An efficient aldol-based approach for the synthesis of dihydrokawain-5-ol

Article abstract of DOI:10.1016/j.tetasy.2009.08.006

An efficient and simple aldol-based convergent approach toward the total synthesis of (+)- and (-)-dihydrokawain-5-ol is described. The key features of this synthetic strategy include Evans' aldol reaction and an ethyl acetate addition reaction for the formation of the six-membered ring.

Full text of DOI:10.1016/j.tetasy.2009.08.006

Tetrahedron: Asymmetry 20 (2009) 1936–1939
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An efficient aldol-based approach for the synthesis of dihydrokawain-5-ol
*
Ahmed Kamal , Papagari Venkat Reddy, S. Prabhakar
Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and simple aldol-based convergent approach toward the total synthesis of (+)- and (ꢀ)-
dihydrokawain-5-ol is described. The key features of this synthetic strategy include Evans’ aldol reaction
and an ethyl acetate addition reaction for the formation of the six-membered ring.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 26 June 2009
Accepted 6 August 2009
Available online 31 August 2009
1. Introduction
later the synthesis of (+)-dihydrokawain-5-ol was accomplished by
Arai et al.10b utilizing chiral sulfoxides, whereas Singh et al.10c have
The d-lactone ring system is found in a number of natural prod-
ucts and is also featured in many intermediates that are required
for the synthesis of biologically important compounds.1 These d-
lactones have been shown to exhibit a wide range of biological
activities such as antibiotic, anticancer, anti-inflammatory, antimi-
crobial and insecticidal.2 The d-lactone, (+)-dihydrokawain-5-ol 1b
(6-alkyl-5-hydroxy-5,6-dihydropyran-2-one) has been isolated
from the methanol extracts of the kava plant (Piper mythisticum),
a Polynesian shrub of the pepper family, which is mostly found
in the South Pacific islands including Fiji and Hawaii.3 Tradition-
ally, the roots and rhizomes of this plant are ground and made into
a liquid beverage for consumption during formal, social, or reli-
gious engagements.4
The extracts of this plant contain at least six pharmacologically
active compounds referred to as kavapyrones,5 which mediate the
local anesthetic, sedating, anticonvulsive, muscle relaxant, and
sleep stimulating effects.6 The potential use of this kava extracts
is being considered in the treatment of fear and anxiety-related
disorders.7 Kava has been found to be superior to placebos and
effectively relieves anxiety as well as tension.8 However, the FDA
and CDC have issued warnings about the severe cases of liver in-
jury probably associated with the use of kava-containing dietary
supplements. This has prompted the investigation of all the major
compounds in a systematic manner that are present in kava. There-
fore, the synthesis of various kava-based compounds particularly
in their enantiopure form is of importance (Fig. 1).
obtained its (+)-form and the other stereoisomers from a-D-glucose.
Recently, we have reported the synthesis of both the (+)- and (ꢀ)-
dihydrokawain-5-ol from dihydrocinnamaldehyde utilizing Sharp-
less asymmetric dihydroxylation process.10d
O
O
O
O
O
O
O
O
Ph
Ph
O
Ph
Ph
O
O
Ph
Ph
OH
1a
OH
1b
OH
1c
O
O
O
O
O
O
O
OH
1d
O
1e
1f
O
O
O
O
O
O
O
O
1g
1h
The absolute (5R,6S)-configuration in (+)-dihydrokawain-5-ol 1b
has been assigned by its synthesis through SeO2 allylic oxidation of
(+)-dihydrokawain 1e, derived from kawain 1f.9 Some approaches
have been developed in the literature for the synthesis of (+)-
dihydrokawain-5-ol 1b by employing different protocols. Friesen
et al.10a synthesized dihydrokawain-5-ol 1b in a racemic form while
Figure 1. Kavalactones.
2. Results and discussion
As part of our continuing studies directed toward the synthesis of
lactones and other biologically active molecules,11 we herein report
a new synthetic route to (+)- and (ꢀ)-dihydrokawain-5-ol employ-
ing the well-known and widely used Evans’ asymmetric aldol
* Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.006

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1936–1939
1937
reaction12 as the key step in their preparation. By using this method-
ology, two syn-hydroxyl groups are introduced at the C5 and C6 posi-
tions in their skeleton. Our initial retrosynthetic plan is outlined in
Scheme 1. Retrosynthetically, (ꢀ)-dihydrokawain-5-ol can be ob-
tained from intermediate 9a, which can be formed by the condensa-
tion of the aldehyde of Weinreb amide 7a with ethyl acetate.
Moreover, this Weinreb amide can be produced by the transamida-
tion of aldol product 5a. This aldol product can be prepared from the
commercially available dihydrocinnamaldehyde.
The synthesis of 1a starts by the coupling of the 2-(benzyl-
oxy)acetic acid derivative with oxazolidinone 3a by employing
Ho’s protocol13 to afford (4S)-4-benzyl-3-[2-(benzyloxy)acetyl]-
1,3-oxazolan-2-one 4a in 90% yield. Aldol reaction of hydrocinna-
maldehyde with 4a using dibutylboron triflate and triethylamine
in CH2Cl2 at ꢀ78 °C for 4 h gives the syn-aldol product14 5a in good
yield (81%) as a single diastereomer. The chiral auxiliary in 5a is re-
moved by transamidation to afford Weinreb amide 6a in 84% yield.
The hydroxyl group of 6a is protected as the TBDMS ether using
TBDMS triflate and triethylamine at ꢀ78 °C for 4 h to provide 7a
in 83% yield. At this stage the condensation of 7a with ethyl acetate
using different bases in a variety of solvents was attempted, how-
ever, the desired product 9a was not obtained. Therefore the Wein-
reb amide was initially treated with DIBAL-H to afford the
aldehyde, which without further purification underwent EtOAc
addition at ꢀ78 °C (EtOAc/LiHMDS/THF/ꢀ78 °C) to give the diaste-
reomeric alcohol 8a in 68% yield. Compound 8a upon oxidation
with Dess–Martin periodinate in CH2Cl2 forms the b-keto ester
9a in good yield.
Treatment of compound 9a with PTSA in methanol15 resulted in
the deprotection of the TBDMS ether as well as the formation of a
cyclized lactone 10a, which was not isolated. Upon treatment with
Me2SO4 and K2CO3 in acetone the desired precursor 11a was ob-
tained in good yield. After the lactone formation benzyl-protected
alcohol was then deprotected. Compound 11a was then treated
with TiCl4 in CH2Cl216,10d at 0 °C to afford the required target com-
pound (ꢀ)-dihydrokawain-5-ol 1a. The spectroscopic and analyti-
cal data were comparable to the previously reported data in the
literature.10c,d
Similarly the synthesis of (+)-dihydrokawain-5-ol 1b, was car-
ried out by employing (4R)-4-benzyl-3-[2-(benzyloxy)acetyl]-1,3-
oxazolan-2-one as the starting material, followed by the same set
of reactions as in Scheme 2, as depicted in Scheme 3. The spectro-
O
O
OH
O
O
OTBDMS
Ph
O
OTBDMS
Ph
O
O
O
N
Ph
EtO
EtO
1a
1b
N
N
OBn
5a
OBn
OBn
Ph
O
7a
9a
H
Ph
O
O
OTBDMS
Ph
O
O
OH
O
OTBDMS
Ph
O
N
Ph
OBn
OBn
OBn
9b
7b
5b
Ph
Scheme 1. Retrosynthetic analysis of 1a and 1b.
O
O
O
O
O
OH
OH
b
a
O
N
O
N
Ph
OBn
O
OBn
OBn
2
O
NH
Ph
Ph
4a
5a
3a
c
Ph
O
OH
O
OTBDMS
Ph
OBn
7a
O
OH OTBDMS
Ph
O
O
O
N
O
d
e
Ph
N
EtO
OBn
OBn
8a
6a
f
O
O
O
OTBDMS
O
g
h
i
EtO
Ph
1a
O
Ph
O
Ph
OBn
OBn
OBn
10a
9a
11a
Scheme 2. Reagents and conditions: (a) pivolyl chloride, Et3N, THF, 3a, LiCl, Et3N, 90%; (b) Bu2BOTf, Et3N, CH2Cl2, ꢀ78 °C, 4 h, 81%; (c) N-methoxy-N-methylamine
hydrochloride, Me3Al, THF, 0 °C to rt, 1 h, 84%; (d) TBDMS triflate, Et3N, ꢀ78 °C–rt, 4 h, 83%; (e) (i) DIBAL-H, CH2Cl2, ꢀ78 °C, 2 h; (ii) EtOAc, LiHMDS, THF, ꢀ78 °C, 1 h, 68%; (f)
Dess–Martin periodinate, CH2Cl2, 0 °C to rt, 1 h; (g) PTSA, methanol, 8 h, 0 °C to rt, (h) Me2SO4, K2CO3, acetone, 10 h; (i) TiCl4, CH2Cl2, 0 °C–rt, 15 min, 89%.

1938
A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1936–1939
4.3. (2S,3R)-2-(Benzyloxy)-3-hydroxy-N-methoxy-N-methyl-5-
phenylpentanamide 6a
O
O
O
O
O
a
O
O
N
OH
O
Ph
To a stirred solution of N,O-dimethylhydroxylamine hydrochlo-
ride (4.6 g, 47.93 mmol) in dry THF (100 mL) at 0 °C was added
trimethylaluminum (17.97 mL, 35.94 mmol, 2 M in toluene) drop-
wise. Then the mixture was allowed to stir at room temperature for
30 min and recooled to 0 °C. Compound 5a (5.5 g, 11.98 mmol) in
dry THF (10 mL) was added dropwise and then stirred at room
temperature for 2 h. After completion of the reaction, the reaction
was slowly quenched with dil HCl. Next, THF was evaporated and
extracted with EtOAc (2 ꢁ 100 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under vacuo.
The residue was purified by column chromatography (silica gel,
60–120 mesh, EtOAc–hexane 40: 60) to afford the compound 6a
OBn
4b
OBn
O
NH
OH
1b
Ph
3b
2
Ph
Scheme 3. Reagents and conditions: (a) pivolyl chloride, Et3N, THF, 3b, LiCl, Et3N.
scopic and analytical data were comparable to the previously re-
ported data in the literature.10b–d
3. Conclusion
(3.45 g, 84%) as a colorless liquid. ½a D25
ꢂ
¼ ꢀ13:5 (c 1.1, CHCl3); IR
In conclusion, we have developed an efficient and convenient
approach for the synthesis of (+)- and (ꢀ)-dihydrokawain-5-ol. In
this protocol, stereocenters are established by an Evans’ asymmet-
ric aldol reaction that has been chosen as the key step for the syn-
thesis of these molecules by using simple commercially available
starting materials. The syntheses of related compounds of this
family are currently underway in this laboratory.
(neat):
c
max: 3430, 2931, 1660, 1454, 750, 700 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d = 7.36–7.08 (m, 10H), 4.53 (dd, J = 11.7 Hz,
2H), 4.17 (d, J = 4.4 Hz, 1H), 3.81 (m, 1H), 3.46, (s, 3H), 3.17 (s,
3H), 2.85–2.52 (m, 2H), 2.01–1.6 (m, 2H); 13C NMR (75 MHz,
CDCl3): d = 171.1, 141.6, 137.1, 128.3, 128.2, 128.1, 127.96, 125.7,
77.4, 71.9, 71.3, 61.1, 34.7, 32.3, 31.7; ESI–MS: m/z = 344.6 (M+H)+.
4. Experimental
4.4. (2S,3R)-2-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-N-
methoxy-N-methyl-5-phenylpentanamide 7a
4.1. General experimental
To a stirred solution of Weinreb amide 6a (3.2 g, 9.32 mmol) in
dry CH2Cl2 (40 mL) at ꢀ78 °C were added TBSOTf (2.35 mL,
10.26 mmol) and triethylamine (1.55 mL, 11.19 mmol) and al-
lowed to stir at room temperature for 4 h. After completion of
the reaction, the reaction was quenched by satd NH4Cl solution
(20 mL) and the reaction mixture was extracted with CHCl3
(2 ꢁ 75 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 60–120 mesh, EtOAc–hexane 5:95) to afford 7a
Reagents and chemicals were purchased from Aldrich. All sol-
vents and reagents were purified by standard techniques. THF
was freshly distilled from LiAlH4. Crude products were purified
by column chromatography on 60–120 silica gel. IR spectra were
recorded on Perkin–Elmer 683 spectrometer. Optical rotations
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. Mass spectra were recorded on VG
micromass-7070H (70 Ev).
(3.53 g, 83%) as a colorless liquid. ½a D25
ꢂ
¼ ꢀ4:4 (c 1.4, CHCl3); IR
(neat):
c
max: 2930, 1670, 1458, 1113, 835, 777 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d = 7.35–7.06 (m, 10H), 4.55 (dd, J = 11.9 Hz,
2H), 4.24 (d, J = 6.4 Hz, 1H), 4.1–4.03 (m, 1H), 3.5 (s, 3H), 3.15 (s,
3H), 2.71–2.49 (m, 2H), 1.85–1.74 (m, 1H), 1.7–1.58 (m, 1H),
0.908 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3):
d = 171.5, 142.4, 137.6, 128.2, 128.06, 127.64, 127.61, 125.6, 79.3,
72.9, 72.9, 60.9, 35.3, 32.2, 31.5, 25.5, 18.1, ꢀ4.1, ꢀ4.7; ESI–MS:
m/z = 458.6 (M+H)+.
4.2. (4S)-4-Benzyl-3-[(2S,3R)-2-(benzyloxy)-3-hydroxy-5-
phenylpentanoyl]-1,3-oxazolan-2-one 5a
To a stirred solution of chiral auxiliary 4a (5 g, 15.38 mmol) in
dry CH2Cl2 (50 mL) at ꢀ78 °C was added triethylamine (2.56 mL,
18.46 mmol) followed by the dropwise addition of dibutylboron
triflate (16.92 mL, 16.92 mmol, 1 M solution in CH2Cl2) and stirred
for 1 h at the same temperature. The solution was warmed to 0 °C
for 45 min and recooled to ꢀ78 °C. Dihydrocinnamaldehyde
(2.22 mL, 16.92 mmol) solution in CH2Cl2 (5 mL) was added drop-
wise via a cannula. The reaction mixture was allowed to stir at
ꢀ78 °C for 2 h. The reaction was quenched with MeOH (25 mL) fol-
lowed by pH 7 buffer (12 mL). After 1 h, 30% aqueous H2O2 (5 mL)
was added dropwise and stirred at 0 °C for 1 h. The organic layer
was separated and the aqueous layer was extracted with CH2Cl2
(2 ꢁ 100 mL). The combined organic layers were dried over anhy-
drous Na2SO4 and concentrated under vacuo. The residue was puri-
fied by column chromatography (silica gel, 60–120 mesh, EtOAc–
hexane 30:70) to afford the compound 5a (5.71 g, 81%) as a solid.
4.5. Ethyl(4R,5R)-4-(benzyloxy)-5-[1-(tert-butyl)-1,1-dimethyl
silyl]oxy-3-hydroxy-7-phenylheptanoate 8a
To a stirred solution of compound 7a (3.3 g, 7.22 mmol) in dry
CH2Cl2 (50 mL) at ꢀ78 °C was added DIBAl-H (3.97 mL, 7.94 mmol,
2 M in toluene) and stirred for 1 h at the same temperature. After
completion of the reaction, the reaction was quenched with so-
dium potassium tartarate solution, and the reaction mixture was
stirred for 30 min at room temperature and extracted with CH2Cl2
(2 ꢁ 50 mL). The combined organic layers were dried over anhy-
drous Na2SO4 and concentrated under vacuo to afford the crude
aldehyde, which was used for the next step without purification.
To a stirred solution of ethyl acetate (2.13 mL, 21.85 mmol) in
THF at ꢀ78 °C was added LiHMDS (18.21 mL, 18.21 mmol, 1 M in
THF) dropwise and stirred for 45 min. To this reaction mixture
the aldehyde (2.9 g, 7.28 mmol) obtained above was taken in THF
(8 mL) and added slowly with stirring for 2 h at ꢀ78 °C. After com-
pletion of the reaction, the reaction was quenched with aqueous
ammonium chloride solution. Next THF was evaporated and
extracted with CHCl3 (2 ꢁ 50 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo.
Mp: 97–99 °C. ½a 2D5
ꢂ
¼ þ70:5 (c 1.5, CHCl3); IR (neat):
cmax: 3507,
2928, 1788, 1685, 1453, 1211, 757, 701 cmꢀ1
;
1H NMR (200 MHz,
CDCl3): d = 7.35–7.11 (m, 15H), 5.1 (d, J = 2.9 Hz, 1H), 4.64–4.57
(m, 1H), 4.54 (q, J = 11.7 Hz, 2H), 4.27–4.09 (m, 2H), 3.85 (br s,
1H), 3.27 (dd, J = 2.9, 13.2 Hz, 1H), 2.87–2.49 (m, 3H), 2.23 (br s,
1H), 1.93 (q, 2H); 13C NMR (75 MHz, CDCl3): d = 170.5, 153.3,
141.6, 136.9, 134.9, 129.2, 128.8, 128.4, 128.3, 128.2, 128.1,
127.3, 125.68, 79.2, 72.8, 72.1, 66.9, 55.4, 37.5, 35.6, 31.74; ESI–
MS: m/z = 460.6 (M+H)+.

A. Kamal et al. / Tetrahedron: Asymmetry 20 (2009) 1936–1939
1939
The residue was purified by column chromatography (silica gel,
for 15 min. After completion of the reaction, the reaction was
quenched with aqueous sodium bicarbonate solution, and the
reaction mixture was extracted with CH2Cl2 (2 ꢁ 25 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and con-
centrated under vacuo. The residue was purified by column
chromatography (silica gel, 60–120 mesh, EtOAc–hexane 60:40)
60–120 mesh, EtOAc–hexane 10:90) to afford compound 8a
(2.38 g, 68%) as a colorless liquid. ½a D25
ꢂ
¼ þ33:4 (c 1.1, CHCl3); IR
(neat):
c
max: 3507, 2931, 1733, 1095, 837, 775 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d = 7.35–7.18 (m, 10H), 4.72–4.57 (m, 2H),
4.11 (q, J = 7.5, 14.3 Hz, 2H), 4.28–4.2 (m, 1H), 3.89 (m, 1H), 3.31
(t, 1H), 2.78–2.43 (m, 5H), 2.08–1.97 (m, 1H), 1.88–1.75 (m, 1H),
1.24 (t, J = 7.5, 14.3 Hz, 3H), 0.91 (s, 9H), 0.05 (s, 3H), 0.01 (s,
3H); 13C NMR (75 MHz, CDCl3): d = 171.7, 142.1, 137.9, 128.42,
128.35, 128.32, 127.93, 125.7, 82.5, 73.8, 71.6, 67.3, 60.5, 39.7,
34.2, 32.1, 25.8, 18.1, 14.1, ꢀ4.1, ꢀ4.6; ESI–MS: m/z = 487 (M+H)+.
to afford compound 1a (0.26 g, 89%) as
¼ ꢀ63:2 (c 1.1, CHCl3); IR (neat): max: 3381, 1685, 1630,
1225, 1051, 749, 700 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.31–
a colorless liquid.
½
a 2D5
ꢂ
c
;
7.07 (m, 5H), 5.1 (s, 1H), 4.21–4.04 (m, 1H), 3.85 (br s, 1H), 3.75
(s, 3H), 2.89–2.71 (m, 2H), 2.36–2.23 (m, 1H), 2.06–1.95 (m, 1H);
13C NMR (75 MHz, CDCl3): d = 172.7, 166.78, 140.69, 128.43,
128.4, 126.06, 91.19, 78.32, 65.90, 56.27, 30.93, 30.78; ESI–MS:
m/z = 249 (M+H)+.
4.6. Ethyl (4S,5R)-4-(benzyloxy)-5-[1-(tert-butyl)-1,1-
dimethylsilyl]oxy-3-oxo-7-phenylheptanoate 9a
Acknowledgments
To a stirred solution of compound 8a (2.1 g, 4.33 mmol) in
CH2Cl2 (40 mL), Dess–Martin periodinate (2.02 g, 4.77 mmol) was
added at 0 °C and stirred for 1 h. After completion of the reaction,
the reaction was quenched with aqueous sodium thiosulfate solu-
tion (20 mL) and saturated aqueous sodium bicarbonate solution
(10 mL). The reaction mixture was extracted with CH2Cl2
(2 ꢁ 50 mL), dried over anhydrous Na2SO4, and concentrated in va-
cuo. The residue was purified by column chromatography (silica
gel, 60–120 mesh, EtOAc–hexane 7: 93) to afford 9a (1.92 g, 92%)
The authors P.V.R. and S.P.R. wish to thank UGC and CSIR, New
Delhi for the award of research fellowships.
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as a yellow liquid. ½a D25
ꢂ
¼ þ6:8 (c 1.1, CHCl3); 1H NMR (200 MHz,
CDCl3): d = 7.39–7.11 (m, 10H), 4.76 (d, J = 11.6 Hz, 1H), 4.46 (d,
J = 11.6 Hz, 1H), 4.36–4.25 (m, 1H), 4.17 (q, J = 7.2, 13.8 Hz, 2H),
4.04–3.82 (m, 1H), 3.72–3.51 (m, 2H), 2.58 (m, 2H), 2.13–1.94
(m, 1H), 1.81–1.56 (m, 1H), 1.3 (t, J = 7.2, 13.8 Hz, 3H), 0.94 (s,
9H), 0.08 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3):
d = 204.6, 167.3, 141.5, 137.1, 128.4, 128.3, 128.2, 128.1, 128.05,
125.85, 86.2, 73.3, 73.0, 61.2, 47.2, 35.1, 31.6, 25.8, 18.0, 14.0,
ꢀ4.6, ꢀ4.7; IR (neat):
cmax: 2931, 2858, 1746, 1722, 1254, 837,
776, 699 cmꢀ1. ESI–MS: m/z = 485.6 (M+H)+.
4.7. (5S,6R)-5-(Benzyloxy)-4-methoxy-6-phenethyl-5,6-dihydro-
2H-2-pyranone 11a
To a stirred solution of 9a (1.7 g, 3.51 mmol) in dry MeOH
(20 mL) at 0 °C was added PTSA (0.06 g, 0.35 mmol) and stirred
at room temperature for 8 h. After completion of the starting mate-
rial, methanol was evaporated. To the above crude compound in
acetone at 0 °C was added Me2SO4 (0.665 mL, 7.02 mmol) followed
by K2CO3 (0.96 g, 7.02 mmol). The reaction mixture was stirred for
10 h. After completion of the reaction, solid K2CO3 was filtered, and
acetone was evaporated and extracted with EtOAc (2 ꢁ 40 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under vacuo. The residue was purified by column
chromatography (silica gel, 60–120 mesh, EtOAc–hexane 40:60)
to afford the compound 11a (0.89 g, 75%) as a solid. Mp 85–
5. Dharmaratne, H. R.; Nanayakkara, N. P.; Khan, A. Phytochemistry 2002, 59, 429–
433.
6. Bilia, A. R.; Gallon, S.; Vincieri, F. F. Life Sci. 2002, 70, 2581–2597.
7. Singh, Y. N.; Singh, N. N. CNS Drugs 2002, 16, 731–743.
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9. Achenbach, H.; Huth, H. Tetrahedron Lett. 1974, 15, 119–120.
10. For a racemic synthesis see: (a) Friesen, R. W.; Vanderwal, C. J. Org. Chem. 1996,
61, 9103–9110; For asymmetric synthesis of (+)-dihydrokawain-5-ol see: (b)
Arai, Y.; Masuda, T.; Yoneda, S.; Masaki, Y.; Shiro, M. J. Org. Chem. 2000, 65,
258–262; (c) Singh, R. P.; Singh, V. K. J. Org. Chem. 2004, 69, 3425–3430; (d)
Kamal, A.; Krishnaji, T.; Reddy, P. V. Tetrahedron: Asymmetry 2007, 18, 1775–
1779.
11. (a) Kamal, A.; Reddy, P. V.; Prabhakar, S. Tetrahedron: Asymmetry 2009, 20,
1120–1124; (b) Kamal, A.; Krishnaji, T.; Reddy, P. V. Tetrahedron: Asymmetry
2007, 18, 1775–1779; (c) Kamal, A.; Krishnaji, T.; Reddy, P. V. Tetrahedron Lett.
2007, 48, 7232–7235; (d) Kamal, A.; Krishnaji, T.; Khanna, G. B. R. Tetrahedron
Lett. 2006, 47, 8657–8660.
12. (a) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 1981, 125, 13531–13540; (b) Evans,
D. A.; Dow, R. L. Tetrahedron Lett. 1986, 27, 1007–1010; (c) Evans, D. A.; Sjogren,
E. B. Tetrahedron Lett. 1986, 27, 3119–3122; (d) Mapp, A. K.; Heathcock, C. H. J.
Org. Chem. 1999, 64, 23–27; (e) Yokoe, H.; Sasaki, H.; Yoshimura, T.; Shindo, M.;
Yoshida, M.; Shishido, K. Org. Lett. 2007, 4, 969–971; (f) Evans, D. A.; Welch, D.
S.; Speed, A. W. H.; Moniz, G. A.; Reichelt, A. J. Am. Chem. Soc. 2009, 131, 3840–
3841.
88 °C. ½a 2D5
ꢂ
¼ ꢀ118:9 (c 1.5, CHCl3); IR (neat):
cmax: 1711, 1633,
1221, 1059, 700 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d = 7.33–7.1
(m, 10H), 5.14 (s, 1H), 4.61 (dd, J = 12.1 Hz, 2H), 4.16–4.08 (m,
1H), 3.71 (s, 3H), 3.66–3.65 (m, 1H), 2.84–2.64 (m, 2H), 2.41–
2.29 (m, 1H), 1.92–1.8 (m, 1H); 13C NMR (75 MHz, CDCl3):
d = 171.7, 165.9, 140.7, 137.1, 128.41, 128.4, 128.3, 127.7, 126.0,
92.2, 77.8, 72.3, 71.2, 55.9, 31.2, 30.8; ESI–MS: m/z = 339 (M+H)+.
13. Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271–2273.
14. (a) Evans, D. A.; Bartroli, J. A.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129;
(b) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799–802; (c) Jones, T.
K.; Reamer, R. A.; Desmond, R.; Miles, S. G. J. Am. Chem. Soc. 1990, 112, 2998; (d)
Hulme, A. N.; Rosser, E. M. Org. Lett. 2002, 9, 265–267; (e) Sharma, G. V. M.;
Cherukupalli, G. R. Tetrahedron Asymmetry 2006, 17, 1081–1088.
15. Crouch, R. D. Tetrahedron 2004, 60, 5833–5871. and references cited therein.
16. Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989, 54, 1346–1353.
4.8. (5S,6R)-5-Hydroxy-4-methoxy-6-phenethyl-5,6-dihydro-
2H-2-pyranone 1a
To a stirred solution of 10a (0.4 g, 1.18 mmol) in dry CH2Cl2
(15 mL) at 0 °C was added TiCl4 (0.258 mL, 2.36 mmol) and stirred