Enantioselective total synthesis of both the stereoisomers of dihydrokawain-5-ol

Article abstract of DOI:10.1016/j.tetasy.2007.07.032

The enantioselective synthesis of both the stereoisomers of dihydrokawain-5-ol is described. The key features of the synthetic strategy include (a) Sharpless asymmetric dihydroxylation, (b) Wittig olefination, and (c) formation of β-keto ester to access t

Full text of DOI:10.1016/j.tetasy.2007.07.032

Tetrahedron: Asymmetry 18 (2007) 1775–1779
Enantioselective total synthesis of both the stereoisomers
of dihydrokawain-5-ol
Ahmed Kamal,* Tadiparthi Krishnaji and P. Venkat Reddy
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 3 May 2007; revised 24 July 2007; accepted 28 July 2007
Abstract—The enantioselective synthesis of both the stereoisomers of dihydrokawain-5-ol is described. The key features of the synthetic
strategy include (a) Sharpless asymmetric dihydroxylation, (b) Wittig olefination, and (c) formation of b-keto ester to access the highly
enantiomerically pure kavalactones.
ꢀ 2007 Published by Elsevier Ltd.
O
O
O
1. Introduction
O
R
O
S
O
R
Kavalactones are isolated from the kava plant Piper
methystcum (Piperaceae), which is found mostly in the
South Pacific islands1 including Fiji and Hawaii. Tradition-
ally, the roots and rhizomes of the plant are ground down
and made into a liquid beverage for consumption during
formal social or religious engagements.2 The extract of this
plant contains at least six pharmacologically active com-
pounds referred to as kavapyrones,3 which mediate the lo-
cal anesthetic sedating, anticonvulsive, muscle relaxant and
sleep stimulating effects of the plant.4 The potential use of
this kava extract is being considered in the treatment of
fear and anxiety-related disorders.5 In clinical trials, kava
has been found to be superior to placebo and effectively re-
lieved anxiety as well as tension.6 However, the FDA and
CDC have issued warnings about the severe cause of liver
injury probably associated with the use of kava containing
dietary supplements. This has prompted the investigation7
of all the major compounds in a systematic manner that are
present in kava. Therefore, the synthesis of various kava-
based compounds particularly in enantiopure form is of
much importance (Fig. 1).
S
R
R
Ph
Ph
OMe
OMe
Ph
Ph
OMe
OMe
Ph
OMe
OMe
OH
OH
OH
1c
1a
1b
O
O
O
O
O
S
O
S
Ph
OH
1f
1e
1d
O
O
O
O
O
O
OMe
OMe
MeO
1g
1h
Figure 1. Kavalactones.
tion as the source of chirality starting from commercially
available hydrocinnamaldehyde, in a short and efficient
manner. However, the syntheses of dihydrokawain-5-ol
have previously been reported in the literature,7 although
most of them have their limitations.
As part of our studies directed towards the synthesis of
these kavalactones,8a and other biologically active mole-
cules,8b–d we herein report the synthesis of the functional-
ized moieties of these molecules in suitably protected
forms, employing the Sharpless asymmetric dihydroxyla-
2. Results and discussion
Our initial retrosynthetic plan is outlined in Scheme 1.
Strategic disconnection of the target dihydrokawain-5-ols
1a and 1b at the C2–C3 double bond and a choice of the
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189;
e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@iictnet.org
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.07.032

1776
A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 1775–1779
O
OH
OH
O
O
O
OH
OEt
OMe
OH
OBn
12a
OH
O
O
1a
5a
OEt
3
OH
OH
O
O
O
OH
OEt
OMe
OH
OBn
12b
OH
5b
1b
Scheme 1. Retrosynthetic analysis of dihydrokawain-5-ols 1a and 1b.
selective 1,3-protection of triol 5a provides the appropriate
precursor 12a for the synthesis of proposed dihydroka-
wain-5-ol 1a. Compound 12a could be derived from triol
5a. The syn-diol [(5R,6S) and (5S,6R)] stereochemistries
can be introduced by Sharpless asymmetric dihydroxyla-
tion of an allylic alcohol 4, that could be obtained by the
reduction of a,b-unsaturated ester 3 with DIBAL–H. This
ester 3 could inturn be derived from Wittig homologation
of 2.
3. Conclusion
In conclusion, we have accomplished a short and efficient
linear total synthesis of both the stereoisomers of
dihydrokawain-5-ol with high enantioselectivities, in which
the stereocentres were established by Sharpless asymmetric
dihydroxylation from commercially available starting
materials. The synthesis of related compounds of this fam-
ily is currently underway in our laboratory.
Accordingly, we commenced the synthesis of target mole-
cule 1a from the commercially available hydrocinnamalde-
hyde as the starting material. This aldehyde, upon Wittig
olefination with the stabilized ylide (ethoxycarbonyl
methylene)triphenylphosphorane in benzene under reflux
conditions exclusively furnished the E-isomer in the form
of a,b-unsaturated ester 3. Ester 3 was reduced by DI-
BAL–H to E-allylic alcohol 4 in quantitative yield. Com-
pound 4 upon Sharpless asymmetric dihydroxylation9
using AD-mix-b at 0 ꢁC furnished triol 5a in 90% yield with
95% ee. Selective 1,3-protection of triol 5a gave a six-mem-
bered acetal as p-methoxybenzylidene acetal 6a [p-meth-
oxybenzaldehyde dimethylacetal, CSA, CH2Cl2] in 85%
yield, along with 1,2-protection of the five-membered
p-methoxybenzaldehyde acetal 7a in 10% yield. These
two acetals 6a and 7a were separated by column
chromatography.
4. Experimental
4.1. General
All solvents and reagents were purified by standard tech-
niques. Crude products were purified by column chroma-
tography on silica gel of 60–120 mesh. IR spectra were
recorded on Perkin–Elmer 683 spectrometer. Optical rota-
tions were obtained on a Horiba 360 digital polarimeter.
1H and 13C NMR spectra were recorded in CDCl3 solution
on a Varian Gemini 200, Brucker Avance 300. Chemical
shifts are reported in ppm with respect to the internal
TMS. Coupling constants (J) are quoted in Hertz. Mass
spectra were recorded on VG micromass-7070H (70 eV).
THF was freshly distilled from LiAlH4. DIBAL–H was
purchased from Merck while all the remaining chemicals
were purchased from Aldrich and used as received.
The hydroxyl group of 6a was protected as benzyl ether 8a
(BnBr, NaH, THF) and subsequently, this upon regioselec-
tive reduction by DIBAL–H gave unmasked primary alco-
hol 9a using the literature procedure.10 Compound 9a upon
oxidation using Dess–Martin periodinate11 in CH2Cl2 gave
aldehyde 10a in good yield. Aldehyde 10a, without further
purification, was treated with ethyl diazoacetate in the
presence of a catalytic amount of anhydrous tin(II)chlo-
ride12 in CH2Cl2 to afford b-keto ester 11a. Intermediate
11a upon PMB deprotection13 using ZrCl4 in acetonitrile
at 0 ꢁC gave 12a. Lactonization and methylation of 12a
gave the benzylated ether of dihydrokawain-5-ol 13a,
which upon debenzylation using titanium chloride in
CH2Cl2, provided the required dihydrokawain-5-ol 1a as
depicted in Scheme 2. Similarly, the other stereoisomer
dihydrokawain-5-ol 1b was also obtained from 4 using
AD-mix-a and by following a similar sequence of reac-
tions, as illustrated in Scheme 3.
4.2. 5-Phenylpent-2-enoicacidethylester 3
To a stirred solution of aldehyde 2 (1.0 g, 7.46 mmol) in
benzene, Wittig ylide Ph3PCHCO2Et (2.6 g, 7.46 mmol)
was added for 6 h under reflux conditions. After comple-
tion of the reaction, benzene was evaporated and the result-
ing crude was purified by column chromatography to give
a,b-unsaturated ester 3 as a liquid (1.44 g, 95%). IR (KBr)
m
max: 1719, 1653, 1267 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 1.29 (t, 3H, J = 6.8 Hz), 2.46–2.58 (m, 2H), 2.77 (t, 2H,
J = 7.5 Hz), 4.16 (q, 2H, J1 = 7.5 Hz, J2 = 14.3 Hz), 5.81
(d, 1H, J = 15.1 Hz), 6.90–7.03 (m, 1H), 7.09–7.30 (m,
5H) ppm; 13C NMR (75 MHz, CDCl3): d 14.2, 33.8, 34.3,
60.1, 121.8, 126.0, 128.3, 128.4, 140.7, 147.9, 166.5 ppm;
LCMS (m/z): 227 (M+Na)+; HRMS (M+H)+: Calcd for
C13H17O2: 205.1228. Found: 205.1233.

A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 1775–1779
1777
O
O
OH
a
b
OEt
3
2
4
PMP
O
OH
OH
O
c
d
OH
O
+
O
7a (10%)
OH
OR
PMP
R = H 6a (85%)
R = Bn
5a
e
8a
OR'
O
O
OPMB
OPMB
CHO
h
g
f
OEt
OH
8a
OR
R' = PMB
12a
OR
OR
11a
9a
10a
i
R' = H
O
O
j
k
OMe
1a
OBn
13a
Scheme 2. Reagents and conditions: (a) Ph3PCHCO2Et, benzene, 6 h, reflux, 95%; (b) DIBAL–H, ꢀ78 ꢁC, 2 h, 93%; (c) AD-mix-b, t-BuOH–H2O,
MeSONH2, 20 h, 0 ꢁC, 90%; (d) PMB(OMe)2, CH2Cl2, CSA, 0 ꢁC to rt, 1 h, 85%; (e) BnBr, NaH, THF, 0 ꢁC to rt, 4 h, 88%; (f) DIBAL–H, CH2Cl2, 0 ꢁC,
1 h, 88%; (g) Dess–Martin periodinate, CH2Cl2, 0 ꢁC to rt, 1 h; (h) N2CHCO2Et, anhydrous SnCl2, CH2Cl2, 0 ꢁC to rt, 80% for two steps; (i) ZrCl4,
CH3CN, 0 ꢁC to rt, 2 h, 85%; (j) K2CO3, MeOH, 0 ꢁC to rt, 2 h, then acetone, Me2SO4, 10 h, 75%; (k) TiCl4, CH2Cl2, 0 ꢁC to rt, 15 min, 90%.
of t-BuOH–H2O (10 mL/10 mL). The resulting mixture
was stirred at room temperature for 5 min. The mixture
OH
a
OH
was then cooled to 0 ꢁC and a solution of compound 4
(2.0 g, 12.35 mmol) in dichloromethane (10 mL) was added.
After stirring the reaction mixture for 20 h at 0 ꢁC, TLC
shows that the reaction was complete. A 10% Na2S2O3 solu-
tion was then added to quench the reaction. The mixture
was filtered through a layer of Celite and the filtrate was ex-
tracted with EtOAc. The organic layer was combined, dried
over Na2SO4 and evaporated. The residue was dissolved in
THF (3 mL) and TBAF (3 mL, 1 M in THF) was added.
The resulting mixture was stirred at room temperature for
4 h after which saturated sodium bicarbonate solution
was added. The mixture was extracted with EtOAc and
the organic layers were combined, dried over Na2SO4 and
evaporated. The residue was purified by column chroma-
tography to afford the desired compound 5a as a solid
(2.17 g, 90%). The enantiomeric excess (ee) of 5a is 95 and
determined by HPLC (chiral column AS–H; Daicel)
employing hexane–2-propanol (90:10) as mobile phase at
4
1b
OH
5b
Scheme 3. Reagents and conditions: (a) AD-mix-a, t-BuOH–H2O,
MeSONH2, 20 h, 0 ꢁC, 90%.
4.3. 5-Phenylpent-2-en-1-ol 4
To a stirred solution of a,b-unsaturated ester 3 (1.0 g,
5.0 mmol) in dichloromethane at ꢀ78 ꢁC, DIBAL–H
(5.3 mL, 7.5 mmol, 20% wt in toluene) was added for 2 h.
After completion of the reaction, Roche’s salt solution
was added and stirred for 1 h. The organic layer was sepa-
rated and the aqueous layer extracted with dichlorometh-
ane (2 · 50 mL). The combined organic layers were dried
over anhydrous Na2SO4 and evaporated. The residue was
purified by column chromatography to give allylic alcohol
4 as a liquid (0.74 g, 93%). IR (KBr) mmax: 3363, 2926,
2856, 1496, 1453 cmꢀ1 1H NMR (200 MHz, CDCl3): d
;
0.5 mL/min and monitored by UV (220 nm). Mp: 75–
23:5
78 ꢁC; ½aꢁD ¼ þ20:2 (c 1.8, CHCl3); IR (KBr) mmax: 3351,
2.28–2.43 (m, 2H), 2.62–2.76 (m, 2H), 3.90–4.17 (m, 2H),
5.50–5.80 (m, 2H), 7.07–7.31 (m, 5H) ppm; 13C NMR
(75 MHz, CDCl3): d 34.0, 35.6, 63.4, 125.9, 128.4, 128.5,
129.8, 131.9, 141.8 ppm; LCMS (m/z): 185 (M+Na)+;
HRMS (M+Na)+: Calcd for C11H14ONa: 185.0942.
Found: 185.0946.
2941, 2908, 1455 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
1.62–1.90 (m, 2H), 2.44–2.98 (m, 3H), 3.38–3.78 (m, 3H),
7.31–7.60 (m, 5H) ppm; 13C NMR (75 MHz, CDCl3): d
31.7, 35.2, 64.6, 71.8, 73.9, 125.9, 128.4, 141.7 ppm; LCMS
(m/z): 219 (M+Na)+; HRMS (M+Na)+: Calcd for
C11H16O3Na: 219.0997. Found: 219.1008.
4.4. (2R,3R)-5-Phenylpentane-1,2,3-triol 5a
4.5. (2S,3S)-5-Phenylpentane-1,2,3-triol 5b
AD-mix-b (19.0 g, 24.69 mmol) and methane sulfonamide
(1.16 g, 12.35 mmol) were dissolved in a solvent mixture
23:5
Ee 92%, ½aꢁD ¼ ꢀ19:2 (c 1.0, CHCl3).

1778
A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 1775–1779
4.6. (5R,6R)-2-(4-Methoxyphenyl)-6-phenethyl-[1,3]dioxan-
5-ol 6a
20% wt in toluene) was added dropwise at 0 ꢁC. The mix-
ture was stirred at 0 ꢁC for another 1 h and after comple-
tion of the reaction, the excess DIBAL–H was quenched
with 10% Roche’s salt solution. The mixture was stirred
at room temperature for 2 h. The two layers were sepa-
rated and the aqueous layer was extracted dichlorometh-
ane (2 · 50 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated. The residue
To a stirred solution of 5a (1.5 g, 7.65 mmol) in dichloro-
methane (15 mL), p-methoxybenzylidene dimethylacetal
(2 mL, 11.5 mmol) and CSA (10 mg) were sequentially
added. The mixture was stirred at 23 ꢁC for 1 h and after
completion of the reaction, was quenched with Et3N (two
drops). The mixture was concentrated and the residue puri-
fied by column chromatography to afford the desired com-
was purified by column chromatography to afford the de-
23:5
sired compound 9a as a liquid (0.9 g, 88%). ½aꢁD
¼
pound 6a (2.0 g, 85%) along with 7a (0.24 g, 10%) as a
þ25:4 (c 1.0, CHCl3); IR (KBr) mmax: 3446, 2926, 2862,
23:5
liquid. ½aꢁD ¼ þ75:9 (c 2.0, CHCl3); IR (KBr) mmax: 3439,
1610, 1513 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.67–
;
2931, 1613, 1517, 1248 cmꢀ1; 1H NMR (200 MHz, CDCl3):
d 1.77–1.93 (m, 1H), 2.06–2.23 (m, 1H), 2.52 (d, 1H,
J = 12.1 Hz), 2.61–2.82 (m, 2H), 3.36 (d, 1H, J = 11.3 Hz),
3.82 (s, 3H), 3.94 (d, 1H, J = 11.3 Hz); 4.15 (d, 1H,
J = 11.3 Hz), 5.42 (s, 1H), 6.85 (d, 2H, J = 8.3 Hz), 7.09–
7.42 (m, 7H) ppm; 13C NMR (75 MHz, CDCl3): d 30.8,
32.5, 55.2, 65.5, 72.6, 78.6, 101.2, 113.5 (2C), 125.8, 127.1
(2C), 128.3, 128.4 (2C), 130.4, 141.4, 159.9 ppm; LCMS
(m/z): 315 (M+H)+, 337 (M+Na)+; HRMS (M+Na)+:
Calcd for C19H22O4Na: 337.1415. Found: 337.1418.
1.82 (m, 1H), 1.88–2.03 (m, 2H), 2.43–2.59 (m, 1H),
2.64–2.79 (m, 1H), 3.44–3.64 (m, 3H), 3.67–3.76 (m, 1H),
3.78 (s, 3H), 4.28–4.50 (q, 2H, J1 = 11.3, J2 = 27.1 Hz),
4.53 (s, 2H), 6.81 (d, 2H, J = 8.3 Hz), 7.02–7.40 (m,
12 H) ppm; 13C NMR (75 MHz, CDCl3): d 31.5, 31.9,
55.2, 61.7, 72.2, 72.6, 77.9, 79.4, 113.8, 125.7, 127.7,
127.8, 128.3, 128.4, 128.7, 129.6, 130.3, 138.2, 141.8,
159.3 ppm; LCMS (m/z): 429 (M+Na)+; HRMS
(M+Na)+: Calcd for C26H30O4Na: 429.2041. Found:
429.2048.
4.7. (5S,6S)-2-(4-Methoxyphenyl)-6-phenethyl-[1,3]dioxan-
5-ol 6b
4.11. (2S,3S)-2-Benzyloxy-3-(4-methoxybenzyloxy)-5-
phenylpentan-1-ol 9b
23:5
½aꢁD ¼ ꢀ71:9 (c 1.0, CHCl3).
23:5
½aꢁD ¼ ꢀ24:6 (c 1.0, CHCl3).
4.8. (5R,6R)-5-Benzyloxy-2-(4-methoxyphenyl)-6-phenethyl-
[1,3]dioxane 8a
4.12. (4S,5R)-4-Benzyloxy-5-(4-methoxybenzyloxy)-3-oxo-
7-phenylheptanoicacidethylester 11a
To a stirred solution of the compound 6a (1.0 g,
3.18 mmol) in dry THF (15 mL), sodium hydride (0.25 g,
4.77 mmol), and benzyl bromide (0.82 g, 4.77 mmol) were
added at 0 ꢁC and stirred at room temperature for 4 h.
After completion of the reaction, THF was evaporated,
crushed ice was added, extracted with dichloromethane
(2 · 50 mL), dried over anhydrous Na2SO4 and evapo-
rated. The residue was purified by column chromatography
To a stirred solution of compound 9a in CH2Cl2, Dess–
Martin periodinate (2.12 g, 5 mmol) was added at 0 ꢁC
for 1 h. After completion of the reaction, the reaction mix-
ture was quenched with saturated sodium thiosulfate solu-
tion (10 mL) and saturated aqueous sodium bicarbonate
solution (10 mL). The reaction mixture was extracted with
dichloromethane (2 · 50 mL), dried over anhydrous
Na2SO4 and concentrated at 30 ꢁC. The residue of alde-
hyde 10a was used directly in the next step without further
purification.
to afford the desired compound 8a as a solid (1.03 g, 88%).
23:5
Mp: 82–85 ꢁC; ½aꢁD ¼ þ57:75 (c 1.0, CHCl3); IR (KBr)
m
max: 2862, 1613, 1515, 1546, 1249 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 1.70–1.90 (m, 1H), 2.20–2.42 (m,
1H), 2.56–2.77 (m, 2H), 3.13 (s, 1H), 3.80 (s, 3H), 3.68–
3.78 (m, 2H), 4.45 (dd, 2H, J1 = J2 = 12.1 Hz), 4.81 (d,
1H, J = 12.5 Hz), 5.45 (s, 1H), 6.84 (d, 2H, J = 8.0 Hz),
7.07–7.47 (m, 12H) ppm; 13C NMR (75 MHz, CDCl3): d
30.9, 32.4, 55.1, 67.8, 70.7, 70.8, 78.2, 101.1, 113.4, 125.7,
127.5, 127.8, 128.2, 128.4, 130.9, 138.1, 141.7, 159.7 ppm;
LCMS (m/z): 405 (M+H)+, 427 (M+Na)+; HRMS: Calcd
for C26H28O4Na (M+Na)+: 427.1885. Found: 427.1896.
To a stirred solution of aldehyde 10a (1.0 g, 2.5 mmol) in
dichloromethane (15 mL), ethyl diazoacetate (0.4 mL,
3.75 mmol) and anhydrous SnCl2 (0.05 g, 0.25 mmol) were
added sequentially at 0 ꢁC for 1 h. After completion of the
reaction, the reaction mixture was washed with aqueous
sodium bicarbonate, dried over anhydrous Na2SO4 and
concentrated. The residue was purified by column chroma-
tography to afford the desired compound 11a as a liquid
23:5
(0.96 g, 80%). ½aꢁD ¼ ꢀ21:0 (c 1.2, CHCl3); IR (KBr)
4.9. (5S,6S)-5-Benzyloxy-2-(4-methoxyphenyl)-6-phenethyl-
[1,3]dioxane 8b
m ;
max: 1748, 1725 cmꢀ1 1H NMR (200 MHz, CDCl3): d
1.27 (t, 3H, J = 7.3 Hz), 1.68–2.09 (m, 2H), 2.31–2.70 (m,
2H), 3.50–3.70 (m, 2H), 3.81 (s, 3H), 3.98–4.78 (m, 8H),
6.82 (d, 2H, J = 8.8 Hz), 7.00–7.43 (m, 12H) ppm; 13C
NMR (75 MHz, CDCl3): d 13.9, 31.4, 31.6, 46.8, 55.1,
61.1, 72.0, 73.3, 78.8, 84.5, 90.8, 113.6, 127.7, 128.1,
128.2, 128.3, 128.4, 129.7, 136.8, 141.2, 159.2, 167.3,
204.8 ppm; LCMS (m/z): 513 (M+Na)+; HRMS
(M+Na)+: Calcd for C30H34O6Na: 513.2253. Found:
513.2232.
23:5
½aꢁD ¼ ꢀ53:7 (c 1.5, CHCl3).
4.10. (2R,3R)-2-Benzyloxy-3-(4-methoxybenzyloxy)-5-
phenylpentan-1-ol 9a
To a stirred solution of compound 8a (1.0 g, 2.5 mmol) in
dichloromethane (15 mL), DIBAL–H (3.6 mL, 5 mmol,

A. Kamal et al. / Tetrahedron: Asymmetry 18 (2007) 1775–1779
1779
4.13. (4R,5S)-4-Benzyloxy-5-(4-methoxybenzyloxy)-3-
oxo-7-phenylheptanoicacidethylester 11b
at 0 ꢁC for 15 min. After completion of the reaction, the mix-
ture was taken into dichloromethane, washed with aqueous
sodium bicarbonate (10 mL), water (10 mL), dried (Na2SO4)
and concentrated under reduced pressure. The residue was
purified by column chromatography to afford the desired
compound 1a as a liquid (0.13 g, 90%) with 94% ee. Enantio-
23:5
½aꢁD ¼ þ23:4 (c 1.2, CHCl3).
4.14. (4S,5R)-4-Benzyloxy-5-hydroxy-3-oxo-7-phenyl-
heptanoicacidethylester 12a
meric excess (ee) was calculated on HPLC using chiral Dia-
23:5
cel OD column. ½aꢁD ¼ ꢀ62:5 (c 2.0, CHCl3); {lit.7b
25
To a stirred solution of compound 11a (1.0 g, 2.0 mmol) in
dry acetonitrile (15 mL), ZrCl4 (0.1 g, 0.412 mmol) was
added and the mixture stirred at room temperature for
2 h. The solvent was removed under reduced pressure. The
residue was dissolved in EtOAc (50 mL), washed with brine
(1 · 10 mL), water (1 · 10 mL), dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified
½aꢁD ¼ ꢀ66:3 (c 1.02, CHCl3)}; IR (KBr) mmax: 3367, 1683,
1630, 1225 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.85–
;
2.43 (m, 2H), 2.65–2.96 (m, 2H), 3.76 (s, 3H), 3.96 (s, 1H),
4.04–4.26 (m, 1H), 5.10 (s, 1H), 7.08–7.48 (m, 5H) ppm;
13C NMR (50 MHz, CDCl3): d 30.7, 30.8, 56.3, 65.7, 78.3,
91.6, 126, 128.3, 128.3, 140.6, 166.9, 172.7 ppm; LCMS
(m/z): 271 (M+Na)+; HRMS (M+Na)+: Calcd for
C14H16O4Na: 271.0946. Found: 271.0947.
by column chromatography to afford the desired compound
23:5
12a as a liquid (0.64 g, 85%). ½aꢁD ¼ ꢀ40:6 (c 1.0, CHCl3);
IR (KBr) mmax: 1748, 1725, 1611, 1512 cmꢀ1
;
1H NMR
4.19. (5R,6S)-5-Hydroxy-4-methoxy-6-phenethyl-5,6-
dihydro-2H-pyran-2-one 1b
(200 MHz, CDCl3): d 1.09–1.49 (m, 3H), 1.62–1.94 (m,
2H), 2.90–2.92 (m, 2H), 3.33–3.90 (m, 4H), 4.00–4.82 (m,
4H), 6.93–7.53 (m, 10H) ppm; 13C NMR (75 MHz, CDCl3):
d 13.9, 31.6, 34.9, 46.0, 61.3, 71.4, 73.6, 90.9, 125.8, 128.1,
128.2, 128.3, 128.4, 128.5, 136.5, 141.2, 167.2, 205.3 ppm;
LCMS (m/z): 393 (M+Na)+; HRMS (M+Na)+: Calcd for
C22H26O5Na: 393.1677. Found: 393.1673.
23:5
Mp 88–90 ꢁC [lit.7b 90–91 ꢁC]; ½aꢁD ¼ þ61:0 (c 2.0,
25
CHCl3), {lit.7b ½aꢁD ¼ þ68:1 (c 1.01, CHCl3)}.
Acknowledgements
The authors T.K. and P.V.R. wish to thank CSIR and
UGC, New Delhi, for the award of fellowship.
4.15. (4R,5S)-4-Benzyloxy-5-hydroxy-3-oxo-7-phenyl-
heptanoicacidethylester 12b
References
23:5
½aꢁD ¼ þ36:2 (c 1.5, CHCl3).
1. Achenbach, H.; Wittman, G. Tetrahedron Lett. 1970, 37,
3259–3262.
2. Pepping, J. J. Health Syst. Pharmacol. 1999, 56, 957–958.
3. Dharmaratne, H. R.; Nanayakkara, N. P.; Khan, I. A.
Phytochemistry 2002, 59, 429–433.
4. Bilia, A. R.; Gallon, S.; Vincieri, F. F. Life. Sci. 2002, 70,
2581–2597.
5. Singh, Y. N.; Singh, N. N. CNS Drugs 2002, 16, 731–743.
6. Pittler, M. H.; Ernst, E. J. Clin. Psychopharmacol. 2000, 20,
84–89.
7. For a racemic synthesis see: (a) Friesen, R. W.; Vanderwal, C.
J. Org. Chem. 1996, 61, 9103–9110; (b) Singh, R. P.; Singh, V.
K. J. Org. Chem. 2004, 69, 3425–3430; (c) Arai, Y.; Masuda,
T.; Yoneda, S.; Masaki, Y.; Shiro, M. J. Org. Chem. 2000, 65,
258–262; (d) Achenbach, H.; Huth, H. Tetrahedron Lett.
1974, 15, 119–120.
8. (a) Kamal, A.; Krishnaji, T.; Khanna, G. B. R. Tetrahedron
Lett. 2006, 47, 8657–8660; (b) Kamal, A.; Krishnaji, T.;
Khan, M. N. A. J. Mol. Catal. B 2007, 47, 1–5; (c) Kamal, A.;
Shaik, A. A.; Sandbhor, M.; Malik, M. S. Tetrahedron:
Asymmetry 2004, 15, 935; (d) Kamal, A.; Ramana, K. V.;
Rao, M. V. J. Org. Chem. 2001, 66, 997.
9. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996,
35, 448–451; (b) Kolb, H. C.; Van Nieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
10. (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem.
Lett. 1983, 1593–1596; (b) Corey, E. J.; Jones, G. B. J. Org.
Chem. 1992, 57, 1028–1029.
11. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–
4156; (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991,
113, 7277–7287.
4.16. (5S,6R)-5-Benzyloxy-4-methoxy-6-phenethyl-5,6-
dihydro-2H-pyran-2-one 13a
To a stirred solution of compound 12a (0.5 g, 1.35 mmol)
in methanol (10 mL), K2CO3 (0.37 g, 2.7 mmol) was added
for 2 h. After completion of the reaction, methanol was
evaporated, redissolved in acetone (10 mL), and Me2SO4
(0.25 mL, 2.7 mmol) and stirred for 10 h. The residue was
purified by column chromatography to afford the desired
compound 13a as a solid (0.35 g, 75%). Mp 85–88 ꢁC;
23:5
½aꢁD ¼ ꢀ120:5 (c 4.5, CHCl3); IR (KBr) mmax: 1704,
1629 cmꢀ1; H NMR (200 MHz, CDCl3): d 1.77–2.06 (m,
1
1H), 2.24–2.43 (m, 1H), 2.61–2.85 (m, 2H), 3.61–3.68 (m,
1H), 3.71 (s, 3H), 4.17 (m, 1H), 4.61 (dd, 2H,
J1 = J2 = 12.1 Hz), 5.15 (s, 1H), 7.06–7.36 (m, 10H) ppm;
13C NMR (50 MHz, CDCl3): d 30.8, 31.3, 56.0, 71.3,
72.3, 77.9, 92.3, 126.0, 127.8, 128.3, 128.4, 128.4, 137.1,
140.7, 166.0, 171.6 ppm; LCMS (m/z): 339 (M+H)+, 361
(M+Na)+; HRMS (M+H)+: Calcd for C21H23O4:
339.1596. Found: 339.1605.
4.17. (5R,6S)-5-Benzyloxy-4-methoxy-6-phenethyl-5,6-
dihydro-2H-pyran-2-one 13b
23:5
½aꢁD ¼ þ116:0 (c 3.0, CHCl3).
4.18. (5S,6R)-5-Hydroxy-4-methoxy-6-phenethyl-5,6-
dihydro-2H-pyran-2-one 1a
12. Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54,
3258–3260.
To a stirred solution of 13a (0.2 g, 0.6 mmol) in dichloro-
methane (10 mL), TiCl4 (0.08 mL, 0.72 mmol) was added
13. Sharma, G. V. M.; Reddy, Ch. G.; Krishna, P. R. J. Org.
Chem. 2003, 68, 4574–4575.