Stereoselective Synthesis of (3S, 4R)-5-Phenylpentane-1, 3, 4-Triol
R Venkateshwarlu, S Purushotham Reddy, P Venkateswara Rao* and S Aravind*
Department of Chemistry, Osmania University, India
Submission: May 03, 2018; Published: May 09, 2018
*Corresponding author: P Venkateswara Rao and S Aravind, Department of Chemistry, Osmania University, India;
How to cite this article: R Venkateshwarlu, S P Reddy, P V Rao, S Aravind. Stereoselective Synthesis of (3S, 4R)-5-Phenylpentane-1, 3, 4-Triol. Organic
& Medicinal Chem IJ. 2018; 6(4): 555691. DOI: 10.19080/OMCIJ.2018.06.555691
We describe an efficient synthesis of (3S, 4R)-5-Phenylpentane-1, 3, 4-triol (1) from commercially available 3-phenylpropanal for the first time. The key reactions involved in this synthesis are proline catalyzed hydroxylation, followed by (Z)-selective Wittig olefination, and Sharpless asymmetric epoxidation (Figure 1).
Keywords: Natural product; Triol; Wittig olefination; Total synthesis; Alzheimers; Parkinsons
Polyhydroxylated compounds are ubiquitous structural motifs found in a multitude of naturally occurring compounds, pharmaceuticals and material interest [1-5]. In addition to this their synthetic analogues are important as lead structures or drug candidates for the discovery of novel drugs [6-9]. These compounds have explicitly exhibited a broad spectrum of biological activities including antibacterial, antitumoral, antimicrobial, antifeedant, herbicidal, plant growth inhibition and the inhibition of cholesterol biosynthesis properties [10-14]. Recently Hirokazu Kawagishi et al. isolated the triol compound named (3S,4R)-5-Phenylpentane-1,3,4-triol (1, Scheme 1) from the EtOH extract of edible mushroom Mycoleptodonoides aitchisonii . It exhibits protective activity against endoplasmic reticulum (ER) stress-dependent cell death. ER stress is caused by abnormalities in cell function such
as changes in calcium channel functioning or accumulation of misfolded protein and this may be responsible for Parkinson’s, Alzheimer’s and prion type of human neuronal diseases, and also other diseases (diabetes, atherosclerosis, and heart & liver disease) [16,17]. Therefore, development of efficient strategies
for the preparation of natural and unnatural products, which exhibits protective activity against endoplasmic reticulum stress-dependent cell death, is of great significance. Due to its interesting structural features and evident pharmacological potential, the synthesis of 1 has attracted much attention for the synthetic and medicinal chemists. In continuation of our research on the synthesis of biologically significant natural products from simple starting materials [18,19]. We herein, report a first total synthesis of 1, starting from 3-phenylpropanal (2) in a six steps with 45% overall yield.
Our approach to the asymmetric synthesis of (3S, 4R)-
5-Phenylpentane-1, 3, 4-triol (1) is shown in scheme 1. We
envisioned that the target molecule can be derived from allyl
alcohol 5 via Sharpless asymmetric epoxidation protocol.
The allylic alcohol 5 from 3-phenylpropanal (2) using proline
catalyzed sequential -aminooxylation and Horner-Wadsworth-
Emmons olefination. The synthetic sequence began with the
preparation of ester fragment 3 from commercially available
3-phenylpropanal (2, scheme 2). Thus, phenylpropanal (2) was
subjected to aminooxylation process by using nitrosobenzene
as an oxygen source and L-proline as a catalyst at -20C,
followed by in situ (Z)-selective Wittig olefination reaction
with the triethyl phosphonoacetate, LiCl and DBU to furnish
crude -aminooxy ester . Subsequent reduction of the
-aminooxy compound with 30 mol % CuSO4.5H2O in methanol
provided the hydroxy unsaturated ester 3 in 69% yield. The
enantiomeric purity of the hydroxyl ester 3 was determined
as 99% by using chiral HPLC analysis. The protection of the
hydroxy group in compound 3 with TBS-Cl, imidazole in THF
gave silyl ether compound 4 in 96% yield . The reduction of
ester functionality in compound 4 was carried out with Dibal-H
in THF at room temperature to afford allylic alcohol 5 in 92%
yield . Next, installation of chiral epoxide on intermediate
5, has been achieved using Sharpless asymmetric epoxidation
protocol with (-)-di-isopropyl tartrate, tert-butyl hydroperaxide
and titanium tetra (isopropaxide) in tert-butanol and water
at -20C for 12h, gave the chiral epoxide 6 in 91% yield .
Opening of the epoxide in a compound 6 with Red-Al provided
diol 7 in 86% yield . Finally, deprotection of the silyl group
in 1, 3-diol 7 with TBAF in THF yielded the title compound, (3S,
4R)-5-Phenylpentane-1, 3, 4-triol (1) in 95% yield.
In conclusion, the first asymmetric synthesis of (3S, 4R)-
5-phenylpentane-1, 3, 4-triol (1) starting from commercially
available 2-phenylpropioal has been achieved in a six steps with
45% overall yield. The key reactions include, a proline-catalyzed
-aminooxylation, followed by (Z)-selective Wittig olefination
and Sharpless asymmetric epoxidation.
To a stirred mixture of powdered molecular sieves (4Å, 4.0g)
and titanium tetraisopropoxide (1.37mL, 1.37mmol, 1M solution
in CH2Cl2, 0.2equiv.) in (20mL) cooled at -20°C was added a
(-)-di-isopropyl tartrate in CH2Cl2 (0.64g, 2.74mmol, 0.4equiv.).
The mixture was stirred at -20°C for 10min, and a solution of
allylic alcohol 5(2.00g, 6.84mmol, 1equiv.) in CH2Cl2(15mL) and
a 5M solution (1,2-dichloroethane) of tert-butylhydroperoxide
(2.46g, 5.47mL, 27.40mmol, 4equiv.) were added, successively.
The resulting mixture was stirred at -20°C for 12h and quenched
with 3mL H2O and 0.8ml 20% NaOH. After the mixture was stirred
at rt for 45min, the organic layer was separated, and filtered the
reaction mixture. The aqueous layer was extracted with CH2Cl2
(2 x 30mL). The organic layer and the extracts were combined,
washed with brine, dried over Na2SO4, and concentrated. The
residual oil was purified by column chromatography over silica
gel using hexanes/ethyl acetate (80:20) to give 6(1.92g, 91%) as
a colorless oil.
To an ice cold solution of silyl ether 7 (0.50 g, 1.61 mmol, 1
equiv.) in THF (20mL) was added TBAF (2.41 mL, 1.0 M solution
in THF, 2.41 mmol, 1.5 equiv.). The solution was stirred at room
temperature for 5 h and diluted with saturated NH4Cl (20 mL)
and ethyl acetate (20mL). The organic layer was separated and
the aqueous layer was extracted with ethyl acetate (2 x 30mL).
The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure to obtain an oily residue,
which was purified by chromatography over silica gel using
hexanes/ethyl acetate (70:30) to afford 1 (300mg, 95% yield);
[α]D20 +63.9 (c 0.12, MeOH); 1H NMR (300 MHz, CDCl3): δ 7.27-
7.32 (m, 2H), 7.19-7.24 (m, 3H), 3.77-3.87 (m, 4H), 2.83 (dd, J
= 14.0, 3.7 Hz, 1H), 2.69 (dd, J = 13.9, 9.0 Hz, 1H), 1.75-1.81 (m,
2H); 13CNMR (75 MHz, CDCl3): δ 138.3, 129.3, 128.5, 126.4, 75.3,
73.4, 60.7, 38.4, 33.0; IR (KBr): νmax = 3351, 2924, 1464, 1224,
1171, 725 cm-1; MS (ESI): m/z 219 (M+Na)+; HRMS (ESI):m/z
calcd for C11H16NaO3 (M+Na)+: 219.0992, found: 219.0995.