Enantioselective synthesis of paraconic acids

Article abstract of DOI:10.1002/chem.200390019

The development of a new method for the enantioselective synthesis of disubstituted γ-butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (-)-roccellaric acid, (-)-nephrosteranic acid and (-)-protopraesorediosic acid, and the formal total synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(i)-catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(i)-catalyzed, intermolecular cross metathesis reactions.

Full text of DOI:10.1002/chem.200390019

FULL PAPER
Enantioselective Synthesis of Paraconic Acids
Rakeshwar B. Chhor, Bernd Nosse, Sebastian Sˆrgel, Claudius Bˆhm, Michael Seitz,
[
a]
and Oliver Reiser*
Dedicated to Professor Volker J‰ger on the occasion of his 60th birthday
Abstract: The development of a new method for the enantioselective synthesis of
disubstituted g-butyrolactones is reported. Based on this strategy, the total synthesis
of three paraconic acids, that is (À)-roccellaric acid, (À)-nephrosteranic acid and (À)-
protopraesorediosic acid, and the formal total synthesis of (À)-methylenolactocin
and (À)-protolichesterinic acid is described, which are important because of their
antibiotic and antitumor properties. Key steps of the synthesis are copper(i)-catalyzed
asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allyla-
tions, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and
ruthenium(ii)-catalyzed, intermolecular cross metathesis reactions.
Keywords: asymmetric synthesis ¥
lactones metathesis natural
products ¥ total synthesis
¥
¥
Introduction
g-Butyrolactones are a most frequently occurring structural
element in organic compounds and are present in about 10%
of all natural products.[ They are equivalent to 4-hydroxy-
carbonyl compounds (homoaldols),[ but in comparison to the
vast methodology available for the synthesis of aldol com-
pounds[ (3-hydroxycarbonyl compounds), there are relative-
ly few asymmetric methods known for their de novo syn-
thesis.[
1]
2]
3]
4]
Trisubstituted g-butyrolactones,[5] especially paraconic
acids (ˆ 3-carboxylic acid substituted g-butyrolactones) have
attracted considerable interest because of their antibiotic and
antitumor properties.[ Therefore a number of syntheses have
been developed leading to these natural products either in
racemic[ or enantiopure form using starting materials from
Scheme 1. Retrosynthetic analysis of paraconic acids.
6]
7]
building blocks.[12] Most relevant to our work, Rei˚ig et al.
have elegantly demonstrated the use of cyclopropanols (rac)-
[8]
[9]
the chiral pool, chiral auxiliaries, or applying catalytic
asymmetric methodology.[ We present here a strategy for
the catalytic asymmetric synthesis of anti-2,3-disubstituted g-
butyrolactones 1 from furancarboxylic methyl esters 2
10]
4
for the synthesis of lactols (rac)-3 as precursors to paraconic
[13]
acids (Scheme 2). While in the latter approach all cyclo-
propyl carbon atoms of (rac)-3 end up in the lactol ring, our
synthesis of g-butyrolactones 5 or 6, respectively, is achieved
from the cyclopropanol 7 utilizing two of the cyclopropane
ring carbons while the third atom forms the exocyclic
carboxylic acid function as the decisive structural element
found in all paraconic acids. What makes this strategy
especially attractive is the fact that 7 and consequently 5
and 6 can be readily synthesized in a highly diastereo- and
enantioselective manner in both optical forms from furan-2-
carboxylic ethyl ester using an asymmetric copper-catalyzed
cyclopropanantion as the key step.
(
Scheme 1) and the subsequent synthesis of a several para-
[11]
conic acids.
Vicinal substituted hydroxycyclopropane carboxylates have
been widely recognized as versatile surrogates for acyclic
[
a] Prof. Dr. O. Reiser, Dr. R. B. Chhor, Dipl.-Chem. B. Nosse,
Dipl.-Chem. S. Sˆrgel, Dr. C. Bˆhm, Dipl.-Chem. M. Seitz
Institut f¸r Organische Chemie
Universit‰t Regensburg
Universit‰tsstrasse 31, 93053 Regensburg (Germany)
260
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Chem. Eur. J. 2003, 9, No. 1

2
60±270
Table 1. Asymmetric cyclopropanation of 2 with diazoacetates.[a]
Entry Furan 2 Diazoaceate Ligand
Product
Yield[b]
[%]
Selectivity[c]
[%] ee
3
R
1
2
3
4
5
6
7
8
9
0
1
2
3
2a
2b
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
Me
Et
Et
Me
Me
Et
9a
9a
9b
9a
9b
9b
9c
8a-Me
8b-Et
8b-Et
8c-Me
8c-Me
8c-Et
8c-Et
7
27
22
45
55
63
35 (77)
51
74
74
69
85
91[
f]
[
[
d]
d]
[e]
[e]
[f]
Et
Et
81
75
[f]
(ent)-(9c) (ent)-8c-Et 33 (71)
9c
10a
10b
10c
10d
95[
94
91
91
85
f]
tBu
Me
Me
Me
Me
8c-tBu
8c-Me
8c-Me
8c-Me
8c-Me
38
23
36
18
31
1
1
1
1
[
[
1
a] 3 equiv 2c, 1 equiv diazoacetate, 2.0 mol% Cu(OTf)
b] Isolated yield based on diazoacetate. [c] Measured by HPLC. [d] 1 equiv 2c,
equiv diazoacetate, 0.66 mol% Cu(OTf) , 0.83 mol% ligand. [e] Isolated yield
based on conversion of 2c. [f] > 99% ee after single crystallization [isolated yield
2
, 2.5 mol% ligand.
Scheme 2. Cyclopropanols as precursors to g-butyrolactols and g-buty-
rolactones.
2
5
3% (entry 6), 32% (entry 7), 29% (entry 8) and 27% (entry 9)].
Asymmetric cyclopropanation of furans: The copper(i)- or
rhodium(ii)-catalyzed cyclopropanation of furans with diazo
esters[ or diazomethane
14]
[15]
has been described to yield
-oxa[3.1.0]bicyclohexenes. We have been able to render this
2
as well as selectivity (entry 1). We therefore turned our
attention to substituted furans 2b and 2c following the
precedent set by Anderson et al. for the asymmetric cyclo-
process asymmetric by treating furans 2 with methyl diazo-
acetate in the presence of catalytic amounts of chiral copper(i)
bisoxazoline complexes[
16]
(Scheme 3, Table 1). However,
[17]
propanation of 2,3-dihydrofurans.
furan 2a proved to be a poor substrate both in terms of yield
The reaction proceeds regioselectively for furans 2b and
2
c; only the less-substituted double bond was cyclopropa-
nated, as well as diastereoselectively, orienting the ester group
exclusively on the convex face of the bicyclic framework. We
have not been able to detect any of the corresponding endo-
diastereomers or products that would be expected to have
formed by a retro-Claisen rearrangement.[ The apparent
high diastereoselectivity was somewhat surprising since endo-
products were always observed in the cyclopropanation of 2,3-
18]
[17]
dihydrofurans. Last but not least, chiral ligands such as the
bisoxazolines 9[ or the azabisoxazoline 10 promoted the
19]
[20]
reaction with high enantioselectivity. The ester group at
2
-position of the furan proved to be advantageous compared
to the one in 3-position, both, in terms of yield as well as
enantioselectivity. Thus, 8c-Me (Table 1, entries 4 ± 5, 10 ± 13)
was obtained in up to 94% ee (entry 10), but the best result
was obtained with bisoxazoline 9b, which gave 8c-Et with
91% ee and in good yield (entry 6). Moreover, in contrast to
Scheme 3. Asymmetric cyclopropanation of 2 with diazoacetates.
8
c-Me, 8c-Et is a crystalline adduct, which allows isolation of
enantiomerically pure material by a remarkably effective and
single crystallization. Therefore, for large-scale preparation of
Abstract in German: Aufbauend auf einer neuen,allgemein
anwendbaren Strategie zur Synthese von disubstituierten g-
Butyrolactonen gelang die enantioselektive Totalsynthese von
drei verschiedenen Paracons‰uren,( À)-Roccellarins‰ure,( À)-
Nephrosteranins‰ure und (À)-Protopraesoridiosins‰ure,sowie
die formale Totalsynthese von (À)-Methylenolactocin und (À)-
Protolichesterins‰ure,die aufgrund ihrer antibiotischen und
Antitumoreigenschaften von Bedeutung sind. Schl¸sselschritte
der Synthesen sind Kupfer-katalysierte,asymmetrische Cyclo-
propanierungen von Furanen,hoch diastereoselektive Sakurai
Allylierungen,Lewiss‰ure- oder basenkatalysierte Retroaldol-
Lactonisierungskaskaden sowie Ruthenium-katalysierte,inter-
molekulare Metathese Reaktionen.
8
9
8
c or (ent)-8c the use of the ligands 9c or its enantiomer (ent)-
c or 10d, with still good selectivities of 75 ± 85% ee (entries 7,
, 13), might be advantageous since they are obtained from
inexpensive valine readily available in both enantiomers,
while 9b and 10b are derived from the considerable more
expensive tert-butyl leucine. Thus, 8c-Et or (ent)-8c-Et were
prepared on a 20 ± 60 g scale in the presence of 0.66 mol%
Cu(OTf) /0.83 mol% 9c or (ent)-9c. Moreover, furan 2c was
2
readily reisolated by distillation, giving rise to up to 77% yield
of 8c-Et or (ent)-8c-Et based on conversion of 2c. Using tert-
butyl diazoacetate[ as the carbene source even higher
enantioselectivities can be achieved (cf. entries 7 and 9).
Nevertheless, the preparation of ethyl diazoacetate is more
21]
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261

O. Reiser et al.
FULL PAPER
convenient[22] especially on large scale making the latter the
reagent of choice for the synthesis of 8c.
The absolute configuration of 8c-Et was unambiguously
proven by X-ray structure analysis (Figure 1);[ its subse-
quent transformations to paraconic acids have already been
described in the literature.[
23]
9, 10]
The configuration of all other
derivatives 8 was assigned by
analogy.
Compound 8c-Et was read-
ily transformed to the cyclo-
propane carbaldehyde 11 by
ozonolysis, followed by reduc-
tive workup (Scheme 4). We
already demonstrated that nu-
Figure 1. Ortep drawing of
8
c-Et.
cleophiles can selectively be added to (rac)-11, giving the
Felkin ± Anh[ adduct (rac)-12 with diastereoselectivities of
24]
Scheme 5. Formation of lactones 5 or 6 through retroaldol/lactonization
of 13.
[25]
8
0:20 to ꢀ95:5.
It occurred to us that if a retro-aldol
reaction in 12 can be initiated, thus breaking the bond
between C-4 and C-6, g-butyrolactones should be obtained by
lactonization of the hydroxyl group at C-2 with the C-5 carbon
of the ethyl ester group.
(anti/syn) was identical, which indicates that no epimerization
during the retroaldol/lactonization sequences occurs.
The lactones 5a, b and 6a seemed to be ideal precursors for
the synthesis of a broad variety of the enantiomeric series of
natural occurring paraconic acids.[
Indeed, we were able to develop two different protocols
leading selectively either to 5 or 6 (Schemes 4 and 5, Table 2).
Addition of allylsilanes or silyl enol ethers to 11 catalyzed by
BF ¥ Et O resulted in the adducts 12 with diastereoselectiv-
27]
3
2
Most easily, the formal synthesis of (À)-methylenolactocin
(18) was accomplished by hydrogenation of the diene 5b
(Scheme 6) followed by oxidation of the aldehyde with
ities ꢀ95:5, which were directly converted to the lactones 5 or
6
without the need of isolation. Upon treatment of crude 12
[28]
with base the lactones 5 were obtained, having the aldehyde
group available in unprotected form for further synthetic
transformations.
Alternatively, using Otera×s SnIV catalyst[26] 15 in the
presence of ethylene glycol resulted in the smooth formation
of 6, in which saponification to 13 followed by ring opening to
NaClO using the variant introduced by Dalcanale.
The
2
resulting product was recrystallized to remove the minor cis-
diastereomer giving rise to the known carboxylic acid 17 in
diastereomeric and enantiomeric pure form in 86% yield. The
final introduction of an exo-methylene group into 18 to yield
[
9e]
(À)-methylenolactocin (17) had been already reported.
14, acetalization of the aldehyde group and lactonization, all
For the synthesis of paraconic acids being substituted with
alkyl chains of various lengths the lactones 5a or 6a were
employed (Scheme 7). We envisioned that the allyl group
could be used in metathesis reactions to directly introduce the
desired side chains. While ring-
had taken place in a single step (Scheme 5, Table 2). In all
cases, the diastereomeric ratio of the cyclopropanes 12
(
Felkin-Anh/anti-Felkin-Anh at C-2) and the lactones 5 or 6
closing metathesis (RCM)[
29]
has been widely used in organic
synthesis, there are considera-
bly fewer examples for inter-
[
30]
molecular reactions,
most
likely due to the potential for-
mation of homocoupled dimers
at the expense of the desired
heterocoupled products.
Compound 6a (trans/cis ratio
9
5:5) was treated with 1-dode-
cene in the presence of Grubb×s
catalyst 23. In order to avoid
the homocoupling of 6a,
1
.5 equivalents of the alkene
had to be employed
Scheme 8). Thus, only the ho-
(
mocoupling product of 1-dode-
cene was produced as an unpo-
lar, thus readily removable by-
Scheme 4. Synthesis of lactones 5 or 6 via cyclopropane carbaldehyde 11.
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Chem. Eur. J. 2003, 9, No. 1

Paraconic Acids
260±270
1
Table 2. g-Butyrolactone synthesis 5 or 6 by addition of nucleophiles R M to 11 followed by retroaldol/lactonization sequence.
1
Method[a]
Entry
Aldehyde
R M
ROH
Lactone
Yield [%]
trans/cis ratio
1
2
3
4
11-Et
11-Et
11-Et
11-Et
A
B
C
A
n/a
5a
5a
6a
5b
64
49
72
66
95:5
95:5
95:5
97:3
n/a
HOCH
n/a
2
CH
2
OH
OH
5
(rac)-11-Me
A
n/a
(rac)-5c
73
80:20
6
7
(rac)-11-Me
(rac)-11-Me
C
HOCH
n/a
2
CH
2
(rac)-6b
(rac)-5d
26
44
95:5
96:4
A
[
a] Allylation to 12: 11 (1.0 equiv), BF
3
¥ Et
¥ 8H
2
O (1.0 ± 1.25 equiv), corresponding allylsilanes (1.0 ± 1.25 equiv), CH
2
Cl
2
, À788C; saponification and ring-
opening to 5 or 6: method A: Ba(OH)
2
2
O (1 equiv), MeOH, 08C; method B: NaOMe (1 equiv), MeOH, 08C; method C: 15 (0.05 mol%), ROH.
[
9d]
formed to (À)-protolichesterinic acid (21)
and to (À)-
roccellaric acid (19) as depicted in Scheme 8.[ We were able
to improve the conversion of 26 to 19 (96% yield instead of
9c]
5
5%) by employing NaHMDS (2.2 equiv) and an excess of
methyl iodide.
Scheme 6. Formal synthesis of methylenolactocin (18).
Scheme 8. Total synthesis of (À)-roccellaric acid (19) and (À)-protoliches-
terinic acid (21).
Scheme 7. Retrosynthetic analysis for 19 to 22.
In an analogous way, (À)-nephrosteranic acid (20) was
synthesized starting from the lactone 5a (Scheme 9). The
unprotected aldehyde group in 5a dictated the use of the
more active metathesis catalyst 27,[ nevertheless, 28 was only
obtained in 45% yield along with 30% recovered starting
material using 1.5 equivalents of 1-decene. Attempts to
improve this yield by using a total of 4 equiv of 1-decene in
the cross metathesis were only moderately successful: In this
case, 28 was isolated in 53% yield along with 27% of
recovered 5a. It should be noted that catalyst 27 gave a much
higher (E)-selectivity in the cross coupling product than 23 (cf.
Scheme 8).
product along with the desired 24 as a 3.5:1 E/Z-mixture. The
latter was without consequence, since the double bond in 24
was subsequently hydrogenated to 25, followed by simulta-
neous cleavage and oxidation of the acetal under acidic
conditions. Compound 26 was obtained in this way as a single
stereoisomer after one recrystallization, which removed the
minor cis-diastereomer. Its structure could be unequivocally
32]
established by X-ray structure analysis (Figure 2).[
31]
More-
over, 26 was synthesized before and subsequently trans-
Finally, the first total synthesis of protopraesorediosic acid
(
22) was accomplished (Scheme 10) starting with the cross
metathesis of lactone 5a and the alkene 31. The heterocou-
pled alkene 32 was obtained in a clean reaction, although the
Figure 2. Ortep drawing of 26.
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263

O. Reiser et al.
FULL PAPER
dried by standard methods. Chromatography: Macherey ± Nagel silica gel
(
0.03 ± 0.06 mm). Enantiomeric excesses were determined by analytical
HPLC using a ™Chiracel OD-H∫ column (50 Â 4.6 mm, 10 mm, flow:
À1
1
mLmin , 208C) and a UV detector at 254 nm. TLC: commercially
precoated silica gel aluminium sheets 60F254 (Merck). Uncorrected melting
point: B¸chi SMP 20. IR: Mattson Genesis series FT-IR, Perkin ± Elmer
À1
1
13
2
98, Bruker IFS 66, nÄ in cm . H NMR and C NMR: Bruker ARX400,
Avance 300, AC250F, d in ppm, J in Hz. Multiplicities were determined by
DEPT (distortionless enhancement by polarization transfer) measure-
ments. MS: Finnigan MAT 95, Varian MAT 311A. Elemental analysis:
Heraeus CHN-Rapid. XRD: Stoe Imaging Plate System, Siemens Stoe
AED2. Optical rotation: Perkin ± Elmer polarimeter PE 241.
(
1S,5R,6S)-2-Oxabicyclo[3.1.0]hex-3-ene-4,6-dicarboxylic 6-ethyl ester-3-
methyl ester (8b-Et): Phenylhydrazine (1 drop) in CH Cl (1 mL) was
added under nitrogen at 08C to a mixture of 2b (1.14 g, 9.0 mmol,
2
2
3
0
.0 equiv), Cu(OTf)
.075 mmol, 2.5 mol%). After 5 min, a solution of ethyl diazoacetate
Cl (10 mL) was added slowly with a
2
(22 mg, 0.06 mmol, 2.0 mol%) and 9b (66 mg,
(
342 mg, 3.0 mmol, 1 equiv) in dry CH
2
2
syringe pump over 8 h. The reaction mixture was filtered through a short
pad of basic alumina and solvent was evaporated in vacuo. The residue was
purified by chromatography on silica gel (hexanes/ethyl acetate 10:1) to
Scheme 9. Total synthesis of (À)-nephrosteranic acid (20).
1
provide 8b-Et as a pale yellow oil (140 mg, 22%, 74% ee). H NMR
(
7
4
(
(
250 MHz, CDCl
.1 Hz, 3H, CH
), 3.10 (ddd, J ˆ 5.7, 2.9, 0.5 Hz, 1H, 5-H), 3.77 (s, 3H, CH
.15 (q, J ˆ 7.1 Hz, 2H, CH ), 5.02 (ddd, J ˆ 5.7, 1.0, 0.9 Hz, 1H, 1-H), 7.21
ddd, J ˆ 0.9, 0.6, 0.5 Hz, 1H, 3-H); C NMR (62.9 MHz, CDCl
3
): d ˆ 1.14 (ddd, J ˆ 2.9, 1.0, 0.5 Hz, 1H, 6-H), 1.27 (t, J ˆ
3
3
),
2
1
3
3
): d ˆ 14.2
), 68.9 (‡,
‡, CH
3
), 21.7 (‡, C-5), 29.5 (‡, C-6), 51.4 (‡, CH
3
), 61.0 (À, CH
2
C-1), 156.3 (‡, C-3), 164.0 (Cquat, CO), 171.4 (Cquat, CO); IR (film): nÄ ˆ
À1
3
109, 2986, 2957, 1730, 1604, 1031 cm ; MS (EI, 70 eV): m/z (%): 212.2 (12)
‡
[
M ], 184.1 (11), 139.1 (100), 127.1 (16), 126.1 (11), 111.1 (129), 108.1 (18),
1
07.1 (24), 99.1 (61), 95.1 (13), 83.1 (11), 79.1 (15), 58.1 (16), 43.1 (64), 29.1
(
36); elemental analysis calcd (%) for C10 (212.2): C 56.60, H 5.70;
12 5
H O
found C 56.64, H 5.58.
(
3
1S,5S,6S)-(À)-2-Oxabicyclo[3.1.0]hex-3-ene-3,6-dicarboxylic 6-ethyl ester
-methyl ester (8c-Et)
Method A: Phenylhydrazine (89 mg, 0.82 mmol, 2.0 mol%) was added
under nitrogen at 08C to a mixture of 2c (12.9 mL, 120 mmol, 3 equiv),
Cu(OTf)
2
(297 mg, 0.82 mmol, 2.0 mol%) and 9b (303 mg, 1.02 mmol,
.5 mol%). After 30 min, solution of ethyl diazoacetate (4.685 g,
1.1 mmol, 1 equiv) in dry CH Cl (70 mL) was added continuously with
2
4
a
2
2
a syringe pump over 12 h in four equal amounts. After each addition,
CH Cl was evaporated by passing nitrogen through the flask. Excess of
2
2
furan-2-carboxylic methyl ester was evaporated under high vacuum at
room temperature, and the residue was purified by chromatography on
silica gel (hexanes/EE 10:1) to provide 8c-Et as a colorless oil (5.494 g,
Scheme 10. Total synthesis of (À)-protopraesorediosic acid (22).
6
3%). Enantiopure product 8c-Et could be obtained by recrystallization
from n-pentane (4.622 g, 53%).
conversion of 5a was again low. After hydrogenation and
oxidation following the examples outlined above, the ester 34
was saponified to the diacid 35 in high yield. For the final
introduction of the exo-methylene group into a lactone
Method B: Phenylhydrazine (241 mL, 2.44 mmol, 0.83 mol%) was added
under nitrogen at 08C to a solution of 2c (37.0 g, 0.293 mol, 1.0 equiv),
Cu(OTf)
2
(700 mg, 1.94 mmol, 0.66 mol%) and (À)-9c (649 mg, 2.44 mmol,
.83 mol%). After 20 min, a solution of ethyl diazoacetate (30.6 mL,
.293 mol, 1.0 equiv) in dry CH Cl (200 mL) was added through a
0
0
2
2
[33]
various methods are known in the literature. In our hands
the procedure described by Greene et al.[ worked best to
give 22 in 62% yield.
dropping funnel over 13 h. The reaction mixture was filtered through a
short pad of basic alumina and solvent was evaporated in vacuo.
33a]
Unconverted 2c was removed by distillation (5 mbar, b.p. 63 ± 648C,
À4
2
1
7
0.0 g, 54%) and the residue was purified by kugelrohr distillation (10
0
±
In conclusion, we have developed an asymmetric synthesis
towards g-butyrolactones using catalytic asymmetric method-
ology in the key step. The utility of this method was
demonstrated in the synthesis of a variety of paraconic acids,
which are obtained in 7 ± 9 steps in overall yields of 7 ± 21%
from inexpensive furan carboxylic methyl ester as starting
material.
À5
mbar, 888C) to provide 8c-Et as a yellowish oil (22.0 g, 35% yield,
7% yield based on conversion of 2c, 81% ee) which after crystallization
from n-pentane appeared as yellowish crystals (20.12 g, 32%, 99% ee). R
f
2
0
1
(PE/EE 5:1) ˆ 0.14; m.p. 428C; [a]
250 MHz, CDCl
): d ˆ 1.16 (dd, J ˆ 2.7, 1.1 Hz, 1H, 6-H), 1.23 (t, J ˆ
.1 Hz, 3H, CH
D
ˆ À272 (c ˆ 1.0, CH
2 2
Cl ); H NMR
(
3
7
3
), 2.87 (ddd, J ˆ 5.3, 2.9, 2.7 Hz, 1H, 5-H), 3.78 (s, 3H,
OCH
6
CH
3
), 4.12 (q, J ˆ 7.1 Hz, 2H, CH
2
), 4.97 (dd, J ˆ 5.3, 1.1 Hz, 1H, 1-H),
): d ˆ 14.2 (‡,
), 61.0 (À, CH ), 67.5 (‡,
13
.39 (d, J ˆ 2.9 Hz, 1H, 4-H); C NMR (62.9 MHz, CDCl
3
3
), 21.5 (‡, C-6), 31.9 (‡, C-5), 52.1 (‡, OCH
3
2
C-1), 116.0 (‡, C-4), 149.3 (Cquat, C-3), 159.5 (Cquat, CO), 171.7 (Cquat, CO);
IR (KBr): nÄ ˆ 3118, 2956, 1720, 1617, 1428, 1380, 1297, 1166, 1124, 1041, 954,
Experimental Section
À1
‡
‡
8
CO
31, 725 cm ; MS (70 eV, EI): m/z (%): 212.1 [M ] (9.8), 153.0 [M
À
‡
2
Me] (11.5), 139.0 [M À CO
2
Et] (100), 124.9 (24.4), 98.9 (28.6), 96.9
General remarks: Reactions with moisture-sensitive chemicals were
performed under nitrogen in a flame-dried reaction flask. Solvents were
(31.7), 78.9 (11.3), 59.0 (13.5), 52.1 (11.5); elemental analysis calcd (%) for
10 12 5
C H O (212.2): C 56.60, H 5.70; found C 56.51, H 5.73.
264
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0264 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 1

Paraconic Acids
260±270
(
1S,5S,6S)-(À)-2-Oxabicyclo[3.1.0]hex-3-ene-3,6-dicarboxylic 6-tert-butyl
NaOMe (0.365 g, 6.77 mmol, 1 equiv) in dry methanol (15 mL). After
135 min, the solvent was evaporated under vacuo. The residue was
ester 3-methyl ester (8c-tBu): Phenylhydrazine (11.5 mL, 116.77 mmol,
0
1
9
.83 mol%) was added under nitrogen at 08C to a mixture of 2c (1.77 g,
4.07 mmol, 1.0 equiv), Cu(OTf) (33.6 mg, 92.85 mmol, 0.66 mol%) and
c (31.1 mg, 116.77 mmol, 0.83 mol%). After 30 min, a solution of tert-
Cl (30 mL) was
dissolved in CH
aqueous layer was extracted with CH
organic layers were dried, filtered and concentrated in vacuo. Chromatog-
raphy on silica gel (hexane/EE 1:1) yielded 5a as a colorless oil (0.510 g,
2
Cl
2
(40 mL) and washed with water (2 Â 20 mL). The
2
2
Cl
2
(5 Â 30 mL). The combined
butyl diazoacetate (2.0 g, 14.07 mmol, 1.0 equiv) in dry CH
2
2
2
0
added slowly with a syringe pump over 9 h. The reaction mixture was
filtered through a short pad of basic alumina and solvent was evaporated in
vacuo. The residue was purified by chromatography on silica gel (hexanes/
EE 10:1) to provide 8c-tBu as a yellowish crystals (1.30 g, 38%, 95% ee)
which after crystallization from dichloromethane and n-pentane appeared
49%, dr 95:5). R
f
(hexanes/EE 1:1) ˆ 0.17; [a]
D
ˆ À31.7 (c ˆ 1.35 in
1
CH
2
Cl
2
); H NMR (250 MHz, CDCl
3
): d ˆ 2.35 ± 2.59 (m, 2H, 1'-H), 2.71
(dd, J ˆ 18.2, 9.9 Hz, 1H, 3-H), 2.89 (dd, J ˆ 18.2, 7.5 Hz, 1H, 3-H), 3.19
(dddd, J ˆ 10.0, 7.3, 6.0, 1.2 Hz, 1H, 4-H), 4.74 (dd, J ˆ 11.9, 6.2 Hz, 1H,
5-H), 5.10 ± 5.27 (m, 2H, 3'-H), 5.75 (dddd, J ˆ 17.3, 10.0, 7.0, 3.5 Hz, 1H, 2'-
H), 9.69 (d, J ˆ 1.2 Hz, 1H, CHO), characteristic signals of the diaster-
eomer (2R): d ˆ 3.00 (dd, J ˆ 17.7, 5.8 Hz, 1H, 3-H), 9.82 (d, J ˆ 1.7 Hz, 1H,
CHO); IR (film): nÄ ˆ 3080, 2980, 2939, 2841, 1774, 1727, 1642, 1419, 1359,
as white needle crystals (0.92 g, 27%, >99% ee). R
f
(PE/EE 5:1) ˆ 0.16;
); H NMR (250 MHz, CDCl ):
d ˆ 1.08 (dd, J ˆ 2.7, 1.1 Hz, 1.1 Hz, 1H, 6-H), 1.44 (s, 9H, C(CH ), 2.79
), 4.90 (dd, J ˆ 5.3,
m.p. 688C; [a]2
0
ˆ À226 (c ˆ 1.0, CH
Cl
1
D
2
2
3
3 3
)
À1
‡
(
1
ddd, J ˆ 5.3, 2.9, 2.7 Hz, 1H, 5-H), 3.80 (s, 3H, OCH
3
1193, 1111, 1000, 924 cm ; MS (EI, 70 eV): m/z (%): 154.2 (5) [M ], 113.1
1
3
‡
.1 Hz, 1H, 1-H), 6.37 (d, J ˆ 2.9 Hz, 1H, 4-H); C NMR (62.9 MHz,
(100) [M À C
3 5
H ], 85.1 (95), 57.1 (95); elemental analysis calcd (%) for
CDCl
3
): d ˆ 22.5 (‡, C-6), 28.2 (‡, C(CH
3
)
3
), 31.6 (‡, C-5), 52.1 (‡, OCH
3
),
8 10 3
C H O (154.2): C 62.33, H 6.54; found: C 62.36, H 6.83.
6
7.4 (‡, C-1), 81.4 (Cquat, C(CH
3
)
3
), 116.3 (‡, C-4), 149.2 (Cquat, C-3), 159.6
(
(
(
2S/R,3R)-(À)-3-Formyl-5-oxo-2-(pentadien-2',4'-yl)-tetrahydrofuran
(
C
quat, CO), 171.0 (Cquat, CO); IR (KBr): nÄ ˆ 3056, 2983, 1729, 1698, 1621,
5b): A solution of 11-Et (527 mg, 2.16 mmol, 1.0 equiv) in dry CH
2
Cl
2
À1
1
7
1
440, 1384, 1309, 1162, 1110, 1022, 971, 879, 829, 750, 715 cm ; MS (EI,
10 mL) was cooled to À788C. BF
3 2
¥ Et O (340 mL, 2.66 mmol, 1.25 equiv)
‡
0 eV): m/z (%): 240.1 (3.83) [M ], 183.9 (16.8), 166.9 (16.8), 151.9 (11.5),
and 1,3-pentadienyltrimethylsilane (379 mg, 2.66 mmol, 1.25 equiv) were
38.9 (70.8), 124.8 (36.8), 96.9 (39.0), 57.1 (100), 52.1 (14.5), 41.1 (26.6);
added through a syringe and the solution was stirred for 12 h at À788C.
elemental analysis calcd (%) for C12
0.04, H 6.76.
1S,2S,3S)-(À)-Oxalic acid 2-ethoxycarbonyl 3-formyl-cyclopropyl ester
methyl ester (11-Et): A solution of (À)-8c-Et (2.50 g, 11.78 mmol) in dry
CH Cl
16 5
H O (240.3): C 59.99, H 6.71; found C
3
Saturated NaHCO solution (0.4 mL) was added and the mixture was
6
warmed to 08C. After separating the layers the organic layer was dried,
filtered and concentrated in vacuo to yield 12b (762 mg, 2.37 mmol, quant.)
(
1
as a colorless oil (dr 97:3). H NMR (250 MHz, CDCl ): d ˆ 1.25 (t, J ˆ
3
2
2
(125 mL) was cooled to À788C and treated with ozone until the
7.0 Hz, 3H, CH ), 1.81 ± 1.92 (m, 1H, 2-H), 2.15 (dd, J ˆ 6.2, 2.7 Hz, 1H,
3
mixture turned blue. Excess ozone was expelled by passing oxygen through
the solution, followed by addition of dimethyl sulfide (4.3 mL, 58.91 mmol,
3-H), 2.31 ± 2.51 (m, 4H), 3.70 (ddd, J ˆ 7.3, 7.3, 5.4 Hz, 1H, 1'-H), 3.88 (s,
3H, CO CH ), 4.13 (q, J ˆ 7.0 Hz, 2 H, CO CH CH ), 4.72 (dd, J ˆ 7.5,
2
3
2
2
3
5
.0 equiv). The reaction mixture was allowed to warm to room temperature
and stirring was continued for 24 h. Saturated NaHCO (10 mL) was added
and layers were separated. The organic layer was washed with water (2 Â
0 mL), dried, filtered and evaporated. The residue was recrystallized from
Et
O at À278C to yield (À)-11-Et as a colorless solid (2.70 g, 94%). M.p.
28C; [a]2
.28 (t, J ˆ 7.1 Hz, 3H, CH
2.8 Hz, 1H, 1-H), 5.14 ± 5.22 (m, 2H, 4'-H), 5.76 ± 5.93 (m, 1H, 3'-H),
characteristic signals of the diastereomer (2R): d ˆ 4.14 (q, J ˆ 7.0 Hz, 2H,
3
1
3
CO CH CH ), 4.67 (dd, J ˆ 6.9, 3.0 Hz, 1H, 1-H); C NMR (62.9 MHz,
2
2
3
1
CDCl ): d ˆ 14.1 (‡, CH ), 24.7 (‡, C-3), 31.3 (‡, C-2), 41.7 (À, C-2'), 53.8
3
3
2
(‡, CO CH ), 58.8 (‡, C-1), 61.3 (À, CO CH CH ), 67.8 (‡, C-1'), 118.8
2
3
2
2
3
0
1
5
1
2
2
D
ˆ À37.7 (c ˆ 1.0, CH
CH
), 2.79 (ddd, J ˆ 7.3, 6.0, 4.0 Hz, 1H, 2-H),
.90 (dd, J ˆ 6.0, 3.6 Hz, 1H, 3-H), 3.91 (s, 3H, CO CH ), 4.19 (q, J ˆ 7.1 Hz,
H, CH CH
), 4.83 (dd, J ˆ 7.3, 3.6 Hz, 1H, 1-H), 9.45 (d, J ˆ 4.0 Hz, 1H,
): d ˆ 14.1 (‡, CH ), 26.4 (‡, C-3), 34.9
), 58.9 (‡, C-1), 62.0 (À, CO CH CH ), 156.6
quat, CO), 156.9 (Cquat, CO), 168.1 (Cquat, CO CH CH
2
Cl
2
); H NMR (250 MHz, CDCl
3
): d ˆ
(À, C-4'), 133.4 (‡, C-3'), 157.2 (C , CO), 157.2 (C , CO), 170.6 (C
quat
,
quat
quat
2
3
CO CH ), characteristic signals of the diastereomer (2R): d ˆ 25.1 (‡, C-3),
2
3
2
3
41.3 (À, C-2'), 53.6 (‡, CO CH ), 58.6 (‡, C-1), 61.2 (À, CO CH CH ), 68.6
2
3
2
2
3
2
3
(‡, C-1'), 118.6 (À, C-4'), 133.5 (‡, C-3').
The alcohol 12b (762 mg) was dissolved in methanol (20 mL) at 08C and
treated dropwise with a solution of Ba(OH) ¥ 8H O (340 mg, 1.08 mmol,
.5 equiv) in methanol (15 mL). Then CH Cl (20 mL) and H O (20 mL)
were added and layers were separated. The aqueous layer was extracted
with CH Cl
(5 Â 15 mL). The combined organic layers were dried, filtered
and concentrated in vacuo. Chromatography on silica gel (hexanes/EE 1:1)
1
3
CHO); C NMR (62.9 MHz, CDCl
3
3
(
(
‡, C-2), 54.0 (‡, CO
2
CH
3
2
2
3
2
2
C
2
2
3
), 192.7 (‡, CHO);
0
2
2
2
IR (KBr): nÄ ˆ 3066, 3015, 2963, 2892, 1785, 1751, 1735, 1706, 1445, 1345,
À1
1
313, 1210, 1167, 1086, 1011, 963, 867, 790, 715, 613, 495 cm ; MS (DCI,
2
2
‡
NH
3
): m/z (%): 262.0 [M ‡NH
4
] (100), 176.0 (20), 160.0 (55), 120.9 (15);
(244.2): C 49.19, H 4.95; found C
elemental analysis calcd (%) for C10
9.22, H 4.99.
2S/R,3R)-2-Allyl-5-oxotetrahydrofuran-3-carbaldehyde (5a): A solution
of 11-Et (5.00 g, 20.5 mmol) in dry CH Cl (200 mL) was treated with BF
Et
O (3.0 mL, 20.5 mmol) at À788C. After 10 minutes allyltrimethylsilane
5.0 mL, 30.75 mmol, 1.5 equiv) was added and stirring was continued for
4 h. The reaction was quenched with saturated NaHCO (6.0 mL) and the
mixture was allowed to warm to 08C. After separation of the organic layer
and drying with MgSO , the solvent was evaporated under vacuo to yield
the corresponding alcohol 12a as a colorless oil (5.82 g, 100% crude yield,
dr 95:5). 1H NMR (250 MHz, CDCl
),
12 7
H O
yielded 5b as a colorless oil (258 mg, 66%, dr 97:3). R
f
(hexanes/EE 1:1) ˆ
4
1
0
.17; H NMR (250 MHz, CDCl
3
): d ˆ 2.56 ± 2.63 (m, 2H, 1'-H), 2.74 (dd,
(
J ˆ 18.0, 10.0 Hz, 1H, 4-H), 2.92 (dd, J ˆ 18.0, 7.5 Hz, 1H, 4-H), 3.19 (dddd,
J ˆ 10.0, 7.5, 6.2, 1.3 Hz, 1H, 3-H), 4.75 (dd, J ˆ 12.0, 6.0 Hz, 1H, 2-H),
5.04 ± 5.24 (m, 2H, 5'-H), 5.62 (dt, J ˆ 14.4, 7.3 Hz, 1H, 2'-H), 6.12 ± 6.39 (m,
2H, 3'-H, 4'-H), 9.73 (d, J ˆ 1.2 Hz, 1H, CHO), characteristic signals of the
2
2
3
¥
2
(
2
diastereomer (2R): d ˆ 9.84 (d, J ˆ 1.6 Hz, 1H, CHO); 13
3
C NMR
(62.9 MHz, CDCl ): d ˆ 28.9 (À, C-4), 37.9 (À, C-1'), 51.4 (‡, C-3), 78.1
3
4
(‡, C-2), 117.8 (À, C-5'), 125.8 (‡, C-2'), 136.1 (‡, C-3'), 136.2 (‡, C-4'),
‡
173.8 (C , C-5), 197.1 (‡, CHO); MS (EI, 70 eV): m/z (%): 180.2 [M
quat
]
): d ˆ 1.25 (t, J ˆ 7.0 Hz, 3H, CH
3
(10), 113.1 [M À C H ] (80), 85.1 (100), 57.1 (90), 29.1 (75); HRMS: calcd
‡
3
5
7
1
.81 ± 1.92 (m, 1H, 2-H), 2.15 (dd, J ˆ 6.2, 2.7 Hz, 1H, 3-H), 2.31 ± 2.51 (m,
for C H NO : 198.11302 [M
‡
‡NH ], found: 198.11285.
1
0
16
3
4
4
H), 3.70 (ddd, J ˆ 7.3, 7.3, 5.4 Hz, 1H, 1'-H), 3.88 (s, 3H, CO
CH CH
), 4.72 (dd, J ˆ 7.5, 2.8 Hz, 1H, 1-H), 5.14 ± 5.22
m, 2H, 4'-H), 5.76 ± 5. 93 (m, 1H, 3'-H), characteristic signals of the
diastereomer: d ˆ 4.14 (q, J ˆ 7.0 Hz, 2H, CO CH CH ), 4.67 (dd, J ˆ 6.9,
.0 Hz, 1H, 1-H).
Method A: The alcohol 12a (5.78 g, 20.0 mmol) was dissolved in methanol
2 3
CH ), 4.13 (q,
(
2S*/R*,3R*)-3-Formyl-5-oxo-2-(2'-acetoxymethyl-propen-2'-yl)-tetrahy-
drofuran (5c): A solution of (rac)-11-Me (1.150 g, 5.00 mmol, 1 equiv) in
dry CH Cl ¥ Et O (690 mL, 5.50 mmol,
(25 mL) was cooled to À788C. BF
.1 equiv) and 2-acetoxymethyl allyltrimethylsilane (1.025 g, 5.50 mmol,
.1 equiv) were added through a syringe and the solution was stirred for
solution (1 mL) was added and the
J ˆ 7.0 Hz, 2H, CO
2
2
3
(
2
2
3
2
2
2
3
1
1
3
1
2 h at À788C. Saturated NaHCO
3
(
(
H
200 mL) at 08C and treated dropwise with a solution of Ba(OH)
3.15 g, 10.0 mmol, 0.5 equiv) in methanol (200 mL). CH Cl (100 mL) and
O (100 mL) were added and the layers were separated. The aqueous
layer was extracted with CH Cl
2 2
¥ 8H O
mixture was warmed to 08C. After separating the layers the organic layer
was dried, filtered and concentrated in vacuo to yield 12c as a colorless oil
in quantitative yield (trans/cis 80:20).
1H NMR (250 MHz, CDCl
2
2
2
2
2
(10 Â 100 mL). The combined organic
): d ˆ 1.81 ± 1.91 (m, 1H, 2-H), 2.04 (s, 3H,
3
layers were dried, filtered and concentrated in vacuo. Chromatography on
silica gel (hexane/EE 1:1) yielded 5a as a colorless oil (2.02 g, 64%, dr
CH
brs, 1H, OH), 3.66 (s, 3H, CO
CO CH ), 4.51 (m, 2H, CH
), 4.67 (dd, J ˆ 7.4, 2.7 Hz, 1H, 1-H), 5.05 (m,
1H, 4'-H), 5.13 (m, 1H, 4'-H), characteristic signals of the diastereomer:
d ˆ 1.86 ± 1.96 (m, 1H, 2-H), 2.05 (s, 3H, CH ), 2.17 (dd, J ˆ 6.1, 2.7 Hz, 1H,
3
), 2.14 (dd, J ˆ 6.1, 2.7 Hz, 1H, 3-H), 2.32 ± 2.44 (m, 2H, 2'-H), 2.89
(
2
CH ), 3.72 (m, 1H, 1'-H), 3.86 (s, 3H,
3
9
5:5).
2
3
2
Method B: The alcohol 12a (1.842 g, 6.77 mmol, 1 equiv) was dissolved in
dry methanol (30 mL) at 08C and treated dropwise with a suspension of
3
Chem. Eur. J. 2003, 9, No. 1
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0265 $ 20.00+.50/0
265

O. Reiser et al.
FULL PAPER
3
1
3
-H), 3.67 (s, 3H, CO
H, 1-H); 13C NMR (62.9 MHz, CDCl
1.6 (‡, C-2), 41.5 (À, C-2'), 52.2 (‡, CO
), 67.4 (‡, C-1'), 116.1 (À, C-4'), 140.1 (Cquat, C-3'), 157.0
CO), 157.1 (Cquat CO), 170.5 (Cquat CO CH ), 170.8 (Cquat
CH ),
), characteristic signals of the diastereomer: d ˆ 20.9 (‡, CH
5.2 (‡, C-3), 31.5 (‡, C-2), 41.0 (À, C-2'), 52.2 (‡, CO CH ), 53.8 (‡,
CO CH
quat, CO), 170.6 (Cquat, CO
2
CH
3
), 3.87 (s, 3H, CO
): d ˆ 20.7 (‡, CH
CH
), 53.7 (‡, CO
2
CH
3
), 4.65 (dd, J ˆ 7.4, 2.7 Hz,
), 24.8 (‡, C-3),
CH
), 58.7 (‡,
was added and the mixture was concentrated in vacuo. After chromatog-
3
3
raphy on silica gel (hexanes/EE 1:1, 1 vol% NEt
pale yellow oil (712 mg, 72%, cis/trans 93:7). R
3
), 6a was obtained as a
(PE/EE 1:1) ˆ 0.34;
2
3
2
3
f
1
C-1), 66.5 (À, CH
2
H NMR (250 MHz, CDCl
CH O), 4.51 (m, 1H, CH), 4.86 (m, 1H, 2-H), 5.11 ± 5.21
(m, 2H, 3'-H), 5.79 (ddt, J ˆ 16.7, 10.6, 6.9 Hz, 1H, 2'-H), characteristic
signals of the diastereomer: d ˆ 4.06 ± 4.18 (m, 4H, OCH CH O), 4.60
(ddd, J ˆ 8.3, 6.7, 5.8 Hz, 1H, 2-H), 4.98 (d, J ˆ 3.7 Hz, 1H, CH), 5.85 (ddt,
3
): d ˆ 2.39 ± 2.67 (m, 5H, 1'-H, 3-H, 4-H), 3.83 ±
(
C
quat
,
,
,
2
3
,
4.01 (m, 4H, OCH
2
2
CO
2
2
3
3
2
3
2
2
2
3
), 58.4 (‡, C-1), 66.9 (À, CH
2
), 67.8 (‡, C-1'), 116.2 (À, C-4'), 157.5
1
3
(
C
2
CH ), 170.7 (Cquat, CO
3
2
CH
3
); IR (film): nÄ ˆ
J ˆ 7.2, 10.2, 6.7 Hz, 1H, 2'-H); C NMR (62.9 MHz, CDCl
C-4), 39.2 (À, C-1'), 42.5 (‡, C-4), 65.4, 65.5 (À, OCH CH
C-2), 103.5 (‡, CH), 119.3 (À, C-3'), 132.0 (‡, C-2'), 175.9 (Cquat, CO),
characteristic signals of the diastereomer: d ˆ 29.26 (À, CH ), 34.9 (À,
CH
3
): d ˆ 29.6 (À,
3
8
2
506, 2957, 1779, 1736, 1442, 1374, 1315, 1234, 1201, 1160, 1028, 980, 915,
60 cm ; MS (DCI, NH
00.1 (18); HRMS (DCI): calcd for C15
2
2
O), 79.7 (‡,
À1
‡
3
): m/z (%): 362.2 (100) [M ‡NH
4
], 258.1 (69),
‡
H
24NO
9
: 362.1451 [M ‡NH
4
],
2
found: 362.1438.
The crude product was dissolved in MeOH (50 mL). At 08C a solution of
Ba(OH) ¥ 8H O (1.735 g, 5.50 mmol, 1.1 equiv) in MeOH (30 mL) was
added dropwise. Then H O (50 mL) was added and the mixture was
extracted with CH Cl
(10 Â 30 mL). The combined organic layers were
dried and concentrated in vacuo. Chromatography on silica gel (hexanes/
C-1'), 41.4 (‡, C-4), 65.1, 65.6 (À, OCH
2
2
O), 80.3 (‡, C-2), 101.8 (‡,
CH), 118.3 (À, C-3'), 133.2 (‡, C-2'); IR (film): nÄ ˆ 3078, 2953, 2890, 2760,
À1
1
782, 1642, 1420, 1356, 1187, 1131, 1025, 994, 945, 922 cm ; MS (DCI, NH
3
):
] (5), 216.2
(198.2): C
2
2
‡
‡
m/z (%): 250.3 [MH À 3NH
3
] (10), 233.2 [MH ‡2NH
3
2
‡
[
M ‡NH
4
] (100); elemental analysis calcd (%) for C10
H
14
O
4
2
2
6
0.59, H 7.12; found: C 60.76, H 7.12.
EE 1:1) yielded 5c as a colorless oil (828 mg, 73%, trans/cis 80:20). R
f
(PE/
(2S*/R*,3R*)-3-(1,3-dioxolan-2-yl)-5-oxo-2-(2-oxo-2-phenylethyl)-tetra-
hydrofuran (6b): A solution of (rac)-11-Me (230 mg, 1.0 mmol) in dry
CH Cl (5 mL) was treated with BF ¥ OEt (126 mL, 1.0 mmol, 1 equiv) at
2 2 3 2
1
EE 1:1) ˆ 0.07; H NMR (250 MHz, CDCl
3
): d ˆ 2.08 (s, CH
3
, 3H), 2.47
(
(
(
dd, J ˆ 14.7, 6.0 Hz, 1H, 1'-H), 2.61 (dd, J ˆ 14.7, 7.0 Hz, 1H, 1'-H), 2.76
dd, J ˆ 18.0, 10.0 Hz, 1H, 4-H), 2.90 (dd, J ˆ 17.9, 7.7 Hz, 1H, 4-H), 3.21
OAc), 4.87 (dd,
À788C. After 30 min 1-phenylvinyl trimethylsilyl ether (226 mL, 1.1 mmol,
dddd, J ˆ 9.9, 7.7, 6.4, 1.3 Hz, 1H, 3-H), 4.54 (s, 2H, CH
2
1 equiv) was added and stirring continued for 12 h. The reaction was
J ˆ 13.0, 6.4 Hz, 1H, 2-H), 5.13 (s, 1H, CˆCH), 5.25 (s, 1H, CˆCH), 9.71 (d,
quenched with saturated NaHCO
allowed to warm to 08C. After drying (MgSO
solution (0.2 mL) and the mixture was
) the mixture was filtered and
3
J ˆ 1.3 Hz, 1H, CHO), characteristic signals of the diastereomer: d ˆ 9.82
4
1
3
(
2
d, J ˆ 1.7 Hz, 1H, CHO); C NMR (62.9 MHz, CDCl
3
): d ˆ 20.8 (‡, CH
OAc), 77.2 (‡,
), 138.3 (Cquat, C-2'), 170.5 (Cquat, CO), 173.7 (Cquat
3
),
concentrated. The intermediate product was dissolved in benzene, treated
with the tin-catalyst 15 (2.4 mg, 0.56 mol%) and ethane-1,2-diol (123 mL,
2.2 mmol, 2.2 equiv) and refluxed with a Dean-Starktrap for 6 h. The
8.9 (À, C-4), 39.0 (À, C-1'), 51.7 (‡, C-3), 66.6 (À, CH
2
C-2), 117.7 (À, CˆCH
,
2
CO), 197.2 (Cquat, CO), characteristic signals of the diastereomer: d ˆ 28.9
organic layer was washed with saturated NaHCO
with H
O (2 Â 10 mL). The combined aqueous layers were extracted with
Et
O (3 Â 10 mL). The combined organic layers were dried, filtered and
concentrated at 208C. After chromatography on silica gel (hexanes/EE 1:1,
3
solution (10 mL) and
(
(
À, C-4), 66.6 (À, CH
2
OAc), 117.7 (À, CˆCH
2
), 197.9 (Cquat, CO); IR
2
À1
film): nÄ ˆ 3090, 2938, 1777, 1736, 1655, 1436, 1373, 1233, 1029, 920 cm
;
2
‡
MS (EI, 70 eV): m/z (%): 226.2 [M ] (5), 113.1 (40), 85.1 (50), 57.1 (40), 43.1
(
100); elemental analysis calcd (%) for C11
H
14
O
5
(226.2): C 58.40, H 6.24;
1 vol% NEt
3
), 6b was obtained as a colorless solid (71 mg, 26%). R
f
(PE/
1
found: C 58.61, H 6.87.
EE 1:1) ˆ 0.21; m.p. 94 ± 958C; H NMR (250 MHz, CDCl
3
): d ˆ 2.57 ± 2.80
(
m, 3H, 3-H, 4-H), 3.37 (dd, J ˆ 17.4, 5.7 Hz, 1H, 1'-H), 3.49 (dd, J ˆ 17.4,
.1 Hz, 1H, 1'-H), 3.83 ± 4.03 (m, 4H, OCH CH
O), 5.01 (d, J ˆ 3.4 Hz, 1H,
CH), 5.08 (dd, J ˆ Hz, 11.2, 5.6 Hz, 1H, 2-H), 7.41 ± 7.51 (m, 2H, Ar-H),
(
(
2S*/R*,3R*)-2-(2-Methylallyl)-5-oxotetrahydrofuran-3-carbaldehyde
5d): A solution of (rac)-11-Me (500 mg, 2.17 mmol, 1.0 equiv) in dry
6
2
2
CH
.0 equiv) and trimethyl-(2-methyl-allyl)-silane (279 mg, 2.17 mmol,
.0 equiv) were added through a syringe and the solution was stirred for
6 h at À788C. Saturated NaHCO solution (1.0 mL) was added and the
mixture was warmed to 08C. After drying with MgSO the reaction mixture
was filtered and concentrated in vacuo to yield the corresponding alcohol
2d as a colorless oil. The alcohol was directly dissolved in methanol
17 mL) at 08C and treated dropwise with a solution of Ba(OH) ¥ 8H
720 mg, 2.28 mmol, 1.05 equiv) in methanol (10 mL). CH Cl (20 mL) and
O (35 mL) were added and layers were separated. The aqueous layer
was extracted with CH Cl
(5 Â 20 mL). The combined organic layers were
dried, filtered and concentrated in vacuo. Chromatography on silica gel
2
Cl
2
(11 mL) was cooled to À788C. BF
3 2
¥ Et O (273 mL, 2.17 mmol,
1
3
7
.55 ± 7.63 (m, 1H, Ar-H), 7.88 ± 7.99 (m, 2H, Ar-H); C NMR (62.9 MHz,
CDCl
): d ˆ 29.5 (À, C-4), 43.3 (À, C-1'), 42.4 (À, C-4), 65.3, 65.4 (À,
OCH CH
1
1
1
3
2
2
O), 76.3, 76.7 (‡, C-2), 103.4 (‡, CH), 128.0, 128.7, 133.6, 136.4
3
(
2
Ar-C), 175.6 (Cquat, CO), 196.2 (C-2'); IR (KBr): nÄ ˆ 2961, 2882, 2360,
4
À1
342, 1769, 1685, 1387, 1196, 1013, 939 cm ; MS (EI, 70eV): m/z (%): 276.1
‡
(
5) [M ], 149.1 (15), 105.1 (70), 73.1 (100); elemental analysis calcd (%) for
1
(
(
15 16 5
C H O (276.3): C 65.21, H 5.84; found C 65.02, H 5.84.
2
2
O
2
2
(2S/R,3R)-(À)-3-Formyl-5-oxo-2-pentyl-tetrahydrofuran (16): A solution
of 5b (134 mg, 0.744 mmol, 1.0 equiv) and Pd/C (40 mg, 5 mol%) in
methanol (10 mL) was stirred under hydrogen atmosphere (1 atm) at RT
for 24 h. After filtration, evaporation of the solvent and chromatography
H
2
2
2
(
hexanes/EE 1:1) yielded 5d as a colorless oil (162 mg, 44%, trans/cis 96:4).
on silica gel 16 was obtained as a colorless oil in quantitative yield (137 mg,
1
20
H NMR (300 MHz, CD
3
OD): d ˆ 1.79 (s, 3H, CH
-C1'), 2.59 (dd, J ˆ 14.1, 6.5 Hz, 1H, CH
8.0, 9.9 Hz, 1H, CH
-C4), 2.92 (ddd, J ˆ 18.0, 7.5, 0.5 Hz, 1H, CH
.22 (dddd, J ˆ 9.9, 7.5, 6.2, 1.2 Hz, 1H, C3-H), 4.79 ± 4.90 (m, 2H, C2-H,
CH ), 4.95 (s, 1H, ˆCH ), 9.72 (dd, J ˆ 1.1, 0.5 Hz, 1H, CHO), character-
3
), 2.40 (dd, J ˆ 14.1,
-C1'), 2.76 (dd, J ˆ
-C4),
dr 97:3). R
H NMR (250 MHz, CDCl
f
(hexanes/EE 1:1) ˆ 0.17; [a]
D
ˆ À42.9 (c ˆ 1.1 in CH
2 2
Cl );
), 1.24 ± 1.56 (m,
1
7.0 Hz, 1H, CH
2
2
3
): d ˆ 0.85 ± 0.92 (m, 3H, CH
3
1
3
ˆ
2
2
6H, CH
2
), 1.65 ± 1.82 (m, 2H, CH
2
), 2.74 (dd, J ˆ 17.9, 9.9 Hz, 1H, 4-H),
2.91 (dd, J ˆ 17.9, 7.6 Hz, 1H, 4-H), 3.11 (dddd, J ˆ 9.9, 7.6, 6.3, 1.5 Hz, 1H,
3-H), 4.65 (ddd, J ˆ 7.4, 6.3, 5.5 Hz, 1H, 2-H), 9.73 (d, J ˆ 1.5 Hz, 1H,
CHO), characteristic signals of the diastereomer (2R): d ˆ 9.81 (d, J ˆ
2
2
1
3
istic signals of the diastereomer: 9.84 (d, J ˆ 1.7 Hz, CHO); C NMR
75.4 MHz, CD ), 28.85 (À, CH ), 51.76 (‡, CH),
OD): d ˆ 22.66 (‡, CH
1
3
(
7
3
3
2
2.0 Hz, CHO); C NMR (62.9 MHz, CDCl
3
): d ˆ 13.9 (‡, CH ), 22.4 (À,
3
7.50 (‡, CH), 115.11 (À, CH
2
), 139.81 (Cquat), 174.06 (Cquat), 197.51 (‡,
CH
2
), 24.8 (À, CH
2
), 29.0 (À, C-4), 31.3 (À, CH ), 35.5 (À, C-1'), 52.6 (‡,
2
CHO), characteristic signals of the diastereomer: 198.28 (‡, CHO); IR
C-3), 79.1 (‡, C-2), 174.1 (Cquat, C-5), 197.3 (‡, CHO), characteristic signals
of the diastereomer (2R): d ˆ 80.5 (‡, C-2); IR (film): nÄ ˆ 2933, 2860, 1773,
À1
(
(
1
film): nÄ ˆ 3078, 2937, 2830, 1790, 1779, 1700, 1651, 1446, 144 cm ; MS
‡
À1
‡
DCI, NH
68.0786, found 169.0865 [M ‡H].
3
): m/z (%): 186.1 (100.0) [M ‡NH
4
]; HRMS: calcd for C
9
H
12
O
3
:
1665, 1362, 1199 cm ; MS (EI, 70 eV): m/z (%): 184.2 [M ] (5), 113.1 [M À
‡
‡
C
5
H
11 ] (100), 85.1 (70), 57.1 (60), 43.1 (60), 29.2 (45); elemental analysis
calcd (%) for C10
(2S,3R)-(À)-Tetrahydro-5-oxo-2-pentyl-3-furan carboxylic acid (17): A
solution of KH PO (14 mg, 0.101 mmol) in H O (0.5 mL), NaClO
(32 mg, 0.27 mmol, 1.6 equiv) and 30% H (15 mL) were added at 08C
to a solution of 16 (50 mg, 0.169 mmol, 1.0 equiv) in CH CN (5 mL). The
mixture was stirred for 1.5 h. Then Na SO (80 mg) was added and stirring
was continued for an additional hour. The solution was acidified to pH 2 by
addition of an aqueous solution of 1n KH SO solution. The mixture was
extracted with CH Cl
(10 Â 5 mL), the organic layers were dried and
evaporated at room temperature. After crystallization from ethyl acetate
16 3
H O (184.2): C 65.19, H 8.75; found: C 64.89, H 8.50.
(
2S*/R*,3R*)-3-(1,3-Dioxolan-2-yl)-5-oxo-2-(propen-2-yl)-tetrahydrofur-
an (6a): A solution of the aldehyde (rac)-11-Me (1.151 g, 5.0 mmol) in dry
CH Cl (25 mL) was treated with BF ¥ OEt (630 mL, 5.0 mmol, 1 equiv) at
2
2
3
2
2
4
2
2
À788C. After 30 min trimethylallysilane (159 mL, 1.0 mmol, 1 equiv) was
2 2
O
added and stirring continued for 12 h. The reaction was quenched with
3
saturated NaHCO
to 08C. After drying (MgSO
The intermediate product was dissolved in benzene, treated with the tin-
catalyst 15 (22 mg, 1 mol%) and ethane-1,2-diol (587 mL, 10.5 mmol,
3
solution (1 mL) and the mixture was allowed to warm
) the mixture was filtered and concentrated.
2
3
4
2
4
2
2
2
.1 equiv) and refluxed with a Dean ± Starktrap for 48 h. Toluene (40 mL)
266
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0266 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 1

Paraconic Acids
260±270
2
0
[9d]
20
1
7 was obtained as colorless solid (29 mg, 86%). M.p. 1058C; [a]
D
ˆ À52
); H NMR (250 MHz,
), 1.25 ± 1.58 (m, 6H, CH ), 1.65 ±
), 2.83 (dd, J ˆ 17.9, 9.6 Hz, 1H, 4-H), 2.95 (dd, J ˆ 17.9,
.3 Hz, 1H, 4-H), 3.10 (ddd, J ˆ 9.5, 8.3, 7.1 Hz, 1H, 3-H), 4.63 (ddd, J ˆ 7.6,
EE/HOAc 90:8:2) ˆ 0.24; m.p. 1088C, lit.:
109 ± 1118C, [a]
D
ˆ À40.5
[
10c]
1
[9d]
1
(
c ˆ 0.5 in CHCl
3
), lit.:
À52 (c ˆ 0.52 in CHCl
3
(c ˆ 0.32, CHCl
3
), lit.:
À41 (c ˆ 0.5, CHCl
3
); H NMR (400 MHz,
CDCl
3
): d ˆ 0.90 (t, J ˆ 7.1 Hz, 3H, CH
3
2
CDCl
1.60 (m, 2H, CH
1H, 4-H), 2.95 (dd, J ˆ 17.9, 8.3 Hz, 1H, 4-H), 3.10 (ddd, J ˆ 9.6, 8.3, 7.2 Hz,
1H, 3-H), 4.62 (ddd, J ˆ 7.4, 7.3, 4.8 Hz, 1H, 2-H), 8.64 (brs, 1H, CO H);
), 25.2 (À,
), 29.52 (À, CH ), 29.63
), 31.91 (À, CH ), 31.94 (À, CH ),
3
): d ˆ 0.88 (t, J ˆ 6.7 Hz, 3H, CH
3
), 1.26 (brs, 18H, CH
2
), 1.40 ±
1.85 (m, 2H, CH
2
2
), 1.72 ± 1.83 (m, 2H, CH
2
), 2.83 (dd, J ˆ 17.9, 9.6 Hz,
8
7
1
3
.1, 4.8 Hz, 1H, 2-H), 8.64 (brs, 1H, COOH); C NMR (62.9 MHz,
2
1
3
CDCl ), 22.4 (À, CH ), 24.8 (À, CH ), 31.3 (À, CH ),
3
): d ˆ 13.9 (‡, CH
3
2
2
2
C NMR (62.9 MHz, CDCl
CH
3
): d ˆ 14.1 (‡, CH
3
), 22.7 (À, CH
2
3
1
1.9 (À, CH
2
), 35.3 (À, CH
2
), 45.4 (‡, C-3), 81.9 (‡, C-2), 174.6 (Cquat, C-5),
2
), 29.2 (À, CH
2
), 29.37 (À, CH
2
), 29.42 (À, CH
2
2
‡
76.4 (Cquat, CO
2
H); MS (EI, 70 eV): m/z (%): 201.2 [MH ] (2), 182.2
(À, CH
2
), 29.67 (À, CH
2
), 29.70 (À, CH
2
2
2
‡
‡
[
M
À H
2
O] (5), 129.1 [M À C
5
H
11] (60), 101.1 (100), 55.0 (70).
35.40 (À, CH
2
), 45.4 (‡, C-3), 81.8 (‡, C-2), 174.2 (Cquat, CO), 175.9 (Cquat
,
CO).
(
2
2
(
E)/(Z)-(4R,5S/R)-(À)-4-[1,3]Dioxolan-2-yl-5-tridec-2-enyl-dihydrofuran-
-one (24): Compound 5a (327 mg, 1.65 mmol), 1-dodecene (550 mL,
(2S,3R,4R)-(À)-4-Methyl-5-oxo-2-tridecyltetrahydrofuran-3-carboxylic
.48 mmol, 1.5 equiv) and 23 (68 mg, 5 mol%) were given into dry CH Cl
2
2
acid, roccellaric acid (19): A solution of 26 (20 mg, 0.064 mmol) in dry THF
(1.4 mL) was added to a solution of sodium bis(trimethylsilyl)amide (1m in
THF, 140 mL, 0.140 mmol, 2.2 equiv) at À788C under Argon over
30 minutes. The mixture was stirred at À788C for 3 h. Methyl iodide
(40 mL, 0.61 mmol, 9.6 equiv) was slowly added and the mixture was stirred
for additional 12 h. The mixture was allowed to warm to À208C. 2n HCl
25 mL), refluxed for 8 h and stirred for additional 10 h at 308C. After
chromatography on silica gel (hexanes/EE 2:1), 24 was obtained as
colorless oil (317 mg, 57%, dr 95:5, E/Z 3.5:1). R
(hexanes/EE 1:1) ˆ 0.50;
); H NMR (250 MHz, CDCl
): d ˆ 0.86 (t,
), 1.23 (brs, 16H, CH
), 1.99 (ddt, J ˆ 7.0, 7.0, 0.4 Hz,
H, 4'-H), 2.27 ± 2.60 (m, 5H, 1'-H, 3-H, 4-H), 3.81 ± 4.03 (m, 4H,
OCH CH
O), 4.43 ± 4.57 (m, 1H, CH), 4.86 (dt, J ˆ 2.3, 1.3 Hz, 1H, 5-H),
.37 (dtt, J ˆ 15.2, 6.9, 1.2 Hz, 1H,ˆCH-), 5.58 (dtt, J ˆ 15.2, 6.6, 1.2 Hz, 1H,
CH-), characteristic signals of the diastereomer: d ˆ 4.99 (d, J ˆ 3.6 Hz,
f
2
0
1
[
a]
D
ˆ À13.4 (c ˆ 0.85, CH
2
Cl
2
3
J ˆ 6.5 Hz, 3H, CH
3
2
2
(2 mL) was added, the mixture was extracted with Et
combined organic layers was washed with saturated Na
dried. 27 was obtained as a colorless solid (20 mg, 96%). R
2
O (5 Â 2 mL) and the
SO solution and
(CHCl /EE/
ˆ À26 (c ˆ 0.5,
): d ˆ
), 1.37 (d, J ˆ 7.1 Hz,
2
2
2
3
5
f
3
[
8b]
20
D
ˆ
HOAc 90:8:2) ˆ 0.25; m.p. 1108C, lit.:
1088C; [a]
); H NMR (400 MHz, CDCl
3 3
), 1.18 ± 1.47 (m, 21H, CH
3 2
3
), 1.48 ± 1.59 (m, 1H, 1'-H), 1.65 ± 1.77 (m, 1H, 1'-H), 1.78 ± 1.88 (m,
1
3
[8b]
1
1
H, CH), Major diastereomer: C NMR (62.9 MHz, CDCl
CH ), 29.16 (À, CH ), 29.26 (À, CH ), 29.32 (À, CH
), 22.7 (À, CH
), 29.51 (À, CH ), 29.60 (À, C-3, CH ), 31.9 (À, CH ), 32.62 (À,
), 38.0 (À, CH ), 42.2 (‡, C-4), 65.3, 65.4 (À, OCH CH O), 80.22 (‡,
3
): d ˆ 14.1 (‡,
CHCl
3
), lit.: À26 (c ˆ 1.93, CHCl
), 29.47
0.88 (t, J ˆ 6.5 Hz, 3H, CH
3
2
2
2
2
(
À, CH
2
2
2
2
3H, CH
CH
2
2
2
2
1H, 1'-H), 2.70 (dd, J ˆ 11.4, 9.1 Hz, 1H, 3-H), 2.99 (dq, J ˆ 11.4, 7.1 Hz,
1
3
C-5), 103.6 (‡, CH), 122.9 (‡, ˆCH-), 135.8 (‡, ˆCH-), 176.1 (Cquat, CO),
characteristic signals of the diastereomer: d ˆ 29.15 (À, CH ), 29.23 (À,
CH ), 34.9 (À, C-1'), 41.4 (‡, C-4), 65.1, 65.6
), 29.9 (À, C-3), 33.7 (À, CH
À, OCH CH
1H, 4-H), 4.48 (ddd, J ˆ 9.1, 8.7, 4.1 Hz, 1H, 2-H); C NMR (100.6 MHz,
CDCl ),
29.22 (À, CH
CH
), 29.64 (À, CH
2
3
): d ˆ 14.1 (‡, CH
), 29.34 (À, CH
), 29.67 (À, CH
3
), 14.5 (‡, CH
), 29.38 (À, CH
), 31.91 (À, CH
3
), 22.7 (À, CH
2
), 25.3 (À, CH
2
2
2
2
), 29.50 (À, CH
2
), 29.60 (À,
2
2
(
ˆ
2
2
O), 80.94 (‡, C-5), 101.9 (‡, CH), 124.1 (‡,ˆCH-), 134.7 (‡,
2
2
2
2
), 34.92 (À, CH
2
), 39.8
CH-), characteristic signals of the diastereomer: d ˆ 27.5 (À, CH ), 29.30
2
(‡, C-3), 53.8 (‡, C-4), 79.3 (‡, C-2), 175.3 (Cquat, CO), 176.5 (Cquat, CO).
(
8
À, CH
2
), 29.43 (À, CH
2
), 29.62 (À, CH
2
), 32.60 (À, CH
2
), 42.5 (‡, C-4),
(
E)/(Z)-(2S/R,3R)-(À)-5-Oxo-2-undec-2-enyltetrahydrofuran-3-carbalde-
0.24 (‡, C-5), 122.2 (‡, ˆCH-), 134.4 (‡, ˆCH-), 175.9 (Cquat, CO),
hyde (28): A mixture of 5a (310 mg, 2.01 mmol), 1-decene (800 mL, 95%
purity (Acros), 4.03 mmol, 2.0 equiv) and 27 (51.2 mg, 3 mol%) in dry
characteristic signals of the diastereomer: d ˆ 80.76 (‡, C-5), 123.1 (‡,
ˆ
CH-); IR (film): nÄ ˆ 2924, 2853, 1781, 1465, 1421, 1354, 1181, 1133, 1031,
2 2
CH Cl (40 mL) was heated under reflux for 7 h. Since the TLC showed still
À1
‡
9
74, 945, 920 cm ; MS (EI, 70 eV): m/z (%): 338.0 [M ] (1), 210.0 (3), 154.9
9), 98.9 (4), 82.9 (3), 72.9 (100), 55.0 (6), 45.0 (7), 43.0 (6); elemental
analysis calcd (%) for C20 (338.5): C 70.97, H 10.12; found: C 70.70, H
0.02.
starting material, 27 (34 mg, 2 mol%) and 1-decene (400 mL, 1.0 equiv)
were added and refluxing continued for 23 h. 1-Decene (400 mL, 1.0 equiv)
was added again and refluxing was continued for additional 20 h. After
evaporation of the solvent and chromatography on silica gel (hexanes/EE
(
34 4
H O
1
1
:1), 28 (284 mg, 53%, dr 95:5, E/Z 7:1) as an oil and 5a (85 mg, 27%) [R
f
(
4R,5S/R)-(À)-4-[1,3]Dioxolan-2-yl-5-tridecyl-dihydrofuran-2-one (25): A
solution of 24 (280 mg, 0.83 mmol) and Pd/C (50 mg, 5 mol%) in methanol
50 mL) was stirred under H atmosphere at room temperature for 24 h.
After filtration and evaporation of the solvent, 25 was obtained as a
(
(
(
hexanes/EE 1:1) ˆ 0.25] were obtained (conversion yield ˆ 73%). R
f
2
0
1
hexanes/EE 1:1) ˆ 0.36; [a]
250 MHz, CDCl
): d ˆ 0.87 (t, J ˆ 6.5 Hz, 3H, CH
.01 (ddt, J ˆ 6.9, 6.9, 0.4 Hz, 2H, 4'-H), 2.41 ± 3.23 (m, 5H, 1'-H, 4-H, 3-H),
4.71 (dt, J ˆ 6.1, 2.3, 1H, 2-H), 5.37 (dtt, J ˆ 15.3, 7.0, 1.2 Hz, 1H, ˆCH-),
.67 (dtt, J ˆ 15.3, 6.8, 1.2 Hz, 1H, ˆCH-), 9.71 (d, J ˆ 1.29 Hz 1H,): major
diastereomeric aldehyde (2S); 9.73 (d, J ˆ 1.26 Hz): minor diastereomeric
D
ˆ À13.4 (c ˆ 1.55 in CHCl
3
); H NMR
(
2
3
3
), 1.25 (m, 12H, CH
2
),
2
colorless solid (281 mg, quant., dr 95:5). R
4
0
CH
(
f
(hexanes/EE 2:1) ˆ 0.30; m.p.
); H NMR (250 MHz, CDCl
): d ˆ
), 1.25 (brs, 22H, CH ), 1.61 ± 1.72 (m, 2H,
), 2.42 ± 2.69 (m, 3H, 3-H, 4-H), 3.87 ± 4.03 (m, 4H, OCH CH O), 4.46
dt, J ˆ 7.3, 5.0 Hz, 1H, CH), 4.88 (d, J ˆ 4.9 Hz, 1H, 2-H), characteristic
68C; [a]2
0
1
D
ˆ À26.5 (c ˆ 1.0, CH
2
Cl
2
3
5
.86 (t, J ˆ 6.5 Hz, 3H, CH
3
2
2
2
2
1
3
aldehyde (2R); C NMR (62.9 MHz CDCl
3
): d ˆ 14.05 (‡, CH ), 22.65 (À,
3
1
3
CH ), 28.87 (À, CH ), 29.16 (À, 2C, CH ), 29.24 (À, CH ), 29.39 (À, CH ),
signals of the diastereomer: d ˆ 4.98 (d, J ˆ 3.8 Hz, 1H, CH); C NMR
2
2
2
2
2
5
1.25 (‡, C-3), 78.54 (‡, C-2), 121.75 (‡, ˆCH-), 137.17 (‡, ˆCH-), 174.06
(
(
62.9 MHz, CDCl
À, CH ), 29.33 (À, CH
), 29.66 (À, CH ), 31.9 (À, CH
5.41 (À, OCH CH O), 81.0 (‡, C-5), 103.6 (‡, CH), 176.1 (Cquat, CO),
characteristic signals of the diastereomer: d ˆ 26.3 (À, CH ), 29.35 (À,
CH ), 29.52 (À, CH ), 29.61 (À, CH ), 29.9 (À, C-3), 31.9
), 29.46 (À, CH
À, CH ), 41.6 (‡, C-4), 65.1, 65.6 (À, OCH CH O), 81.4 (‡, C-5), 102.1 (‡,
3
): d ˆ 14.1 (‡, CH
), 29.43 (À, CH
), 35.6 (À, CH
3
), 22.7 (À, CH
), 29.51 (À, CH
), 43.6 (‡, C-4), 65.36,
2
), 25.6 (À, CH
2
), 29.25
), 29.63 (À, C-3,
(
C
quat), 197.25 (‡, -CHO); IR (film): nÄ ˆ 3427, 2925, 2854, 2360, 1772, 1457,
2
2
2
2
À1
1
2
363, 1194, 1024, 927 cm ; HRMS: calcd for C16
26 3
H O : 266.1900, found:
CH
6
2
2
2
2
66.1881.
2
2
2
(2S,3R)-(À)-5-Oxo-2-undecyltetrahydrofuran-3-carbaldehyde
(29):
2
2
2
2
1.4 mol% Pd/C (15 mg) was added to a solution of 28 (266 mg, 1 mmol)
in methanol (50 mL) and stirred under hydrogen atmosphere at room
temperature for 24 h. After filtration, evaporation of the solvent and
recrystallization from ethyl acetate 29 was obtained as a viscous oil
(
2
2
2
CH); IR (KBr): nÄ ˆ 2919, 2849, 1764, 1466, 1427, 1214, 1153, 1063, 982, 941,
À1
‡
‡
7
21 cm ; MS (DCI, NH
3
): m/z (%): 358.5 [M ‡NH
4
] (100), 344.5 [M ]
(340.5): C 70.55, H
2
0
(
2), 136.2 (6); elemental analysis calcd (%) for C20
H
36
O
4
(240 mg, 90%). R (CHCl /MeOH 95:5) ˆ 0.35; [a] ˆ À24.8 (c ˆ 1.70 in
f
3
D
1
1
0.66, found: C 70.37, H 10.60.
2S,3R)-(À)-5-Oxo-2-tridecyltetrahydrofuran-3-carboxylic acid (26):
solution of the 25 (259 mg, 0.761 mmol) in acetone (10 mL) was treated
with freshly prepared Jones reagent (760 mg CrO SO
‡ 0.75 mL H
.5 mL H O) at 08C. After 48 h of stirring at 08C (TLC), 2-propanol
10 mL) was added to destroy the excess reagent. The reaction mixture was
diluted with H O (10 mL) and acetone was removed under reduced
pressure. The residue was extracted with CH Cl
(3 Â 15 mL). The
combined organic layers were concentrated, taken up in ethyl acetate
and washed with H
O (3 Â 5 mL). The organic layer was dried, filtered and
concentrated. After chromatography on silica gel (CHCl /EE/HOAc
0:8:2), 26 was obtained as a colorless solid (209 mg, 88%). R (CHCl
CHCl ); H NMR (250 MHz, CDCl ): d ˆ 0.87 (t, J ˆ 6.5 Hz, 3H, CH ),
3
3
3
1.25 (m, 18H, CH
2
), 1.62 ± 1.81 (m, 2H, CH
2
), 2.69 ± 3.15 (m, 3H, 3-H, 4-H),
(
A
1
3
4
.66 (dt, J ˆ 7.0, 6.3 Hz, 1H, 2-H), 9.73 (s, 1H, CHO); C NMR (100 MHz):
d ˆ 13.66 (‡, CH ), 22.63 (À, CH ), 25.09 (À, CH ), 28.98 (À, CH ), 29.15
À, CH ), 29.29 (À, CH ), 29.35 (À, CH ), 29.45 (À, CH ), 29.55 (À, CH ),
1.80 (À, CH
3
2
4
‡
3
2
2
2
(
3
2
2
2
2
2
1
(
2
2
), 35.61 (À, CH ), 52.13 (‡, C-3)), 78.91 (‡, C-2), 174.07
2
(
C
quat), 197.15 (‡,-CHO); IR (film): nÄ ˆ 3418, 2922, 2852, 1731, 1651, 1466,
2
À1
1
2
417, 1377, 1221, 1103 cm ; HRMS: calcd for C16
68.2038.
28 3
H O : 268.2000; found:
2
2
2
(2S,3R)-(À)-5-Oxo-2-undecyltetrahydrofuran-3-carboxylic acid (30):
solution of KH PO (96 mg, 0.72 mmol) in H O (1 mL), NaClO (166 mg,
1.8 mmol) and 30% H (42 mg) was added at 08C to a solution of 29
A
3
2
4
2
2
9
f
3
/
2 2
O
Chem. Eur. J. 2003, 9, No. 1
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0267 $ 20.00+.50/0
267

O. Reiser et al.
FULL PAPER
(
150 mg, 0.56 mmol) in CH
Then Na SO (114 mg) was added and stirring was continued for an
additional hour. The solution was acidified to pH 2 by addition of an
aqueous solution of 1n KH SO solution. The mixture was extracted with
CH Cl (200 mL), the organic layers were dried and evaporated at room
temperature. After crystallization from ethyl acetate 30 was obtained as
3
CN (13 mL). The mixture was stirred for 48 h.
29.24 (À, CH
(À, CH
2
), 29.42 (À, CH
2
), 29.43 (À, CH
2
), 29.55 (À, 2C, CH
2
), 32.63
),
2
3
2
), 34.12 (À, CH
2
), 38.09 (À, CH
2
), 51.23 (‡, CH), 51.39 (‡, CH
3
78.51 (‡, CH), 121.73 (‡, ˆCH), 137.13 (‡, ˆCH), 174.07 (Cquat), 174.33
(Cquat), 197.27 (‡, -CHO); IR (film) nÄ ˆ 3442, 2926, 2854, 1777, 1739, 1594,
2
4
À1
2
2
1437, 1363, 1196, 1114, 1022, 973 cm ; MS (EI, 70 eV): m/z (%): 366.2 (2.0)
‡
[M ], 334.1 (15.7), 316.2 (31.0), 113.0 (100.0), 85.0 (65.9); HRMS: calcd
‡
colorless microcrystals (114.6 mg, 72%). R
0
CDCl
(
1
CH
3
CH
f
(CHCl
3
/EE/HOAc 90:8:2) ˆ
C
21
H
34
O
5
: 366.2406; found: 366.2409 [M ].
.24; m.p. 1218C; [a]2
0
ˆ À47.4 (c ˆ 0.35 in CHCl
); H NMR (250 MHz,
), 1.26 (m, 18H, CH ), 1.66 ± 2.11
3 2
1
D
3
(
2S,3R)-15-(3-Formyl-5-oxotetrahydrofuran-2-yl)-pentadecanoic methyl
ester (33): Pd/C (57 mg, 5 mol%) was added to a solution of 32 (392 mg,
.07 mmol) in methanol (40 mL), and stirred under H atmosphere at room
3
): d ˆ 0.88 (t, J ˆ 6.5 Hz, 3H, CH
2
m, 2H, CH ), 2.70 ± 2.90 (m, 2H, 4-H), 3.37 ± 3.40 (m, 1H, 3-H), 4.61 (m,
1
2
H, 2-H); 13C NMR (62.9 MHz, CDCl
): d ˆ 14.65 (‡, CH
), 23.56 (À,
), 30.46 (À, CH ),
), 32.91 (À, CH ), 34.39 (À,
3
3
temperature for 18 h. After filtration and evaporation of the solvent 33 was
obtained as a colorless oil (347 mg, 88%). H NMR (250 MHz, CDCl
d ˆ 1.21 ± 1.84 (m, 28H, CH
2
), 26.53 (À, CH
2
), 30.31 (À, CH
2
), 30.36 (À, CH
2
2
1
):
3
0.52 (À, CH
2
), 30.59 (À, CH
2
), 30.61 (À, CH
2
2
2
), 2.30 (t, J ˆ 7.6 Hz, 2H, CH
CO Me), 2.76
2 2
2
), 36.44 (À, CH ), 49.41 (‡, C-3), 85.60 (‡, C-2), 174.18 (Cquat), 174.86
2
(
(
2
dd, J ˆ 17.8, 9.9 Hz, 1H, 4-H), 2.92 (dd, J ˆ 17.8, 7.7 Hz, 1H, 4-H), 3.12
(
1
C
quat); IR (KBr): nÄ ˆ 3442, 2922, 2853, 1749, 1599, 1466, 1424, 1236, 1095,
dddd, J ˆ 9.9, 7.7, 6.3, 1.5 Hz, 1H, 3-H), 3.67 (s, 3H, CH
3
), 4.66 (m, 1H,
): d ˆ
), 29.19 (À,
), 29.48 (À, CH ),
), 35.58
À1
020 cm ; HRMS: calcd for C16
H
28
O
4
284.200; found: 284.1987.
13
-H), 9.74 (d, J ˆ 1.5 Hz, 1H, CHO); C NMR (62.9 MHz, CDCl
3
(
2S,3R,4R)-(À)-4-Methyl-5-oxo-2-tridecyltetrahydrofuran-3-carboxylic
24.97 (À, CH
CH
), 29.27 (À, CH
29.59 (À, 2C, CH ), 29.61 (À, CH
(À, CH ), 51.47 (‡, CH
2
), 25.15 (À, CH
2
), 29.03 (À, CH
2
), 29.16 (À, CH
2
acid, nephrosteranic acid (20): A solution of 30 (50 mg, 0.176 mmol) in dry
THF (30 mL) was added to sodium bis(trimethylsilyl)amide (1m solution in
THF, 630 mL, 0.63 mmol, 3.6 equiv) at À788C under argon over 30 minutes.
The mixture was stirred at À788C for 24 h. Methyliodide (2.71 mmol,
2
2
), 29.39 (À, CH
2
), 29.45 (À, CH
2
2
2
2
), 29.62 (À, CH
2
), 34.14 (À, CH
2
2
3
), 52.57 (‡, CH), 79.14 (‡, CH), 174.11 (Cquat),
‡
174.43 (Cquat), 197.30 (‡, CHO); MS (DCI): m/z (%): 369.3 (29.6) [MH ],
2
00 mL) was slowly added and the mixture was stirred for additional 24 h.
337.2 (100.0, DCH
3
OH); HRMS: calcd for C21
H
36
O
5
: 369.2641; found:
‡
The mixture was allowed to warm to À208C. HCl (1n, 3.1 mL) was added,
the mixture was extracted with Et
O (3 Â 10 mL) and the organic layer was
washed with brine and dried. 20 was obtained as colorless microcrystals
(
1
CHCl
CH
(
2
2
369.2640 [M ].
2
(
2S,3R)-(À)-2-(14-Methoxycarbonyl-tetradecyl)-5-oxo-tetrahydrofuran-3-
carboxylic acid (34): A solution of the 33 (309 mg, 0.839 mmol) in acetone
7 mL) was treated with 2 mL of freshly prepared Jones reagent (2.5 g CrO
47.2 mg, 90%). R
f
(CHCl
3
/ethyl acetate/HOAc 90:80:2) ˆ 0.25; m.p.
(
3
098C; [a]2
0
ˆ À27.7 (c ˆ 0.90 in CHCl
), [a]
ˆ À28.1 (c ˆ 1.02 in
D
3
D
‡
3 mL H
SO
‡ 25 mL H
2
O) at 08C until the color was presisted. After
2
4
);[9b] H NMR (400 MHz, CDCl
1
): d ˆ 0.88 (t, J ˆ 6.5 Hz, 3H,
3
3
7
h of stirring at 08C (controlled by TLC), 2-propanol (7 mL) was added to
3
), 1.20 ± 1.47 (m, 20H, CH
2
), 1.38 (d, J ˆ 7.1 Hz, 3H, CH
3
), 2.65 ± 2.75
destroy the excess reagent. The reaction mixture was diluted with H
5 mL) and acetone was removed under reduced pressure. The residue was
extracted with CH Cl
(4 Â 20 mL). The combined organic layers were
washed with brine (30 mL), dried and concentrated in vacuo to give 34 as
2
O
m, 1H, 4-H), 2.93 ± 3.08 (m, 1H, 3-H), 4.48 (ddd, J ˆ 9.0, 8.7, 4.2 Hz, 1H,
(
-H); 13C NMR (62.9 MHz, CDCl
2.65 (À, CH ), 25.34 (À, CH ), 29.24 (À, CH
), 29.51 (À, CH ), 29.61 (À, CH ), 31.91 (À, CH
): d ˆ 14.10 (‡, CH
), 14.50 (‡, CH
),
3
3
3
2
2
2
2
2
), 29.32 (À, CH
2
), 29.40 (À,
CH
3
2
2
2
2
), 34.94 (À, CH
2
),
colorless solid (311 mg, 96%). R
f
(CHCl
3
1
/MeOH 9:1) ˆ 0.22; m.p. 120 ±
9.34 (‡, C-3), 53.55 (‡, C-4), 79.05 (‡, C-2), 175.58 (Cquat), 176.66 (Cquat);
20
D
1
248C; [a]
ˆ À26.0 (c ˆ 0.75 in CHCl
), 1.55 ± 1.82 (m, 2H, 15'-H), 2.3 (t, J ˆ 7.5 Hz, 2H, 2'-H),
.75 ± 3.14 (m, 3H, 4-H, 3-H), 3.67 (s, 3H, OCH ), 4.56 ± 4.67 (m, 1H, 2-H);
), 25.10 (À, CH ), 29.09 (À,
), 29.38 (À, CH ),
), 29.53 (À,
), 45.00 (‡, CH), 51.27
3
); H NMR (250 Hz, CDCl
3
): d ˆ
IR (KBr): nÄ ˆ 3456, 2921, 2852, 1748, 1469, 1260, 1201, 1172. 1100, 1026,
1
2
.25 (brs, 24H, CH
2
À1
8
02 cm ; HRMS: calcd for C17
H
30
O
4
: 298.2100; found: 298.2144.
3
1
3
C NMR (100 MHz, CDCl
CH ), 29.28 (À, CH
), 29.18 (À, CH
9.40 (À, CH ), 29.47 (À, CH
CH ), 34.10 (À, CH
), 31.90 (À, CH
3
): d ˆ 24.90 (À, CH
2
2
Tetradec-13-enoic-acid methylester (31): A solution of tetradec-13-enoic
acid (4.17 g, 18.4 mmol) and conc. H SO (1 mL) in MeOH (100 mL) was
refluxed for 12 h. The mixture was concentrated to half of its original
volume, diluted with H O (250 mL), and the remaining methanol was
evaporated. The mixture was extracted with pentane (500 mL), and the
organic layer was washed with saturated NaHCO solution and concen-
2
2
2
), 29.34 (À, CH
2
2
2
4
2
2
2
), 29.50 (À, CH
2
), 29.52 (À, CH
2
2
2
2
), 35.31 (À, CH
2
2
(
(
‡, CH ), 81.75 (‡, CH), 174.45 (Cquat), 174.69 (Cquat), 175.71 (Cquat); IR
3
film): nÄ ˆ 3449, 3116, 2921, 2850, 1748, 1464, 1436, 1394, 1358, 1239, 1194,
3
À1
1
171, 1114, 973 cm ; HRMS: calcd for C21
H
36
O
6
: 384.2500; found:
trated. After chromatography on silica gel (hexanes/EE 10:1), 31 was
‡
1
383.2428 [M À H].
obtained as colorless oil (4.0 g, 90%). R
250 MHz, CDCl
f
(hexanes/EE 1:1) ˆ 0.74; H NMR
(
3
): d ˆ 1.23 (brs, 16H, CH
2
), 1.54 ± 1.71 (m, 2H, CH
2
),
),
(2S,3R)-(À)-2-(14-Carboxy-tetradecyl)-5-oxo-tetrahydrofuran-3-carboxyl-
ic acid (35): Compound 34 (100 mg, 0.3 mmol) was added to a mixture of
MeOH (60 mL) and saturated aqueous LiOH solution (10 mL) and the
mixture was stirred for 2 d. The mixture was acidified with 20% HCl
solution and saturated with NaCl (pH ꢀ 7). The mixture was extracted with
CH Cl several times (TLC), dried and concentrated to get the crude
1
4
1
.97 ± 2.10 (m, 2H, CH
2
), 2.30 (t, J ˆ 7.6 Hz, 2H, CH
2
), 3.67 (s, 3H, OCH
3
.91 (ddt, J ˆ 10.1, 2.3, 1.2 Hz, 1H, 14-H), 4.98 (ddt, J ˆ 17.1, 2.2, 16. Hz, 1H,
1
3
4-H), 5.80 (ddt, J ˆ 17.1, 10.1, 6.7 Hz, 1H, 13-H); C NMR (100 MHz,
): d ˆ 24.92 (À, CH ), 28.91 (À, CH ), 29.10 (À, CH ), 29.11 (À,
), 29.22 (À, CH ), 29.40 (À, CH ), 29.45 (À, CH ), 29.53 (À, CH ),
), 139.18 (‡,
CDCl
CH
3.79 (À, CH
3
2
2
2
2
2
2
2
2
2
2
3
2
), 34.08 (À, CH
2
), 51.38 (‡, CH
3
), 114.03 (À, CH
2
product which after chromatography on silica gel (CHCl /MeOH/AcOH
3
CH), 174.3 (‡, CO); IR (film): nÄ ˆ 3077, 2926, 2854, 1743, 1641, 1436, 1362,
9:8:2) gave 35 as a colorless solid (91 mg, 94%). R (CHCl /MeOH 9:1) ˆ
f
3
À1
20
1
1
247, 1196, 1171, 1117, 994, 909 cm ; HRMS: calcd for C15
H
28
O
2
: 249.2100;
(240.21): C
0.12; m.p. 1288C; [a] ˆ À15.0 (c ˆ 0.90 in MeOH); H NMR (400 MHz,
D
found: 240.2089; elemental analysis calcd (%) for C15
7
H
28
O
2
CDCl /CD OD): d ˆ 1.28 (brs, 22H, CH ), 1.59 ± 1.64 (m, 2H, CH ), 1.69 ±
3
3
2
2
4.95; H 11.74 found: C 74.89; H 11.82.
1.88 (m, 2H, CH ), 2.29 (t, J ˆ 7.5 Hz, 2H, 2'-H), 2.81 (dd, J ˆ 17.9, 9.6 Hz,
2
1
1
H, 4-H), 2.93 (dd, J ˆ 17.9, 8.1 Hz, 1H, 4-H), 3.09 (ddd, J ˆ 9.6, 8.3, 6.9 Hz,
13
(
E)/(Z)-(2S/R,3R)-(À)-15-(3-Formyl-5-oxo-tetrahydrofuran-2-yl)-penta-
H, 3-H), 4.62 ± 4.70 (m, 1H, 2-H); C NMR (100 MHz, CDCl
3
/CD
), 28.63
), 28.91 (À, 2C,
),
3
OD):
dec-13-enoic acid methylester (32): Compound 5a (500 mg, 3.25 mmol,
drˆ 95:5), 31 (1.0 g, 4.16 mmol, 1.3 equiv) and 27 (75 mg, 2.7 mol%) were
d ˆ 24.31 (À, CH
À, CH ), 28.75 (À, CH
CH ), 31.41 (À, CH
), 28.94 (À, 2C, CH
2
), 24.60 (À, CH
2
), 28.47 (À, CH
2
), 28.55 (À, CH
2
(
2
2
), 28.80 (À, CH
2
), 28.83 (À, CH
2
2 2
added into dry CH Cl (60 mL) and the resulting soltuion was heated under
2
2
2
), 33.44 (À, CH
2
), 34.65 (À, CH
2
reflux for 24 h. After chromatography on silica gel (hexanes/EE 1:1), 30
was obtained as an oil (448 mg, 38%, dr 95:5, E/Z 7:1) and 5a (282 mg,
5
0
1
2
9
4
4.93 (‡, CH), 82.32 (‡, CH), 172.62 (Cquat), 175.71 (Cquat), 176.10 (Cquat);
IR (film): nÄ ˆ 3448, 3140, 2921, 2849, 2679, 1747, 1718, 1462, 1436, 1278,
6%) were recovered (conversion yield ˆ 86%). R
f
(hexanes/EE 1:1) ˆ
); H NMR (250 MHz, CDCl
): d ˆ
), 1.51 ± 1.70 (m, 2H, CH ), 1.94 ± 2.09 (m, 2H, CH ),
.30 (t, J ˆ 7.4 Hz, 2H, 2'-H), 2.39 ± 2.62 (m, 2H, CH ), 2.71 (dd, J ˆ 17.8,
.9 Hz, 1H, 4-H), 2.92 (dd, J ˆ 18.0, 7.3 Hz, 1H, 4-H), 3.19 (dddd, J ˆ 9.9,
), 4.66 ± 4.76 (m, 1H, 3-H),
À1
.37; [a]2
0
1
1238, 1194, 1114, 857 cm ; HRMS: calcd for C20
H
34
O
6
: 370.2400; found:
D
ˆ À9.5 (c ˆ 2.45 in CHCl
3
3
‡
3
69.2281 [M À H].
.26 (brs, 16H, CH
2
2
2
2
(2S,3R)-(À)-2-(14-Carboxytetradecyl)-4-methylen-5-oxo-tetrahydrofuran-
3-carbonic acid, (À)-protopraesorediosic acid (22): Magnesium methylcar-
bonate (5.6 mL, 11.28 mmol, 38.0 equiv, 2m in DMF (Stiles reagent)) was
added under argon atmosphere to 35 (110 mg, 0.297 mmol, 1.0 equiv) and
the solution was stirred at 1358C for 66 h. After cooling CH
was added and the solution was acidified with cold 10% HCl. The aqueous
layer was extracted with CH Cl
(4 Â 30 mL) and the combined organic
7
5
1
.3, 6.0, 1.3 Hz, 1H, 3-H), 3.67 (s, 3H, OCH
3
.28 ± 5.42 (m, 1H, ˆCH-), 5.57 ± 5.72 (m, 1H, ˆCH-), 9.70 (d, J ˆ 1.3 Hz,
H, -CHO) characteristic signals of the diastereomer (2R): 9.72 (d, J ˆ
2 2
Cl (35 mL)
1
(
.3 Hz, CHO); 13C NMR (100.6 MHz, CDCl
3
): d ˆ 24.90 (À, CH
2
), 24.81
À, CH
2
), 28.90 (À, CH
2
), 29.14 (À, CH
2
), 29.18 (À, CH
2
), 29.19 (À, CH ),
2
2
2
268
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0268 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 1

Paraconic Acids
260±270
layers were washed with saturated NaCl solution (20 mL), and concen-
trated in vacuo. The residue was treated with 1.85 mL of a freshly prepared
Stocksolution (20 mL HOAc, 15 mL 37% formaldehyde in water, 5.2 mL
N-methylaniline and 600 mg NaOAc) and stirred under argon for 2.5 h at
[6] a) M. S. Maier, D. I. G. Marimon, C. A. Stortz, M. T. Adler, J. Nat.
Prod. 1999, 62, 1565 ± 1567; b) B. K. Park, M. Nakagawa, A. Hirota,
M. Nakayama, J. Antibiot. 1988, 41, 751 ± 758.
[7] a) T.-P. Loh, P.-L. Lye, Tetrahedron Lett. 2001, 41, 561 ± 565; b) P. K.
Mandal, S. C. Roy, Tetrahedron 1999, 55, 11395 ± 11398; c) J. Lertvor-
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room temperature. Et
2
O (20 mL) and sat. NaCl solution (10 mL, containing
1
mL conc. HCl) were added and the aqueous layer was extracted with
Et
2
O (4 Â 15 mL). The combined organic layers were washed with sat.
NaCl solution (15 mL, containing 10 drops conc. HCl) and aqueous layer
was re-extracted with Et
O (2 Â 15 mL). The combined organic layers were
dried and the solvent was evaporated. After recrystallization from CHCl
pentane 22 was obtained as colorless microcrystals (71 mg, 62%,
2
3
/
0
.1856 mmol).
R
f
(CHCl
3
/MeOH/HOAc 90:8:2) ˆ 0.25; m.p. 1238C;
2
0
20
[
a]
D
ˆ À8.9 (c ˆ 1.12 in MeOH), [a]
D
ˆ ‡9.1 (MeOH) for the enantiom-
[
34]
1
er.
H NMR (250 MHz, CD
3
OD): d ˆ 1.30 (brs, 24H, CH
), 2.27 (t, J ˆ 7.4 Hz, 2H, 2'-H), 3.71
ddd, J ˆ 5.7, 3.0, 2.7 Hz, 1H, 3-H), 4.78 (dt, J ˆ 5.7, 6.4 Hz, 1H, 2-H), 5.99
2
), 1.52 ± 1.66
(
(
(
(
2 2
m, 2H, CH ), 1.68 ± 1.78 (m, 2H, CH
1
3
d, J ˆ 2.7 Hz, 1H, ˆCH
62.9 MHz, CD
0.35 (À, CH
CH
4.97 (À, CH
), 6.31 (d, J ˆ 3.0 Hz, 1H, ˆCH
2
); C NMR
2
3
OD): d ˆ 26.01 (À, CH
2
), 26.12 (À, CH
2
), 30.26 (À, CH
2
),
3
2
), 30.44 (À, CH
2
), 30.58 (À, CH
2
), 30.62 (À, CH
2
), 30.65 (À,
2
), 30.72 (À, CH
2
), 30.73 (À, CH
2
), 30.74 (À, CH
2
), 30.75 (À, CH
2
),
3
2
), 36.59 (À, CH ), 51.03 (‡, CH), 81.29 (‡, CH), 125.21 (À,
2
ˆ
2 quat quat quat quat
CH ), 135.64 (C ), 170.65 (C ), 172.58 (C ), 177.73 (C ); IR (film):
À1
nÄ ˆ 3442, 2922, 2852, 1744, 1714, 1257 cm ; HRMS: calcd for C21
34 6
H O :
‡
3
82.2355 (381.2275 for [M À H ], found: 381.2275.
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Acknowledgements
We thankDr. M. Zabel, Department of Inorganic Chemistry at the
University of Regensburg for performing the X-ray structure analyses of
c-Et and 26. This workwas supported by the Deutsche Forschungsge-
meinschaft (Re948/5-1), the Fonds der Chemischen Industrie and the
International Quality Network–Medicinal Chemistry (DAAD; fellowship
for R.B.C.). B.N. is grateful to the Studienstiftung des Deutschen Volkes for
a fellowship.
8
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Chem. Eur. J. 2003, 9, No. 1
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269

O. Reiser et al.
FULL PAPER
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Received: June 4, 2002 [F4153]
270
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0901-0270 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 1