Asymmetric synthesis of a structurally simplified analogue of the antibiotic heptelidic acid

Article abstract of DOI:10.1007/s706-002-8242-9

A structurally simplified analogue of the antibiotic (+)-heptelidic acid was synthesized in ten steps with an overall yield of 9%. Key step was a conjugate addition of a silyl protected vinylcuprate to an asymmetrically shielded enoate, which gave an addu

Full text of DOI:10.1007/s706-002-8242-9

Monatshefte fuÈr Chemie 133, 127±137 ꢀ2002)
Asymmetric Synthesis of a Structurally
Simpli®ed Analogue of the Antibiotic
Heptelidic Acida
Ã
Maria Krenn and Ernst Urban
Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria
Summary. A structurally simpli®ed analogue of the antibiotic ꢀ ‡ )-heptelidic acid was synthesized
in ten steps with an overall yield of 9%. Key step was a conjugate addition of a silyl protected
vinylcuprate to an asymmetrically shielded enoate, which gave an adduct as a single diastereomer.
Transesteri®cation in the presence of triethylamine allowed a selective cleavage of the chiral auxiliary
and afforded an enantiomerically pure methyl ester. This easily enolizable ꢀ-ketoester was trans-
formed to the trans con®gurated methylene derivative using a four-step reaction sequence. Finally,
the desired epoxylactone was accessible from the methylene derivative by lactone ring formation and
successive oxidation in four steps.
Keywords. Antibiotics; Asymmetric synthesis; Conjugate addition; Cuprates; Helmchen's auxiliary.
Introduction
ꢀ ‡ )-Heptelidic acid ꢀ1) is a sesquiterpene lactone of fungal origin which shows
selective activity against Bacteroides fragilis [1], an anaerobic pathogen causing
serious septic infections, and is active against the human malaria parasite
Plasmodium falciparum [2]. In studies about the mechanism of action it has turned
out that 1 is a high-af®nity active site directed inhibitor of glyceraldehyde-
3-phosphate dehydrogenase [3], which is an important enzyme of the anaerobic
glycolytic pathway. The epoxide moiety of 1 has been postulated to be the essential
structural element responsible for enzyme inactivation caused by covalent binding
of 1 to the thiol groups at the active site of the enzyme [4].
A total synthesis of ꢀÆ)-heptelidic acid has been published by Danishefsky [5]
in 1988. Our contribution in this ®eld of research has been the development of a
synthetic method allowing an access to enantiomerically pure 6-alkenyl-2-oxo-
cyclohexane-carboxylates [6] which have been key intermediates for the ®rst
asymmetric synthesis of ꢀ ‡ )-heptelidic acid [7±10].
Only few papers [11±13] have been published on structural modi®cations of 1
until now, mainly for the purpose of structure determination of the natural product.
a
Dedicated to Prof. Wilhelm Fleischhacker with our best wishes on the occasion of his 70th birthday
Ã
Corresponding author. E-mail: urban@speedy.pch.univie.ac.at

128
M. Krenn and E. Urban
Scheme 1
Syntheses have started exclusively from 1, modifying the reactive epoxide or
lactone ring. Recently, 1 has been transformed to its chlorohydrine derivative
which shows antitumor activity [13]. Hence, an interesting progress in this area of
research would be the total synthesis and biological evaluation of derivatives of
1 which are not accessible from the fermentatively produced natural product by
semisynthetic transformations.
Conserving the pharmacophoric groups and modifying the remaining structure
pattern is generally recognized as a reliable method to design analogues of an agent
with improved activity. A comparison of the structural lead ꢀ‡ )-heptelidic acid ꢀ1)
with pentalenolactone ꢀ2) [14], which both inhibit glyceraldehyd-3-phosphate
dehydrogenase, has persuaded us that the oxirane moiety, the lactone ring, and the
acrylic acid substructure are essential for the activity of 1 and 2. Surprisingly,
the disposition of the pharmacophoric groups and the underlying ring system are
quite different in 1 and 2, although both antibiotics have the same mechanism of
action. Hence, it is an interesting question how far the nature of the substituent at
the carbocyclic ring of 1 or the ring size of the carbocyclic ring may be changed
without loss of activity.
Results and Discussion
In this contribution we want to present an asymmetric synthesis of the epoxylactone
16, which is a structurally simpli®ed analogue of 1 bearing no alkyl substituent in
the six-membered carbocyclic ring. Whereas the synthesis of 1 requires an alkyl
substituted building block, which must be prepared by a ®ve step reaction sequence
including a chromatographic separation of diastereomers [7], the synthesis of
the simpli®ed analogue 16 starts from the easily accessible 2-oxo-cyclohexane-
carboxylate 6 [6].
In the ®rst step of the synthesis the vinylcuprate 5 was added to the asym-
metrically protected enoate 6, giving the adduct 7 ꢀ82%) as a single diastereomer.
This result was in accordance with our previous observations on high diastereo-
selectivity obtained in additions of simpler organocopper compounds to enoate 6
[7]. The thienylcyanocuprate 5 was the reagent of choice for this reaction step,
because only one equivalent of this readily accessible reagent was required for a
1
complete conversion of 6 at À78ꢀC. H and 13C NMR spectra of the adduct 7
showed a mixture of keto and enol forms in a ratio of 40:60 which is typical for
alkenyl substituted 2-oxo-cyclohexane-carboxylates [6].
In the next reaction step, the chiral auxilary was selectively removed from the
sterically highly crowded ꢀ-ketoester 7 by transesteri®cation with an excess of

Synthesis of a Heptelidic Acid Analogue
129
Scheme 2
Scheme 3
methanol in the presence of triethylamine at 115ꢀC. We obtained a mixture of the
methyl ester 8 and Helmchen's auxilary 3 ꢀRÃOH) which was separated by column
chromatography to give the enantiomerically pure methyl ester 8 ꢀ93%). The
presence of triethylamine was essential to avoid a cleavage of the silyl ether protect-
ing groups from the chiral building block 8.

130
M. Krenn and E. Urban
Next, we focused our efforts on the preparation of the methylene derivative
12a. Transformation of the keto group of 8 to the methylene substituent was not
quite trivial, because literature-known reagents usually failed due to the ꢀ-ketoester
1
substructure of 8. The enolization potential of 8 was indicated by its H and 13C
NMR spectra which showed a mixture of keto and enol forms in a ratio of 31:69
and 43:57, respectively. Nevertheless, we obtained derivatives 12a,b in good
yields using a four-step sequence ꢀsee Scheme 3) which had previously been
used successfully for the synthesis of heptelidic acid [9]. Thus, ꢀ-ketoester 8
was transformed to enol phosphate 9, which was subsequently reacted with
trimethylsilylmethylmagnesium chloride to the allylsilane derivative 10. Next, a
change of the silylether protecting groups to acetyl groups was necessary to avoid
cleavage during the protodesilylation step. This was achieved by reaction of the
silylether derivative 10 with FeCl3 in acetic anhydride to give the diacetate 11.
Protodesilylation of the allylsilane derivative 11 using tri¯uoroacetic acid in
dichloromethane gave a mixture of 12a and 12b in a ratio of 4:1. This result was in
accordance with our previous observations on the synthesis of 1 [9]. Obviously,
presence or absence of an isopropyl substituent in position 5 of 11 gave no dif-
ference in the diastereoselectivity during formation of the diastereomeric methyl-
ene derivatives.
The mixture of diastereomeric methylene derivatives 12a,b was separated by
column chromatography to give the diastereomerically pure methyl ester 12a. The
structures of 12a and 12b were assigned based upon characteristic H NMR shift
1
effects [9] of the carboxyl group on methylene hydrogens ꢀ12a: 4.56 and 4.87 ppm;
12b: 4.85 and 4.87 ppm).
Cyclization of the lactone ring was achieved by removal of the ester protecting
groups by means of sodium hydroxide, extraction of the free dihydroxy acid, and
cyclization using N,N-bis-ꢀ2-oxo-3-oxazolidinyl)-phosphorodiamidic chloride [15]
Table 1. 13C NMR shifts ꢀppm) of cyclohexanecarboxylates 7±12
7
8
9
10
11
12a
12b
Ketone Enol
Ketone Enol
C-1
62.46 101.86
63.28 100.92 119.32 123.67 122.11
55.20
53.18
C-2
205.93 172.29 205.23 172.99 151.42 148.86 150.76 144.21 144.76
C-3
41.37
24.71
30.76
39.29
29.11
17.93
30.76
30.36
40.93
25.04
31.03
40.26
29.02
17.82
29.57
30.22
28.54
19.40
28.66
33.77
33.98
19.48
29.74
33.95
34.00
19.36
29.15
34.58
34.66
25.67
31.00
39.60
31.47
26.07
27.92
39.46
C-4
C-5
C-6
COO
OCH3
CH2Si
SiꢀCH3)3
ˆCH2
±HCˆ
ˆC<
CH2O
CH2O
168.62 171.34 169.52 172.90 166.54 169.11 168.72 172.65 172.11
±
±
±
±
±
±
±
±
51.84
51.21
51.30
50.64
27.36
À0.71
±
50.65
27.55
À0.79
±
51.47
51.49
±
±
±
±
±
±
±
±
±
±
±
±
±
109.49 111.98
127.89 131.83 125.66 129.42 126.55 128.98 138.73 137.06 137.26
140.25 137.24 139.76 136.46 139.02 137.24 128.41 129.96 129.34
65.00
59.17
64.54
58.98
64.17
59.13
64.71
58.90
64.43
58.72
64.53
58.88
66.45
60.01
66.19
60.04
66.45
59.75

Synthesis of a Heptelidic Acid Analogue
131
Scheme 4
to yield 13a. During the hydrolysis of 12a two equivalents of acetic acid are
formed which must be removed before cyclization to avoid the formation of the
acetate derivative 13b as a byproduct.
Selective oxidation of the allylalcohol moiety of 13a was obtained by reaction
with manganese dioxide, which proved to give higher yields ꢀ87%) of aldehyde 14
than the reaction with Jones reagent ꢀ51%). Diastereoselective epoxidation of
14 was achieved using t-butylhydroperoxide in the presence of molybdenum
hexacarbonyl affording the epoxyaldehyd 15 in satisfying yield ꢀ67%) as a single
diastereomer. This result was in accordance with our previous observations
Table 2. 13C NMR shifts ꢀppm) of 3,5a,6,7,8,8a-Octahydro-1H-cyclopent[c]oxepin-1-ones
13a
13b
14
15
16
C-1
172.76
64.00
134.60
132.88
41.02
33.15
25.90
35.26
141.31
46.58
66.50
±
171.99
63.92
130.13
136.77
40.98
32.86
25.74
35.11
140.98
46.25
67.73
±
171.53
59.03
137.51
157.34
42.25
32.10
25.83
35.00
139.84
45.48
±
169.92
59.20
137.76
155.94
40.95
31.15
23.25
33.82
57.76
45.00
±
170.57
61.93
128.32
147.14
41.82
31.99
24.53
35.21
58.64
44.57
±
C-3
C-4
C-5
C-5a
C-6
C-7
C-8
C-9
C-9a
CH2OH
CHO
COOH
ˆCH2
Epoxide CH2
191.37
±
191.08
±
±
±
±
167.26
±
112.43
±
112.63
±
113.55
±
±
52.15
51.65

132
M. Krenn and E. Urban
obtained on the oxidation of ꢀ ‡ )-heptaldehyde [9]. Obviously, presence or
absence of an isopropyl substituent in position 6 of 14 gave no difference of
diastereoselectivity during formation of epoxylactones. The structure of 15 was
assigned according to characteristic shift effects [9] of the carboxyl group to the
oxirane hydrogens ꢀ2.59 and 3.96 ppm). In the last reaction step, the epoxyaldehyd
15 was oxidized with sodium chlorite in sodium dihydrogenphosphate buffered
t-butanol to afford the desired carboxylic acid 16.
In conclusion, we obtained the simpli®ed heptelidic acid analogue 16 starting
from the asymmetric protected enoate 6 in ten steps with an overall yield of 9%.
Experimental
1
Melting points were determined on a Ko¯er melting point apparatus and are uncorrected. H and
13C NMR spectra were measured with a Bruker Avance DPX 200 or a Varian Unity Plus 300
spectrometer using TMS as an internal standard. Optical rotations were measured on a Perkin Elmer
241 polarimeter. Microanalyses were performed by J.Theiner ꢀInstitute of Physical Chemistry,
University of Vienna) and corresponded to the calculated values with an accuracy of 0.4%.
!1R,2R,3S,4S)-!3-!N-Benzenesulfonyl-N-!3,5-dimethylphenyl)-amino)-2-bornyl)-!1S,6S)-
6-!3-t-butyldimethylsilyloxy-2-!t-butyldimethylsilyloxy)-methyl-prop-1-en-1-yl)-
2-oxo-cyclohexanecarboxylate ꢀ7; C47H73NO7SSi2)
A solution of 11.86 g vinylbromide 4 ꢀ30.0 mmol) in 120 cm3 diethylether was cooled to À78ꢀC. A
solution of 22.52 g t-BuLi in pentane ꢀ1.65 M, 57.0 mmol) was added, and the mixture was stirred at
À78ꢀC for 2 h. Then the mixture was transferred with a double-tipped needle to a precooled ꢀÀ78ꢀC)
solution of 132.0 cm3 lithium 2-thienyl-cyanocuprate ꢀ0.25 M in THF, 33.0 mmol), and the resulting
mixture was stirred at À78ꢀC for 1 h. A solution of 16.07 g 6 ꢀ30.0 mmol) in 120 cm3 THF was
added, and stirring was continued at À78ꢀC for 2 h. Then the reaction mixture was transferred to a
¯ask containing a mixture of 500 cm3 CH2Cl2 and 500 cm3 of a NH4Cl solution ꢀ5%). The mixture
was stirred at 20ꢀC for 1 h and extracted with 2 Â 250 cm3 CH2Cl2. The organic layer was dried
ꢀNa2SO4), and the solvent was distilled off at reduced pressure. Puri®cation of the residue by ¯ash
chromatography ꢀ2  750 g silica gel, hexane:EtOAc ˆ 9:1) gave 21.00 g ꢀ82%) 7 as a colourless oil.
1H NMR ꢀ300 MHz, CDCl3, ꢁ, ketone:enol ꢀk:e) ˆ 40:60): À0.06 ꢀs, 3H, SiCH3, k), À0.04
ꢀs, 3H, SiCH3, k), 0.02 ꢀs, 6H, SiCH3, e), 0.06 ꢀs, 6H, SiCH3, k), 0.13 ꢀs, 3H, SiCH3, e), 0.16 ꢀs, 3H,
SiCH3, e), 0.62±2.60 ꢀm, 15H, CH3, H-30, H-40, H-50, k ‡ e), 0.81 ꢀs, 9H, t-Bu CH3, k), 0.87 ꢀs, 9H,
t-Bu CH3, e), 0.89 ꢀs, 9H, t-Bu CH3, k), 0.94 ꢀs, 9H, t-Bu CH3, e), 3.46 ꢀm, 1H, H-60, k), 3.51 ꢀd,
J ˆ 8.6 Hz, 1H, H-10, k), 3.59 ꢀm, 1H, H-60, e), 4.00±4.37 ꢀm, 4H, H-3, CH2O, k ‡ e), 4.43 ꢀd, J ˆ
11.8 Hz, 1H, CH2O, k), 4.49 ꢀd, J ˆ 12.0 Hz, 1H, CH2O, e), 5.37 ꢀd, J ˆ 6.0 Hz, 1H, ˆ CH±, e), 5.40
ꢀd, J ˆ 6.0 Hz, 1H, ˆCH±, k), 5.47 ꢀd, J ˆ 8.8 Hz, 1H, H-2, e), 5.51 ꢀd, J ˆ 9.4 Hz, 1H, H-2, k), 5.87 ꢀs,
1H, NAr H-2, k), 6.39 ꢀs, 1H, NAr H-2, e), 6.59 ꢀs, 1H, NAr H-6, e), 6.78 ꢀs, 1H, NAr H-4, e), 6.82
ꢀs, 1H, NAr H-4, k), 7.08 ꢀs, 1H, NAr H-6, k), 7.28±7.43 ꢀm, 4H, SO2ArH, k ‡ e), 7.43±7.56 ꢀm, 1H,
SO2ArH, k ‡ e), 12.09 ꢀs, 1H, ˆC±OH, e) ppm; 13C NMR ꢀ75 MHz, CDCl3, ꢁ, ketone:enol
ꢀk:e) ˆ 40:60): À5.41 ꢀOSi CH3, e), À5.35 ꢀOSi CH3, k), À5.28 ꢀOSi CH3, k), 13.44 ꢀCH3, e), 14.22
ꢀCH3, k), 18.17 ꢀt-Bu C, e), 18.22 ꢀt-Bu C, e), 18.26 ꢀt-Bu C, k), 19.28 ꢀCH3, e), 19.36 ꢀCH3, k), 19.48
ꢀCH3, e), 19.51 ꢀCH3, C-5, k), 19.91 ꢀC-5, e), 21.17 ꢀAr±CH3, k ‡ e), 25.89 ꢀt-Bu CH3, k ‡ e), 26.71
ꢀC-6, k), 27.01 ꢀC-6, e), 45.18 ꢀC-7, e), 45.70 ꢀC-7, k), 49.49 ꢀC-4, k), 50.72 ꢀC-1, e), 50.89
ꢀC-4, e), 51.46 ꢀC-1, k), 58.93 ꢀC-3, e), 59.32 ꢀC-3, k), 75.14 ꢀC-2, e), 77.03 ꢀC-2, k), 127.97 ꢀNAr C-2,
C-6, k ‡ e), 128.01 ꢀSO2Ar C-3, C-5, e), 128.08 ꢀSO2Ar C-3, C-5, k), 128.49 ꢀSO2Ar C-2, C-6, e),
128.69 ꢀSO2Ar C-2, C-6, k), 129.14 ꢀNAr C-4, k ‡ e), 132.15 ꢀSO2Ar C-4, k), 132.51 ꢀSO2Ar C-4, e),

Synthesis of a Heptelidic Acid Analogue
133
137.50 ꢀNAr C-3, k, C-5, k ‡ e), 136.35 ꢀNAr C-1, e), 137.97 ꢀNAr C-1, k), 138.86 ꢀSO2Ar C-1, e),
139.26 ꢀSO2Ar C-1, k) ppm; for further signals, see Table 1.
Methyl-!1S,6S)-6-!3-t-butyldimethylsilyloxy-2-!t-butyldimethylsilyloxy)-methyl-prop-1-
en-1-yl)-2-oxo-cyclohexanecarboxylate ꢀ8; C24H46O5Si2)
In an autoclave thermostated in an oil bath and equipped with a manometer a solution of 1.97 g 7
ꢀ2.31 mmol) and 230 mg Et3N ꢀ2.31 mmol) in 100 cm3 MeOH was heated for 15 h ꢀꢁ 115ꢀC/3.8 bar).
The pressure was continuously observed and prevented to exceed 4 bar by adjusting the bath
temperature. The solvent was removed under reduced pressure, and the residue was separated by
¯ash chromatography ꢀ200 g silica gel, petroleum ether:ethyl acetate ˆ 80:20) to yield 1.014 g ꢀ93%)
8 ꢀRf ˆ 0.65) as a colourless oil and 0.955 g ꢀ99%) 3 ꢀRf ˆ 0.55) as colourless crystals ꢀMeOH), m.p.:
184ꢀC.
20
D
‰ꢂŠ ˆ ‡41:80 ꢀc ˆ 1.014, CDCl3, ketone:enol ˆ 50:50); 1H NMR ꢀ300 MHz, CDCl3, ꢁ ketone:
enol ꢀk:e) ˆ 31:69): 0.00 ꢀs, 6H, SiCH3, k), 0.03 ꢀs, 12H, SiCH3, k ‡ e), 0.08 ꢀs, 6H, SiCH3, e), 0.89
ꢀs, 9H, t-Bu CH3, k ‡ e), 0.91 ꢀs, 9H, t-Bu CH3, k ‡ e), 1.55±1.95 ꢀm, 4H, k ‡ e), 2.20±2.40 ꢀm, 2H,
k ‡ e), 3.20 ꢀm, 2H, H-1, H-6, k), 3.52 ꢀm, 1H, H-6, e), 3.67 ꢀs, 3H, OCH3, k ‡ e), 4.04 ꢀd, J ˆ
12.2 Hz, 1H, CH2O, k), 4.15 ꢀs, 2H, CH2O, k ‡ e), 4.19 ꢀd, J ˆ 12.0 Hz, 1H, CH2O, e), 4.33 ꢀd,
J ˆ 12.2 Hz, 1H, CH2O, k), 4.37 ꢀd, J ˆ 12.0 Hz, 1H, CH2O, e), 5.30 ꢀd, J ˆ 8.3 Hz, 1H, ˆCH±, k),
5.41 ꢀd, J ˆ 10.0 Hz, 1H, ˆCH±, e), 12.36 ꢀs, 1H, ˆC±OH, e) ppm; 13C NMR ꢀ75 MHz, CDCl3, ꢁ,
ketone:enol ꢀk:e) ˆ 43:57): À5.47 ꢀOSi CH3, k), À5.43 ꢀOSi CH3, e), À5.39 ꢀOSi CH3, k), À5.32
ꢀOSi CH3, k), À5.26 ꢀOSi CH3, k), 18.20 ꢀt-Bu C, k), 18.28 ꢀt-Bu C, e), 18.37 ꢀt-Bu C, e), 18.40
ꢀt-Bu C, k), 25.89 ꢀt-Bu CH3, k ‡ e) ppm; for further signals, see Table 1.
Methyl-!6S)-6-!3-!t-butyldimethylsilyloxy)-2-!!t-butyldimethylsilyloxy)methyl)-prop-1-
en-1-yl)-2-!!diethyoxyphosphoryl)-oxy)-1-cyclohexenecarboxylate ꢀ9; C28H55O8PSi2)
758 mg NaH ꢀ95%, 30 mmol) were suspended in 70 cm3 THF, and the mixture was cooled to 0ꢀC.
Then a solution of 5.65 g 8 ꢀ12 mmol) in 30 cm3 THF was added, and the mixture was warmed to
room temperature and stirred for 20 min. The reaction mixture was again cooled to 0ꢀC, 2.48 g
diethylchlorophosphate ꢀ14.4 mmol) were added, and the mixture was stirred for 2 h at 0ꢀC and for
2 h at room temperature. The reaction mixture was transferred to a ¯ask containing 80 cm3 of a
NaHCO3 solution ꢀ5%) by a needle, stirred for 10 min, and extracted with 3 Â 150 cm3 diethyl ether.
The combined organic layers were dried ꢀNa2SO4), and the solvent was evaporated under reduced
pressure. The residue was puri®ed by ¯ash chromatography ꢀ500 g silica gel, petroleum ether:ethyl
acetate ˆ 80:20) to yield 5.62 g ꢀ77%) 9 ꢀRf ˆ 0.14).
20
‰ꢂŠ ˆ ‡42:60 ꢀc ˆ 0.446, CHCl3); 1H NMR ꢀ200 MHz, CDCl3, ꢁ): 0.02 ꢀs, 3H, OSi±CH3), 0.03
D
ꢀs, 3H, OSi±CH3), 0.07 ꢀs, 6H, OSi±CH3), 0.88 ꢀs, 9H, t-BuCH3), 0.89 ꢀs, 9H, t-BuCH3), 1.33 ꢀm,
6H, PO CH3), 1.50 ꢀm, 1H), 1.65±1.83 ꢀm, 3H), 2.47 ꢀm, 2H, H-3), 3.65 ꢀs, 3H, OCH3), 3.69 ꢀm, 1H,
H-6), 4.11 ꢀd, J ˆ 11.8 Hz, 1H, CH2O), 4.13 ꢀs, 2H, CH2O), 4.18 ꢀm, 4H, PO CH2), 4.35 ꢀd, J ˆ
11.8 Hz, 1H, CH2O), 5.35 ꢀd, J ˆ 10.3 Hz, 1H, ±CH ˆ ) ppm; 13C NMR ꢀ75 MHz, CDCl3, ꢁ): À5.50
ꢀOSi CH3), À5.46 ꢀOSi CH3), À5.42 ꢀOSi CH3), À5.41 ꢀOSi CH3), 15.98 ꢀd, JPC ˆ 6.9 Hz, POCH3),
18.18, ꢀt-Bu C), 18.29 ꢀt-Bu C), 25.80, ꢀt-Bu CH3), 25.85 ꢀt-Bu CH3), 64.37 ꢀd, JPC ˆ 6.2 Hz,
POCH2), 64.43 ꢀd, JPC ˆ 6.2 Hz, POCH2), 119.32 ꢀd, JPC ˆ 7.7 Hz, C-1), 151.42 ꢀd, JPC ˆ 7.7 Hz,
C-2) ppm; for further signals, see Table 1.
Methyl-!6S)-6-!3-!t-butyldimethysilyloxy)-2-!!t-butyl-dimethylsilyloxy)-methyl)-
prop-1-en-1-yl)-2-!!trimethylsilyl)-methyl)-1-cyclohexenecarboxylate ꢀ10; C28H56O4Si3)
In an Ar atmosphere, 75 mg nickel acetylacetonate ꢀ292 mmol) were mixed with a solution of
1.77 g enol phosphate 9 ꢀ2.92 mmol) in 16 cm3 THF, and the mixture was cooled to 0ꢀC. Then,

134
M. Krenn and E. Urban
7.3 cm3 Me3SiCH2MgCl ꢀ1 M in diethyl ether, 7.3 mmol) were added, and the mixture was stirred for
2 h at 0ꢀC and for 26 h at room temperature. The reaction mixture was then transferred to 12 cm3 of a
NH4Cl solution ꢀ20%) with a needle, the organic layer was separated, and the aqueous layer was
extracted with 2 Â 50 cm3 diethyl ether. The combined organic layers were dried ꢀNa2SO4), and the
solvent was evaporated under reduced pressure. Puri®cation of the residue by ¯ash chromatography
ꢀ200 g silica gel, petroleum ether:ethyl acetate ˆ 95:5) yielded 1.313 g ꢀ83%) 10 ꢀRf ˆ 0.49) as a
colourless oil.
20
D
‰ꢂŠ ˆ ‡103:7 ꢀc ˆ 0.190, CHCl3); 1H NMR ꢀ200 MHz, CDCl3, ꢁ): 0.01 ꢀs, 3H, OSi±CH3), 0.02
ꢀs, 3H, OSi±CH3), 0.03 ꢀs, 9H, Si±CH3), 0.08 ꢀs, 6H, OSi±CH3), 0.88 ꢀs, 9H, t-BuCH3), 0.90 ꢀs, 9H,
t-BuCH3), 1.45±1.56 ꢀm, 2H), 1.59±1.74 ꢀm, 2H), 1.94 ꢀdd, J ˆ 12.2 and 1.0 Hz, 1H, SiCH2), 2.07
ꢀm, 2H, H-3), 2.13 ꢀd, J ˆ 12.2 Hz, 1H, SiCH2), 3.59 ꢀs, 3H, OCH3), 3.59 ꢀm, 1H, H-6), 4.14 ꢀs, 2H,
CH2O), 4.17 ꢀd, J ˆ 12.0 Hz, 1H, CH2O), 4.38 ꢀd, J ˆ 12.0 Hz, 1H, CH2O), 5.32 ꢀd, J ˆ 10.5 Hz, 1H,
±CHˆ ) ppm; 13C NMR ꢀ50 MHz, CDCl3, ꢁ): À5.37 ꢀ3  OSi±CH3), À5.31 ꢀOSi±CH3), 18.27 ꢀt-Bu
C), 18.34 ꢀt-Bu C), 25.90 ꢀt-Bu CH3), 25.92 ꢀt-Bu CH3) ppm; for further signals, see Table 1.
Methyl-!6S)-6-!3-!acetoxy)-2-!!acetoxy)-methyl)-prop-1-en-1-yl)-2-!!trimethylsilyl)-
methyl)-1-cyclohexenecarboxylate ꢀ11; C20H32O6Si)
310 mg of the allylsilane 10 ꢀ573 ꢃmol) were dissolved in 0.5 cm3 of acetic anhydride, and the
solution was cooled to 0ꢀC. Then, 27 mg FeCl3 ꢀ172 mmol) were added, and the mixture was stirred at
0ꢀC for 2 h. Afterwards, 404 mg NaHCO3 ꢀ4.81 mmol) were added, the reaction mixture was warmed
to room temperature, and stirring was continued for 20 min. Then, 4 cm3 petroleum ether were added,
and the mixture was ®ltered through 300 mg celite and washed with 50 cm3 of a mixture of petroleum
ether and ethyl acetate ꢀ3:7). The combined organic layers were washed with 20 cm3 of a solution of
NaHCO3 ꢀ5%), dried ꢀNa2SO4), and the solvent was evaporated under reduced pressure. The residue
was puri®ed by ¯ash chromatography ꢀ25 g silica gel, petroleum ether:ethyl acetate ˆ 8:2) to afford
222 mg ꢀ98%) 11.
20
D
‰ꢂŠ ˆ ‡106:2 ꢀc ˆ 0.130, CHCl3); 1H NMR ꢀ200 MHz, CDCl3, ꢁ): 0.03 ꢀs, 9H, Si±CH3), 1.41±
1.58 ꢀm, 2H), 1.64±1.82 ꢀm, 2H), 2.04 ꢀs, 3H, Ac CH3), 2.07 ꢀs, 3H, Ac CH3), 2.10 ꢀm, 4H, H-3, Si±
CH2), 3.61 ꢀs, 3H, OCH3), 3.66 ꢀm, 1H, H-6), 4.53 ꢀs, 2H, CH2O), 4.63 ꢀd, J ˆ 12.3 Hz, 1H, CH2O),
4.89 ꢀd, J ˆ 12.3 Hz, 1H, CH2O), 5.56 ꢀd, J ˆ 10.5 Hz, 1H, ±CHˆ ) ppm; 13C NMR ꢀ50 MHz, CDCl3,
ꢁ): 20.89 ꢀ2 Â Ac CH3), 170.62 ꢀAc COO), 170.83 ꢀAc COO) ppm; for further signals, see Table 1.
Protodesilylation of allylsilane 11
911 mg of the allylsilane 11 ꢀ2.3 mmol) were dissolved in 3 cm3 CH2Cl2, the solution was cooled
to 0ꢀC, and 2.62 g tri¯uoroacetic acid ꢀ23 mmol) were added. The mixture was warmed to room
temperature and stirred for 60 h. Then, the reaction mixture was cooled to 0ꢀC, 1.93 g NaHCO3
ꢀ23 mmol) were added, and the slurry was stirred for 1 h. After addition of 15 cm3 H2O the product
was extracted with 2 Â 30 cm3 CH2Cl2, the combined organic layers were dried ꢀNa2SO4), and the
solvent was evaporated under reduced pressure. The remaining mixture of diastereomeric esters
ꢀ12a:12b ˆ 4:1) was separated by ¯ash chromatography ꢀ200 g silica gel, petroleum ether:ethyl
acetate ˆ 8:2) to yield 121 mg ꢀ16%) 12b ꢀRf ˆ 0.38) as a colourless oil and 530 mg ꢀ71%) 12a
ꢀRf ˆ 0.31) as a colourless oil.
Methyl-!1S,6S)-6-!3-!acetoxy)-2-!acetoxymethyl)-prop-1-en-1-yl)-2-methylen-1-
cyclohexanecarboxylate ꢀ12a; C17H24O6)
20
D
1
‰ꢂŠ ˆ ‡19:09 ꢀc ˆ 0.110, CHCl3); H NMR ꢀ200 MHz, CDCl3, ꢁ): 1.30±1.60 ꢀm, 2H), 1.73±1.85
ꢀm, 2H), 2.06 ꢀs, 6H, Ac CH3), 2.10 ꢀm, 1H), 2.36 ꢀm, 1H), 2.86±2.95 ꢀm, 2H, H-1, H-6), 3.67 ꢀs, 3H,

Synthesis of a Heptelidic Acid Analogue
135
OCH3), 4.53 ꢀs, 2H, CH2O), 4.56 ꢀs, 1H, ˆCH2), 4.57 ꢀd, J ˆ 12.8 Hz, 1H, CH2O), 4.82 ꢀd, J ˆ
12.8 Hz, 1H, CH2O), 4.87 ꢀs, 1H, ˆCH2), 5.55 ꢀd, J ˆ 10.0 Hz, 1H, ±CHˆ ) ppm; 13C NMR
ꢀ50 MHz, CDCl3, ꢁ): 20.85 ꢀ2 Â Ac CH3), 170.55 ꢀAc COO), 170.72 ꢀAc COO) ppm; for further
signals, see Table 1.
Methyl-!1R,6S)-6-!3-!acetoxy)-2-!acetoxymethyl)-prop-1-en-1-yl)-2-methylen-1-
cyclohexanecarboxylate ꢀ12b; C17H24O6)
20
D
‰ꢂŠ ˆ À23:75 ꢀc ˆ 0.160, CHCl3); 1H NMR ꢀ200 MHz, CDCl3, ꢁ): 1.67±1.98 ꢀm, 3H), 2.07 ꢀs, 6H,
Ac CH3), 2.16±2.42 ꢀm, 3H), 2.70 ꢀm, 1H, H-6), 3.26 ꢀd, J ˆ 5.0 Hz, 1H, H-1), 3.65 ꢀs, 3H, OCH3),
4.56 ꢀs, 2H, CH2O), 4.65 ꢀs, 2H, CH2O), 4.85 ꢀs, 1H, ˆCH2), 4.87 ꢀs, 1H, ˆCH2), 5.78 ꢀd, J ˆ
10.0 Hz, 1H, ±CHˆ ) ppm; 13C NMR ꢀ50 MHz, CDCl3, ꢁ ): 20.88 ꢀAc CH3), 20.92 ꢀAc CH3), 170.59
ꢀAc COO), 170.79 ꢀAc COO) ppm; for further signals, see Table 1.
!5aS,9aS)-1,3,5a,6,7,8,9,9a-Octahydro-4-hydroxymethyl-9-methylen-2-benzoxepin-1-one
ꢀ13a; C12H16O3)
423 mg of the triester 12a ꢀ1.30 mmol) were dissolved in 15 cm3 of aqueous NaOH ꢀ10%) and stirred
at room temperature for 65 h. Then, the reaction mixture was cooled to 0ꢀC and acidi®ed with 20 cm3
conc. HCl ꢀ12 N). The aqueous layer was saturated with NaCl and extracted with 3 Â 30 cm3 ethyl
acetate. The combined organic layers were dried ꢀNa2SO4), and the solvent was evaporated under
reduced pressure. The residue was dried in a vaccum desiccator over KOH for 16 h to remove traces
of acetic acid.
The remaining dihydroxy acid ꢀ348 mg) was dissolved in 20 cm3 CH2Cl2 and cooled to 0ꢀC.
Then, 496 mg bis-ꢀ2-oxo-3-oxazolidinyl)-phosphonic chloride ꢀ1.95 mmol), 7.3 mg 4-dimethylamino-
pyridine ꢀ60 mmol), and 373 mg triethylamine ꢀ3.69 mmol) were added, and the mixture was warmed
to room temperature and stirred for 15 h. The reaction mixture was cooled to 0ꢀC, carefully
neutralized with ca. 3.5 cm3 HCl ꢀ0.5 N), the organic layer was separated, and the aqueous layer was
extracted with 3 Â 20 cm3 CH2Cl2. The combined organic layers were washed with 40 cm3 of a
solution of NaHCO3 ꢀ5%), dried ꢀNa2SO4), and the solvent was evaporated under reduced pressure.
The residue was puri®ed by ¯ash chromatography ꢀ30 g silica gel, petroleum ether:ethyl acetate ˆ
1:1) to afford 181 mg ꢀ67%) 13a ꢀRf ˆ 0.23).
If the crude dihydroxy acid was not dried over KOH, lactonization occured, and a mixture of 13a
and 13b was obtained which was separated by ¯ash chromatography ꢀ30 g silica gel, petroleum
ether:ethyl acetate ˆ 1:1) to yield 14 mg ꢀ4%) 13b ꢀRf ˆ 0.66) and 160 mg ꢀ59%) 13a ꢀRf ˆ 0.23).
20
1
‰ꢂŠ ˆ ‡54:4 ꢀc ˆ 0.090, CHCl3); H NMR ꢀ200 MHz, CDCl3, ꢁ): 1.68±2.14 ꢀm, 5H), 2.20±
D
2.50 ꢀm, 3H), 3.70 ꢀd, J ˆ 12.0 Hz, 1H, H-9a), 4.02 ꢀd, J ˆ 13.1 Hz, 1H, CH2O), 4.11 ꢀd, J ˆ 13.1 Hz,
1H, CH2O), 4.40 ꢀd, J ˆ 15.0 Hz, 1H, H-3), 5.07 ꢀs, 1H, ˆ CH2), 5.13 ꢀd, J ˆ 15.0 Hz, 1H, H-3), 5.50
ꢀd, J ˆ 1.3 Hz, 1H, ˆ CH2), 5.64 ꢀd, J ˆ 0.7 Hz, 1H, ±CH ˆ ) ppm; 13C NMR ꢀ50 MHz, CDCl3): see
Table 2.
!5aS,9aS)-1,3,5a,6,7,8,9,9a-Octahydro-4-acetoxymethyl-9-methylen-2-benzoxepin-1-one
ꢀ13b; C14H18O4)
20
D
‰ꢂŠ ˆ ‡44:8 ꢀc ˆ 0.101, CHCl3); 1H NMR ꢀ200 MHz, CDCl3, ꢁ): 1.65±2.15 ꢀm, 5H), 2.06 ꢀs, 3H,
Ac CH3), 2.31±2.52 ꢀm, 2H), 3.67 ꢀd, J ˆ 11.5 Hz, 1H, H-9a), 4.35 ꢀd, J ˆ 15.1 Hz, 1H, H-3), 4.44 ꢀd,
J ˆ 12.4 Hz, 1H, CH2O), 4.53 ꢀd, J ˆ 12.4 Hz, 1H, CH2O), 5.06 ꢀs, 1H, ˆCH2), 5.10 ꢀd, J ˆ 15.1 Hz,
1H, H-3), 5.50 ꢀd, J ˆ 1.5 Hz, 1H, ˆCH2), 5.71 ꢀd, J ˆ 0.7 Hz, 1H, ±CHˆ ) ppm; 13C NMR
ꢀ50 MHz, CDCl3, ꢁ): 20.84 ꢀAc CH3), 170.58 ꢀAc COO) ppm; for further signals, see Table 2.

136
M. Krenn and E. Urban
!5aS,9aS)-1,3,5a,6,7,8,9,9a-Octahydro-9-methylen-1-oxo-2-benzoxepin-4-carbaldehyde
ꢀ14; C12H14O3)
Method A: 70 mg of 13a ꢀ336 mmol) were dissolved in 4 cm3 acetone, and the solution was cooled to
0ꢀC. Then, 147 mg Jones reagent ꢀprepared from 77.9 mg H2O, 41.8 mg H2SO4, and 26.8 mg CrO3)
were added, and the mixture was stirred for 10 min at 0ꢀC. For work-up, 100 mm3 MeOH and 4 cm3
of a NaHCO3 solution ꢀ5%) were added. The mixture was ®ltered through celite, the ®lter agent was
washed with 20 cm3 ethyl acetate, the organic layer was separated, and the aqueous layer was
extracted with 2 Â 10 cm3 ethyl acetate. The combined organic layers were washed with 20 cm3 of a
saturated solution of NaCl, dried ꢀNa2SO4), and the solvent was evaporated under reduced pressure.
The residue was puri®ed by ¯ash chromatography ꢀ7 g silica gel, petroleum ether:ethyl acetate ˆ 3:1)
to afford 35 mg ꢀ51%) 14 ꢀRf ˆ 0.23).
Method B: 408 mg of 13a ꢀ1.96 mmol) were dissolved in 8 cm3 CH2Cl2, 1.7 g manganeseꢀIV)
oxide ꢀ19.6 mmol) were added, and the suspension was heated to re¯ux for 12 h. The mixture was
®ltered through celite, the ®lter cake was washed with 3 Â 40 cm3 ethyl acetate, and the solvent was
evaporated under reduced pressure to afford 350 mg 14 ꢀ87%).
20
1
‰ꢂŠ ˆ À38:1 ꢀc ˆ 0.110, CHCl3); H NMR ꢀ200 MHz, CDCl3, ꢁ): 1.35±1.72 ꢀm, 2H), 1.84±
D
2.22 ꢀm, 3H), 2.47 ꢀdt, J ˆ 13.6 and 4.5 Hz, 1H, H-8), 2.71 ꢀtq, J ˆ 12.0 and 3.0 Hz, 1H, H-5a), 3.75
ꢀd, J ˆ 12.0 Hz, 1H, H-9a), 4.96 ꢀdt, J ˆ 14.3 and 2.0 Hz, 1H, H-3), 5.11 ꢀd, J ˆ 14.3 Hz, 1H, H-3),
5.13 ꢀs, 1H, ˆCH2), 5.60 ꢀd, J ˆ 1.3 Hz, 1H, ˆCH2), 6.63 ꢀdd, J ˆ 3.0 and 2.0 Hz, 1H, ±CHˆ ), 9.40
ꢀs, 1H, aldehyde H) ppm; 13C NMR ꢀ50 MHz, CDCl3): see Table 2.
!5aS,9S,9aS)-1,3,5a,6,7,8,9,9a-Octahydro-1-oxo-spiro-!2-benzoxepin-9,20-oxirane)-
4-carbaldehyde ꢀ15; C12H14O4)
257 mg of the methylene derivative 14 ꢀ1.25 mmol) were dissolved in 12 cm3 dry benzene, 0.35 cm3 t-
BuOOH ꢀ5.5 M in decane, 1.925 mmol) and 20 mg MoꢀCO)6 ꢀ76 mmol) were added, and the mixture
was re¯uxed for 3 h. After cooling to room temperature, 0.33 cm3 dimethylsul®de ꢀ4.48 mmol) were
added, and stirring was continued for 30 min. The solvent was evaporated under reduced pressure, and
the residue was puri®ed by ¯ash chromatography ꢀ20 g silica gel, petroleum ether:ethyl acetate ˆ 6:4)
to yield 184 mg ꢀ67%) 15 ꢀRf ˆ 0.15).
20
‰ꢂŠ ˆ À43:2 ꢀc ˆ 0.200, CHCl3); 1H NMR ꢀ300 MHz, CDCl3, ꢁ): 1.35±1.59 ꢀm, 2H), 1.62±1.89
D
ꢀm, 2H), 2.04 ꢀm, 1H), 2.15 ꢀm, 1H), 2.59 ꢀdd, J ˆ 5.3 and 0.5 Hz, 1H, epoxide CH2), 2.84 ꢀtq, J ˆ 12.0
and 3.2 Hz, 1H, H-5a), 3.50 ꢀd, J ˆ 12.0 Hz, 1H, H-9a), 3.96 ꢀdd, J ˆ 5.3 and 1.6 Hz, 1H, epoxide CH2),
4.92 ꢀdt, J ˆ 15.4 and 2.2 Hz, 1H, H-3), 5.10 ꢀdd, J ˆ 15.4 and 0.5 Hz, 1H, H-3), 6.65 ꢀdd, J ˆ 3.2 and
2.2 Hz, 1H, ±CHˆ ), 9.40 ꢀs, 1H, aldehyde) ppm; 13C NMR ꢀ75 MHz, CDCl3): see Table 2.
!5aS,9S,9aS)-1,3,5a,6,7,8,9,9a-Octahydro-1-oxo-spiro-!2-benzoxepin-9,20-oxirane)-
4-carboxylic acid ꢀ16; C12H14O5)
100.3 mg of 15 ꢀ0.45 mmol) were dissolved in 4 cm3 t-BuOH, 3 cm3 2-methyl-2-butene were added,
and the mixture was cooled to 0ꢀC. Then, a solution of 509 mg NaClO2 ꢀ80%, 4.5 mmol) and 621 mg
NaH2PO4 Á H2O ꢀ4.5 mmol) in 1.6 cm3 H2O were added, and the reaction mixture was allowed to
warm to room temperature and stirred for 2 h. For work-up, the reaction mixture was acidi®ed with
300 mm3 acetic acid, saturated with 600 mg NaCl, and extracted with 5 Â 10 cm3 ethyl acetate. The
combined organic layers were dried ꢀNa2SO4), and the solvent was evaporated under reduced
pressure. Traces of acetic acid were removed by aceotropic distillation using 2Â 4 cm3 benzene. The
residue was puri®ed by ¯ash chromatography ꢀ6 g silica gel, ethyl acetate:acetic acid ˆ 99:1) to give
69.7 mg ꢀ65%) 16 ꢀRf ˆ 0.67).
20
D
1
Colourless crystals ꢀn-hexane), m.p.: 110±112ꢀC; ‰ꢂŠ ˆ À31:3 ꢀc ˆ 0.150, CHCl3); H NMR
ꢀ200 MHz, CDCl3, ꢁ): 1.50±2.20 ꢀm, 7H), 2.45 ꢀd, J ˆ 5.8 Hz, 1H, epoxide CH2), 2.72 ꢀm, 1H, H-5a),

Synthesis of a Heptelidic Acid Analogue
137
3.86 ꢀd, J ˆ 12.0 Hz, 1H, H-9a), 3.89 ꢀdd, J ˆ 5.8 and 1.8 Hz, 1H, epoxide CH2), 4.94 ꢀd, J ˆ 15.2 Hz,
1H, H-3), 5.34 ꢀdt, J ˆ 15.2 and 2.1 Hz, 1H, H-3), 7.04 ꢀt, J ˆ 2.8 Hz, 1H, ±CHˆ ) ppm; 13C NMR
ꢀ75 MHz, acetone-d6): see Table 2.
Acknowledgements
We thank the Austrian Fonds zur Forderung der wissenschaftlichen Forschung ꢀproject number
P11543-MED) for ®nancial support.
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Received July 13, 2001.Accepted August 16, 2001