First asymmetric total synthesis of (R,E)-1-[4-(3-hydroxyprop-1-enyl) phenoxyl]-3-methylbutane-2,3-diol

Article abstract of DOI:10.1080/00397911003707204

(Chemical Equation Presented) A new anti-inflammatory active phenylpropenoid, (R,E)-1-[4-(3-hydroxyprop-1-enyl) phenoxyl]-3-methylbutane-2,3- diol (1), isolated from the stem wood of Zanthoxylum integrifoliolum, has been synthesized for the first time usi

Full text of DOI:10.1080/00397911003707204

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First Asymmetric Total Synthesis
of (R,E)-1-[4-(3-Hydroxyprop-1-
enyl)phenoxyl]-3-methylbutane-2,3-diol
V. Suresh a , K. Rajesh a , J. J. P. Selvam a & Y. Venkateswarlu a
a Natural Products Laboratory, Organic Division I, Indian Institute of
Chemical Technology , Hyderabad , India
Published online: 03 Mar 2011.
To cite this article: V. Suresh , K. Rajesh , J. J. P. Selvam & Y. Venkateswarlu (2011) First Asymmetric
Total Synthesis of (R,E)-1-[4-(3-Hydroxyprop-1-enyl)phenoxyl]-3-methylbutane-2,3-diol, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:7, 993-998, DOI: 10.1080/00397911003707204
To link to this article: http://dx.doi.org/10.1080/00397911003707204
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Synthetic Communications1, 41: 993–998, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003707204
FIRST ASYMMETRIC TOTAL SYNTHESIS OF
(R,E)-1-[4-(3-HYDROXYPROP-1-ENYL)PHENOXYL]-
3-METHYLBUTANE-2,3-DIOL
V. Suresh, K. Rajesh, J. J. P. Selvam, and Y. Venkateswarlu
Natural Products Laboratory, Organic Division I, Indian Institute of
Chemical Technology, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A new anti-inflammatory active phenylpropenoid, (R,E)-1-[4-(3-hydroxyprop-1-
enyl) phenoxyl]-3-methylbutane-2,3-diol (1), isolated from the stem wood of Zanthoxy-
lum integrifoliolum, has been synthesized for the first time using commercially available
4-hydroxy benzaldehyde (2). The key step involves the Sharpless asymmetric dihydroxyla-
tion of olefin (3).
Keywords Phenylpropenoid; (R,E)-1-[4-(3-hydroxyprop-1-enyl)phenoxyl]-3-methylbutane-
2,3-diol; sharpless asymmetric dihydroxylation
INTRODUCTION
Many phenylpropenoids have been isolated from natural sources, some of which
have antimicrobial,[1] cytotoxic, and radical scavenging activities.[2] Natural and syn-
thetic liginins stimulate macrophase nitroblue tetrazolium (NBT)-reducing activity,
polymorphonuclear cell (PMN) iodination, and splenocyte DNA synthesis and inhibit
poly(ADP-ribose) glycohydrolase, RNA-dependent DNA polymerase (reverse tran-
scriptase), and RNA-dependent RNA polymerase activities. The synthetic liginins
are prepared by polymerization of phenylpropanoid precursors.[3] Some phenylprope-
noids are also esterified to phytosterols present in grain products, such as rice and corn
bran, and thus are common components of the human diet.[4] Recently, a new phenyl-
propenoid, (R,E)-1-[4-(3-hydroxyprop-1-enyl)phenoxyl]-3-methylbutane-2,3-diol (1),
was isolated by Chen et al.[5] from Zanthoxylum integrifoliolum (Merr.) Merr.
Received December 3, 2009.
Address correspondence to Y. Venkateswarlu, Natural Products Laboratory, Organic Division I,
Indian Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: luchem@yahoo.com,
luchem@iict.res.in
993

994
V. SURESH ET AL.
Figure 1.
(Rutaceae). It shows anti-inflammatory activity (IC50 ¼ 32.55 ꢀ 7.54) on
N-formylmethionylleucylphenylalanine (fMLP)–induced production of superoxide
anion by neutrophils. Zanthoxylum integrifoliolum (Merr.) Merr. (Rutaceae) is large
evergreen tree that grows only in the northern Philippines and Lanyu Island in
Taiwan.[6] Its bark is utilized as a folk remedy for snakebite by Ya-Mei aborigines
in Lanyu Island, and it is also a good source for antiplatelet agents such as chelerythr-
ine and avicine pseudocyanide.[7] Chemical constituents of this plant’s roots,[8] bark,[9]
and
fruit[10]
yielded
benzo[c]phenanthridines,
coumarins,
quinolines,
N-isobutylamides, liganans, triterpenoids, indolopyridoquinazolines, flavonoids,
and bishordeninyl terpene alkaloids. The biological potential of these compounds
has stimulated significant interest in the synthesis of (R,E)-1-[4-(3-hydroxyprop-1-
enyl)phenoxyl]-3-methylbutane-2,3-diol 1. To the best of our knowledge, there is no
report on the total synthesis of (R,E)-1-[4-(3-hydroxyprop-1-enyl)phenoxyl]-3-
methylbutane-2,3-diol 1. We report here our results on the first asymmetric total syn-
thesis of (R,E)-1-[4-(3-hydroxyprop-1-enyl)phenoxyl]-3-methylbutane-2,3-diol (1)
using the Sharpless asymmetric dihydroxylation.
RESULTS AND DISCUSSION
We commenced the synthesis of target molecule 1 from the commercially avail-
able 4-hydroxybenzaldehyde 2, an inexpensive starting material. The aromatic
hydroxyl group in compound 2 was prenylated using prenyl bromide and K2CO3
in acetone to afford 3 in 98% yield. Sharpless asymmetric dihydroxylation (AD)[11]
of compound 3 with AD-mix-b at 0 ꢁC furnished diol aldehyde 4 in 90% yield with
95.8% ee as established by chiral high-performance liquid chromatographic (HPLC)
analysis. The absolute stereochemistry of compound 4 was assigned, in a preliminary
fashion, as (R) using the Sharpless mnemonic.[12] The diol aldehyde (4), upon Wittig
Scheme 1. Synthesis of compound 1.

(R,E)-1-[4-(3-HYDROXYPROP-1-ENYL) PHENOXYL]-3-METHYLBUTANE-2,3-DIOL 995
olefination with the stabilized ylide[13] (ethoxycarbonyl methylene) triphenylpho-
sphorane in benzene at room temperature exclusively furnished the E-isomer in
the form of a,b-unsaturated ester 5 in 92% yield, which on selective reduction with
diisobutylaluminiumhydride (DIBAL-H)[14] in CH2Cl2 at ꢂ78 ꢁC gave the desired
compound (R,E)-1-[4-(3-hydroxyprop-1-enyl)phenoxyl]-3-methylbutane-2,3-diol (1)
in 90% yield. The physical and spectroscopic data of compound 1 [mass spectra
1
(MS H and 13C NMR, infrared (IR), optical rotation] were found to be identical
with those reported natural product[5] (Scheme 1).
CONCLUSION
In conclusion, we have achieved a simple, short, and efficient first asymmetric
total synthesis of (R,E)-1-[4-(3-hydroxyprop-1-enyl)phenoxyl]-3-methylbutane-2,3-
diol (1) from the readily available starting material 4-hydroxybenzaldehyde 2 utiliz-
ing Sharpless asymmetric dihydroxylation of olefin (3).
EXPERIMENTAL
All solvents and reagents were purified by standard techniques. Crude products
were purified by column chromatography on silica gel of 60–120 mesh. Fourier
transform (FTIR–spectra were measured with a Thermo Nicolet Nexus 670 spec-
trometer. Optical rotations were recorded on a Horiba highly sensitive polarimeter,
1
in a 10-mm cell. H and 13C NMR spectra were recorded in CDCl3 solution on
Varian Gemini 400, 500, and Brucker Avance 300 instruments. Chemical shifts were
reported in parts per million with respect to internal tetramethylsilane (TMS).
Coupling constants (J) are quoted in hertz. Mass spectra were acquired on a
micromass Quattro micro atmospheric photo ionization (API) (Waters) and
high-resolution Qstarxl hybrid MS=MS system (Applied Biosystems, USA) mass
spectrometers.
Preparation of 4-(3-Methylbut-2-enyloxy)benzaldehyde (3)
Prenyl bromide (0.73 g, 0.56 mL, 4.90 mmol) was added through a syringe to a
stirred solution of 4-hydroxybenzaldehyde 2 (0.5 g, 4.09 mmol) and K2CO3 (2.82 g,
20.45 mmol) in dry acetone (10 mL), and stirring continued at room temperature
for 9 h. After completion of the reaction, acetone was removed under reduced
pressure, diluted with water (20 mL), and extracted into ethyl acetate (2 ꢃ 30 mL).
Combined ethyl acetate extract was washed with brine (30 mL), dried (Na2SO4),
and concentrated under reduced pressure to yield the crude 3, which was purified
on a silica-gel column (60–120 mesh) using EtOAc–hexane (1:9) to give 3 (0.76 g,
98% yield) as a white solid; IR (neat): 2975, 2930, 2736, 1690, 1601, 1251, 1162,
1
833 cmꢂ1; H NMR (300 MHz, CDCl3): d 9.85 (s, 1H), 7.77 (d, 2H, J ¼ 8.68 Hz),
6.95 (d, 2H, J ¼ 8.68 Hz), 5.46 (m, 1H), 4.56 (d, 2H, J ¼ 6.79), 1.80 (s, 3H), 1.75
(s, 3H); 13C NMR (75 Mz, CDCl3): d 189.83, 163.61, 138.22, 131.59, 129.64,
118.88, 114.62, 64.8, 25.5, 18.0; EI-MS: m=z 190 [M]þ.

996
V. SURESH ET AL.
Preparation of 4-{[(2R)-2,3-Dihydroxy-3-methylbutyl]oxy}-
benzaldehyde (4)
AD-mix-b (3.68 g, 2.63 mmol) and MeSO2NH2 (0.25 g 0.26 mmol) were added
to a solution of tert-butylalcohol and water (10:10 mL) and stirred at room tempera-
ture until both phases were clear, then cooled to 0 ꢁC. The olefin (3, 0.5 g, 2.63 mmol)
was added at once to this solution and the heterogeneous slurry was stirred vigor-
ously at 0 ꢁC for about 20 h. After completion of the reaction, the reaction was
quenched at 0 ꢁC by addition of sodium sulfite (1 g), warmed to room temperature,
and stirred for 30 min. The reaction mixture was poured into water (30 mL) and
extracted into EtOAc (3 ꢃ 40 mL). The combined organic layer was washed with
brine (30 mL) and dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure to yield the crude diol, which was purified on a silica gel column
(60–120 mesh) using EtOAc–hexane (7:3) to yield pure diol (4, 530 mg, 90% yield,
95.8% ee) as a colorless liquid; [a]D þ 30.6 (c 0.1, CHCl3). IR (film): 3429 (OH),
2973, 1684, 1598, 1256, 1161 cmꢂ1 1H NMR (300 Mz, CDCl3): d 9.88 (s, 1H),
.
7.82 (d, 2H, J ¼ 8.68), 7.01 (d, 2H, J ¼ 8.68), 4.22 (m, 1H), 4.10 (m, 1H), 3.85 (m,
1H), 2.93 (br s, 1H), 2.42 (br s, 1H), 1.34 (s, 3H), 1.29 (s, 3H); 13C NMR (75 Mz,
CDCl3): d 190.75, 163.44, 131.99, 130.33, 114.85, 75.73, 71.60, 69.47, 26.53, 24.97;
ESI-MS: m=z 247 [M þ Na]þ, chiral pak IC 250 ꢃ 4.6 mm, 5 m, mobile phase: 15%
IPA in hexane, flow rate: 0.7 ml=min, detection: 210 nm, ret. time: 24.161–2.096%
and 25.701–97.904%, 95.8% ee.
Preparation of Ethyl (E)-3-(4-[(2R)-2,3-Dihydroxy-3-methylbutyl]-
oxyphenyl)-2-propenoate (5)
Wittig ylide Ph3PCHCO2Et (2.16 g, 6.22 mmol) was added at room tempera-
ture to a stirred solution of diol aldehyde 4 (400 mg, 1.78 mmol) in dry benzene
(10 mL) under an inert atmosphere. The reaction mixture was stirred at room tem-
perature for 6 h. After completion of the reaction, the solvent was removed under
reduced pressure and the residue was purified by silica-gel column chromatography
using hexane–ethyl acetate (1:1) to afford the unsaturated ester 5 (483 mg, 92% yield)
as a white solid; [a]D þ 16.8 (c 0.2, CHCl3). IR (film): 3380 (OH), 3336 (OH), 1677,
1
1599, 1174 cmꢂ1. H NMR (500 Mz, CDCl3): d 7.56 (s, 1H, J ¼ 15.27), 7.44 (d, 2H,
J ¼ 8.14), 6.88 (d, 2H, J ¼ 9.16), 6.25 (d, 1H, J ¼ 15.27), 4.25–4.07 (m, 3H), 4.01 (m,
1H), 3.77 (m, 1H), 2.65 (dd, 1H, OH, J ¼ 10.18, 3.05), 1.33 (t, 3H, J ¼ 7.12), 1.31 (s,
3H), 1.25 (s, 3H), 13C NMR (75 Mz, CDCl3): d 166.89, 160.20, 143.79, 129.30,
126.94, 115.49, 114.67, 75.63, 71.18, 69.20, 59.94, 25.91, 24.74, 14.01; ESI-MS: m=
z 317 [M þ Na]þ.
(R,E)-1-(4-(3-Hydroxyprop-1-enyl)phenoxy)-3-methylbutane-
2,3-diol (1)
DIBAL-H (1.09 mL, 1.4 M, 1.53 mmol in hexane) was added drop wise to a
stirred solution of ester 5 (100 mg, 0.34 mmol) in dry THF (5 mL) at ꢂ78 ꢁC over
a period of 5 min under a nitrogen atmosphere. After completion of the reaction,
the reaction was quenched with MeOH (0.5 mL), and a saturated aqueous solution

(R,E)-1-[4-(3-HYDROXYPROP-1-ENYL) PHENOXYL]-3-METHYLBUTANE-2,3-DIOL 997
of sodium potassium tartarate (5 mL) was added and extracted into CH2Cl2
(2 ꢃ 20 mL). The combined organic layer was washed with water and brine solution
and dried over anhydrous Na2SO4 concentrated under vacuum. The crude product
was purified on silica-gel column using hexane–ethyl acetate (1:9) to afford
(R,E)-1-(4-(3-hydroxyprop-1-enyl)phenoxy)-3-methylbutane-2,3-diol 1 (77 mg, 90%
yield) as a colorless oil; [a]D þ 15.5 (c 0.1, CHCl3). IR (film): 3381 (OH), 1604,
1
1510, 1461, 1246 cmꢂ1; H NMR (400 Mz, CDCl3): d 7.28 (d, 2H, J ¼ 8.05), 6.85
(d, 2H, J ¼ 8.79), 6.55 (d, 1H, J ¼ 15.38), 6.25 (dt, 1H, J ¼ 15.38, 5.86), 4.29 (d,
2H, J ¼ 5.86), 4.15 (dd, 1H, J ¼ 9.52, 2.93), 4.03 (dd, 1H, J ¼ 9.52, 8.05), 3.80 (m,
1H), 3.15 (br s, 1H, OH), 2.67 (br s, 1H, OH), 1.32 (s, 3H), 1.27 (s, 3H), 13C
NMR (75 Mz, CDCl3): d 157.09, 129.69, 129.19, 126.74, 125.75, 113.74, 74.73,
70.71, 68.27, 62.77, 25.62, 24.09; HREI-MS: m=z 275.1269 [M þ Na]þ.
ACKNOWLEDGMENTS
The authors (V. S., K. R., and J. J. P. S.) are thankful to the University Grants
Commission and the Council of Scientific and Industrial Research, New Delhi,
India, for financial support and to Dr. J. S. Yadav, director, Indian Institute of
Chemical Technology, for his encouragement.
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