[2+2+2]-Cycloaddition of 4-Hydroxy-Substituted Enediynes to 2-Hydroxy-Substituted Decahydrophenanthrenes

Article abstract of DOI:10.1002/ejoc.200300432

Enediynes rac-4 were prepared in seven steps with an overall yield of 31% starting from 4-pentyn-1-ol (5). A cobalt mediated [2+2+2]-cycloaddition of these enediynes and subsequent removal of the metal fragment afforded the decahydrophenanthrenes rac-3/13

Full text of DOI:10.1002/ejoc.200300432

FULL PAPER
[2؉2؉2]-Cycloaddition of 4-Hydroxy-Substituted Enediynes to 2-Hydroxy-
Substituted Decahydrophenanthrenes[‡]
Ulrich Groth,*[a] Norbert Richter,[a] and Aris Kalogerakis[a]
Keywords: Cycloaddition / Cobalt / Zinc
Enediynes rac-4 were prepared in seven steps with an over- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
all yield of 31% starting from 4-pentyn-1-ol (5). A cobalt
mediated [2+2+2]-cycloaddition of these enediynes and sub-
sequent removal of the metal fragment afforded the decahy-
drophenanthrenes rac-3/13 in 37−56% yield.
Germany, 2003)
Introduction
ditions investigated to establish the diastereoselective out-
come of this cyclization (Scheme 2).
Aliphatic enediynes[2] with an internal double bond af-
ford decahydrophenanthrene derivatives upon a cobalt me-
diated [2ϩ2ϩ2]-cycloaddition[3] and subsequent oxidative
decomplexation. The configuration of the double bond is
retained under these reaction conditions, e.g. enediynes
with a trans-double bond undergo cyclization to decahydro-
phenanthrenes with a trans-configuration at C-4aϪC-4b.[4]
In the course of our synthetic studies towards ergosterine
derivatives, we were interested as to whether the stereogenic
centers at C-7Ј of enediyne 2 might have any influence on
the formation of the new stereogenic centers at C-9 and C-
10 in the ergosterine derivative 1 (Scheme 1). The formation
of these stereogenic centers would otherwise be controlled
by the substituents at C-2 and C-3 of the cyclopentane moi-
ety of enediyne 2. Consequently, the O-protected enediynes
rac-4 needed to be prepared and their [2ϩ2ϩ2] cycload-
Scheme 2
Results and Discussion
Enediynes rac-4 were prepared as follows (Scheme 3).
Cp2ZrCl2 catalyzed carbo-alumination of 4-pentyn-1-ol (5)
gave the corresponding vinyl-alane which was treated with
iodine to afford the (E)-vinyl iodide 6.[5] The hydroxy group
was protected with TBDMS-Cl/imidazole as its silyl ether
7. The next step, a [PPh3]4Pd catalyzed coupling[6] of 7 with
the zinc organyl derived from 1-bromo-6-(trimethylsilyl)-5-
hexyne (8)[7] which itself was prepared in two steps from 6-
(trimethylsilyl)-5-hexyn-1-ol,[8] turned out to be cumber-
some. The conversion of 8 into its magnesium derivative
was always accompanied by an undesired ring closure reac-
tion to the cyclopentylidene magnesium compound. Com-
pound 8 was therefore treated with magnesium in the pres-
ence of zinc chloride to afford the corresponding zinc or-
ganyl without any side reactions. This organozinc com-
pound was coupled with the vinyl iodide 7 in the presence
of 5 mol % of [PPh3]4Pd to afford the enyne 9 in 84% yield.
Enyne 9 could be completely desilylated with nBu4NF hy-
drate to alcohol 10 which was oxidized under Swern con-
ditions[9] to aldehyde 11. Addition of propargylmagnesium
bromide gave the desired enediyne rac-12 after aqueous
workup. The hydroxy group at C-4 was protected as its silyl
ether rac-4a[10] with TBDPSϪCl/imidazole, as its MEM-
Scheme 1
[‡]
Stereoselective Synthesis of Steroids and Related Compounds,
VI. Part V: Ref.[1a]; Metal Catalyzed Reactions in Organic
Synthesis V. Part IV: Ref.[1b]
[a]
Fachbereich Chemie der Universität Konstanz, Fach M-720,
Universitätsstr. 10, 78457 Konstanz, Germany
Fax: (internat.) ϩ 49-7531-884155
E-mail: Ulrich.Groth@uni-konstanz.de
4634
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300432
Eur. J. Org. Chem. 2003, 4634Ϫ4639

Synthetic Studies towards Ergosterine Derivatives
FULL PAPER
Table 1. [2ϩ2ϩ2]-Cycloaddition of enediynes 4
PG (rac-4)
Yield of rac-3/rac-13 (%)
Ratio rac-3:rac-13
a) TBDPS
b) MEM
c) Me
37
56
43
1.7:1
1.9:1
1.4:1
group in the homoallylic position was able to tolerate the
harsh reaction conditions. The stereogenic center at C-4 has
no influence on the formation of the two stereogenic centers
at C-4a and C-4b of the decahydrophenanthrene. Based on
this result, a diastereoselective synthesis of ergosterole is
under current investigation following the D Ǟ ABCD ap-
proach.
Scheme 3. Reagents and conditions: (a) (i) Cp2ZrCl2, AlMe3,
CH2Cl2, 0 °C, 15 min, then 5, 45 °C, 76 h, (ii) I2, 45 °C, 2 h, (b)
TBDMSϪCl, imidazole, DMF, 0 °C to room temp., 5 h, (c) 8, Mg,
ZnCl2, THF, 45 °C, 2 h, then Pd(PPh3)4, 7, 25 °C, 24 h, (d) TBAF,
THF, 25 °C, 4 h, (e) oxalyl chloride, DMSO, Ϫ65 °C, 20 min, then
10, triethylamine, Ϫ65 °C to room temp., 30 min, (f) Mg, propargyl
bromide, THF, 5 °CϪ15 °C, 1 h, then 11, Ϫ15 °C to room temp.,
1 h, (g) (i) for PG ϭ tBuPh2SiϪ: TBDPSϪCl, imidazole, DMF, 0
Experimental Section
°C to room temp., 8 h, (89%), (ii) for PG
ϭ
Infrared spectra were recorded on PerkinϪElmer 298 and
CH3OCH2CH2OCH2Ϫ: MEMϪCl, diisopropylamine, CH2Cl2, 0
°C to room temp., 18 h, (91%), (iii) for PG ϭ CH3Ϫ: KOH, MeI,
DMSO, 25 °C, 30 min, (82%).
1
PerkinϪElmer FT IR 1600 spectrometers. H and 13C NMR spec-
tra were acquired using a Varian XL 200, a Varian VXR 200, a
Bruker AC 250 or a Jeol JNMϪLA 400 spectrometer with chemical
shifts (δ) given in parts per million relative to tetramethylsilane as
an internal standard. Mass spectra were recorded using a Varian
MAT 731 or 311 A or a Finnigan MAT 312 instrument. TLC
analyses were performed using Polygram Sil G/UV254 silica gel
plates. Silica gel (0.030Ϫ0.060 mm) from Baker was used for flash
chromatography. Combustion analyses were carried out at the
Microanalytical laboratory of the University of Konstanz. All reac-
tions were carried out under argon except those involving aqueous
workup procedures. All reagents were purified and dried if neces-
sary before use. THF was freshly distilled from LiAlH4 prior to
use. The glassware used for the cobalt mediated cyclizations was
rinsed with hexamethyldisilazane and dried in vacuo with a burner
prior to use.
ether rac-4b[11] with MEMϪCl/Hünig base or as its methyl
ether rac-4c[12] with methyl iodide/KOH.
The [2ϩ2ϩ2]-cycloadditions of the enediynes rac-4 were
carried out with 1.2 equivalents of CpCo(CO)2 in toluene
at reflux and with exposure to visible light (Scheme 4). Ac-
cording to analysis by TLC the cyclization was complete
after between 90 min and 2 h. Oxidative decomplexation of
the resultant cyclohexadiene cobalt complexes was investi-
gated using iodine, copper()chloride or ferric() chloride
as the oxidizing agent. The decomplexation of the cobalt
complexes with iodine or copper()chloride led to complete
decomposition of the ligands. Decomplexation with 1.5
equivalents of ferric() chloride hexahydrate in acetonitrile/
pentane at Ϫ20 °C was more successful. The decahydro-
phenanthrenes rac-3/13 were obtained in 37Ϫ56% yields as
almost 1:1 mixtures of diastereomers. These compounds
proved to be sensitive to air and light and could only be
stored under argon at Ϫ30 °C in the dark. The best results
were achieved by using the MEM substituent as a protect-
ing group (PG) for the homoallylic hydroxy function
(Table 1).
6-(Trimethylsilyl)-5-hexyn-1-ol: Sodium hydride (1.32 g, 55 mmol)
was suspended in THF (70 mL). A solution of 5-hexyn-1-ol[13]
(4.90 g, 50 mmol) in THF (10 mL) was added with stirring which
was maintained until the evolution of hydrogen had ceased. A solu-
tion of n-butyllithium in hexane (1.6 , 40 mL, 64 mmol) was then
added at Ϫ30 °C with stirring. Stirring was continued for 30 min
after which trimethylsilyl chloride (16.30 g, 150 mmol) was added
at Ϫ70 °C. The reaction mixture was allowed to warm to room
temperature and stirring was continued for 4 h. The solvent was
removed in vacuo (40 °C/18 Torr) and diethyl ether (150 mL), a
saturated aqueous NH4Cl solution (50 mL) and 1  HCl (150 mL)
were added to the residue. The organic layer was separated and the
solvent removed in vacuo (30 °C/18 Torr). The residue was dis-
solved in a solution of anhydrous HCl in methanol (1 , 150 mL)
with stirring which was continued at room temperature for 1 h.
Most of the solvent was removed in vacuo (30 °C/18 Torr), H2O
(80 mL) was added to the residue and the resultant mixture was
extracted three times with diethyl ether (50 mL each). The com-
bined organic layers were dried with MgSO4 and the solvent was
removed in vacuo (25 °C/18 Torr). After distillation, 6-(trimethyl-
silyl)-5-hexyn-1-ol (7.92 g, 47 mmol, 93%) was obtained. B.p. 85 °C/
0.01 Torr. IR (neat): ν˜ ϭ 3500Ϫ3150 (OH), 2170 [CϵCϪSi(CH3)3]
Scheme 4
Conclusion
cmϪ1
.
1H NMR (200 MHz, CDCl3): δ ϭ 0.15 [s, 9 H, Si(CH3)3],
It has been demonstrated that 4-hydroxysubstituted en-
ediynes can be cyclized in a [2ϩ2ϩ2]-fashion to 2-hydroxy-
1.50Ϫ1.85 (m, 5 H, CH2CH2 and OH), 2.14 (t, J ϭ 7 Hz, 2 H,
substituted decahydrophenanthrene derivatives. A hydroxy CH2ϪCϵCϪSi(CH3)3], 3.46 (t, J ϭ 7 Hz, 2 H, CH2-OH) ppm.
Eur. J. Org. Chem. 2003, 4634Ϫ4639
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4635

U. Groth, N. Richter, A. Kalogerakis
FULL PAPER
C9H18OSi (170.3): calcd. C 63.47, H 10.65; found C 63.24, H 10.51. (CϭC), 1250 (CϪSi) cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ 0.05
[s, 6 H, Si(CH3)2], 0.88 [s, 9 H, SiC(CH3)3], 1.82 [s, 3 H, C(CH3)ϭ
1-Bromo-6-(trimethylsilyl)-5-hexyne (8): To a stirred solution of 6-
CH], 1.22Ϫ1.95 (m, 3 H, HOϪCH2CH2), 2.24 [t, J ϭ 7 Hz, 2 H,
(trimethylsilyl)-5-hexyn-1-ol (7.82 g, 46 mmol) in dichloromethane
(80 mL) were added triethylamine (9.56 mL, 69 mmol) and meth-
ane sulfonyl chloride dropwise at Ϫ10 °C and stirring was con-
tinued for a further hour. The reaction mixture was poured into
CH2C(CH2)ϭCH], 3.40Ϫ3.76 (m, 2 H, HOϪCH2ϪCH2), 5.85 (s,
1 H, CϭCH) ppm. C12H25OISi (340.2): calcd. C 42.33, H 7.41, I
37.30; found C 42.09, H 7.28, I 37.22.
ice/1  HCl and the organic layer was separated and washed with
a saturated aqueous NaHCO3 solution and H2O (40 mL each). The
organic layer was dried with MgSO4 and the solvent removed in
vacuo (15 °C/18 Torr) to afford 10.42 g (42 mmol, 91%) of the cor-
responding mesylate which was used for the next reaction step
without any further purification.
(E)-1-(tert-Butyldimethylsilyloxy)-4-methyl-11-(trimethylsilyl)-
undec-4-en-10-yne (9): Anhydrous zinc chloride (1.90 g, 14 mmol)
was melted under a nitrogen atmosphere. At room temperature the
molten zinc chloride was dissolved in THF (20 mL) and mag-
nesium (0.63 g, 26 mmol), iodine (3 mg) and 1,2-dibromoethane
(0.1 mL) were added with stirring. After the reaction mixture had
become colorless and cloudy, a solution of 1-bromo-6-(trimethyl-
silyl)-5-hexyne (3.30 g, 14 mmol) in THF (15 mL) was added and
stirring was continued at 45 °C for 2 h. At room temperature the
solution was removed from the excess magnesium via syringe and
added to a solution of [PPh3]4Pd (0.58 g, 0.5 mmol) and vinyl iod-
ide 7 (3.40 g, 10 mmol) in THF (10 mL). The reaction mixture was
allowed to stir for 24 h at room temperature and the solvent was
then removed in vacuo (25 °C/18 Torr). Diethyl ether (120 mL) and
a saturated aqueous NH4Cl solution (40 mL) were added to the
residue, the organic layer was extracted with a saturated aqueous
NaHCO3 solution and H2O (50 mL each), dried with MgSO4 and
the solvent was removed in vacuo (30 °C/18 Torr). After chromato-
graphic purification with diethyl ether/petroleum ether (1:10) on
silica gel (50 g) 9 (3.07 g, 8.40 mmol, 84%) was obtained as a color-
less oil. Rf ϭ 0.79. IR (neat): ν˜ ϭ 2175 (CϵCϪSi(CH3)3], 1640
(CϭC), 1250 (SiϪC) cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ 0.03
[s, 6 H, Si(CH3)2], 0.13 (s, 9 H, CϵCϪSi(CH3)3], 0.88 [s, 9 H,
C(CH3)3], 1.24Ϫ1.78 [m, 8 H, (CH2)3CϵC and CH2CH2ϪOSi),
1.57 [[d, 4J ϭ 1 Hz, 3 H, C(CH3)ϭCH], 1.92Ϫ2.09 [m, 2 H,
C(CH3)ϭCHϪCH2], 2.15 [t, J ϭ 7 Hz, 2 H, CH2C(CH3)ϭCH],
To a stirred solution of this mesylate (10.42 g, 42 mmol) in acetone
(100 mL) was added lithium bromide (17.4 g, 200 mol) and stirring
was continued at 40 °C for 72 h. Most of the solvent was then
removed in vacuo (0 °C/18 Torr) and diethyl ether (250 mL) and
H2O (40 mL) were added to the residue. The organic layer was
washed with a saturated aqueous NaHSO3 solution, a saturated
aqueous NaHCO3 solution and H2O (40 mL each) and dried over
MgSO4. After removal of the solvent in vacuo (0 °C/18 Torr) distil-
lation of the residue afforded 1-bromo-6-(trimethylsilyl)-5-hexyne
(8.60 g, 37 mmol, 88%) as a clear colorless liquid. B.p. 110 °C/
12 Torr. IR (neat): ν˜ ϭ 2175 [CϵCϪSi(CH3)3] cmϪ1 1H NMR
.
(200 MHz, CDCl3): δ ϭ 0.19 [s, 9 H, Si(CH3)3], 1.35Ϫ2.10 (m, 4
H, CH2CH2), 2.17 [t, J ϭ 7 Hz, 2 H, CH2ϪCϵCϪSi(CH3)3], 3.31
(t, J ϭ 7 Hz, 2 H, CH2Br) ppm. C9H17BrSi (233.2): calcd. C 46.35,
H 7.35, Br 34.26; found C 46.21, H 7.29, Br 34.08.
(E)-5-Iodo-4-methyl-4-penten-1-ol (6): To a stirred solution of
Cp2ZrCl2 (5.0 g, 17 mmol) in dichloromethane (90 mL) was added
a solution of trimethylaluminum in hexane (2.4 , 62.5 mL,
150 mmol) at 0 °C. Stirring was continued for 15 min. 4-Pentyne-
1-ol (5) (4.2 g, 50 mmol) was added and the reaction stirred at 45
°C for 76 h. Iodine (19.0 g, 75 mmol) was then added in small por-
tions at room temperature and stirring was continued at this tem-
perature for 2 h. A saturated aqueous NaHCO3 solution (15 mL)
was added carefully and the aluminum salts were dissolved by ad-
dition of 2  HCl (70 mL). The organic layer was washed with H2O
until the aqueous layer was pH neutral, dried with MgSO4 and
the solvent was removed in vacuo (30 °C/18 Torr). Bulb to bulb
distillation of the residue afforded the vinyl iodide 6 (10.4 g,
46 mmol, 92%) as a pale yellow liquid. B.p. 70Ϫ80 °C/0.01 Torr.
IR (neat): ν˜ ϭ 3120Ϫ3580 (OH), 3050 (CϭCϪH), 1650 (CϭC)
4
3.56 (t, J ϭ 7 Hz, 2 H, CH2ϪOSi), 5.11 [tq, J ϭ 7, J ϭ 1 Hz, 1
H, C(CH3)ϭCH] ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ Ϫ5.27
[Si(CH3)2], 0.18 (CϵCϪSi(CH3)3], 15.95 [C(CH3)ϭCH), 19.76,
25.69, 27.34, 28.24, 28.97, 31.15 u. 35.81 [6 CH2 and SiC(CH3)3],
25.81 [SiC(CH3)3], 62.83 (CH2OSi), 84.24 (CϵCϪSi(CH3)3], 107.53
[CϵCϪSi(CH3)3], 124.29 [C(CH3)ϭCH], 134.88 [C(CH3)ϭCH]
ppm. C21H42OSi2 (366.5): calcd. C 68.76, H 11.55; found C 68.69,
H 11.32.
(E)-4-Methylundec-4-en-10-yn-1-ol (10): To a stirred solution of
tetra-n-butylammonium fluoride trihydrate (6.95 g, 22 mmol) in
THF (50 mL) was added a solution of 9 (3.30 g, 9 mmol) in THF
(15 mL) at room temperature and stirring was continued for an
additional 4 h. The solvent was removed in vacuo (30 °C/18 Torr),
the residue dissolved in diethyl ether (150 mL) and a saturated
aqueous NaHCO3 solution (50 mL) was added. The organic layer
was washed with H2O (50 mL), dried with MgSO4 and the solvent
was removed in vacuo (20 °C/18 Torr). After chromatographic puri-
fication of the residue with diethyl ether/petroleum ether (2:1) on
silica gel (50 g) 10 (1.37 g, 7.60 mmol, 85%) was obtained as a col-
cmϪ1 1H NMR (200 MHz, CDCl3): δ ϭ 1.50Ϫ1.80 (m, 2 H,
.
HOϪCH2ϪCH2), 1.78 [s, 3 H, C(CH3)ϭCH], 2.07 (s, 1 H, OH),
2.23 (t, J ϭ 7 Hz, 2 H, CH2OH), 3.43 [t, J ϭ 6 Hz, 2 H,
CH2(CH3)ϭCH], 5.80 [s, 1 H, C(CH3)ϭCH] ppm. C6H11OI
(226.0): calcd. C 31.86, H 4.91, I 56.15; found C 31.98, H 5.13,
I 55.89.
(E)-5-(tert-Butyldimethylsilyloxy)-1-iodo-2-methyl-1-pentene (7): To
a solution of the vinyl iodide 6 (4.52 g, 20 mmol) and tert-butyldi-
methylchlorosilane (3.62 g, 24 mmol) in DMF (35 mL) at 0 °C was orless liquid. Rf ϭ 0.40. IR (neat): ν˜ ϭ 3300 (OH), 3280 (CϵCϪH),
1
added imidazole (3.40 g, 50 mmol) and the reaction mixture stirred
at room temperature for 5 h. Petroleum ether (40 mL) and then a
2100 (CϵC) cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 1.31Ϫ1.75
4
(m, 7 H, 3 CH2 and OH), 1.59 [d, J ϭ 1 Hz, 3 H, C(CH3)ϭCH],
saturated aqueous NH4Cl solution were added until the two layers 1.92 (t, 4J ϭ 2.7 Hz, 1 H, CϵCϪH), 1.93Ϫ2.07 (m, 4 H,
had cleanly separated. The layers were separated, the aqueous layer
was extracted three times with petroleum ether (25 mL each), the
combined organic layers washed twice with H2O (30 mL each) and
then dried with MgSO4. After the solvent had been removed in
vacuo (25 °C/18 Torr) the residue was purified by bulb to bulb dis-
CH2ϪC(CH3)ϭCHϪCH2), 2.17 (dt, J ϭ 7, 4J ϭ 2.7 Hz, 2 H,
CH2ϪCϵCH), 3.61 (t, J ϭ 6.5 Hz, 2 H, CH2OH), 5.14 [tq, J ϭ 7,
4J ϭ 1 Hz, 1 H, C(CH3)ϭCH] ppm. 13C NMR (50.3 MHz,
CDCl3): δ ϭ 15.90 [C(CH3)ϭCH], 18.32 (CH2ϪCϵCH), 27.36,
28.09, 28.87, 30.78 and 35.86 (CH2), 62.48 (CH2OH), 68.27
tillation to afford 7 (6.30 g, 18.52 mmol, 93%) as a pale yellow oil. (CH2ϪCϵCϪH), 84.60 (CH2ϪCϵCϪH), 124.53 [C(CH3)ϭCH],
B.p. 110Ϫ120 °C/0.1 Torr. IR (neat): ν˜ ϭ 3050 (CϭCϪH), 1620
134.90 [C(CH3)ϭCH] ppm. MS (70 eV): (m/z) (%) ϭ 149 (2) [Mϩ
4636
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 4634Ϫ4639

Synthetic Studies towards Ergosterine Derivatives
FULL PAPER
Ϫ CH2OH], 85 (100) [C5H9Oϩ], 81 (16) [(CH2)4ϪCϵCHϩ], 53 (10) and 84.60 (C-2, C-13), 124.84 (C-8), 134.76 (C-7) ppm. C15H22O
[(CH2)2ϪCϵCHϩ]. C12H20O (180.2): calcd. C 79.93, H 11.19; (218.2): calcd. C 82.51, H 10.16; found C 82.71, H 10.25.
found C 79.87, H 11.02.
(E)-4-(tert-Butyldiphenylsilyloxy)-7-methyltetradec-7-ene-1,13-diyne
(rac-4a): To a solution of enediyne rac-12 (0.26 g, 1.2 mmol) and
(E)-4-Methylundec-4-en-10-yn-1-al (11): To a solution of oxalyl
tert-butyldiphenylchlorosilane (0.39 g, 1.4 mmol) in DMF (4 mL)
chloride (1.0 mL, 10.7 mmol) in dichloromethane (15 mL) at Ϫ65
at 0 °C was added imidazole (0.20 g, 2.9 mmol) and the reaction
°C was added a solution of DMSO (1.5 mL, 21.3 mmol) in di-
mixture was stirred at room temperature for 8 h. Petroleum ether
chloromethane (10 mL) with vigorous stirring over 10 min. Stirring
(10 mL) and then a saturated aqueous NHCl4 solution were added
was continued for an additional 10 min and a solution of the al-
cohol 10 (1.75 g, 9.7 mmol) in dichloromethane (8 mL) was then
until the two layers had cleanly separated. The layers were sepa-
rated, the aqueous layer extracted twice with petroleum ether
added. After 10 min. triethylamine (6.8 mL, 48.5 mmol) was added
(10 mL each), the combined organic layers washed twice with H2O
and the reaction mixture was allowed to warm to room temperature
(10 mL each) and dried with MgSO4. The solvent was removed in
over 30 min. Diethyl ether (150 mL) and a dilute aqueous NHCl4
vacuo (25 °C/18 Torr) and the residue purified by chromatography
solution (50 mL) were added, the layers were separated and the
organic layer extracted with 1  HCl, H2O, a saturated aqueous
NaHCO3 solution and again with H2O (50 mL each). After drying
with MgSO4 the solvent was removed in vacuo (25 °C/18 Torr) and
on silica gel (20 g) with diethyl ether/petroleum ether (1:10) to af-
ford the enediyne rac-4a (0.49 g, 1.07 mmol, 89%). Rf ϭ 0.79. IR
(neat): ν˜ ϭ 3300 (CϵCϪH), 2100 cmϪ1 (CϵC). 1H NMR
(200 MHz, CDCl3): δ ϭ 1.07 [s, 9 H, SiC(CH3)3], 1.29Ϫ1.82 [m, 6
the residue was purified by chromatography on silica gel (35 g) with
H, CH2ϪC(CH3)ϭCHϪ(CH2)2], 1.48 [d, 4J
ϭ
1 Hz,
3 H,
diethyl ether/petroleum ether (1:4) to afford the aldehyde 11 (1.30 g,
7.30 mmol, 75%) as a colorless oil. Rf ϭ 0.40. IR (neat): ν˜ ϭ 3280
C(CH3)ϭCH], 1.83Ϫ2.08 [m,
CHϪCH2ϪCH2 and 2 CϵCH], 2.17 (dt, J ϭ 7, J ϭ 2 Hz, 2 H,
CH2ϪCH2CϵCH), 2.25Ϫ2.39 (m, 2 H, CHϪCH2CϵCH), 3.84
6
H, CH2ϪCH2ϪC(CH3)ϭ
4
1
(CϵCϪH), 2100 (CϵC), 1715 cmϪ1 (CϭO). H NMR (200 MHz,
CDCl3): δ ϭ 1.32Ϫ1.60 [m, 4 H, (CH2)2ϪCH2ϪCϵCH], 1.61 [d,
4
(dddd, J ϭ 6, 6, 6 and 6 Hz; 1 H, CHϪOSi), 5.01 [tq, J ϭ 7, J ϭ
4
4J ϭ 1 Hz, 3 H, C(CH3)ϭCH], 1.94 (t, J ϭ 2 Hz, 1 H, CϵCH),
1 Hz, 1 H, C(CH3)ϭCH], 7.31Ϫ7.45 (m, 6 H, meta and para-H),
7.60Ϫ7.74 (m, 4 H, ortho-H) ppm. 13C NMR (50.3 MHz, CDCl3):
δ ϭ 15.73 [C(CH3)ϭCH], 18.20, 19.23, 26.30, 27.19, 27.94, 28.71,
34.20 and 34.71 [C-3, C-5, C-6, C-9, C-10, C-11, C-12 and
SiC(CH3)3], 26.88 [SiC(CH3)3], 68.06 and 69.94 (C-1 and C-14),
71.03 (C-4), 81.13 and 84.48 (C-2 and C-13), 124.06 (C-8), 127.40,
127.44, 129.51, 133.89, 134.02, 134.84 and 135.77 (aromat. CH, C
and C-7) ppm. C31H40OSi (456.6): calcd. C 81.52, H 8.83; found C
81.36, H 8.84.
2.00 [dt, J ϭ 7 Hz and 7 Hz, 2 H, C(CH3)ϭCHϪCH2], 2.19 (dt,
J ϭ 7, 4J ϭ 2 Hz; CH2ϪCϵCH), 2.32 [t, J ϭ 8 Hz, 2 H,
CH2ϪC(CH3)ϭCH], 2.53 (dt,
J ϭ 8 Hz and 1 Hz, 2 H,
4
CH2ϪCHO), 5.18 [tq, J ϭ 7, J ϭ 1 Hz, 1 H, C(CH3)ϭCH], 9.81
(t, J ϭ 1 Hz, 1 H, CHO) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ
16.09 [C(CH3)ϭCH], 18.29 (CH2ϪCϵCH), 27.34, 28.02, 28.71 and
31.82 (4 CH2), 42.14 (CH2ϪCHO), 68.21 (CϵCH), 84.50 (CϵCH),
125.26 [C(CH3)ϭCH], 133.27 [C(CH3)ϭCH], 202.33 (CHO) ppm.
C12H18O (178.2): calcd. C 80.85, H 10.18; found C 80.74, H 10.16.
(E)-4-(β-Methoxyethoxymethoxy)-7-methyltetradec-7-ene-1,13-
diyne (rac-4b): To a solution of enediyne rac-12 (0.22 g, 1.0 mmol)
and diisopropylethylamine (0.2 mL, 1.6 mmol) in dichloromethane
(E)-7-Methyltetradec-7-ene-1,13-diyn-4-ol (rac-12): To a stirred sus-
pension of magnesium (0.32 g, 13.2 mmol) in THF (20 mL) were
added iodine (5 mg), HgCl2 (5 mg) and 1,2-dibromoethane
(0.05 mL). After the reaction mixture had become colorless and
cloudy a solution of propargyl bromide (1.0 mL, 13.2 mmol) in
THF (10 mL) was added at 5 °C with stirring which was main-
tained at 15 °C for 1 h. Titration of this solution with 0.1  HCl
indicated that this solution of propargyl magnesium bromide in
THF was 0.34 . A solution of the aldehyde 11 (0.98 g, 5.5 mmol)
in THF (5 mL) was added at Ϫ15 °C to a solution of propargyl
magnesium bromide in THF (0.34 , 18 mL, 6.1 mmol) with stir-
ring. The reaction mixture was allowed to warm to room tempera-
ture and stirring was continued for 1 h. Diethyl ether (20 mL) and a
saturated aqueous NHCl4 solution (10 mL) were added, the layers
separated and the organic layer extracted with a saturated aqueous
NaHCO3 solution and a saturated aqueous NaCl solution (20 mL
each). After drying with MgSO4 the solvent was removed in vacuo
(40 °C/18 Torr) and the residue purified by chromatography on sil-
ica gel (40 g) with diethyl ether/petroleum ether (2:1) to afford the
enediyne rac-12 (0.91 g, 4.17 mmol, 76%) as a colorless oil. Rf ϭ
0.56. IR (neat): ν˜ ϭ 3350 (OH), 3270 (CϵCϪH), 2100 (CϵC)
(5 mL) at
0 °C was added β-methoxyethoxymethyl chloride
(0.3 mL, 1.6 mmol) and the reaction mixture stirred at room tem-
perature for 18 h. Diethyl ether and a saturated aqueous NHCl4
solution (10 mL each) were then added. The layers were separated,
the aqueous layer extracted twice with diethyl ether (10 mL each)
and the combined organic layers washed twice with H2O (10 mL
each) and dried with MgSO4. The solvent was removed in vacuo
(25 °C/18 Torr) and the residue purified by chromatography on sil-
ica gel (15 g) with diethyl ether/petroleum ether (1:4) to afford the
enediyne rac-4b (0.28 g, 0.91 mmol, 92%). Rf ϭ 0.14. IR (neat):
ν˜ ϭ 3290 (CϵCϪH), 2110 (CϵC), 1660 (CϭC) cmϪ1 1H NMR
.
(200 MHz, CDCl3): δ ϭ 1.30Ϫ2.32 (m, 14 H, CH2 and CϵCH),
4
1.63 [d, J ϭ 1 Hz, 3 H, C(CH3)ϭCH], 2.49 (dd, J ϭ 7 and 3 Hz,
2 H, CHϪCH2ϪCϵCH), 3.39 (s, 3 H, OCH3), 3.52Ϫ3.88 (m, 5 H,
OCH2CH2O and CHϪO), 4.70 and 4.87 (AB signal, JAB ϭ 8 Hz,
2 H, OCH2O), 5.15 [tq, J ϭ 6.5, 4J ϭ 1 Hz, 1 H, C(CH3)ϭCH]
ppm. C19H30O3 (306.3): calcd. C 74.47, H 9.87; found C 74.52,
H 9.82.
cmϪ1
.
1H NMR (200 MHz, CDCl3): δ ϭ 1.27Ϫ1.80 (m, 6 H, 3 (E)-4-Methoxy-7-methyltetradec-7-ene-1,13-diyne (rac-4c): Pow-
4
4
CH2), 1.62 [d, J ϭ 1 Hz, 3 H, C(CH3)ϭCH], 1.94 (t, J ϭ 2 Hz,
dered potassium hydroxide (0.62 g, 11 mmol) was suspended in
1 H, CϵCH), 1.97Ϫ2.13 [m, 5 H, CH2C(CH3)ϭCH-CH2 and OH], DMSO (10 mL) with vigorous stirring. Enediyne rac-12 (0.61 g,
2.08 (t, 4J ϭ 2 Hz, 1 H, CHϪCH2ϪCϵCH), 2.19 (dt, 2 H, J ϭ 2.8 mmol) and methyl iodide (0.35 mL, 5.7 mmol) were added and
6.5, 4J
ϭ
2 Hz, CH2ϪCH2ϪCϵCH), 2.25Ϫ2.51 (m,
2 H, stirring was continued for 30 min. H2O was then added to the reac-
CHϪCH2ϪCϵCH), 3.75 (dddd, J ϭ 5.8, 5.8, 5.8, and 5.8 Hz, 1 tion mixture until everything had completely dissolved. The reac-
H, CHOH), 5.18 [tq, J ϭ 7, J ϭ 1 Hz; 1 H, C(CH3)ϭCH] ppm.
tion mixture was extracted three times with dichloromethane
13C NMR (50.3 MHz, CDCl3): δ ϭ 15.93 [C(CH3)ϭCH], 18.32 (C- (10 mL each) and the combined organic layers were washed twice
12), 27.29, 27.36, 28.07 and 28.82 (C-3, C-6, C-10, C-11), 34.27 and with H2O (10 mL each) and dried with MgSO4. The solvent was
35.75 (C-5, C-9), 68.23, 69.67 and 70.79 (C-1, C-4, C-14), 80.90
removed in vacuo (25 °C/18 Torr) and the residue purified by chro-
Eur. J. Org. Chem. 2003, 4634Ϫ4639
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4637

U. Groth, N. Richter, A. Kalogerakis
FULL PAPER
matography on silica gel (20 g) with diethyl ether/petroleum ether C31H40OSi (456.6): calcd. C 81.52, H 8.83; found C 81.24, H 8.71.
(1:20) to afford the enediyne rac-4c (0.53 g, 2.30 mmol, 82%). Rf ϭ
trans-1,2,3,4,4a,4b,5,6,7,8-Decahydro-2-(β-methoxyethoxymethoxy)-
0.23. IR (neat): ν˜ ϭ 3280 (CϵCϪH), 2100 (CϵC) cmϪ1. 1H NMR
4a-methylphenanthrene (rac-3b/13b): According to the general pro-
(200 MHz, CDCl3): δ ϭ 1.40Ϫ1.83 [m, 6 H, (CH2)2CH2-CϵCH
cedure, enediyne rac-4b (0.22 g, 0.72 mmol) and CpCo(CO)2
4
and OCHϪCH2CH2], 1.65 [d, J ϭ 1 Hz, 3 H, C(CH3)ϭCH], 1.98
(0.18 g, 1.0 mmol) were used to prepare rac-3b/13b (0.12 g,
[t, 4J ϭ 2 Hz, 1 H, (CH2)2CϵCH], 2.04 (t, 4J ϭ 2 Hz, 1 H,
0.40 mmol, 56%) as a colorless liquid after chromatography with
CHϪCH2ϪCϵCH), 2.00Ϫ2.17 [m, 4 H, CH2C(CH3)ϭCHϪCH2],
2.23 (dt, J ϭ 7, J ϭ 2 Hz, 2 H, CH2ϪCH2ϪCϵCH), 2.40Ϫ2.51
(m, 2 H, CHϪCH2ϪCϵCH), 3.32 (dddd, J ϭ 6, 6, 6 and 6 Hz, 1
H, CHϪOCH3), 3.42 (s, 3 H, OCH3), 5.20 [tq, J ϭ 7 Hz and J ϭ
diethyl ether/pentane (1:4) on silica gel (15 g); Rf ϭ 0.15. dia-
4
stereomeric ratio 1.9:1. IR (neat): ν˜ ϭ 3040 (CϭCϪH), 1625 (Cϭ
1
C) cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 0.87, (s, 3 H, CH3 of
4
3b), 0.89 (s, 3 H, CH3 of 13b), 1.04Ϫ2.28 (m, 15 H, CH2 and CH),
3.38 (s, 3 H, OCH3), 3.44Ϫ3.82 (m, 5 H, OCH2CH2O and CHϪO),
4.72 and 4.81 (AB signal, JAB ϭ 8 Hz, 2 H, OCH2O), 5.48 (s, 2 H,
CϭCH) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 15.92 and 16.02
(CH3), 23.84, 24.39, 25.01, 25.06, 25.41, 26.33, 29.04, 32.64, 32.67,
33.79, 35.67, 37.02, 37.86, 38.06 (7 CH2 and C-4a), 47.42 and 47.59
(C-4b), 58.97 (OCH3), 66.62, 66.68, 69.41 and 70.89 (OCH2CH2O),
71.73 and 75.64 (C-2), 93.26 and 93.58 (OCH2O), 117.48, 117.62,
119.39 and 119.76 (C-9 and C-10), 137.67, 138.96, 139.82 and
140.04 (C-8a and C-10a). C19H30O3 (306.3): calcd. C 74.47, H 9.87;
found C 74.13, H 9.64.
1 Hz, 1 H, C(CH3)ϭCH] ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ
15.91 [C(CH3)ϭCH], 18.32 (C-12), 23.04, 27.33, 27.36, 28.08, 31.87
and 35.32 (C-3, C-5, C-6, C-9, C-10, C-11), 56.98 (OCH3), 68.21
and 69.91 (C-1 and C-14), 78.66 (C-4), 81.04 and 84.58 (C-2 and
C-13), 124.58 (C-8), 134.76 (C-7) ppm. C16H24O (232.3): calcd. C
82.70, H 10.41; found C 82.76, H 10.51.
Cobalt Mediated [2؉2؉2]-Cycloaddition of Enediynes rac-11 to De-
cahydrophenanthrenes rac-12/13. General Procedure: A solution of
the enediyne rac-4 (1 mmol) in toluene (30 mL) was cooled to Ϫ70
°C and the apparatus was evacuated for 3 min (0.5 Torr). The flask
was allowed to warm to room temperature and argon was admitted
to the apparatus. The solution of the enediyne in toluene was again
cooled to Ϫ70 °C and the above procedure was repeated a further
two times. CpCo(CO)2 (1.2 mmol) was added and the reaction mix-
ture was heated to reflux with concomitant irradiation with visible
light until no more starting material could be detected by TLC
analysis. The reaction mixture was cooled down to room tempera-
ture and volatile components were removed in vacuo (20 °C/
0.1 Torr). The residue was dissolved in degassed diethyl ether/pen-
tane (1:4, 5 mL) and filtered through celite under an argon atmos-
phere. Ferric chloride hexahydrate (0.49 g, 1.8 mmol) was dissolved
in acetonitrile (20 mL), pentane (20 mL) was added and the mix-
ture cooled to Ϫ20 °C. At this temperature the filtrate was added
with stirring which was continued for 30 min. The reaction mixture
was then cooled to Ϫ60 °C and the pentane layer was removed
from the frozen acetonitrile layer. The acetonitrile layer was al-
lowed to warm to Ϫ20 °C, pentane (15 mL) was added and the
above procedure was repeated four times. The pentane layers were
combined, the solvent was removed in vacuo (30 °C/18 Torr) and
the residue purified by chromatography on silica gel.
trans-1,2,3,4,4a,4b,5,6,7,8-Decahydro-2-methoxy-4a-methyl-
phenanthrene (rac-3c/13c): According to the general procedure, en-
ediyne rac-4c (0.28 g, 1.20 mmol) and CpCo(CO)2 (0.36 g,
2.0 mmol) were used to prepare rac-3c/13c (0.12 g, 5.17 mmol,
43%) as a colorless liquid after chromatography with diethyl ether/
pentane (1:10) on silica gel (15 g); Rf ϭ 0.34. Diastereomeric ratio
1.4:1. IR (neat): ν˜ ϭ 3015 (CϭCϪH), 1645 (CϭC), 1195 (CϪO)
1
cmϪ1. H NMR (200 MHz, CDCl3): δ ϭ 0.88 and 0.89 ppm(2s, 3
H, CH3), 1.10Ϫ2.60 (m, 15 H, CH2 and CH), 3.08Ϫ3.26 (m, 1 H,
CHϪOCH3), 3.31 and 3.38 (2s, 3 H, OCH3), 5.42Ϫ5.56 (m, 2 H,
CϭCHϪCHϭC) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 15.99
and 16.07 (CH3), 24.02, 24.45, 25.10, 25.33, 25.47, 28.23, 32.68,
32.72, 33.55, 35.19, 37.09, 37.23, 37.33 and 38.00 (7 CH2 and C-
4a), 47.39 and 47.70 (C-4b), 55.55 and 55.64 (OCH3), 74.93 and
79.13 (C-2), 117.60, 117.76, 119.47 and 119.77 (C-9 and C-10),
137.45, 138.20, 139.07 and 140.32 (C-8a and C-10a) ppm. MS
(70 eV): (m/z) (%) ϭ 232 (21) [Mϩ], 201 (35) [Mϩ Ϫ O CH3], 183
(100) [Mϩ Ϫ OCH3 Ϫ H2O]. C16H24O (232.3): calcd. C 82.70, H
10.41; found C 82.36, H 10.12.
trans-1,2,3,4,4a,4b,5,6,7,8-Decahydro-2-tert-butyldiphenylsilyloxy-
4a-methylphenanthrene (rac-3a/13a): According to the general pro-
cedure, enediyne rac-4a (0.18 g, 0.40 mmol) and CpCo(CO)2
(0.11 g, 0.60 mmol) were used to prepare rac-3a/13a (68 mg,
0.15 mmol, 37%) as a colorless liquid after chromatography with
diethyl ether/petroleum ether (1:50) on silica gel (15 g); Rf ϭ 0.49.
diastereomeric ratio 1.7:1. IR (neat): ν˜ ϭ 3050, 3020 (CϭCϪH),
Acknowledgments
Financial support from the Fonds der Chemischen Industrie is
gratefully acknowledged. We thank the Bayer AG for providing
valuable starting materials. N. R. thanks the Cusanus Werk Ϫ
Bischöfliche Hochbegabtenförderung for a doctoral fellowship.
1645 (CϭC), 1580 (aromat. CϭC), 1100 (CϪO) cmϪ1 1H NMR
.
[1] [1a]
U. Groth, W. Halfbrodt, T. Köhler, P. Kreye, Liebigs Ann.
(200 MHz, CDCl3): δ ϭ 0.85 (s, 3 H, CH3 of 3a), 0.88 (s, 3 H, CH3
of 13a), 1.08 [s, 9 H, SiC(CH3)3], 1.20Ϫ2.50 (m, 15 H, CH2 and
CH), 3.57Ϫ3.74 (m, 1 H, CHϪOSi), 5.32Ϫ5.47 (m, 2 H, Cϭ
CHϪCHϭC), 7.10Ϫ7.50 (m, 6 H, meta and para-H),7.60Ϫ7.80 (m,
4 H, ortho-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 15.73 and
16.15 (CH3), 19.15, 19.39, 23.93, 24.45, 25.08, 25.11, 27.00, 29.46,
32.15, 32.65, 32.71, 33.65, 36.77, 37.15, 38.07 and 38.30 (7 CH2
and C-4a), 25.47 [SiϪC(CH3)3], 41.06 [SiϪC(CH3)3], 47.49 and
47.60 (C-4b), 67.74 and 72.07 (C-2), 117.52, 118.00, 118.98 and
119.79 (C-9 and C-10), 127.36, 127.46, 127.48, 129.44, 134.61,
134.71, 134.78, 135.74 and 135.93 (aromat. CH and C), 137.35,
138.07, 139.95 and 140.95 (C-8a and C-10a) ppm. MS (70 eV): (m/
z) (%) ϭ 456 (8) [Mϩ], 399 (10) [Mϩ Ϫ C4H9], 239 (6)
[Si(C6H5)2(C4H9)ϩ], 199 (100), [Mϩ Ϫ Si(C6H5)2(C4H9) Ϫ H2O].
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Eur. J. Org. Chem. 2003, 4634Ϫ4639

Synthetic Studies towards Ergosterine Derivatives
FULL PAPER
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Received July 11, 2003
Eur. J. Org. Chem. 2003, 4634Ϫ4639
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4639