A simple strategy for the synthesis of optically pure trans-hydrindane systems

Article abstract of DOI:10.1016/j.tetlet.2006.01.038

A new strategy for the synthesis of optically pure trans-hydrindane systems is reported from an easily available starting material.

Full text of DOI:10.1016/j.tetlet.2006.01.038

Tetrahedron Letters 47 (2006) 2029–2032
A simple strategy for the synthesis of optically pure
trans-hydrindane systems
Ganesh Pandey* and Sanjay B. Raikar
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
Received 9 November 2005; revised 20 December 2005; accepted 11 January 2006
Available online 3 February 2006
Abstract—A new strategy for the synthesis of optically pure trans-hydrindane systems is reported from an easily available starting
material.
Ó 2006 Elsevier Ltd. All rights reserved.
A multitude of bioactive natural products such as ste-
R2
R2
roids, hormones, vitamin D, some of the higher terpenes
and related natural products contain a trans-hydrindane
moiety as a core structural feature.1 In particular, the
trans-hydrindane moiety of 1a,25-dihydroxyvitamin
D3, functionalized at C-12 is shown to modulate
strongly, the affinity of the vitamin D receptors.2a Simi-
larly, C-16 substituted 1a,25-dihydroxyvitamin D3 is
also known2b to alter the ligand–enzyme interactions
causing significant slowing down of the rate of the enzy-
matic side-chain oxidation. Therefore, there has been in-
tense research activity over the years towards developing
a suitable synthetic strategy for the construction of
substituted trans-hydrindane moieties.1b,2b The principal
challenge in the synthesis of this moiety lies in the con-
struction of trans-stereocenters at the ring junction. The
known synthetic routes for the preparation of this moi-
ety may be categorized into three classes as depicted in
Scheme 1.
Reduction
O
O
H
R1
R1
Type I: Reduction of the double bond at the ring junction of
Hajos-Parrish-Wiechert (H-P-W) type ketones.
X-
SiR3
O
R4
IMDA
Polyene
cyclization
H
R3
R5
R1
R2
Type II: Direct one-step construction of the trans-hydrindane
skeleton from acyclic precursors
O
R3
R4
R1
R2
or
Although, stereoselective reduction of the double bond
at the ring junction in Hajos–Parrish–Wiechert type
ketones (type I approach)3 represents one of the most
explored strategies, the dependence of stereoselectivities
on the stereoelectronic features of R1 and R2 limits its
utility. The type II approaches, in which the trans-
hydrindane skeleton is constructed in one-step directly
from acyclic precursors either by polyene cyclization
or an intramolecular Diels–Alder reaction (IMDA), suf-
H
Type III: Stereoselective annulation of either six-membered
rings over five-membered rings or vice-versa.
Scheme 1. Synthetic routes to the trans-hydrindane skeleton.
fer from low stereocontrol in general.3 Furthermore, this
strategy may not be suitable for the synthesis of func-
tional derivatives of the hydrindane moiety. The best
stereochemical control has been achieved through type
III approaches involving stereoselective annulation of
either cyclopentane over cyclohexane or vice versa.
However, these approaches suffer from the difficulty of
Keywords: Stereoselective synthesis; trans-Hydrindane; Terpenes; Clai-
sen rearrangement; Vicinal stereocenters; Fused rings system.
*
Corresponding author. Tel.: +91 20 2590 2324; fax: +91 20 2589
3513; e-mail: gp.pandey@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.038

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G. Pandey, S. B. Raikar / Tetrahedron Letters 47 (2006) 2029–2032
procuring suitably substituted six- or five-membered
ring precursors.
ment furnished diester 2 (93% yield), which possessed
vicinal quaternary and tertiary stereocenters in the
desired trans-fashion (Scheme 3).11 The stage was now
set for exploring the utility of 2 for the synthesis of
varied structures of trans-hydrindane systems.
Therefore, considering the importance of the trans-
hydrindane moiety and the difficulties encountered in
its construction, we envisaged a common precursor 2
from which a range of structurally modified trans-
hydrindane derivatives could be synthesized. The syn-
thesis of 2 was envisioned from compound 4 (Scheme
2), easily obtainable from a cheap aromatic starting
material using Schultz’s asymmetric Birch reduction–
alkylation protocol.4 In this letter, we describe the suc-
cess of our endeavors for developing a simple protocol
for the synthesis of trans-hydrindane systems.
In order to synthesize trans-hydrindane derivative 15,
compound 2 was first subjected to one carbon homolo-
gation, employing the well-known Arndt–Eistert reac-
tion, to give 14 in 78% yield. Dieckmann cyclization of
14 using NaHMDS in THF yielded the corresponding
b-ketoester in 94% yield. Finally, demethoxycarbonyla-
tion of the b-ketoester was carried out by heating with
DABCO in o-xylene12 to afford the trans-hydrindane
25
system 15 (½aꢀD +7.38, c 0.8, CH2Cl2) in 82% yield.13
Our synthetic strategy began with the synthesis of a
common precursor 2 from ketone 4, readily available
by the asymmetric Birch reduction–alkylation protocol
(88% yield) developed by Schultz et al.4 In this context,
4 was first converted to the corresponding dioxolane
derivative 5, which upon LAH reduction5 produced
the corresponding aldehyde 6 in 89% yield.6 The chiral
auxiliary was also recovered in 85% yield. Compound
6 was subsequently transformed to ester 7 by NaClO2
oxidation followed by esterification using diazomethane.
Allylic oxidation of 7 using PDC and tert-butylhydro-
peroxide7 followed by reduction under Luche’s condi-
tions8 gave the corresponding allylic alcohol 8 in 90%
yield as a 1:1 diastereomeric mixture, as established by
With the successful synthesis of 15, we moved on to pre-
pare compounds 13 and 17 using 2 as a common precur-
sor. For the synthesis of 13, substrate 2 was converted to
the corresponding deoxygenated compound 11 via
reduction of the corresponding dithiolane derivative 10
using nBu3SnH. Our initial experiment for the reduction
of 10 by refluxing with nBu3SnH and a catalytic amount
of AIBN in benzene failed to yield any product. How-
n
ever, refluxing a neat mixture of 10 and Bu3SnH with
the addition of several small portions of AIBN over a
period of 24 h furnished the desired compound 11 in
25
96% yield.14 Conversion of 11 to 13 (½aꢀD +5.625,
c 0.16, CH2Cl2) was achieved in a similar manner as
described for 15 (Scheme 4) earlier.15
1
GC as well as H NMR spectral studies. In order to
transform this mixture of diastereomers into the pure
trans-diastereomer, we first converted it into lactone 9,
which on methanolysis afforded the corresponding cis-
isomer.9 Mitsunobu inversion of this cis-isomer easily
produced the desired trans-isomer 3 in 92% yield.10 Sub-
jecting 3 to the Johnson’s orthoester Claisen rearrange-
During the proposed conversion of compound 2 to 17
via acyloin condensation of 11, it was anticipated that
it would produce the trans-hydrindane system with an
a-hydroxy ketone in the five-membered ring. However,
when 11 was subjected to the acyloin condensation by
R1
O
O
O
O
O
O
O
COOMe
COOEt
R2
N
COOMe
HO
H
1
2
3
4
OMe
Scheme 2. Retrosynthetic strategy.
O
O
O
O
O
O
O
COOMe
CHO
c
a
b
d
N
N
O
O
4
5
6
7
OMe
O
OMe
O
O
COOMe
O
COOMe
O
O
g
e
f
COOMe
COOEt
O
O
O
O
8
3
9
H
OH
OH
2
H
Scheme 3. Synthesis of common intermediate 2. Reagents and conditions: (a) (CH2OH)2, p-TsOH, toluene, reflux, 98%; (b) LAH, THF, ꢁ20 to 0 °C,
t
89%; (c) (i) NaClO2, H2O2, CH3CN/H2O (1:1.7), 0 °C to rt; (ii) CH2N2, Et2O, 0 °C to rt, 95%; (d) (i) PDC, BuO2H, DCM, 10 °C to rt, 68%; (ii)
NaBH4, CeCl3Æ7H2O, MeOH, 0 °C to rt, 90%; (e) (i) LiOH, THF/H2O (1.3:1), rt, 92%; (ii) BF3ÆOEt2, DCM, 0 °C, 82%; (f) (i) NaOMe, MeOH, reflux,
96%; (ii) DIAD, PPh3, BzOH, THF, 0 °C to rt; (iii) 1N NaOH, MeOH, rt, 92%; (g) CH3C(OEt)3, propionic acid, 137 °C, 93%.

G. Pandey, S. B. Raikar / Tetrahedron Letters 47 (2006) 2029–2032
2031
O
O
O
S
S
H
O
O
H
COOMe
COOEt
11
d
c
a
COOMe
COOEt
b
COOMe
COOMe
2
H
H
15
10
14
a, b
c
O
O
O
O
COOMe
d
e
f
11
OH
16
O
COOMe
H
17
13
H
H
H
12
Scheme 4. Synthesis of 13, 15, and 17. Reagents and conditions: (a) (i) 10% HCl, THF, rt, 93%; (ii) ethanedithiol, BF3ÆOEt2, DCM, 0 °C to rt, 97%;
(b) nBu3SnH, AIBN, 130 °C, 96%; (c) (i) 1 equiv NaOH, MeOH, reflux, 87%; (ii) SOCl2, pyridine, PhH, rt; (iii) CH2N2, Et2O, 0 °C to rt; (iv) Ag2O,
MeOH, reflux, 78%; (d) (i) NaHMDS, THF, 0 °C to rt, 94%; (ii) DABCO, o-xylene, 150 °C, 82%; (e) Na, liq. NH3, ꢁ78 °C, 63%; (f) (CH2OH)2,
p-TsOH, toluene, 90 °C, 94%.
obtained selectively by reverse addition of a slurry of LAH
in THF to a stirred solution of 5 at low temperature
treatment with sodium in liquid ammonia at ꢁ78 °C,
compound 16 was obtained as the major product and
(ꢁ20 °C).
the expected a-hydroxy ketone was not produced in iso-
25
6. Compound 6: ½aꢀD ꢁ30.42 (c 0.76, CHCl3); IR (film) mmax
lable amounts.16 Therefore, compound 16 was subjected
2957, 1724, 1454, 1361, 1245, 1099, 1026, 756 cmꢁ1
;
1H
to dioxolane protection under controlled conditions
NMR (CDCl3, 200 MHz) 1.16 (s, 3H), 1.79 (t,
d
(ethylene glycol, p-TsOH, toluene, 90 °C, 6 h) to afford
J = 6.3 Hz, 2H), 2.14–2.33 (m, 2H), 3.84–4.12 (m, 4H),
5.33 (dt, J = 10.1, 2.0 Hz, 1H), 5.88 (dt, J = 10.2, 3.5 Hz,
1H), 9.68 (s, 1H); 13C NMR (CDCl3, 50 MHz) d 16.4,
24.3, 28.4, 55.5, 64.7, 64.9, 109.4, 127.3, 128.9, 201.3; Anal.
Calcd for C10H14O3 (182.22): C, 65.91; H, 7.71. Found: C,
65.83; H, 8.00.
25
17 (½aꢀD +6.27 (c 0.35, CH2Cl2)) as the sole product
(Scheme 4).17
In summary, we have successfully developed a new
approach for the stereoselective construction of trans-
hydrindane systems, present in a large number of bio-
active natural products and analogues starting from the
readily accessible ketone 4. The functionalities present
at suitable positions provide the means for their conver-
sion into more complex molecular entities. Further stud-
ies are in progress to utilize this strategy in the synthesis
of some biomedically important compounds possessing
vicinal quaternary and tertiary stereocenters in trans-
fashion in cyclohexane ring systems.
7. Chidambaram, N.; Chandrasekaran, S. J. Org. Chem.
1987, 52, 5048–5051.
8. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
9. Stork, G.; Franklin, P. J. Aust. J. Chem. 1992, 45, 275–
284.
25
10. Compound 3: ½aꢀD ꢁ42.73 (c 0.68, CH2Cl2); IR (film) mmax
1
3447, 2985, 1733, 1438, 1255, 1117, 1038 cmꢁ1; H NMR
(CDCl3, 200 MHz) d 1.33 (s, 3H), 1.91 (dd, J = 13.7,
4.0 Hz, 1H), 2.46 (dd, J = 13.7, 5.2 Hz, 1H), 3.70 (s, 3H),
3.98–4.07 (m, 4H), 4.29–4.36 (m, 1H), 5.61 (dd, J = 10.0,
0.9 Hz, 1H), 5.90 (dd, J = 9.8, 3.1 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) d 17.9, 38.6, 52.0, 55.7, 63.7 (2C), 68.9,
111.7, 131.5, 133.4, 165.8; GC–MS (m/z) 228 (M+), 180,
166, 152, 137, 112, 107, 93, 74 (100), 60, 41; Anal. Calcd
for C11H16O5 (228.25): C, 57.88; H, 7.07. Found: C, 57.72;
H, 6.95.
Acknowledgements
S.B.R. thanks CSIR, New Delhi, for the award of
Research Fellowship. We sincerely thank Dr. H. R.
Sonawane for fruitful discussions.
25
11. Compound 2: ½aꢀD +21.70 (c 0.84, CH2Cl2); IR (film) mmax
2996, 1736, 1730, 1633, 1440, 1371, 1250, 1053, 712 cmꢁ1
;
1H NMR (CDCl3, 200 MHz) d 1.15 (t, J = 7.1 Hz, 3H),
1.54 (s, 3H), 2.12–2.56 (m, 5H), 3.72 (s, 3H), 3.89–4.08 (m,
4H), 4.22 (q, J = 7.0 Hz, 2H), 5.43–5.98 (m, 2H); 13C
NMR (CDCl3, 50 MHz) d 9.1, 22.0, 28.2, 34.4, 36.5, 52.3,
53.0, 63.7, 65.1, 65.4, 112.0, 121.4, 125.6, 173.9 (2C); GC–
MS (m/z) 253 (M+ꢁOEt), 237, 227, 210, 195, 181, 169,
152, 151, 125, 107, 86, 79, 57 (100), 43; Anal. Calcd for
C15H22O6 (298.34): C, 60.39; H, 7.43. Found: C, 60.31; H,
7.23.
References and notes
1. (a) Zeelen, F. J. Nat. Prod. Rep. 1994, 11, 607–612; (b)
Zhu, G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877–
1952; (c) Corey, E. J.; Cheng, X.-M. The Logic of
Chemical Synthesis; John Wiley and Sons: New York,
1989; (d) Nicolaou, K. C.; Sorensen, E. J. Classics in Total
Synthesis; VCH: Weinheim, 1996.
12. Huang, B.-S.; Parish, E. J.; Miles, D. H. J. Org. Chem.
1974, 39, 2647–2648.
´
´
2. (a) Gonzalez-Avion, X. C.; Mourino, A. Org. Lett. 2003,
˜
25
13. Compound 15: ½aꢀD +7.38 (c 0.8, CH2Cl2); IR (film) mmax
5, 2291–2293; (b) Posner, G. H.; Kahraman, M. Eur. J.
Org. Chem. 2003, 3889–3895.
3. Jankowski, P.; Marczak, S.; Wicha, J. Tetrahedron 1998,
54, 12071–12150.
4. Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras,
A. G.; Welch, M. J. Am. Chem. Soc. 1988, 110, 7828–7841.
5. Addition of 5 to a slurry of LAH in THF led to the
formation of the corresponding amine. Aldehyde 6 was
2964, 1736, 1461, 1404, 1178, 1091, 1043, 910, 732 cmꢁ1
;
1H NMR (CDCl3, 200 MHz) d 1.06 (s, 3H), 1.55 (t,
J = 6.3 Hz, 2H), 1.85–2.11 (m, 3H), 2.17–2.37 (m, 1H),
2.52–2.71 (m, 1H), 4.11 (s, 4H) 5.54–5.82 (m, 2H); 13C
NMR (CDCl3, 50 MHz) d 18.2, 21.7, 24.6, 33.6, 38.4, 40.7,
65.8 (2C), 114.3, 125.7, 129.1, 221.7; GC–MS (m/z) 208
(M+), 180, 165, 138, 126, 113, 94, 79, 67, 41; Anal. Calcd

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G. Pandey, S. B. Raikar / Tetrahedron Letters 47 (2006) 2029–2032
for C12H16O3 (208.26): C, 69.21; H, 7.74. Found: C, 69.07;
H, 7.91.
14. Compound 11: ½aꢀD +12.4 (c 1.49, CH2Cl2). IR (neat film)
mmax 3022, 2983, 1730, 1654, 1448, 1373, 1247, 1045 cmꢁ1
C10H14O (150.22): C, 79.96; H, 9.39. Found: C, 79.83; H,
9.62.
25
25
16. Compound 16: ½aꢀD +5.24 (c 0.76, CH2Cl2); IR (film) mmax
3020, 1703, 1525, 1398, 1215, 757 cmꢁ1; 1H NMR (CDCl3,
200 MHz) d 1.41 (s, 3H), 1.49–1.72 (m, 2H), 1.84–2.15 (m,
2H), 2.81–2.97 (m, 1H), 5.52–5.81 (m, 2H), 6.45 (d,
J = 6.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d 21.7,
22.1, 31.4, 44.2, 45.3, 126.6, 128.4, 130.2, 149.6, 209.3;
GC–MS (m/z) 164 (M+), 149, 136, 121, 107, 91, 77, 55, 40;
Anal. Calcd for C10H12O2 (164.20): C, 73.15; H, 7.37.
Found: C, 72.91; H, 7.55.
;
1H NMR (CDCl3, 300 MHz): d = 1.10 (s, 3H), 1.26 (t,
J = 7.0 Hz, 3H) 1.55–1.80 (m, 2H), 1.85–2.20 (m, 4H),
2.25–2.50 (m, 1H), 3.70 (s, 3H), 4.13 (q, J = 7.0 Hz, 2H),
5.50 (dt, J = 10.2, 2.4 Hz, 1H) 5.67 (dd, J = 10.2, 2.4 Hz,
1H); 13C (CDCl3, 75 MHz) 13.7, 16.3, 21.6, 31.0, 35.7,
36.8, 43.5, 51.5, 60.0, 125.7, 128.0, 172.0, 177.4; GC–MS
(m/z) 240 (M+), 208, 194, 180, 166, 151, 135, 121, 107, 93,
74, 61, 41; Anal. Calcd for C13H20O4 (240.30): C 64.98, H
8.39. Found C 65.23, H 8.24.
25
17. Compound 17: ½aꢀD +6.27 (c 0.35, CH2Cl2); IR (film) mmax
2976, 1732, 1455, 1113, 1077 cmꢁ1 1H NMR (CDCl3,
;
25
15. Compound 13: ½aꢀD +5.63 (c 0.16, CH2Cl2); IR (film) mmax
200 MHz) d 1.07 (s, 3H), 1.33–1.62 (m, 2H), 1.99–2.40 (m,
4H), 2.61–2.80 (m, 1H), 4.02 (s, 4H), 5.48–5.91 (m, 2H);
13C NMR (CDCl3, 50 MHz) d 21.4, 24.0, 29.1, 31.8, 34.5,
37.3, 76.2 (2C), 116.3, 127.5, 128.4, 218.3; GC–MS (m/z)
208 (M+), 180, 178, 165, 151, 126, 113, 105, 91, 69, 65, 41;
Anal. Calcd for C12H16O3 (208.26): C, 69.21; H, 7.74.
Found: C, 68.98; H, 7.62.
3020, 2927, 1735, 1217 cmꢁ1; 1H NMR (CDCl3, 200 MHz)
d 1.05 (s, 3H,), 1.32–1.41 (m, 2H), 1.60–1.80 (m, 2H),
1.90–2.00 (m, 2H), 2.15–2.40 (m, 3H), 5.52–5.81 (m, 2H);
13C NMR (CDCl3, 125 MHz) d 21.6, 21.8, 26.2, 27.0,
35.9, 43.6, 47.2, 127.5, 129.0, 223.4; GC–MS (m/z) 151
(M++1), 137, 110, 109, 95, 79, 57, 41; Anal. Calcd for