Asymmetric synthesis of (R)-(-)-rhododendrol, the aglycone of the hepatoprotective agent rhododendrin

Article abstract of DOI:10.1080/00397910701265614

Starting from 2,3-O-isopropylidene-D-glyceraldehyde (3) as chiral material, (R)-(-)-rhododendrol 2, the aglycone of the naturally occurring rhododendrin 1 was synthesized. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701265614

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Asymmetric Synthesis of
(R)‐(-)‐Rhododendrol, the Aglycone of the
Hepatoprotective Agent Rhododendrin
Gowravaram Sabitha a , B. Thirupathaiah a & J. S. Yadav a
a Organic Division I, Indian Institute of Chemical Technology, Hyderabad,
India
Published online: 22 May 2007.
To cite this article: Gowravaram Sabitha , B. Thirupathaiah & J. S. Yadav (2007) Asymmetric Synthesis of
(R)‐(-)‐Rhododendrol, the Aglycone of the Hepatoprotective Agent Rhododendrin , Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:10, 1683-1688, DOI:
10.1080/00397910701265614
To link to this article: http://dx.doi.org/10.1080/00397910701265614
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Synthetic Communicationsw, 37: 1683–1688, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701265614
Asymmetric Synthesis of (R)-(2)-
Rhododendrol, the Aglycone of the
Hepatoprotective Agent Rhododendrin
Gowravaram Sabitha, B. Thirupathaiah, and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology,
Hyderabad, India
Abstract: Starting from 2,3-O-isopropylidene-D-glyceraldehyde (3) as chiral material,
(R)-(2)-rhododendrol 2, the aglycone of the naturally occurring rhododendrin 1 was
synthesized.
Keywords: aglycone, melanin inhibitor, natural product, rhododendrin, rhododendrol
INTRODUCTION
The glycoside rhododendron, along with its aglycone rhododendrol, was isolated
for the first time from leaves of Rhododendron chrysanthum Linn. in 1901.[1]
Later Khan et al.[2] isolated rhododendrin as the major component of the
aqueous extract of the leaves of Taxus baccata L., which possessed good tranqui-
lizing activity.[3] This glycoside was alsoisolated from the bark of the white birch,
Betula alba L.,[4] and from Rhododendron fauriae var. rufescens.[5] More
recently, rhododendrin was found in Bergenia,[6] Abies webbiana Lindl.,[7]
Rhodiola,[8] Alnus glutinosa Gaertn,[9] and Cotyledon wallichii.[10] Recently,
rhododendrol and its glycoside have been used as a melanin inhibitor and in
skin-lightening cosmetics.[11] Rhododendrin exhibited hepatoprotective
activity against two hepatotoxins in rats. The aglycone (–)-rhododendrol is
Received August 21, 2007
IICT Communication No. 060333.
Address correspondence to Gowravaram Sabitha, Organic Division I, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: gowravaramsr@
yahoo.com
1683

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G. Sabitha, B. Thirupathaiah, and J. S. Yadav
found to co-occur in many species. It has been unequivocally established that
the carbohydrate moiety is attached via the aliphatic hydroxyl group.[12]
From X-ray diffraction studies, the absolute configuration at the chiral
center in the aglycone portion has been found to be R.[13] Syntheses of (R)-
(–)-rhododendrol by enantioselective addition of diallyl zinc to an aldehyde
using chiral tricarbonyl chromium (0) catalyst[14a] and resolution of racemic
rhododendrol by lipase-catalyzed enatioselective acetylation[14b] were
reported. In continuation of our studies on the synthesis of biologically
active molecules,[15] we herein report a simple and practical synthesis of
(R)-(–)-rhododendrol from a chiral pool material.
RESULTS AND DISCUSSION
The chiral center in the molecule can be elaborated from (R)-isopropylidene
glyceraldehyde (3), which can easily be synthesized from oxidative cleavage
of readily available 1,2:5,6-di-O-isopropylidene-D-mannitol.[16] The (R)-
acetonide 3 thus synthesized from D-mannitol on a large scale, was subjected
to the Wittig reaction[17] with 4-benzyloxybenzylphosphonium bromide to give
a mixture of Z and E olefin (6 4) 4 in an overall yield of 80%. Hydrogenation
of compound 4 (mixture of Z and E olefin) over 10% Pd/C gave a saturated
compound 5 in 78% yield in which simultaneously debenzylation also
occured. Thus, the protection of phenolic -OH was carried out using benzyl
bromide to afford benzyl ether 6. Hydrolysis of the acetonide afforded diol 7
in 92% yield. Selective tosylation of the primary hydroxyl group of 7 with
TsCl in dry pyridine produced tosylate 8 in 80% yield, and further reduction
with lithium aluminium hydride (LAH) in THF afforded mono hydroxy
compound 9. Finally, the synthesis of target molecule 2 was achieved in 85%
yield by debenzylation using Pd/C. The physical (mp), optical rotation [aD–
17.4 (c 0.5, MeOH) lit.[13] aD–17 (c 0.5, MeOH)], and spectral data (1H NMR,
13C NMR, and mass) are identical to those of the natural product (Scheme 1).
In conclusion, we have developed a synthetic route for the synthesis of
(R)-(2)-rhododendrol from a chiral source.
EXPERIMENTAL
All solvents were distilled before use. Dry solvents were prepared according to
the standard procedures. All reactions were carried out under an N2

(R)-(2)-Rhododendrol
1685
Scheme 1. Reagents and conditions: a) [BnOC6H4CH2Ph3P]þBr2 (1.0 eq), n-BuLi
(1.0 eq), THF, 08C, 2 h, 80%; b) H2, 10% Pd-C, MeOH, rt, on, 78%; c) PhCH2Br,
acetone, K2CO3, TBAI, rt, 6 h, 88%; d) PTSA, MeOH, 3 h, rt, 92%; e) TsCl
(1.1 eq), dry DCM, DMAP, 08C, 4 h, 80%; f) LAH, THF, 08C to rt, 6 h, 78%; g) H2,
10% Pd-C, MeOH, rt, on, 85%.
atmosphere and monitored by thin-layer chromatography (TLC) on silica gel
(60–120 mesh, Merck). NMR spectra were recorded on Bruker (300 MHz 1H;
1
75 MHz 13C) and Varian (200 MHz H; 50 MHz 13C) NMR spectrometers
using CDCl3 as solvent. ESI-mass spectra were recorded with LC-MSD-
Trap-SL (Agilent Technologies). IR spectra were recorded with FTIR
(Thermo Nicolet Nexus 670 spectrometer). Optical rotations were measured
with Jasco DIP-370 polarimeter at 208C.
(4S)-4-f(E)-2-[4-(Benzyloxy)phenyl]-1-ethenylg-2,2-dimethyl-1,3-
dioxolane (4)
To a solution of Wittig salt, 4-benzyloxybenzylphosphonium bromide (9.17 g,
1.2 eq, 19.99 mmol) in dry THF (20 ml) under N2 at 08C, n-butyl lithium
(12.5 ml, 1.6 M) was added dropwise at 08C. Immediately the solution
became red. After 30 min, the solution of aldehyde 3 (3 g, 16.66 mmol) in
dry THF was added at 08C and allowed to stir for 3–4 h. Then, the reaction
mixture was filtered and extracted with ethyl acetate, dried over Na2SO4, con-
centrated on vacuum, and purified by silica-gel column chromatography to get a
mixture of Z and E olefin 4 (6:4) (4.6 g, 80%). Data for Z-olefin: IR (KBr): 3025,
2986, 1607, 1511, 1379, 1245, 1062, 844 cm21. 1H NMR (200 MHz, CDCl3): d
1.39 (s, 3H), 1.48 (s, 3H) 3.64 (t, J ¼ 7.8 Hz, 1H), 4.12 (dd, J ¼ 6.2, 7.8 Hz,

1686
G. Sabitha, B. Thirupathaiah, and J. S. Yadav
1H), 4.81–4.93 (m, 1H), 5.10 (s, 2H), 5.60 (dd, J ¼ 9.3, 11.7 Hz, 1H), 6.62
(d, J ¼ 11.7 Hz, 1H), 6.95 (d, J ¼ 8.5 Hz, 2H), 7.20 (d, J ¼ 8.5 Hz, 2H),
7.26–7.48 (m, 5H). FAB mass: 310 (Mþ).
4-f2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]ethylgphenol (5)
Compound 4 (5 g, 16.12 mmol) was dissolved in MeOH (40 mL), then cat.
10% Pd/C was added and hydrogenated overnight. Then the reaction
mixture was filtered, and MeOH was removed in vacuo. The residue was
purified by column chromatography using silica gel to afford the saturated
compound 5 (2.8 g, 78%). [a]2D5: þ4.4 (c ¼ 0.015, MeOH). IR (KBr): 3391,
1
3012, 2986, 1515, 1375, 1217, 1064 cm21. H NMR (200 MHz, CDCl3):
d 1.34 (s, 3H) 1.39 (s, 3H), 1.69–2.02 (m, 2H), 2.47–2.86 (m, 2H), 3.42–
3.61 (m, 1H), 3.80–4.05 (m, 2H), 6.65 (d, J ¼ 8.4 Hz, 2H), 7.00
(d, J ¼ 8.4 Hz, 2H), 8.45 (s, -OH). 13C NMR (75 MHz, CDCl3): 27.8, 28,
30, 34, 75, 79, 108, 115, 129, 133, 155. LCMS: 221 (M-1). Anal. calcd. for
C13H18O3 (222.28): C, 70.25; H, 8.16. Found: C, 68.58; H, 7.70.
(4S)-4-[4-(Benzyloxy)phenethyl]-2,2-dimethyl-1,3-dioxolane (6)
To a stirred solution of compound 5 (10 g, 81.96 mmol) in dry acetone (80 ml),
K2CO3 (4 eq, 45.2 g) was added at room temperature under N2. After 30 min,
benzyl bromide (1 eq, 9.74 ml) was added slowly, followed by the addition
of a catalytic amount of TBAI, and the reaction mixture was allowed to stir
for 6 h at room temperature. Acetone was removed under vacuum, and the
residue was extracted with ethyl acetate, dried over Na2SO4, and concentrated.
The crude product was purified by silica-gel column chromatography to afford
compound 6 (15.2 g, 88%). [a]2D5: þ7.3 (c ¼ 0.015, MeOH). IR (KBr): 3031,
1
2985, 1610, 1510, 1239, 1065, 847 cm21. H NMR (300 MHz, CDCl3): d
1.32 (s, 3H), 1.38 (s, 3H), 1.67–2.01 (m, 2H), 2.51–2.82 (m, 2H), 3.83–4.13
(m, 3H), 5.01 (s, 2H), 6.84 (d, J ¼ 8.3 Hz, 2H), 7.06 (d, J ¼ 8.3 Hz, 2H),
7.24–7.39 (m, 5H). 13C NMR (75 MHz, CDCl3): 29, 36, 69,70, 75, 106, 114,
128–132 (8C), 156. LCMS: 313 (M þ 1). Anal. calcd. for C20H24O3
(312.40): C, 76.89; H, 7.74. Found: C, 74.17; H, 7.31.
(2S)-4-[4-(Benzyloxy)phenyl]butane-1,2-diol (7)
To a solution of compound 6 (4 g, 12.82 mmol) in MeOH, a catalytic amount
of PTSA was added and allowed to stir for 3 h at room temperature. MeOH
was removed under vaccum, then the residue was extracted with ethyl
acetate and dried over Na2SO4. The crude product was purified by column
chromatography to get compound 7 (3.2 g, 92%). [a]2D5: 216.0 (c ¼ 0.015,
MeOH). IR (KBr): 3371, 3037, 2925, 1611, 1511, 1102, 1015, 813, 736,

(R)-(2)-Rhododendrol
1687
1
695 cm21. H NMR (200 MHz, CDCl3 þDMSO): d 1.56–1.67 (m, 2H),
2.49–2.79 (m, 2H), 3.25–3.59 (m, 3H), 3.90–3.97 (d, J ¼ 5.4 Hz, 2H),
5.02 (s, 2H), 6.82 (d, J ¼ 8.5 Hz, 2H), 7.09 (d, J ¼ 8.5 Hz, 2H), 7.26–7.42
(m, 5H). 13C NMR (50 MHz, CDCl3): 29, 34, 65, 68, 72, 113, 128–133
(8C), 155. LCMS: 295 (M þ Na). Anal. calcd. for C17H20O3 (272.34): C,
74.97; H, 7.40. Found: C, 73.52; H, 6.71.
(2S)-4-[4-(Benzyloxy)phenyl]-2-hydroxybutyl 4-methyl-1-benzene
Sulfonate (8)
p-Toluene sulphonyl choride (1 eq) and a catalytic amount of DMAP were
added to a stirred solution of compound 7 (2 g, 7.35 mmol) in dry DCM at
08C and left stirring for 4 h. Then the reaction mixture was extracted with
DCM, concentrated under vacuum, dried over Na2SO4, and purified by
column chromatography to give compound 8 (2.3 g, 80%). [a]2D5: þ6.6
(c ¼ 0.0075, MeOH). IR (KBr): 3568, 3034, 2924, 1608, 1512, 1351, 1174,
1
1090, 949 cm21. H NMR (200 MHz, CDCl3): d 1.58–1.76 (m, 2H), 2.45
(s, 3H), 2.54–2.74 (m, 2H), 3.72–3.81 (m, 1H), 3.86 (t, J ¼ 9.8 Hz, 1H),
3.98 (dd, J ¼ 3.0, 9.8 Hz, 1H), 5.02 (s, 2H), 6.82 (d, J ¼ 8.3 Hz, 2H), 7.02
(d, J ¼ 8.3 Hz, 2H), 7.26–7.40 (m, 7H), 7.76 (d, J ¼ 8.3 Hz, 2H). LCMS:
449 (M þ Na). Anal. calcd. for C24H26O5S (426.52): C, 67.58; H, 6.14.
Found: C, 67.45; H, 6.63.
(2R)-4-[4-(Benzyloxy)phenyl]butan-2-ol (9)
To a suspension of lithium aluminium hydride (0.3 g, 2 eq) in dry THF,
compound 8 (2 g, 4.69 mmol) was added, and the reaction mixture was
allowed to stir at 08C, then brought to room temperature, and stirred for 6 h.
The reaction mixture was filtered and extracted with ethyl acetate, dried
over Na2SO4, and concentrated, and the residue was purified by column
chromatography to furnish compound 9 (0.84 g, 78%). IR (KBr): 3310,
3035, 1512, 1245, 1175, 1012, 738, 695 cm21 1H NMR (200 MHz,
.
CDCl3): d 1.24 (d, J ¼ 6.0 Hz, 3H), 1.70–1.78 (m, 2H), 2.57–2.76
(m, 2H), 3.75–3.86 (m, 1H), 5.05 (s, 2H), 6.86 (d, J ¼ 8.0 Hz, 2H), 7.09
(d, J ¼ 8.3 Hz, 2H), 7.30–7.44 (m, 5H); LCMS: 279 (M þ Na).
4-(3-Hydroxy-butyl)-phenol [(R)-(2)-rhododendrol] (2)
To a solution of compound 9 (1.5 g, 5.8 mmol) in MeOH, cat. 10% Pd/C was
added and hydrogenated overnight. Then the reaction mixture was filtered,
and filtrate was concentrated in vacuo. The residue was purified by silica-
gel column chromatography to afford the target molecule 2 as a colorless
solid (0.826 g, 85%), mp 808C, lit.[13] 79–808C. [aD–17.4 (c 0.5, MeOH)

1688
G. Sabitha, B. Thirupathaiah, and J. S. Yadav
lit.[13] aD–17 (c 0.5, MeOH)]. IR (KBr): 3367, 3067, 2931, 1614, 1515, 1240,
1071, 819 cm21
.
1H NMR (200 MHz, CDCl3 þ DMSO): d 1.16 (d, J ¼
5.8 Hz, 3H), 1.58–1.75 (m, 2H), 2.44–2.71 (m, 2H), 3.46 (bs, 1H), 3.62–
3.76 (m, 1H), 6.67 (d, J ¼ 8.0 Hz, 2H), 6.95 (d, J ¼ 8.0 Hz, 2H), 8.46
(s, 1H). 13C NMR: (50 MHz, CDCl3 þ DMSO): 30, 39, 40.5, 65.9, 114,
128, 133, 154. EI-MASS: 166 (Mþ), 148, 133, 107 (100%).
ACKNOWLEDGMENT
B. T. thanks Council for Scientific and Industrial Research (CSIR), New
Delhi, for the award of a fellowship.
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