H); General Procedure:
A 10% aq HCl solution (5 mL) was added to a solution of 12
(0.5 mmol) in THF (10 mL). After stirring at r.t. overnight Et2O was
added (20 mL). The solution was washed with H2O (3 × 10 mL). The
product was extracted from the organic phase with several portions of
satd aq KHCO3 solution. After acidification (pH 1–2) of the aq phase
with 10% aq HCl, the product was separated by extraction with Et2O
(3 × 20 mL). The organic phase was dried (Na2SO4) and evaporated
under vacuum affording the product 13 as a colourless oil (Table 2).
MS (70 eV): m/z = 174 (M+, 100), 159 (69), 131 (54), 129 (48), 115
(54), 103 (59), 102 (58), 77 (37), 51 (32), 43 (18), 39 (18).
Spiro-â-lactone 9:
A freshly prepared 1 M solution of CH2N2 in Et2O (10 mL, 10 mmol)
was added to a solution of 8 (110 mg, 0.63 mmol) in Et2O (10 mL) at
0°C. The mixture was allowed to warm up to r.t. overnight and the
solution was evaporated to dryness. The remaining white solid (134
mg, 98%) was recrystallized from Et2O.
1H NMR (CDCl3): δ = 0.90 (d, J = 6.6 Hz, 3 H, CH3), 3.63, 4.73 and
5.00 (ABX, JAB = 17.6 Hz, JAX = 1.1 Hz, JBX = 7.6 Hz, 3 H, 1 CH-Ph,
CH2-pyrazoline), 5.65 (q, J = 6.6 Hz, 1 H, CH), 6.72–7.24 (m, 3 H,
C6H5).
Compound 13c:
NaOMe (66 mg, 1.2 mmol) was added to a solution of 12a (220 mg,
0.82 mmol) in anhyd MeOH (20 mL) at 0°C under stirring. The mix-
ture was allowed to warm up to r.t. and was stirred until the reaction
was complete (TLC, about 12 h), poured into satd aq NH4Cl solution
(10 mL) and extracted with CH2Cl2 (3 × 30 mL). The dried organic
phase (Na2SO4) was concentrated under vacuum and the residue was
submitted to column chromatography on silica gel (hexane/Et2O, 6:1)
to afford 130 mg (73%) of the product 13c.
13C NMR (CDCl3): δ = 17.8 (CH3), 40.0 (CH), 87.5 (CH2), 108.5
(C-pyrazoline), 126.9, 127.0, 129.6 (CHarom), 137.9 (Carom), 164.3
(C=O).
Ethyl (S)-4-Phenyl-1-pyrazoline-3-carboxylate [(S)-5]:
NaOEt (64 mg, 0.93 mmol) was added to a solution of 9 (200 mg, 0.93
mmol) in anhyd EtOH (20 mL). After stirring overnight the solvent
was evaporated under vacuum. The resulting mixture was separated
by column chromatography on silica gel (EtOAc/hexane, 1:1; Rf 0.5);
yield: 73 mg (39%); light yellow oil; [α]D –26 (c = 0.5, CHCl3).
Compound 13d:
Solid K2CO3 (157 mg, 1.13 mmol) was added to a solution of the
spirocyclopropane 12e (234 mg, 1.03 mmol) in anhyd EtOH (20 mL).
The mixture was stirred overnight at r.t. After filtering off the K2CO3,
the filtrate was evaporated to dryness. The residue was dissolved in
EtOAc (20 mL) and the organic phase was washed with aq NH4Cl
solution (2 × 10 mL) and with brine (20 mL). The organic phase was
dried (Na2SO4) and the solvent was stripped off under vacuum afford-
ing 140 mg (75 %) 13d as a colourless oil.
1
1H NMR (CDCl3): δ = 1.14 (t, J = 7.1 Hz, 3 H, CH3), 3.62 (dd, J
= 5.9 Hz, 2J= 10.0 Hz, 1 H, CH), 4.00 (m, 1 H, CH2-pyrazoline), 4.09
(q, J = 7.1 Hz, 2H, OCH2), 4.29 (m, 1 H, CH2-pyrazoline), 6.16 (s,
1 H, NH), 7.16–7.25 (m, 5 H, C6H5).
13C NMR (CDCl3): δ = 14.2 (CH3), 49.3 (CH), 58.1 (CH2N), 61.0
(CH2O), 127.3, 128.4, 129.4 (CHarom), 140.8 (Carom), 145.6 (C=N),
162.2 (C=O).
Ethyl 2-Ethyl-(1-phthalimidoethyl)cyclopropanecarboxylate (14):
Ph3P (100 mg, 0.42 mmol), phthalimide (65 mg, 0.42 mmol) and di-
ethyl azodicarboxylate (72 µL, 0.42 mmol) were added to a solution
of 13d (70 mg, 0.38 mmol) in anhyd THF (10 mL). The resulting
reddish brown solution was stirred at r.t. overnight. The solvent was
removed under vacuum and the crude product was purified by column
chromatography on silica gel (hexane/Et2O, 1:1; Rf 0.5) affording
60 mg (50 %) 14 as a light yellow oil (Table 2).
Ethyl (R)-4-Phenyl-1-pyrazoline-3-carboxylate [(R)-5]:
A mixture of NaOEt (45 mg, 0.66 mmol), pyrazoline 3i (200 mg, 0.66
mmol) and anhyd EtOH (20 mL) was reacted and worked up as shown
for (S)-5 (see above) affording 33 mg (23 %) of (R)-5 as a light yellow
1
oil; [α]D +20 (c = 1, CHCl3). H NMR and 13C NMR spectra were
identical with the spectra of (S)-5.

SYNTHESIS
(3) Amberg, D.; Seebach, D. Chem. Ber. 1990, 123, 2413.
Papers
1654
5-Alkylidene-1,3-dioxan-4-ones 15; General Procedure:
A solution of spiropyrazoline 3 (0.7 mmol) in xylene (20 mL) was
stirred at 130°C for 5 h. The solvent was removed under vacuum and
the crude product was purified by column chromatography (hexane/
EtOAc, 1:1) affording the corresponding 15 as colourless oils.
(4) Carey, F. A.; Sundberg, R. J. Organische Chemie, VCH, 1995,
1079.
(5) Pommier, A.; Pons, J. M. Synthesis 1993, 441.
(6) Adam, W.; Salgado, V. O. N.; Wegener, B.; Winterfeldt, E.
Chem. Ber. 1993, 126, 1509.
(7) Adam, W.; Albert, R.; Hasemann, L.; Navalsagado, V. O.; Nest-
ler, B.; Peters, E. M.; Precht, F.; von Schnering, H. G. J. Org.
Chem. 1991, 56, 5782.
(8) Seebach, D.; Züger, M. Helv. Chim. Acta 1982, 65, 495.
Seebach, D.; Beck, A. K.; Breitschuh, R.; Job, K. Org. Synth.
1992, 71, 39.
We gratefully acknowledge the financial support from the Deutsche
Forschungsgemeinschaft (DFG) and the Fonds der Chemischen
Industrie. We thank Zeneca Biopolymers for donation of polyhydrox-
ybutyrate and Shell AG for a generous gift of pivalaldehyde.
(9) Seebach, D.; Imwinkelried, R. Helv. Chim. Acta 1987, 70, 448.
(10) de Doer, T. J.; Dacher, H. J. Org. Synth., Coll. Vol. IV, 1963,
250.
(1) Bartels, A.; Liebscher, J. Tetrahedron: Asymmetry 1994, 5,
1451; see also Bartels, A. PhD-thesis, Humboldt-University,
1997.
(2) Drewes, S. E.; Emslie, N. D.; Karodia, N.; Abdullah A. Khan
Chem. Ber. 1990, 123, 1447.
(11) Werner, E. A. J. Chem. Soc. 1919, 115, 1097.