A novel approach in drug discovery: Synthesis of estrone-talaromycin natural product hybrids

Article abstract of DOI:10.1002/1521-3765(20001016)6:20<3755::AID-CHEM3755>3.0.CO;2-L

Hetero-Diels - Alder reaction of the steroidal exocyclic enol ethers 14 and 15, obtained from the secoestrones 8 and 9 by reduction, iodoetherification, and elimination, with ethyl O-benzoyldiformylacetate (16) leads to the spiroacetals 17 and 18 as a mixture of four diastereomers. Reduction of the major diastereomers 17a and 18 a with DIBAH and subsequent hydrogenation yields the novel natural product hybrids 21, 23, 24, and 25, which possess the structural features of the steroid estrone (7) and the mycotoxin talaromycin 6.

Full text of DOI:10.1002/1521-3765(20001016)6:20<3755::AID-CHEM3755>3.0.CO;2-L

FULL PAPER
A Novel Approach in Drug Discovery: Synthesis of Estrone ± Talaromycin
Natural Product Hybrids
[a]
LutzF. Tietze,*
Gyula Schneider,*[b] JaÂnos Wölfling,[b] Anja Fecher,[a] Thomas Nöbel,[a]
Sönke Petersen,[a] Ingrid Schuberth,[a] and Christian Wulff[a]
Dedicated to Professor Henning Hopf on the occasion of his 60th birthday
Abstract: Hetero-Diels ± Alder reaction of the steroidal exocyclic enol ethers 14 and
15, obtained from the secoestrones 8 and 9 by reduction, iodoetherification, and
elimination, with ethyl O-benzoyldiformylacetate (16) leads to the spiroacetals 17
and 18 as a mixture of four diastereomers. Reduction of the major diastereomers 17a
and 18a with DIBAH and subsequent hydrogenation yields the novel natural product
hybrids 21, 23, 24, and 25, which possess the structural features of the steroid estrone
(7) and the mycotoxin talaromycin 6.
Keywords: anticancer agents ´ com-
binatorial chemistry ´ cycloadditions
´
spiro compounds
´
steroids ´
talaromycin
Introduction
OH
I2, NaHCO3
92%
The synthesis of hybrid natural products by combining
structurally different naturally occurring compounds with
high biological activities appears to be a promising approach
O
I
2
1
to increase the number and, especially, the diversity of
substances for pharmacological testing. By this means, it
may be possible to improve the probability of finding new
lead structures. Owing to their ability to penetrate cell
membranes and bind to specific receptors, steroids represent
OBz
O
CO2Me
4
DBU
O
62%
toluene,
0 °C to 20 °C
77%
a valuable class of natural products in this context. It has
already been shown that the chemotherapeutic activity of
cytostatics against estrone hormone-receptive tumors can be
increased by linking them to estrone.[1, 2] Our aim was to
3
OBz
combine estrone with mycotoxins to design a new class of
cytotoxic compounds. Recently, we reported the enantiose-
CO2Me
O
1) DIBAH
O
O
O
lective total synthesis of the biologically highly active
2) PtO2, H2
spirocyclic mycotoxin (À)-talaromycin B (6).[3] Our strategy
HO
OH
5
6
was based on an intermolecular hetero-Diels ± Alder reac-
main diastereomer
tion[4] of methyl O-benzoyldiformylacetate (4)[5] as a 1-oxa-
(dr = 3 : 2 : 1.5 : 1)
(–)-Talaromycin B
1,3-butadiene with the exocyclic enol ether 3 obtained from 1
by iodoetherification followed by elimination (Scheme 1).[3d]
Scheme 1. Enantioselective total synthesis of (À)-talaromycin B (6) em-
ploying a hetero-Diels ± Alder reaction.
[a] Prof. Dr. L. F. Tietze, Dipl.-Chem. A. Fecher, Dr. T. Nöbel,
Dipl.-Chem. S. Petersen, Dr. I. Schuberth, Dr. C. Wulff
Institut für Organische Chemie, Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax : (‡49)551-399476
O
We present here the synthesis
of hybrid natural products con-
sisting of estrone (7) and the
mycotoxin talaromycin 6 using
this method, starting from the
d-secoestrones 8 and 9.[6]
H
E-mail: ltietze@gwdg.de
H
H
[b] Prof. Dr. G. Schneider, Dr. J. Wölfling
HO
Department of Organic Chemistry, University of Szeged
Â
Â
Dom ter 8, 6720 Szeged (Hungary)
Fax : (‡36)62-544200
7
Estrone
E-mail: schneider@chem.u-szeged.hu
Chem. Eur. J. 2000, 6, No. 20
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3755

L. F. Tietze, G. Schneider et al.
FULL PAPER
excellent yields. The low diastereoselectivity was of no concern
as the new stereogenic center was destroyed in the next step.
The subsequent elimination to give the exocyclic enol ethers
14 and 15 as single double-bond isomers was achieved under
solvent-free conditions with DBU as the base at 908C. The
methylene-tetrahydropyrans 14 and 15 thus obtained had to
be used directly in the next step without further purification,
since they are rather sensitive and prone to isomerization.
Hetero-Diels ± Alder reactions of 14 and 15 with ethyl O-
benzoyldiformylacetate (16) gave the spiroacetals[8] 17 and 18
in overall yields of 76% and 72%, respectively, as mixtures of
four diastereomers. The diastereomer ratios were determined
as 3.9:3.2:1.0:1.0 for 17 and 4.5:4.0:1.5:1.0 for 18 by HPLC
analysis. The separation of the major diastereomers 17a and
18a was achieved by column chromatography and subsequent
crystallization. The relative configurations of the two com-
pounds were determined by X-ray analysis.[9] It can be
assumed that the formation of the major diastereomers 17a
and 18a results from an exo attack of the heterodiene anti to
the angular methyl group at C-5 in 14 and 15, respectively.
The two ester moieties in 17a and 18a were reduced with
DIBAH to afford the diols 19 and 20 in yields of 70% and
76%, respectively (Scheme 3). The double bonds in 19 and 20
were then hydrogenated in a highly stereoselective manner,
by employing 50 bar of hydrogen pressure and 10 mol% PtO2
as catalyst, to give the protected estrone ± talaromycin hybrids
21 and 22 in quantitative yield. The selective generation of the
newly formed stereogenic centers in 21 and 22 resulted from a
b-addition of hydrogen to the olefinic double bond. The
benzyl group in 22 could be removed by catalytic hydro-
genolysis in the presence of Pd/C under 65 bar to give the
estrone ± talaromycin hybrid 23 in 99% yield. Hydrogenation
of 20 with Pd/C as catalyst led to both cleavage of the benzyl
ether moiety and reduction of the allylic alcohol. This
furnished the diol 24 as a single diastereomer in quantitative
yield.[10] The hybrid 25 was obtained in 90% yield by a Birch
reduction of 20 with lithium in liquid ammonia at À788C. In
this reaction only the benzyl ether is cleaved, while the allylic
alcohol is left mainly untouched.
Results and Discussion
The d-secoestrones 8 and 9, which are easily accessible in five
steps from estrone (7) by employing a Grob fragmentation as
the key step,[7] were reduced to the alcohols 10 and 11 by using
sodium or potassium borohydride (Scheme 2). Subsequent
iodoetherification afforded the iodoethers 12 and 13 as 2:1
and 2.5:1 mixtures, respectively, of both possible epimers in
O
H
OH
a)
H
H
H
H
H
H
RO
RO
8, R = Me
9, R = Bn
10, R = Me
11, R = Bn
O
H
b)
c)
I
H
H
RO
12, R = Me
13, R = Bn
OBz
O
CO2Et
O
2.5 equiv
H
16
H
H
RO
d)
14, R = Me
15, R = Bn
O
H
OBz
CO2Et
H
H
O
RO
17, R = Me
18, R = Bn
Scheme 2. Synthesis of the spiroacetals 17 and 18; a) 8: 10 equiv NaBH4,
MeOH, RT, 30 min; 9: 10 equiv KBH4, MeOH, RT, 30 min, 99% of 11;
b) I2, NaHCO3, Et2O/H2O, RT, 4 h ; 12: 99% from 8 (ds ˆ 2:1); 13: 96%
(ds ˆ 2.5:1); c) DBU (neat), 90 ± 1008C, 30 min; d) toluene/CH2Cl2, RT,
14 h; 17: 76% from 12 (drˆ a:b:c:d ˆ 3.9:3.2:1.0:1.0); 18: 72% from 13
(drˆ a:b:c:d ˆ 4.5:4.0:1.5:1.0); Bn ˆ benzyl, Bz ˆ benzoyl.
The configuration at C-4 of the new compounds 21 and 22
1
was determined by NMR analysis. The H NMR coupling
O
O
O
O
O
H
OBz
H
OH
OH
H
OH
OH
a)
b)
H
H
O
H
H
H
H
CO2Et
RO
RO
RO
17a: R = Me
18a: R = Bn
19: R = Me
20: R = Bn
21: R = Me
22: R = Bn
e)
d)
c)
O
O
O
O
O
O
H
OH
OH
H
H
OH
H
OH
OH
H
H
H
H
H
HO
HO
HO
25
24
23
Scheme 3. Synthesis of the estrone ± talaromycin hybrids 23, 24, and 25; a) 12 equiv DIBAH, THF/CH2Cl2, À78 8C, 21 h; 19: 70%; 20: 76%; b) 10 mol%
PtO2, H2 (50 bar), MeOH/ethyl acetate, RT, 12 h, 99%; c) 10 mol% Pd/C, H2 (65 bar), MeOH/ethyl acetate, RT, 20 h, 99%; d) 10 mol% Pd/C, H2 (65 bar),
MeOH/ethyl acetate, RT, 24 h, 99%; e) Li, NH3 (l), MeOH, À788C, 3 h, 90%.
3756
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Chem. Eur. J. 2000, 6, No. 20

Anticancer Agents
3755±3760
constants of the 4-H signal at d ˆ 3.81 for 21 (J1 ˆ J2 ˆ 10.9 Hz,
J3 ˆ 4.9 Hz) and at d ˆ 3.80 for 22 (J1 ˆ J2 ˆ 10.6 Hz, J3 ˆ
4.8 Hz) result from two axial ± axial couplings and one
axial ± equatorial coupling. This coupling pattern is only
possible in conformation C1 of the given diastereomers 21
and 22 (Scheme 4). Owing to the anomeric effect and the
interesting compounds in combinatorial chemistry. The de-
scribed linkage of estrone to the mycotoxin talaromycin has
led to a new class of natural product hybrids that exhibits
anticancer activity.
Experimental Section
General methods: All solvents were distilled and dried prior to use.
Reagents and materials were obtained from commercial suppliers and were
used without further purification. Analytical thin-layer chromatography
was performed on precoated silica gel SIL G/UV254 plates (Macherey,
Nagel). Silica gel 32 ± 63 (0.032 ± 0.063 mm) (Macherey, Nagel) was used for
column chromatography. HPLC was carried out on a Kontron HPLC
OH
H
H
H
H
O
O
OH
H
4
4
H
H
H
O
O
O
H
H
O
instrument with
a Merck Lichrospher 100RP-18 (5 mm) column and
C3
C1
HPLC-grade solvents (80% CH3CN/20% H2O) for elution at a flow rate
of 0.5 mLminÀ1. Melting points were determined on a Mettler FP61
apparatus and are uncorrected. Optical rotations were measured on a
Perkin ± Elmer 241 polarimeter. IR spectra were recorded from samples in
KBr pellets on Bruker IFS 25 or Vector 22 spectrometers. UV/Vis spectra
were recorded on a Perkin ± Elmer Lambda 9 spectrophotometer with
sample solutions in 1 cm quartz cuvettes. NMR spectra were recorded on
Varian VXR200 [50 MHz (13C)], Bruker AMX300 [300 MHz (1H),
75 MHz (13C)], Varian VXR500 [500 MHz (1H), 125 MHz (13C)], or
Bruker AM400 spectrometers [400 MHz (1H), 100 MHz, (13C)] at room
temperature unless otherwise noted. Chemical shifts (d) are reported in
ppm downfield from tetramethylsilane (TMS, d ˆ 0). Alternatively, spectra
were referenced to the resonances of residual solvent protons. Multi-
plicities of 13C NMR peaks were determined by using the APT pulse
sequence. EI mass spectra were measured on a Varian MAT 311A with an
ionization energy of 70 eV. High-resolution mass spectra (HRMS) were
measured on a Varian MAT 731 (EI) or on a Bruker Bioapex Fourier
transform ion cyclotron resonance mass spectrometer equipped with an
external electrospray ionization source. Elemental analyses were per-
formed in the Microanalytical Laboratory of the Georg-August University
Göttingen. Crystal data were collected on a Stoe-Siemens AED diffrac-
tometer. Programs used: Bruker AXS SAINT (data reduction), SHELXS-
97 (solution), and SHELXL-97 (refinement).[9]
H
OH
O
4
H
O
H
O
4
OH
H
H
O
O
H
H
H
CH2OH
H
C2
C4
Scheme 4. Conformation of the spiroacetal moiety in 21 and 22.
H-bonding interaction, conformation C1 should be more
stable than conformation C2; therefore, it is not surprising
that 21 and 22 mainly exist in the former conformation.
The toxicities of the new hybrid compounds were deter-
mined by performing HTCFA tests (Human tumor colony
forming ability). For this purpose, 102 to 105 human lung
cancer cells of the line A 549 were placed in six-well multi-
plates and cultivated in a culture medium that contained 90%
DMEM (Dulbeccoꢁs modified Eagleꢁs medium) and 10%
FCS (fetal calf serum). After 24 h of cultivation, the medium
was removed, and the cells were incubated with different
concentrations of the synthesized estrone ± talaromycin hy-
brids dissolved in DMSO/culture medium for 24 h. The
remaining cells were cultivated for a further 8 ± 9 days at
378C in air with a CO2 content of 7.5% and dyed with
Löfflerꢁs methylene blue; finally the relative colony-forming
rate was determined.[11] Effective dosage values (ED50) of
23mm for 19, 30mm for 21, 73mm for 23, and 95mm for 24 were
determined. The measured cytotoxicities of the new com-
pounds are comparable with that of the well-known anti-
cancer agent cyclophosphamide. The obtained values repre-
sent the lower limits of the cytotoxicities, since the tested
compounds caused some problems with regard to solubility in
the culture medium. We had expected compound 23 to show
at least the same cytotoxicity as 21; however, the slightly lower
cytotoxicity of the former may be explained in terms of a
reduced ability to penetrate the cell membrane due to its
higher polarity.
Reduction of the aldehydes 8 and 9
Alcohol 11: KBH4 (2.85 g, 52.9 mmol) was added to a solution of the
aldehyde 9 (1.98 g, 5.29 mmol) in methanol (80 mL) at 08C. The mixture
was stirred for 30 min at room temperature, then diluted with water
(150 mL), acidified with 10% H2SO4 (20 mL), saturated with NH4Cl, and
extracted with CH2Cl2 (3 Â 60 mL). The combined organic extracts were
dried with Na2SO4 and concentrated in vacuo. Purification of the residue by
column chromatography on silica gel (petroleum ether/tert-butyl methyl
ether, 5:1) furnished 1.97 g (5.23 mmol, 99%) of 11. Rf ˆ 0.16 (PE/MTBE,
5:1); [a]2D0 ˆ ‡72.0 (c ˆ 0.5 in CHCl3); UV/Vis (CH3CN): lmax (lge) ˆ 200.5
(4.729), 278.5 (3.300), 286.0 nm (3.259); IR (KBr): nÄ ˆ 3408 (OH), 3111,
À1
ˆ
3032 (Ar-H), 2922 (CH3), 2862 (CH), 1608, 1576, 1499 (C C), 841 cm
(Ar-H); 1H NMR (500 MHz, CDCl3): d ˆ 0.78 (s, 3H, 2-CH3), 1.21 ± 1.54
(m, 6H, 10-H2, 4-Ha, 3-Ha, OH, 1-H), 1.74 (mc, 1H, 10a-H), 2.05 (mc, 1H,
3-Hb), 2.13 ± 2.18 (m, 1H, 4-Hb), 2.19 ± 2.34 (m, 3H, 4a-H, 1'-H2), 2.80 ± 2.85
(m, 2H, 9-H2), 3.28 (d, J ˆ 10.1 Hz, 1H, CHaOH), 3.60 (d, J ˆ 10.1 Hz, 1H,
CHbOH), 4.95 (dd, J ˆ 10.0, 3.0 Hz, 1H, 3'-HZ), 5.02 (s, 2H, CH2Ph), 5.05
(dd, J ˆ 17.2, 3.0 Hz, 1H, 3'-HE), 5.91 (dddd, J ˆ 17.2, 10.0, 7.0, 6.0 Hz, 1H,
2'-H), 6.70 (d, J ˆ 2.5 Hz, 1H, 8-H), 6.77 (dd, J ˆ 8.5, 2.5 Hz, 1H, 6-H), 7.21
(d, J ˆ 8.5 Hz, 1H, 5-H), 7.28 ± 7.42 (m, 5H, Ph-H); 13C NMR (50 MHz,
CDCl3): d ˆ 16.25, 26.18, 27.58, 30.44, 32.40, 35.82, 38.89, 41.18, 43.44, 44.24,
69.90, 70.97, 112.3, 114.3, 114.4, 126.4, 127.4 (2C), 127.8, 128.5 (2C), 133.1,
‡
137.3, 137.9, 140.4, 156.7; MS (EI, 70 eV): m/z (%): 376.4 (96) [M] , 91.1
‡
‡
‡
‡
(100) [C7H7] , 57.1 (40) [C4H9] , 43.1 (26) [C3H7] , 41.1 (24) [C3H5] ;
elemental analysis calcd (%) for C26H32O2 (376.2): C 82.94, H 8.57; found C
82.73, H 8.49.
Alcohol 10: Aldehyde 8 (2.68 g, 9.0 mmol) was reduced with NaBH4
(3.38 g, 90 mmol) in methanol (120 mL) as described for 11 to give alcohol
10. The product was used without purification for the next step.
Conclusion
The combination of different natural products showing
pronounced biological activities seems to be a promising
new approach for the generation of pharmacologically
Iodoetherification of 10 and 11
Tetrahydropyran 12: Water (7.5 mL), NaHCO3 (1.13 g, 13.5 mmol), and
iodine (3.43 g, 13.5 mmol) were added to a solution of crude alcohol 10
Chem. Eur. J. 2000, 6, No. 20
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L. F. Tietze, G. Schneider et al.
FULL PAPER
(2.70 g, 9.0 mmol) in diethyl ether (25 mL) at 08C. The resulting mixture
was stirred at room temperature for 4 h, and then the reaction was
quenched by the addition of saturated Na2S2O3 solution (25 mL). The
mixture was extracted with diethyl ether (3 Â 30 mL), and the combined
extracts were dried with Na2SO4 and concentrated in vacuo. Purification of
the residue by column filtration gave 3.84 g (99% yield) of a mixture of the
two diastereomeric tetrahydropyrans 12. Separation of the diastereomers
could be achieved by column chromatography (petroleum ether/tert-butyl
methyl ether 20:1). The major diastereomer was obtained as white crystals.
Analytical data for the major isomer: m.p. 126.48C; [a]2D0 ˆ ‡54.0 (c ˆ 0.5
in CHCl3); IR (KBr): nÄ ˆ 2936 (CH3), 2866 (Ar-H), 2846 cmÀ1 (Ar-H); UV/
Vis (CH3CN): lmax (lge) ˆ 200.0 (4.654), 278.5 (3.299), 286.0 nm (3.255);
1H NMR (400 MHz, CDCl3): d ˆ 1.00 (s, 3H, 5-CH3), 1.10 ± 1.38 (m, 5H,
1'c-H, 1'-H2, 3-H2), 1.40 ± 1.65 (m, 2H, 8'-H2), 1.82 (brd, J ˆ 12.0 Hz, 1H,
4-H), 1.93 ± 2.02 (m, 1H, 2'-Ha), 2.25 ± 2.37 (m, 2H, 2'-Hb, 7'b-H), 2.78 ± 2.90
(m, 2H, 3'-H2), 3.17 (d, J ˆ 10.8 Hz, 1H, 6-Ha), 3.19 ± 3.35 (m, 3H, 2-CH2I,
2-H), 3.57 (d, J ˆ 10.8 Hz, 1H, 6-Hb), 3.78 (s, 3H, 5' ± OCH3), 6.63 (d, J ˆ
2.7 Hz, 1H, 4'-H), 6.72 (dd, J ˆ 8.6, 2.7 Hz, 1H, 6'-H), 7.20 (d, J ˆ 8.6 Hz,
1H, 7'-H); 13C NMR (50 MHz, CDCl3): d ˆ 10.62, 16.62, 25.39, 25.61, 29.85,
30.42, 33.86, 34.96, 38.40, 43.61, 47.09, 55.12, 76.38, 79.84, 111.5, 113.4, 126.0,
filtration through deactivated silica gel (1% NaHCO3) gave 405 mg
(76% based on 12) of 17 as a mixture of four diastereomers in a
3.9:3.2:1.0:1.0 ratio, with 17a as the major isomer (HPLC). Compound 17a
was isolated by crystallization after column chromatography on deacti-
vated silica gel (1% NaHCO3, gradient: petroleum ether/ethyl acetate 10:1
to 5:1). Data for the pure diastereomer 17a: m.p. 167.28C; [a]2D0 ˆ ‡104.0
À
À
(c ˆ 0.5 in CHCl3); IR (KBr): nÄ ˆ 2944 (CH3), 1716 ( CO2 ), 1634, 1502
À1
ˆ
(C C), 714 cm (Ar-H); UV/Vis (CH3CN): lmax (lge) ˆ 196.0 (4.902),
229.5 (4.499), 279.0 nm (3.435); 1H NMR (500 MHz, CDCl3): d ˆ 0.97 (s,
3H, 9-CH3), 1.13 (t, J ˆ 7.1 Hz, 3H, CH2CH3), 1.20 ± 1.36 (m, 4H, 2'-Ha, 1'-
Ha, 10-H, 11-Ha), 1.45 ± 1.54 (m, 2H, 1'-Hb, 8'-Ha), 1.63 (ddd, J ˆ 13.5, 10.5,
2.7 Hz, 1H, 1'c-H), 1.93 ± 1.97 (mc, 1H, 2'-Hb), 2.18 (dd, J ˆ 14.5, 5.1 Hz,
1H, 5-Ha), 2.28 ± 2.38 (m, 4H, 5-Hb, 7'b-H, 8'-Hb, 11-Hb), 2.74 ± 2.92 (m, 2H,
3'-H2), 3.33 (d, J ˆ 10.8 Hz, 1H, 8-Ha), 3.67 (d, J ˆ 10.8 Hz, 1H, 8-Hb), 3.78
(s, 3H, 5'-OCH3), 4.10 (dq, J ˆ 10.8, 7.1 Hz, 1H, CHaCH3), 4.17 (dq, J ˆ
10.8, 7.1 Hz, 1H, CHbCH3), 6.13 (t, J ˆ 5.3 Hz, 1H, 4-H), 6.64 (d, J ˆ 2.8 Hz,
1H, 4'-H), 6.73 (dd, J ˆ 8.4, 2.8 Hz, 1H, 6'-H), 7.20 (d, J ˆ 8.4 Hz, 1H, 7'-H),
7.44 (t, J ˆ 6.1 Hz, 2H, Bz-Hm), 7.56 (tt, J ˆ 6.1, 1.2 Hz, 1H, Bz-Hp), 7.57 (s,
1H, 2-H), 8.04 (dd, J ˆ 8.4, 1.2 Hz, 2H, Bz-Ho); 13C NMR (75 MHz,
CDCl3): d ˆ 14.22, 15.88, 25.33, 25.65, 29.83, 33.25, 33.28, 35.09, 37.74, 38.29,
41.42, 43.53, 55.18, 60.09, 61.00, 73.97, 99.11, 106.1, 111.7, 113.6, 126.1, 128.2
(2C), 129.8 (2C), 131.0, 132.4, 132.6, 137.7, 155.7, 157.6, 166.3, 166.4; MS (EI,
‡
132.3, 137.6, 157.4; MS (EI, 70 eV): m/z (%): 426.4 (100) [M] ; elemental
analysis calcd (%) for C20H27IO2 (426.3): C 56.35, H 6.38; found C 56.10, H
6.10.
‡
‡
70 eV): m/z (%): 546.7 (9) [M] , 441.6 (12) [M À C7H5O] , 424.6 (38) [M À
‡
‡
‡
PhCO2H] , 298.4 (34) [M À PhCO2H À C7H10O2] , 122.2 (86) [PhCO2H] ;
elemental analysis calcd (%) for C33H38O7 (546.7): C 72.51, H 7.01; found C
72.38, H 6.84.
Tetrahydropyran 13: Alcohol 11 (1.97 g, 5.23 mmol) was transformed as
described above in the preparation of 12 to yield the two diastereomeric
tetrahydropyrans 13 (2.52 g, 5.02 mmol, 96%) as a 2.5:1 mixture. Separa-
tion of the diastereomers could be achieved by column chromatography
(petroleum ether/tert-butyl methyl ether, 20:1). Analytical data for the
major isomer: Rf ˆ 0.41 (PE/MTBE, 20:1); m.p. 108.88C; [a]2D0 ˆ ‡46.2
(c ˆ 1.0 in CHCl3); IR (KBr): nÄ ˆ 2935 (CH3), 2860 (Ar-H), 2843 cmÀ1 (Ar-
H); UV/Vis (CH3CN): lmax (lge) ˆ 200.5 (3.993), 278.0 (2.638), 286.0 nm
(2.586); 1H NMR (500 MHz, CDCl3): d ˆ 0.99 (s, 3H, 5-CH3), 1.14 ± 1.36
(m, 5H, 1'c-H, 1'-H2, 3-H2), 1.41 ± 1.57 (m, 2H, 8'-H2), 1.79 (brd, J ˆ
12.4 Hz, 1H, 4-H), 1.93 ± 2.01 (m, 1H, 2'-Ha), 2.24 ± 2.32 (m, 2H, 2'-Hb,
7'b-H), 2.79 ± 2.85 (m, 2H, 3'-H2), 3.16 (d, J ˆ 10.8 Hz, 1H, 6-Ha), 3.21 ± 3.32
(m, 3H, 2-CH2I, 2-H), 3.55 (d, J ˆ 10.8 Hz, 1H, 6-Hb), 5.02 (s, 2H, CH2Ph),
6.70 (d, J ˆ 2.8 Hz, 1H, 4'-H), 6.77 (dd, J ˆ 8.6, 2.8 Hz, 1H, 6'-H), 7.19 (d,
J ˆ 8.6 Hz, 1H, 7'-H), 7.28 ± 7.44 (m, 5H, Ph-H); 13C NMR (50 MHz,
CDCl3): d ˆ 10.63, 16.64, 25.41, 25.63, 29.88, 30.45, 33.90, 35.00, 38.41, 43.69,
47.14, 69.88, 77.36, 79.90, 112.4, 114.5, 126.1, 127.4 (2C), 127.8, 128.5 (2C),
Spiroacetal 18: Reaction of 16 and the crude enol ether 15 as described
above in the preparation of 17 gave 1.29 g (2.07 mmol, 72% based on 13) of
the spiroacetal 18 as a mixture of four diastereomers in a 4.5:4.0:1.5:1.0
ratio, with 18a as the major isomer (HPLC). Compound 18a was isolated
by crystallization after column chromatography on deactivated silica gel
(1% NaHCO3, gradient: petroleum ether/ethyl acetate, 10:1 to 5:1). Rf ˆ
0.32 (PE/EtOAc, 5:1); m.p. 159.98C; [a]2D0 ˆ ‡88.8 (c ˆ 1.0 in CHCl3); IR
À1
À
À
ˆ
ˆ
(KBr): nÄ ˆ 2941 (CH3), 1718 ( CO2 ), 1633 (C C), 1503 (C C), 712 cm
(Ar-H); UV/Vis (CH3CN): lmax (lge) ˆ 229.5 (3.574), 278.5 nm (2.460);
1H NMR (500 MHz, CDCl3): d ˆ 0.97 (s, 3H, 9-CH3), 1.12 (t, J ˆ 7.1 Hz,
3H, CH2CH3), 1.18 ± 1.35 (m, 4H, 1'-Ha, 2'-Ha, 10-H, 11-Ha), 1.42 ± 1.56 (m,
2H, 1'-Hb, 8'-Ha ), 1.61 (ddd, J ˆ 13.3, 10.8, 3.9 Hz, 1H, 1'c-H), 1.89 ± 1.97
(m, 1H, 2'-Hb), 2.16 (dd, J ˆ 14.4, 5.3 Hz, 1H, 5-Ha), 2.26 ± 2.37 (m, 4H,
5-Hb, 7'b-H, 8'-Hb, 11-Hb), 2.72 ± 2.81 (m, 1H, 3'-Ha), 2.86 (mc, 1H, 3'-Hb),
3.31 (d, J ˆ 10.7 Hz, 1H, 8-Ha), 3.65 (d, J ˆ 10.7 Hz, 1H, 8-Hb), 4.08 (dq, J ˆ
10.8, 7.1 Hz, 1H, CHaCH3), 4.16 (dq, J ˆ 10.8, 7.1 Hz, 1H, CHbCH3), 5.02 (s,
2H, CH2Ph), 6.11 (t, J ˆ 5.4 Hz, 1H, 4-H), 6.71 (d, J ˆ 2.6 Hz, 1H, 4'-H),
6.78 (dd, J ˆ 8.5, 2.6 Hz, 1H, 6'-H), 7.19 (d, J ˆ 8.5 Hz, 1H, 7'-H), 7.28 ± 7.45
(m, 7H, 5 Â Bn-H, 2 Â Bz-Hm), 7.55 (mc, 1H, Bz-Hp), 7.65 (s, 1H, 2-H), 8.02
(dd, J ˆ 8.4, 1.1 Hz, 2H, Bz-Ho); 13C NMR (125 MHz, CDCl3): d ˆ 14.13,
15.78, 25.28, 25.75, 29.74, 31.89, 33.17, 34.96, 38.25, 38.28, 41.42, 43.46, 60.10,
62.80, 69.90, 73.92, 101.5, 105.8, 112.4, 114.5, 126.1, 127.4 (2C), 127.8, 128.3
(2C), 128.5 (2C), 129.6 (2C), 130.3, 132.7. 133.0, 137.2, 137.6, 155.5, 156.8,
‡
132.7, 137.2, 137.7, 156.7; MS (EI, 70 eV): m/z (%): 502.3 (36) [M] , 91.1
‡
(100) [C7H7] ; elemental analysis calcd (%) for C26H31IO2 (502.4): C 62.15,
H 6.22; found C 62.45, H 6.16.
Elimination of the iodides 12 and 13
Enol ether 14: All glassware used for this preparation was first washed with
a concentrated solution of potassium hydroxide in water/ethanol (1:1) and
dried in vacuo. The tetrahydropyran 12 (426 mg, 1.0 mmol) and DBU
(244 mg, 1.6 mmol, 240 mL) were heated at 90 ± 1008C for 30 min. The
mixture was then cooled to room temperature and diluted with diethyl
ether (13 mL), CH2Cl2 (13 mL), and water (8 mL). The organic layer was
separated, washed with water (10 mL), dried with Na2SO4, and concen-
trated in vacuo. Crude 14 was used for the next step without further
purification. C20H26O2 (298.4).
‡
165.5, 166.1; MS (EI, 70 eV): m/z (%): 622.4 (4) [M] , 546.5 (25) [M À
‡
‡
‡
C6H5] , 500.4 (19) [M À PhCO2H] , 374.4 (14) [M À PhCO2H À C7H10O2] ,
‡
91.1 (100) [C7H7] ; elemental analysis calcd (%) for C39H42O7 (622.8): C
75.22, H 6.80; found C 75.20, H 6.66.
DIBAH reduction of the diesters 17a and 18a
Enol ether 15: Treatment of iodide 13 (1.45 g, 2.88 mmol) as described in
the preparation of 14 gave the enol ether 15, which was used for the next
step without further purification. C26H30O2 (374.5).
Diol 19: A solution of the diester 17a (111 mg, 0.20 mmol) in THF/CH2Cl2
(30 mL, 1:1) was treated with DIBAH solution in toluene (1m, 2.40 mmol,
2.40 mL) at À788C. The resulting mixture was stirred for 21 h at À788C,
allowed to warm to room temperature, and quenched with saturated
sodium bicarbonate solution (0.1 mL) and 10% aqueous sodium hydroxide
solution (0.2 mL). The resulting mixture was filtered, diluted with CH2Cl2
(100 mL), washed with water (30 mL) and brine (30 mL), and dried with
MgSO4. After evaporation of the solvents, chromatographic purification
(SiO2, petroleum ether/ethyl acetate, 1:1) of the residue gave 57 mg of the
diol 19 (70%) as a white solid. M.p. 146.98C; [a]2D0 ˆ ‡114.7 (c ˆ 0.17 in
Hetero-Diels ± Alder reaction of 14 and 15 with ethyl O-benzoyldiformyl-
acetate (16)
Spiroacetal 17: The anhydrous sodium salt of ethyl diformylacetate
(380 mg, 2.50 mmol), which was obtained by titration of the free acid with
aqueous sodium hydroxide solution and drying in vacuo, was suspended in
toluene (4.0 mL) and treated with benzoyl chloride (351 mg, 2.50 mmol,
290 mL). The resulting suspension was stirred for 1 h at room temperature
and then cooled to 08C. A solution of the crude enol ether 14 (298 mg,
1.00 mmol) in toluene/CH2Cl2 (0.7 mL, 1:1) was added and stirring was
continued for 3 h at 08C and for a further 11 h at room temperature. The
reaction was then quenched by the addition of saturated aqueous sodium
bicarbonate solution (4.0 mL), the layers were separated, and the aqueous
phase was extracted with CH2Cl2 (2 Â 3.0 mL). The combined organic
layers were dried with Na2SO4 and concentrated in vacuo. Column
MeOH); IR (KBr): nÄ ˆ 3426 (OH), 2930 (CH3), 1666 (C C), 840 cmÀ1 (Ar-
ˆ
H); UV/Vis (CH3CN): lmax (lge) ˆ 200.5 (4.694), 278.5 (3.292), 286.0 nm
(3.259); 1H NMR (500 MHz, CDCl3): d ˆ 0.99 (s, 3H, 9-CH3), 1.20 ± 1.50
(m, 7H, 2'-Ha, 8'-H2, 1'-H2, 10-H, OH), 1.65 (mc, 1H, 2'-Hb), 1.85 (dd, J ˆ
13.0, 9.3 Hz, 1H, 5-Ha), 1.94 ± 1.98 (m, 1H, 3'-Ha), 1.96 (dd, J ˆ 13.5, 3.7 Hz,
1H, 11-Ha), 2.24 (dd, J ˆ 13.0, 6.4 Hz, 1H, 5-Hb), 2.30 ± 2.36 (m, 2H, 11-Hb,
1'c-H), 2.78 ± 2.90 (m, 2H, 3'-Hb, 7'b-H), 3.18 (d, J ˆ 10.7 Hz, 1H, 8-Ha),
3758
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0620-3758 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 20

Anticancer Agents
3755±3760
3.48 (d, J ˆ 10.7 Hz, 1H, 8-Hb), 3.78 (s, 3H, 5'-OCH3), 4.15 (d, J ˆ 12.0 Hz,
1H, 3-CHaOH), 4.27 (d, J ˆ 12.0 Hz, 1H, 3-CHbOH), 4.70 (mc, 1H, 4-H),
6.30 (s, 1H, 2-H), 6.63 (d, J ˆ 2.8 Hz, 1H, 4'-H), 6.72 (dd, J ˆ 8.5, 2.8 Hz,
1H, 6'-H), 7.20 (d, J ˆ 8.5 Hz, 1H, 7'-H); 13C NMR (75 MHz, CD3OD): d ˆ
16.35, 26.66, 26.89, 30.84, 34.35, 34.57, 36.36, 39.97, 42.81, 42.85, 45.07, 55.64,
61.17, 62.43, 74.45, 101.1, 112.7, 114.6, 117.5, 126.9, 133.9, 138.9, 140.4, 159.1;
MS (EI, 70 eV): m/z (%): 400.3 (3) [M] , 298.3 (100) [M À C4H6O3] ;
elemental analysis calcd (%) for C24H32O5 (400.5): C 71.97, H 8.05; found C
71.72, H 8.14.
127.3 (2C), 127.5, 128.2 (2C), 132.5, 137.3 (2C), 156.1; MS (EI, 70 eV): m/z
(%): 478.1 (100) [M] , 91.0 (75) [C7H7] ; HRMS: calcd for C30H38O5
478.2719; found 478.2719.
‡
‡
Hybrid compound 23: A suspension of diol 22 (70 mg, 146 mmol) and Pd/C
(16 mg, 10% Pd on charcoal, 15 mmol, 10 mol%) in methanol/ethyl acetate
(15 mL, 1:1) was subjected to 65 bar of hydrogen pressure at room
temperature for 20 h. The catalyst was removed by filtration through a
short pad of silica gel. Evaporation of the solvent from the filtrate gave
56 mg (145 mmol, 99%) of 23 as a white solid. Rf ˆ 0.11 (PE/EtOAc, 1:2);
[a]2D0 ˆ ‡108.4 (c ˆ 0.25 in DMF); IR (KBr): nÄ ˆ 3433 (OH), 3020 (Ar-H),
‡
‡
Diol 20: Reduction of 18a (278 mg, 0.45 mmol) as described above in the
preparation of 19 gave the diol 20 (163 mg, 0.34 mmol, 76%) as a white
solid. Rf ˆ 0.17 (PE/EtOAc, 1:1); m.p. 157.28C; [a]2D0 ˆ ‡146.0 (c ˆ 0.3 in
À1
ˆ
2924 (CH3), 1616, 1582, 1499 (C C), 827 cm (Ar-H); UV/Vis (CH3CN):
lmax (lge) ˆ 199.0 (3.948), 280.0 (2.704), 287.0 nm (2.666); 1H NMR
CHCl3); IR (KBr): nÄ ˆ 3376 (OH), 2929 (CH3), 1664 (C C), 841 cmÀ1 (Ar-
ˆ
(500 MHz, [D7]DMF 458C): d ˆ 0.98 (s, 3H, 9-CH3), 1.10 ± 1.45 (m, 9H,
,
H); UV/Vis (CH3CN): lmax (lge) ˆ 201.5 (4.031), 278.5 (2.536), 286.0 nm
(2.480); 1H NMR (500 MHz, CDCl3): d ˆ 0.97 (s, 3H, 9-CH3), 1.19 ± 1.55
(m, 7H, 2'-Ha, 8'-H2, 1'-H2, 10-H, OH), 1.63 (mc, 2H, 2'-Hb, OH), 1.82 (dd,
J ˆ 12.9, 9.5 Hz, 1H, 5-Ha), 1.87 ± 1.97 (m, 2H, 3'-Ha, 11-Ha), 2.22 (dd, J ˆ
12.9, 6.6 Hz, 1H, 5-Hb), 2.26 ± 2.36 (m, 2H, 11-Hb, 1'c-H), 2.74 ± 2.86 (m,
2H, 3'-Hb, 7'b-H), 3.16 (d, J ˆ 10.7 Hz, 1H, 8-Ha), 3.46 (d, J ˆ 10.7 Hz, 1H,
8-Hb), 4.14 (d, J ˆ 11.9 Hz, 1H, 3-CHaOH), 4.23 (d, J ˆ 11.9 Hz, 1H,
3-CHbOH), 4.67 (brdd, J ˆ 9.5, 6.6 Hz, 1H, 4-H), 5.01 (s, 2H, CH2Ph), 6.28
(s, 1H, 2-H), 6.70 (d, J ˆ 2.6 Hz, 1H, 4'-H), 6.77 (dd, J ˆ 8.5, 2.6 Hz, 1H, 6'-
H), 7.18 (d, J ˆ 8.5 Hz, 1H, 7'-H), 7.27 ± 7.44 (m, 5H, Ph-H); 13C NMR
(125 MHz, CDCl3): d ˆ 15.85, 25.32, 25.58, 29.84, 33.15, 33.44, 35.06, 38.26,
41.22, 41.61, 43.52, 62.59, 63.38, 69.94, 73.33, 99.88, 112.4, 114.6, 114.8, 126.1,
127.4 (2C), 127.8, 128.5 (2C), 132.9, 137.2, 137.8, 140.0, 156.8; MS (EI,
1'-H2, 11-H2, 10-H, 2 Â OH, 2'-Ha, 5-Ha), 1.54 ± 1.67 (m, 2H, 3-H, 1'c-H),
1.71 (dd, J ˆ 13.1, 3.8 Hz, 1H, 2'-Hb), 1.88 ± 2.03 (m, 2H, 8'-Ha, OH), 1.99
(dd, J ˆ 12.1, 5.0 Hz, 1H, 5-Hb), 2.19 ± 2.32 (m, 2H, 7'b-H, 8'-Hb), 2.68 ± 2.80
(m, 2H, 3'-H2), 3.06 (d, J ˆ 10.6 Hz, 1H, 8-Ha), 3.29 (d, J ˆ 10.6 Hz, 1H,
8-Hb), 3.43 (t, J ˆ 11.3 Hz, 1H, 2-Ha), 3.49 (dd, J ˆ 10.6, 7.2 Hz, 1H,
3-CHaOH), 3.75 (dd, J ˆ 11.3, 4.8 Hz, 1H, 2-Hb), 3.81 (td, J ˆ 10.8, 5.0 Hz,
1H, 4-H), 3.82 (dd, J ˆ 10.6, 4.0 Hz, 1H, 3-CHbOH), 6.54 (d, J ˆ 2.6 Hz,
1H, 4'-H), 6.62 (dd, J ˆ 8.5, 2.6 Hz, 1H, 6'-H), 7.09 (d, J ˆ 8.5 Hz, 1H, 7'-H);
13C NMR (125 MHz, [D7]DMF, 458C): d ˆ 16.10, 26.10, 26.23, 30.15, 33.91,
34.92, 35.69, 39.24, 42.35, 44.26, 45.74, 47.48, 61.28, 62.12, 65.49, 72.25, 98.86,
113.5, 115.5, 126.4, 131.6, 138.1, 156.2; MS (EI, 70 eV): m/z (%): 388.1 (81)
‡
‡
[M] , 186.0 (100) [C13H14O] ; HRMS: calcd for C23H32O5 388.2250; found
388.2249.
‡
‡
70 eV): m/z (%): 476.5 (2) [M] , 458.4 (46) [M À H2O] , 374.4 (100) [M À
Diol 24: A suspension of diol 20 (70 mg, 147 mmol) and Pd/C (31 mg, 5%
Pd on charcoal, 15 mmol, 10 mol%) in methanol/ethyl acetate (15 mL, 1:1)
was subjected to 65 bar of hydrogen pressure at room temperature for 24 h.
The catalyst was then removed by filtration through a short pad of silica gel.
Evaporation of the solvent from the filtrate gave 54 mg (146 mmol, 99%) of
compound 24 as a white solid. Rf ˆ 0.38 (PE/EtOAc, 1:2); m.p. 227.98C;
‡
‡
C4H6O3] , 91.1 (60) [C7H7] ; : HRMS: calcd for C30H36O5 476.2563; found
476.2562.
Selective hydrogenation of 19 and 20
Hybrid compound 21: A suspension of diol 19 (40 mg, 100 mmol) and PtO2
(2.3 mg, 10 mmol, 10 mol%) in methanol/ethyl acetate (10 mL, 1:1) was
subjected to 50 bar of hydrogen pressure at room temperature for 12 h. The
catalyst was then removed by filtration through a short pad of silica gel.
Evaporation of the solvent from the filtrate gave 40 mg (99 mmol, 99%) of
21 as a white solid. M.p. 1508C (dec.); [a]2D0 ˆ ‡109.7 (c ˆ 0.3 in MeOH);
[a]2D0 ˆ ‡115.4 (c ˆ 0.5 in DMF); IR (KBr): nÄ ˆ 3455 (OH), 2922 (CH3),
À1
ˆ
1616, 1585, 1499 (C C), 822 cm (Ar-H); UV/Vis (CH3CN): lmax (lge) ˆ
199.0 (3.892), 280.0 (2.588), 287.0 nm (2.543); 1H NMR (500 MHz,
[D7]DMF): d ˆ 0.90 (d, J ˆ 6.7 Hz, 3H, 3-CH3), 0.96 (s, 3H, 9-CH3),
1.10 ± 1.29 (m, 4H, 1'-Ha, 11-Ha, 10-H, 2'-Ha), 1.34 ± 1.52 (m, 4H, 3-H, 5-Ha,
1'-Hb, 2'-Hb), 1.56 (mc, 1H, 1'c-H), 1.70 (dd, J ˆ 13.2, 3.6 Hz, 1H, 11-Hb),
1.89 ± 1.95 (m, 1H, 8'-Ha), 1.98 (dd, J ˆ 12.6, 4.6 Hz, 1H, 5-Hb), 2.19 ± 2.26
(m, 1H, 7'b-H), 2.26 ± 2.33 (m, 1H, 8'-Hb), 2.72 ± 2.76 (m, 2H, 3'-H2), 3.07
(d, J ˆ 10.5 Hz, 1H, 8-Ha), 3.23 (dd, J ˆ 11.3, 11.3 Hz, 1H, 2-Ha), 3.29 (d,
J ˆ 10.5 Hz, 1H, 8-Hb), 3.50 (m, 2H, 2-Hb, 4-H), 4.68 (d, J ˆ 5.7 Hz, 1H,
4-OH), 6.55 (d, J ˆ 2.5 Hz, 1H, 4'-H), 6.63 (dd, J ˆ 8.4, 2.5 Hz, 1H, 6'-H),
7.10 (d, J ˆ 8.4 Hz, 1H, 7'-H), 9.23 (s, 1H, 5-OH); 13C NMR (125 MHz,
[D7]DMF): d ˆ 14.32, 17.05, 27.03, 27.15, 31.00, 34.85, 35.80, 36.61, 40.11,
40.73, 43.81, 45.23, 46.80, 66.12, 70.39, 73.12, 100.2, 114.4, 116.4, 127.5, 132.4,
À
À
ˆ
IR (KBr): nÄ ˆ 3420 (OH), 2926 (CH3), 2872 (Ar O CH3), 1608 (C C),
844 cmÀ1 (Ar-H); UV/Vis (CH3CN): lmax (lge) ˆ 200.0 (4.606), 278.5
(3.276), 286.0 nm (3.242); 1H NMR (500 MHz, CD3OD): d ˆ 0.98 (s, 3H,
9-CH3), 1.15 ± 1.35 (m, 6H, 1'-H2, 8'-H2, 10-H, OH), 1.38 ± 1.50 (m, 3H, 1'c-
H, 3-H, OH), 1.55 ± 1.70 (m, 2H, 5-Ha, 7'b-H), 1.73 (dd, J ˆ 13.1, 3.8 Hz, 1H,
2'-Ha), 1.92 ± 1.96 (mc, 1H, 2'-Hb), 2.00 (dd, J ˆ 12.6, 5.0 Hz, 1H, 5-Hb),
2.23 ± 2.33 (m, 2H, 11-H2), 2.71 ± 2.80 (m, 2H, 3'-H2), 3.08 (d, J ˆ 10.6 Hz,
1H, 8-Ha), 3.33 (d, J ˆ 10.6 Hz, 1H, 8-Hb), 3.46 (t, J ˆ 11.3 Hz, 1H, 2-Ha),
3.49 (dd, J ˆ 11.3, 7.5 Hz, 1H, 2-Hb), 3.72 (s, 3H, 5'-OCH3), 3.76 (dd, J ˆ
11.2, 4.8 Hz, 1H, 3-CHaOH), 3.81 (td, J ˆ 10.9, 4.9 Hz, 1H, 4-H), 3.83 (dd,
J ˆ 11.2, 3.8 Hz, 1H, 3-CHbOH), 6.58 (d, J ˆ 2.6 Hz, 1H, 4'-H), 6.66 (dd,
J ˆ 8.5, 2.6 Hz, 1H, 6'-H), 7.14 (d, J ˆ 8.5 Hz, 1H, 7'-H); 13C NMR
(125 MHz, CD3OD): d ˆ 16.34, 26.71, 26.85, 30.91, 34.51, 35.36, 36.37,
39.93, 42.95, 45.07, 45.73, 47.51, 55.54, 61.73, 62.61, 66.29, 73.16, 99.84, 112.6,
114.4, 127.0, 133.8, 138.8, 159.0; MS (EI, 70 eV): m/z (%): 402.5 (100)
‡
139.0, 157.2; MS (EI, 70 eV): m/z (%): 372.1 (100) [M] , 287.1 (45) [M À
C5H9O] , 186.0 (92) [M]2‡; HRMS (ESI): calcd for C23H33O4 [M‡H] m/z:
‡
‡
373.2379; found 373.2379.
Allylic alcohol 25: Lithium wire (5 mg, 0.72 mmol) was added to a solution
of 20 (30 mg, 63 mmol) in liquid ammonia (3 mL) and methanol (0.6 mL) at
À788C, and the resulting mixture was stirred at this temperature for 3 h.
Solid NH4Cl was then added to remove the excess lithium; thereafter, tert-
butyl methyl ether (10 mL) was added, and the mixture was allowed to
warm to room temperature. After evaporation of the NH3, the residue was
partitioned between ethyl acetate (20 mL) and water (20 mL), the aqueous
phase was extracted with ethyl acetate (3 Â 40 mL), and the combined
organic phases were washed with brine and dried with MgSO4. Evapo-
ration of the solvents and purification of the residue by column
chromatography (petroleum ether/ethyl acetate, 1:1, with 1% MeOH)
yielded 22 mg (57 mmol, 90%) of 25 as a white solid. Rf ˆ 0.16 (PE/EtOAc,
‡
[M] ;HRMS: calcd for C24H34O5 402.2406; found 402.2406; elemental
analysis calcd (%) for C24H34O5 (402.5): C 71.61, H 8.51; found C 71.53, H
8.65.
Hybrid compound 22: The diol 20 (70 mg, 147 mmol) was hydrogenated as
described for 19 to give 70 mg (146 mmol, 99%) of 22 as a white solid. Rf ˆ
0.12 (PE/EtOAc, 1:2); [a]2D0 ˆ ‡98.0 (c ˆ 0.2 in DMF); IR (KBr): nÄ ˆ 3385
(OH), 3063, 3032 (Ar-H), 2926 (CH3), 1608, 1577 cmÀ1 (C C); UV/Vis
ˆ
(CH3CN): lmax (lge) ˆ 200.5 (4.045), 249.5 (3.317), 278.5 (2.627), 286.0 nm
1
(2.581); H NMR (500 MHz, CD3OD): d ˆ 0.98 (s, 3H, 9-CH3), 1.15 ± 1.35
(m, 6H, 1'-H2, 8'-H2, 10-H, OH), 1.38 ± 1.52 (m, 3H, 3-H, OH, 1'c-H), 1.58 ±
1.70 (m, 2H, 5-Ha, 7'b-H), 1.74 (dd, J ˆ 13.1, 3.4 Hz, 1H, 2'-Ha), 1.92 ± 1.97
(mc, 1H, 2'-Hb), 2.01 (dd, J ˆ 12.4, 5.0 Hz, 1H, 5-Hb), 2.22 ± 2.35 (m, 2H, 11-
H2), 2.73 ± 2.84 (m, 2H, 3'-H2), 3.09 (d, J ˆ 10.6 Hz, 1H, 8-Ha), 3.34 (d, J ˆ
10.6 Hz, 1H, 8-Hb), 3.46 (t, J ˆ 11.3 Hz, 1H, 2-Ha), 3.49 (dd, J ˆ 11.3, 7.5 Hz,
1H, 2-Hb), 3.76 (dd, J ˆ 11.2, 4.8 Hz, 1H, 3-CHaOH), 3.80 (td, J ˆ 10.6,
4.8 Hz, 1H, 4-H), 3.84 (dd, J ˆ 11.2, 3.9 Hz, 1H, 3-CHbOH), 5.01 (s, 2H,
CH2Ph), 6.67 (d, J ˆ 2.7 Hz, 1H, 4'-H), 6.73 (dd, J ˆ 8.7, 2.7 Hz, 1H, 6'-H),
7.16 (d, J ˆ 8.7 Hz, 1H, 7'-H), 7.26 ± 7.42 (m, 5H, Ph-H); 13C NMR (75 MHz,
[D6]DMSO): d ˆ 15.61, 25.00, 29.30, 32.94 (2C), 33.80, 34.55, 37.86, 41.06,
42.99, 44.71, 46.22, 59.52, 61.16, 63.62, 68.94, 71.02, 97.77, 112.2, 114.2, 125.8,
1:1); [a]2D0 ˆ ‡134.0 (c ˆ 0.2 in DMF); IR (KBr): nÄ ˆ 3397, 3356 (OH), 2937
À1
ˆ
(CH3), 1618, 1584, 1501 (C C), 822 cm (Ar-H); UV/Vis (CH3CN): lmax
1
(lge) ˆ 199.5 nm (4.079), 280.0 (2.724), 286.5 (2.678); H NMR (500 MHz,
[D7]DMF, 358C): d ˆ 0.98 (s, 3H, 9-CH3), 1.09 ± 1.48 (m, 8H, 2'-Ha, 8'-H2,
1'-H2, 10-H, 2  OH), 1.61 (mc, 1H, 2'-Hb), 1.76 (dd, J ˆ 12.9, 9.4 Hz, 1H,
5-Ha), 1.88 ± 2.04 (m, 3H, 3'-Ha, 11-Ha, OH), 2.16 (dd, J ˆ 12.9, 6.6 Hz, 1H,
5-Hb), 2.22 ± 2.34 (m, 2H, 11-Hb, 1'c-H), 2.70 ± 2.80 (m, 2H, 3'-Hb, 7'b-H),
3.13 (d, J ˆ 10.7 Hz, 1H, 8-Ha), 3.48 (d, J ˆ 10.7 Hz, 1H, 8-Hb), 3.93 (d, J ˆ
12.1 Hz, 1H, 3-CHaOH), 4.25 (d, J ˆ 12.1 Hz, 1H, 3-CHbOH), 4.55 (brdd,
J ˆ 9.1, 7.2 Hz, 1H, 4-H), 6.29 (s, 1H, 2-H), 6.47 (d, J ˆ 2.7 Hz, 1H, 4'-H),
Chem. Eur. J. 2000, 6, No. 20
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3759

L. F. Tietze, G. Schneider et al.
FULL PAPER
6.54 (dd, J ˆ 8.5, 2.7 Hz, 1H, 6'-H), 7.08 (d, J ˆ 8.5 Hz, 1H, 7'-H); 13C NMR
(125 MHz, [D7]DMF): d ˆ 16.08, 26.04, 26.24, 30.17, 33.70, 33.95, 35.58,
39.15, 42.01, 42.62, 44.25, 60.34, 61.34, 73.49, 100.1, 113.5, 115.5, 118.2, 126.6,
Maezaki, K. Hattori, M. Fujita, Y. Moritani, Y. Takemoto, T. Tanaka,
T. Imanishi, Chem. Pharm. Bull. 1993, 41, 946 ± 950; g) G. Guanti, L.
Banfi, E. Narisano, M. T. Zannetti, J. Org. Chem. 1993, 58, 1508 ±
1514.
‡
131.4, 138.0, 138.1, 156.2; MS (EI, 70 eV): m/z (%): 368.1 (17) [M À H2O] ,
‡
‡
284.1 (100) [M À C4H6O3] , 43.1 (35) [C3H7] ; HRMS (ESI): calcd for
[4] a) L. F. Tietze, G. Kettschau, Top. Curr. Chem. 1997, 189, 1 ± 120;
b) L. F. Tietze, G. Kettschau, J. A. Gewert, A. Schuffenhauer, Curr.
Org. Chem. 1998, 2, 19 ± 62.
‡
C23H30O5Na [M‡Na] m/z: 409.1991; found 409.1991.
[5] J. D. White, N.-S. Kim, D. E. Hill, J. A. Thomas, Synthesis 1998, 619 ±
626.
[6] Part of this work has already been published as a communication: L. F.
Tietze, G. Schneider, J. Wölfling, T. Nöbel, C. Wulff, I. Schuberth, A.
Döring, Angew. Chem. 1998, 110, 2644 ± 2646; Angew. Chem. Int. Ed.
1998, 37, 2469 ± 2470.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft
(Sonderforschungsbereich 416), the Fonds der Chemischen Industrie, and
the Bundesministerium für Bildung, Wissenschaft, Forschung, und Tech-
nologie (Project No. UNG-061-96, grants no. OTKAT 032265 and FKFP
0110/2000). We thank Dipl.-Chem. V. König, Institut für Anorganische
Chemie, Göttingen, for determining the X-ray structure of 18a and Dr. J.
Görlitzer for obtaining the ESI mass spectra. A.F. and C.W. thank the
Fonds der Chemischen Industrie for doctoral scholarships and J. W. has
received a Jµnos Bolyai fellowship.
Â
[7] G. Schneider, S. Bottka, L. Hackler, J. Wölfling, P. Sohar, Liebigs Ann.
Chem. 1989, 263 ± 267.
[8] For a review on spiroketals, see: F. Perron, K. F. Albizati, Chem. Rev.
1989, 89, 1617 ± 1661.
[9] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-101429 (17a) and CCDC-139991 (18a). Copies of the data
can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk)..
[10] a) R. L. Augustine, Catalytic Hydrogenation, Marcel Dekker, New
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c) P. N. Rylander, Catalytic Hydrogenation in Organic Syntheses,
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Hydrogenation Methods, Academic Press, New York, 1985, pp. 167 ±
168; e) C. Booma, K. K. Balasubramanian, Tetrahedron Lett. 1992, 21,
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Received: March 7, 2000 [F2346]
3760
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