Catalytic enantioselective annulation using phenylsulfanylmethyl vinyl ketone. An approach to trans-hydrindane building blocks for ent-vitamin D3 synthesis

Article abstract of DOI:10.1016/S0957-4166(99)00142-1

An enantioselective synthesis of the ent-vitamin D₃ northern portion building block is presented. The key step involves phenylalanine-catalyzed annulation of 2-methylcyclopent-2-en-1-one with phenylsulfanylmethyl vinyl ketone.

Full text of DOI:10.1016/S0957-4166(99)00142-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1589–1598
Catalytic enantioselective annulation using phenylsulfanylmethyl
vinyl ketone. An approach to trans-hydrindane building blocks
for ent-vitamin D3 synthesis
Agnieszka Przez´dziecka, Wiaczesław Stepanenko and Jerzy Wicha ∗
Institute of Organic Chemistry, Polish Academy of Sciences, POB 58, 01-224 Warsaw 42, Poland
Received 26 March 1999; accepted 14 April 1999
Abstract
An enantioselective synthesis of the ent-vitamin D3 northern portion building block is presented. The key step
involves phenylalanine-catalyzed annulation of 2-methylcyclopent-2-en-1-one with phenylsulfanylmethyl vinyl
ketone. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Enantioselective amino acid-catalyzed annulation of 2-methylcyclopenta-1,3-dione1–3 (3, Scheme 1)
or 2-methylcyclohexa-1,3-dione4–6 with methyl vinyl ketone, affording optically active hydrindane or
decaline derivatives, respectively, has made possible efficient total synthesis of several natural products
and their analogues (some recent related studies are given in the bibliography7–13 ). Ethyl vinyl ketone
and some alkyl vinyl ketones bearing a remote substituent in the alkyl group were also successfully
employed in this reaction.14–17 However, to date no α,β-unsaturated ketones with an activated methylene
group have been examined (except for preliminary experiments with the Nazarov reagent6). As far as the
catalysts are concerned, it has been generally accepted that homochiral proline or phenylalanine give the
best results.18,19
In conjunction with research on the total synthesis of 1α,25-dihydroxy vitamin D3 (1, Fig. 1) ongoing
in our laboratory,20,21 it was of interest to examine the application of the highly reactive (thiophe-
nyl)methyl vinyl ketone (2, Scheme 1) as an electrophile22 in reaction with dione 3 under asymmetric an-
nulation conditions. Bicyclic sulfide 4a, if formed, could be oxidized at sulfur to afford the corresponding
sulfone 4b. Since it was recently shown that the reduction of related α,β-unsaturated β-phenylsulfonyl
ketones with lithium aluminum hydride occurs with deoxygenation and affords diastereoselectively
∗
Corresponding author. E-mail: jwicha@ichf.edu.pl
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00142-1

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Scheme 1.
saturated sulfone with a trans-ring junction,22,23 we expected that reduction of 4b would yield hydroxy
sulfone 5. The hydroxy group in the latter could be further used to construct the vitamin D side chain.
On the other hand, the phenylsulfonyl group could serve as a handle for the attachment of the ring A
fragment.24 As the synthesis target the CD side-chain portion of the ent-vitamin D3 11 was chosen.
Figure 1.
2. Results and discussion
Our first objective was to examine the transformation of thiophenyl enone 4a into the saturated sulfone
5. Hajos–Parrish–Wiechert ketone 4c (Scheme 1) was oxidized25 into epoxide 6 which was treated with
thiophenol26 to give sulfide 4a. The latter was oxidized with m-chloroperbenzoic acid to give sulfone
4b. Reduction of 4b with lithium aluminum hydride provided stereoselectively the trans-hydrindane
derivative 5 which, without isolation, was oxidized with the Jones reagent to give the keto sulfone 7. The
structure of 7 was confirmed by removing the phenylsulfonyl group (sodium amalgam in THF–methanol)
which yielded known27 trans-7a-methyl-octahydroinden-1-one.

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1591
After confirming our plans regarding the transformation of 4a into 5 we turned our attention to the
annulation reaction. Reaction of 2, prepared immediately before use by oxidation of 1-thiophenyl-2-
hydroxybut-3-ene26 with the Dess–Martin reagent,28 with 3 in aqueous acetic acid (the Hajos–Parrish
conditions29 for the Michael addition step) directly afforded the racemic bicyclic product 4a. Monitoring
the reaction progress by TLC indicated the presence of an intermediate, most likely the corresponding
trione. However, all attempts to isolate this compound failed. When a solution of 2 and 3 in acetonitrile
was treated with (S)-(−)-proline (3 mol%) and some perchloric acid, and the mixture was heated under
reflux (the Schering procedure3), only a small amount of racemic 4a was obtained. Using larger amounts
of proline and carrying the reaction out at room temperature lead to a non-racemic product (Table 1).
Use of DMF as the solvent provided 4a in 60% yield, 56.6% ee (Table 1, entry 3). Further alternations of
the classical procedures failed to improve the reaction outcome. Application of the method developed
by Hagiwara and Uda and their coworkers30,31 with (S)-(−)-phenylalanine as the catalyst, (1S)-(+)-
camphorsulfonic acid (D-CSA) as the dehydrating agent and a gradual increase of the temperature gave
the product 4a in 69–71% yield and 86–89% ee (95–96% ee after one recrystallization from methanol)
(Table 1, entry 4). Under analogous conditions, but with the (R)-(+)-phenylalanine the enantiomer of 4a
was obtained in 71% yield, 89.1% ee (Table 1, entry 5). Replacement of phenylalanine with proline in
the Hagiwara procedure resulted in lowering the product yield and enantiomeric excess (Table 1, entry
6).
Table 1
Having in hand diketo sulfide 4a of high enantiomeric purity, we followed the above described proce-
dure to transform it into the enantiomeric keto sulfone 7. The latter product was treated with triethylphos-
phonoacetate and sodium ethoxide in ethyl alcohol.32 To our disappointment, 7 resisted any changes un-
der standard conditions for 17-oxo steroid transformation. Ultimately, the Horner–Wadsworth–Emmons
reaction was executed by treatment of 7 (Scheme 2) with triethylphosphonoacetate and sodium hydride

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in DMF containing HMPA to give 8 in 80% yield (when DMPU was used instead of HMPA, 8 was
obtained in 58% yield). The unsaturated ester 8 was hydrogenated using palladium catalyst to afford 9.
Scheme 2. Reagents and conditions: (a) NaH–(EtO)2POCH2CO2Et/DMF–HMPA; (b) H2–10% Pd on carbon/EtOH;
(c) LDA–1-iodo-4-methylhexane/THF–HMPA; (d) DIBAH/CH2Cl2–toluene; (e) TsCl–Et3N–DMAP/CH2Cl2; (f)
L-Selectride®/THF
Next, we aimed at selective alkylation of 9 to the carboethoxy group in the presence of the phenylsul-
fonyl group α to the carboethoxy group. It was thought that steric shielding of the phenylsulfonyl group
activated proton would be beneficial. We were pleased to find that treatment of 9 with LDA and then with
isohexyl iodide and some HMPA provided ester 10a in 67% yield after chromatography (ca. 10% of the
unchanged 9 was recovered). Alkylation of 9 with methyl iodide under analogous conditions afforded 12
(75% yield). No diastereomers of the alkylation products could be detected.
Reduction of the carboethoxy group in 10a with DIBAH followed by tosylation of alcohol 10b and
reduction of the tosylate 10c (L-Selectride®) afforded 13. This compound may be used for the synthesis
of ent-vitamin D3 which has not been described until now. Similarly, reduction of ester 12 with DIBAH
yielded alcohol 11 which may also be used for the synthesis of vitamin D stereo-analogues.
In conclusion, an enantioselective synthesis of building blocks 13 and 11 for vitamin D analogue
construction has been developed using asymmetric annulation.
3. Experimental
1
Melting points were determined on a Kofler hot-stage melting point apparatus. H and 13C NMR
spectra were performed in CDCl3 on a Varian Gemini 200 MHz spectrometer and multiplicities were
assigned using DEPT sequence. Mass spectra were determined at an ionizing voltage of 70 eV; (m/z)
relative intensity are given in brackets. Optical rotations were measured on a Perkin–Elmer, model
141 polarimeter in chloroform solutions at concentration (g/100 ml), unless otherwise indicated. HPLC
analyses were performed using a Shimadzu LC-8A chromatograph provided with a SPD-6A variable λ
detector and fitted with a Chiralcel® OD-H column (25×0.46 cm) with the eluent 2-propanol:hexane,

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1:1, flow 0.3 ml/min; detection at λ=254 nm. Air-sensitive reactions were performed in oven- or flame-
dried glassware under argon. Organic extracts were dried over Na2SO4 and solvents were evaporated on
a rotary evaporator.
3.1. 1-Phenylsulfanyl-but-3-en-2-one 2
To a solution of 1-phenylsulfanyl-but-3-en-2-ol26 (3.488 g, 19.38 mmol) in DMSO (1.5 ml), stirred
at 15°C, o-iodoxybenzoic acid (7.645 g, 29.07 mmol) in DMSO (19.5 ml) was added. The mixture was
stirred at 15°C for 1 h and then set aside at rt for 2.5 h and then diluted with cold water and filtered
through a pad of Celite (ca. 1 cm layer). The filtrate was extracted with diethyl ether and the Celite was
washed with diethyl ether. The combined ethereal solutions were washed with water and the solvent was
evaporated. The residue was chromatographed on SiO2 (125 g, hexane:EtOAc, 20:1 to 5:1) to give ketone
2 (2.815 g, 82%).
3.2. (1R,4aR,7aR)-4a-Methyl-tetrahydro-1-oxa-cyclopropa[d]indene-2,5-dione 625
To a solution of endione29 4c ([α]23=−349, c=1.0, toluene) (1.0 g, 6 mmol) in MeOH (15 ml) H2O2
D
(30%, 2 ml, 24 mmol) was added followed, after cooling to 0°C, by 4 N NaOH (750 µl, 3 mmol). The
mixture was set aside at rt for 5 h and then diluted with water. The product was extracted with CHCl3.
The extract was evaporated. Epoxide 6 was obtained (99 mg, 92% yield), mp 75–77°C.
3.3. (7aR)-7a-Methyl-4-phenylsulfanyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione 4a
To a mixture of epoxide 6 (90 mg, 5 mmol), EtOH (2 ml) and 15% aqueous KOH (0.09 ml), stirred
at 0°C, thiophenol (0.51 ml, 5 mmol) in THF (1.5 ml) was added within 30 min. The mixture was set
aside at 0° to +5°C for 24 h and then diluted with water (10 ml). The product was extracted using a
mixture of diethyl ether and toluene (1:1). The organic extract was washed with brine. The solvent was
evaporated and the residue (1.36 g) was chromatographed on SiO2 (34 g, hexane:EtOAc, 9:1). Sulfide 4a
was obtained (1.17 g, 86% yield): mp 152–154°C (MeOH); [α]23=−201.8, (c=0.75, toluene); IR (KBr)
D
1743, 1668, 1600 cm−1; UV (1.29 mg/10 ml EtOH) λmax=193 nm, ε=22139; λmax=248 nm, ε=13943;
1H NMR 7.31–7.09 (m, 5H), 3.41–3.20 (m, 1H), 2.94–1.85 (m, 7H), 1.38 (s, 3H); 13C NMR 215.82 (0),
192.90 (0), 175.14 (0), 135.36 (0), 129.00 (1), 128.77 (0), 128.04 (1), 126.06 (1), 51.20 (0), 35.39 (2),
33.41 (2), 28.06 (2), 27.20 (2), 21.42 (3); EI MS 272 (M+, 76), 230 (5), 215 (4), 163 (100), 139 (6),
135 (14), 121 (31), 110 (23), 105 (6), 93 (12), 77 (13), 65 (5), 51 (6), 41 (4), 39 (5). Anal. calcd for
C16H16O2S (272.37): C, 70.55; H, 5.92. Found: C, 70.33; H, 6.08.
3.4. (7aR)-4-Benzenesulfonyl-7a-methyl-2,3,7,7a-tetrahydro-6H-indene-1,5-dione 4b
To a solution of sulfide 4a (1.0 g, 3.7 mmol) in CH2Cl2 (15 ml), stirred at 0°C, m-CPBA (634 mg, 3.7
mmol) was added and the mixture set aside in rt for 12 h before another portion of m-CPBA (634 mg,
3.7 mmol) was added. After 12 h the mixture was partitioned between CH2Cl2 and saturated aqueous
NaHCO3. The organic layer was washed with saturated aqueous Na2S2O3 and water, and then dried. The
solvent was evaporated and the residue was chromatographed on SiO2 (10 g, hexane:EtOAc, 9:1) to give
sulfone 4b (1.08 g, 97% yield): mp 177–179°C (MeOH); [α]23=−88.2 (c=0.75); UV (0.75 mg/10 ml
D
EtOH), λmax=200 nm, ε=7082; λmax=218 nm, ε=6099; IR (KBr) 1750, 1674, 1595, 1307, 1148 cm−1;
1H NMR 8.05–7.96 (m, 2H), 7.65–7.45 (m, 3H), 4.31–4.14 (m, 1H), 3.50–3.25 (m, 1H), 3.05–1.70 (m,

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6H), 1.41 (s, 3H); 13C NMR 213.97 (0), 190.89 (0), 178.73 (0), 141.09 (0), 134.63 (0), 133.46 (1), 128.66
(1), 128.26 (1), 52.07 (0), 34.59 (2), 33.58 (2), 26.70 (2), 25.83 (2), 22.69 (3); EI MS 304 (M+, 54), 276
(63), 261 (4), 240 (12), 212 (8), 197 (10), 185 (11), 183 (8), 163 (100), 135 (27), 121 (12), 105 (9), 93
(20), 91 (38), 77 (38), 65 (9), 51 (15), 39 (8). EI MS HR: calcd for C16H16O4S (M+): 304.07693. Found:
304.07795.
3.5. (3aS,4S,7aR)-4-Benzenesulfonyl-7a-methyl-octahydro-inden-1-one 7
To a solution of sulfone 4b (90 mg, 2.96 mmol) in THF (10 ml), stirred under argon, LiAlH4 (1 M in
THF) (11.8 ml, 11.8 mmol) was added and the mixture was heated at reflux for 30 min. After cooling, the
excess reagent was decomposed with MeOH and the mixture was poured into a 10% aqueous tartaric acid
solution. The product was extracted with CH2Cl2. The extract was dried and the solvent was evaporated.
The residue (alcohol 5, 87 mg) was dissolved in acetone (10 ml) and the Jones reagent was added
dropwise until a brown color persisted. After 30 min the excess reagent was decomposed with propan-2-
ol and the mixture diluted with water. The product was isolated with CH2Cl2 and chromatographed (SiO2,
30 g, hexane:EtOAc, 19:1) to give ketone 7 (69 mg, 80% yield): mp 201–203°C (MeOH); [α]23=−68.5
D
(c=0.25); IR (KBr) 1737, 1304, 1145 cm−1; 1H NMR 7.95–7.85 (m, 2H), 7.76–7.52 (m, 3H), 3.28–3.10
(m, 1H), 2.60–1.05 (m, 11H), 0.91 (s, 3H); 13C NMR 218.36 (0), 137.59 (0), 133.73 (1), 129.13 (1),
128.66 (1), 62.63 (1), 48.88 (0), 44.22 (1), 35.00 (2), 30.63 (2), 27.56 (2), 23.34 (2), 20.29 (2), 13.77 (3);
EI MS 292 (M+, 9), 167 (20), 151 (100), 133 (86), 109 (81), 91 (19), 81 (34), 67 (34), 55 (12), 51 (4), 41
(11). EI MS HR: calcd for C16H20O3S (M+): 292.11331. Found: 292.11301.
3.6. Annulation reactions
The annulation reactions were carried out under an argon atmosphere, with magnetic stirring, using
ca. 2 mmol of phenylsulfanylmethyl vinyl ketone 2, 150 mol% 2-methyl-1,3-cyclopentadione 3 and the
appropriate amino acid. The reaction was monitored by TLC (hexane:EtOAc, 2:1). Product (4a and its
enantiomer) was isolated with CH2Cl2 and filtered through SiO2 (ca. 10 g, hexane:EtOAc, 9:1). Yields,
specific rotations and ee values (determined by HPLC on a Chiracel column) are given in Table 1.
Reaction of 2 and 3 in water containing acetic acid at rt gave rac-4a in a 75% yield. The starting
material was consumed in ca. 4 h. An intermediate was detected on TLC (hexane:EtOAc, 1:1), but all
attempts to isolate this compound failed. Reaction of 2 and 3 in CH3CN containing S-(−)-proline (3
mol%) and HClO4 at reflux temperature under conditions described by the Schering workers3 gave rac-
4a in a 29% yield.
A mixture of 2 (390 mg, 2.2 mmol), 3 (370 mg, 3.3 mmol), S-(−)-proline (126 mg, 1.1 mmol) and
CH3CN (4 ml) was stirred at rt for 18 h (the starting material was consumed). 96% H2SO4 (0.07 ml)
was then added and the mixture was heated at 90°C for 16 h. Product 4a (262 mg, 44%), [α]23=+29.1
D
(c=0.14) was obtained; 10.2% ee by HPLC.
A mixture of 2 (180 mg, 1 mmol), 3 (170 mg, 1.5 mmol), S-(−)-proline (58 mg, 0.5 mmol) and DMF
(3 ml) was stirred at 70–75°C for 18 h. 96% H2SO4 (0.035 ml) was then added and the mixture was
stirred at 90°C for 48 h. Product 4a (143 mg, 52%), [α]23=+65.6 (c=0.81) was obtained; 45.4% ee.
D
A mixture of 2 (180 mg, 1 mmol), 3 (170 mg, 1.5 mmol), S-(−)-proline (58 mg, 0.5 mmol) and DMF
(3 ml) was stirred at 70–75°C for 18 h. The mixture was allowed to cool to rt and then 96% H2SO4 (0.035
ml) was added. Stirring at rt was continued for 4 days. Product 4a (165 mg, 60%), [α]23=+81.4 (c=0.80)
D
was obtained; 56.6% ee.

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1595
Reaction under the conditions developed by Hagiwara and Uda.31 To a mixture of 2 (348 mg, 1.96
mmol), 3 (328 mg, 2.9 mmol) and DMF (4 ml) was added triethylamine (0.048 ml, 0.2 mmol). The
mixture was stirred at rt for 7 h (the starting material was consumed, TLC). Then S-(−)-phenylalanine
(323 mg, 1.96 mmol) and D-CSA (227 mg, 0.98 mmol) were added. The mixture was stirred at rt for 24 h,
and the temperature was raised by 10°C in every 24 h for 3 days (up to 55°C). After cooling, the mixture
was poured into saturated aqueous NaHCO3 and the product was isolated with CH2Cl2. Product 4a (367
mg, 69%), [α]23=+183.1 (c=0.75) was obtained; 86.2% ee. Recrystallization of the crude product from
D
MeOH gave material of 95.6% ee.
In an analogous experiment with use of R-(+)-phenylalanine and D-CSA, product 4a (71% yield,
89.1% ee) was obtained.
In an analogous experiment with use of S-(−)-proline and D-CSA, product 4a (50% yield, 53.8% ee)
was obtained.
3.7. (Z,3aS,4S,7aR)-(4-Benzenesulfonyl-7a-methyl-octahydro-inden-1-ylidene)-acetic acid ethyl ester 8
Sodium hydride (50% in mineral oil, 0.34 g, 14 mmol) was washed with THF and suspended in DMF
(3 ml). The suspension was cooled to −20°C and then triethyl phosphonoacetate (1.26 g, 5.6 mmol) in
DMF (1 ml) was added followed, after 30 min, by HMPA (1 g, 5.6 mmol). The mixture was allowed to
warm to rt and ketone 7 (218 mg, 0.7 mmol) in DMF (2 ml) was added. The whole was set aside for
12 h and then diluted with water. The product was extracted with diethyl ether. The extract was washed
with water and dried. The solvent was evaporated and the residue (0.32 g) was chromatographed on SiO2
(2 g, hexane:EtOAc, 9:1). Ester 8 was obtained (213 mg, 80% yield): [α]23=+14.0 (c=0.56); IR (film)
D
1
1651, 1306, 1146 cm−1; H NMR 7.92–7.82 (m, 2H), 7.70–7.48 (m, 3H), 5.57–5.53 (m, 1H), 4.15 (q,
2H, J=7.14 Hz), 3.20–3.03 (m, 1H), 2.95–2.82 (m, 2H), 2.40–2.22 (m, 1H), 1.85–1.40 (m, 8H), 1.25 (t,
3H, J=7.14 Hz), 0.86 (s, 3H); 13C NMR 172.89 (0), 166.80 (0), 137.64 (0), 133.49 (1), 128.94 (1), 128.87
(1), 109.35 (1), 63.04 (1), 59.55 (2), 47.57 (1), 45.82 (0), 34.27 (2), 29.88 (2), 27.43 (2), 25.67 (2), 20.79
(2), 18.38 (3), 14.25 (3); EI MS 362 (M+, 10), 317 (3), 275 (2), 221 (25), 205 (2), 193 (8), 175 (24), 159
(2), 147 (100), 133 (12), 119 (8), 105 (17), 91 (14), 77 (8), 67 (5), 55 (6), 41 (6). EI MS HR: calcd for
C16H26O4S (M+): 362.15518. Found: 362.15734.
3.8. (1S,3aS,4S,7aS)-(4-Benzenesulfonyl-7a-methyl-octahydro-inden-1-yl)-acetic acid ethyl ester 9
A mixture of compound 8 (78 mg, 0.2 mmol), EtOH (5 ml) and 10% palladium on carbon (15 mg)
was stirred under hydrogen for 16 h and then filtered through Celite. The Celite was washed with EtOH
and the combined filtrate was evaporated to give 9 (76 mg, 97% yield): [α]23=+16.1 (c=0.13); IR (KBr)
D
1725, 1140 cm−1; 1H NMR 7.92–7.82 (m, 2H), 7.70–7.49 (m, 3H), 4.11 (q, 2H, J=7.14 Hz), 3.11–2.95
(m, 1H), 2.42–0.96 (m, 14H), 1,24 (t, 3H, J=7.14 Hz), 0.62 (s, 3H); 13C NMR 173.16 (0), 137.99 (0),
133.37 (1), 128.91 (1), 128.71 (1), 63.71 (1), 60.28 (2), 47.25 (1), 45.99 (1), 44.11 (0), 36.31 (2), 35.11
(2), 27.76 (2), 27.46 (2), 25.71 (2), 20.87 (2), 14.24 (3), 12.42 (3); EI MS 319 (3), 223 (33), 177 (12), 149
(22), 136 (11), 135 (100), 119 (2), 107 (6), 93 (9), 79 (6), 67 (6), 55 (4), 41 (3). EI MS HR: calculated for
C18H23O3S (M−OC2H5)+: 319.13679. Found: 319.13608. Calcd for C14H23O2 (M−SO2Ph)+: 223.16981.
Found: 223.16944.

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3.9. (2S)-2-[(1S,3aS,4S,7aS)-4-Benzenesulfonyl-7a-methyl-octahydro-inden-1-yl]-6-methyl-heptanoic
acid ethyl ester 10a
To a solution of LDA prepared from diisopropylamine (63 µl, 0.44 mmol), n-BuLi (230 µl, 0.44 mmol,
1.94 M in hexane) and THF (0.5 ml), stirred at −78°C, a solution of ester 9 (81 mg, 0.22 mmol) in THF
(0.75 ml)–HMPA (0.15 ml) was added. The mixture was stirred for 1 h and then 1-iodo-4-methylhexane
(95 µl, 0.44 mmol) in HMPA (100 µl) was added. The whole was stirred at −30 to −20°C for 3 h, and then
left aside at rt for 16 h. Water was added and the product was extracted with diethyl ether. The extract
was washed with water and brine, and then dried and evaporated. The residue was chromatographed on
SiO2 (5 g, hexane:EtOAc, 19:1) to give compound 11 (65 mg, 67% yield) and unchanged 9 (6 mg, eluted
with hexane:EtOAc, 10:1): [α]23=+8.3 (c=0.08); IR (film) 1727, 1305, 1146 cm−1; 1H NMR 7.90–7.79
D
(m, 2H), 7.70–7.48 (m, 3H), 4.08 (q, 2H, J=7.14 Hz), 3.09–2.94 (m, 1H), 2.3–0.96 (m, 20H), 1,24 (t, 3H,
J=7.14 Hz), 0.84 (d, 3H, J=6.59 Hz), 0.83 (d, 3H, J=6.59 Hz), 0.71 (s, 3H); 13C NMR 175.95 (0), 138.12
(0), 133.41 (1), 128.96 (1), 128.77 (1), 63.67 (1), 59.82 (2), 51.69 (1), 47.48 (1), 47.31 (1), 44.20 (0),
38.74 (2), 36.56 (2), 32.20 (2), 27.77 (1), 27.39 (2), 26.77 (2), 24.93 (2), 22.70 (3), 22.33 (3), 20.99 (2),
14.20 (3), 12.04 (3); EI MS 307 (28), 261 (7), 233 (38), 177 (3), 149 (7), 135 (100), 121 (7), 107 (8), 81
(15), 67 (11), 55 (9), 41 (8). EI MS HR: calcd for C10H15 (M−SO2Ph–HCOOC2H5–C7H14)+: 135.11738.
Found: 135.11910.
3.10. (2S)-2-[(1S,3aS,4S,7aS)-4-Benzenesulfonyl-7a-methyl-octahydro-inden-1-yl]-6-methyl-heptan-
1-ol 10b
To a solution of 10a (33 mg, 0.07 mmol) in CH2Cl2 (1 ml) DIBAH (20% in toluene, 60 µl, 0.29
mmol) was added at −20°C. The mixture was stirred at rt for 30 min and then the reaction was quenched
with EtOAc (1 ml), and diluted with water. The product was extracted with EtOAc. The organic extract
was washed consecutively with 2% H2SO4, water and brine, and dried. The solvent was evaporated and
the residue was chromatographed on SiO2 (1 g, hexane:EtOAc, 4:1). Alcohol 10b was obtained (29 mg,
97%): [α]23=+6.8 (c=0.99); IR (film) 3520, 1304, 1143 cm−1; 1H NMR 7.92–7.82 (m, 2H), 7.70–7.48
D
(m, 3H), 3.75–3.58 (m, 2H), 3.12–2.97 (m, 1H), 2.18–0.98 (m, 21H), 0.86 (d, 6H, J=6.59 Hz), 0.71 (s,
3H); 13C NMR 138.19 (0), 133.35 (1), 128.93 (1), 128.75 (1), 63.64 (1), 62.76 (2), 49.58 (1), 48.07 (1),
44.46 (0), 42.07 (1), 39.44 (2), 38.03 (2), 29.57 (2), 27.99 (1), 27.44 (2), 27.07 (2), 25.29 (2), 24.21 (2),
22.75 (3), 22.58 (3), 21.11 (2), 12.21 (3); EI MS 265 (39), 247 (80), 233 (10), 219 (1), 205 (1), 191 (8),
165 (15), 149 (39), 137 (100), 136 (10), 121 (38), 109 (34), 95 (80), 67 (36), 55 (37), 43 (27). EI MS HR:
calcd for C18H33O (M−SO2Ph)+: 265.25314. Found: 265.25274. Calcd for C18H31 (M−SO2Ph–H2O)+:
247.24258. Found: 247.24549.
3.11. (1S,3aS,4S,7aS)-4-Benzenesulfonyl-1-[(1S)-1,5-dimethyl-hexyl]-7a-methyl-octahydro-indene 13
To a solution of alcohol 10b (25 mg, 0.062 mmol) in CH2Cl2 (0.5 ml) containing Et3N (4 µl, 0.031
mmol) and DMAP (0.8 mg, 0.0062 mmol) TsCl (35 mg, 0.186 mmol) was added. The mixture was set
aside for 15 h and then saturated aqueous NaHCO3 (2 ml) was added. The product was extracted with
CH2Cl2. The organic extract was washed with water and brine, and dried. The solvent was evaporated
to give crude tosylate 10c (33 mg). This product was dissolved in THF (1 ml) and L-Selectride® (1
M in THF, 44.8 mg, 0.236 mmol) at 0 to +5°C. The mixture was set aside at rt for 5 h and then the
reaction was quenched with water (2 ml). The product was extracted with diethyl ether. The organic
extract was washed with water and brine, and dried. The solvent was evaporated and the residue was

A. Przez´dziecka et al. / Tetrahedron: Asymmetry 10 (1999) 1589–1598
1597
chromatographed on SiO2 (1 g, hexane:EtOAc, 49:1) to give compound 13 (23 mg, 88% from 10b):
23
1
[α] =+6.0 (c=0.17); H NMR 7.90–7.81 (m, 2H), 7.70–7.48 (m, 3H), 3.12–2.90 (m, 1H), 2.18–0.98
D
(m, 20H), 0.90 (d, 3H, J=7.0 Hz), 0.86 (d, 3H, J=6.7 Hz), 0.86 (d, 3H, J=6.6 Hz), 0.69 (s, 3H); 13C NMR
138.37 (0), 133.32 (1), 128.93 (1), 128.77 (1), 63.84 (1), 55.12 (1), 48.16 (1), 44.68 (1), 39.44 (1), 38.76
(2) 36.09 (2), 35.56 (2), 27.96 (1), 27.40 (2), 25.39 (2), 23.75 (2), 22.79 (3), 22.54 (3), 21.16 (2), 18.74
(3), 11.88 (3); EI MS 249 (67), 233 (10), 193 (26), 165 (24), 151 (24), 137 (57), 123 (57), 109 (77), 95
(100), 81 (71), 71 (56), 57 (71), 43 (53). EI MS HR: calcd for C18H33 (M−PhSO2)+: 249.25823. Found:
249.25929.
3.12. (2S)-2-[(1S,3aS,4S,7aS)-4-Benzenesulfonyl-7a-methyl-octahydro-inden-1-yl]-propionic acid
ethyl ester 12
To a solution of LDA prepared from diisopropylamine (49 µl, 0.344 mmol), n-BuLi (170 µl, 0.344
mmol, 2.03 M in hexane) and THF (0.5 ml), stirred at −78°C, a solution of ester 9 (57 mg, 0.156 mmol) in
THF (0.5 ml)–HMPA (0.1 ml) was added. The mixture was stirred for 1 h and then methyl iodide (17 µl,
0.188 mmol) in HMPA (50 µl) was added. The whole was stirred at −78°C for 5 h, and then left aside at
rt. After 16 h, water was added and the product was extracted with diethyl ether. The extract was washed
with water and brine, and then dried and evaporated. The residue was chromatographed on SiO2 (3 g,
hexane:EtOAc, 19:1) to give the methyl derivative 12 (44 mg, 75% yield): [α]23=+13.6 (c=0.27); IR
D
(film) 1728, 1144, 1305 cm−1; 1H NMR 7.92–7.80 (m, 2H), 7.70–7.48 (m, 3H), 4.07 (q, 2H, J=7.14 Hz),
3.10–2.91 (m, 1H), 2.50–0.80 (m, 13H), 1,24 (t, 3H, J=7.14 Hz), 1.11 (d, 3H, J=6.8 Hz), 0.71 (s, 3H); 13
C
NMR 176.62 (0), 138.12 (0), 133.41 (1), 128.96 (1), 128.77 (1), 63.68 (1), 60.03 (2), 52.34 (1), 47.56 (1),
44.17 (0), 41.04 (1), 36.61 (2), 27.36 (2), 26.40 (2), 24.88 (2), 20.99 (2), 17.29 (3), 14.12 (3), 12.15 (3);
EI MS 333 (1), 249 (2), 237 (18), 223 (3), 207 (1), 191 (8), 177 (2), 163 (27), 160 (9), 136 (10), 135 (100),
121 (3), 107 (8), 93 (9), 81 (26), 57 (7), 55 (9), 41 (7). EI MS HR: calcd for C19H25O3S (M−OC2H5)+:
333.15244. Found: 333.15203. Calcd for C15H25O2 (M−SO2Ph)+: 237.18546. Found: 237.18729.
3.13. (2S)-2-[(1S,3aS,4S,7aS)-(4-Benzenesulfonyl-7a-methyl-octahydro-inden-1-yl)]-propan-1-ol 11
To a solution of ester 12 (24 mg, 0.063 mmol) in CH2Cl2 (1 ml) DIBAH (20% in toluene, 45 µl, 0.222
mmol) was added at −20°C. The mixture was set aside for 1 h at rt and then reaction was quenched with
EtOAc (1 ml). Water was added and the product was extracted with EtOAc. The organic extract was
washed consecutively with 2% H2SO4, water and brine, and then dried and evaporated. The residue was
chromatographed on SiO2 (1 g, hexane:EtOAc, 4:1) to give alcohol 11 (18.5 mg, 87%): [α]23=+15.3
D
(c=0.31); IR (film) 3475, 1304, 1143 cm−1; 1H NMR 7.91–7.80 (m, 2H), 7.70–7.48 (m, 3H), 3.57 (2H,
part AB of ABM system, part A, δ=3.68 ppm, J=10.6, 3.9 Hz; part B, δ=3.46 ppm, J=10.6, 6.6 Hz), 3.03
(dt, 1H, J=11.4, 3.3 Hz), 2.18–0.76 (m, 14H), 0.96 (d, 3H, J=6.64 Hz), 0.71 (s, 3H); 13C NMR 138.28
(0), 133.39 (1), 128.97 (1), 128.78 (1), 66.83 (1), 63.73 (2), 51.39 (1), 48.07 (1), 44.94 (0), 38.07 (2),
37.42 (1), 27.41 (2), 26.90 (2), 25.25 (2), 21.08 (2), 16.56 (3), 12.34 (3); EI MS 195 (50), 177 (94), 163
(13), 149 (5), 137 (100), 133 (5), 121 (37), 107 (26), 95 (95), 81 (73), 67 (33), 55 (38), 43 (15), 41 (28).
EI MS HR: calcd for C13H23O (M−PhSO2)+: 195.17489. Found: 195.17441.

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A. Przez´dziecka et al. / Tetrahedron: Asymmetry 10 (1999) 1589–1598
Acknowledgements
Support by the State Committee of Scientific Research, Poland, Grant No 3 T09A 007 10 is gratefully
acknowledged.
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