The first total synthesis of (R)-7-butyl-6,8-dihydroxy-3-pentylisochroman- 1-one

Article abstract of DOI:10.1016/j.tetasy.2005.06.003

The enantioselective synthesis of 7-butyl-6,8-dihydroxy-(3R)- pentylisochroman-1-one has been achieved for the first time in which Sharpless asymmetric dihydroxylation is the key step.

Full text of DOI:10.1016/j.tetasy.2005.06.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2231–2234
The first total synthesis of
(R)-7-butyl-6,8-dihydroxy-3-pentylisochroman-1-one
Weiguo Quan,a Junying Ma,a Xuanjia Peng,a Tongxing Wu,a
a,
Xuegong Shea,b, and Xinfu Pan
*
*
aDepartment of Chemistry, State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, China
Received 7 April2005; accepted 1 June 2005
Abstract—The enantioselective synthesis of 7-butyl-6,8-dihydroxy-(3R)-pentylisochroman-1-one has been achieved for the first time
in which Sharpless asymmetric dihydroxylation is the key step.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
(3R)-7-Butyl-6,8-dihydroxy-3-pentylisochroman-1-one
1 (Fig. 1), a member of the dihydroisocoumarin deri-
vatives, was isolated by bioassay-guided fractiona-
tion from an endophytic fungus and its absolute con-
figuration was determined to be R,1 which is of great
interest because of its diverse antimalarial and
As shown in Scheme 1, starting from 3,4,5-trimethoxy-
benzaldehyde dimethyl acetal 2, benzaldehyde 3 was eas-
ily prepared according to a previous report.2 Wittig
olefination of 3 with the ylide derived from n-hexyltri-
phenylphosphonium bromide led to 4 as an E:Z (1:1)
mixture as revealed by 1H NMR. Irradiation of this
E:Z diene mixture 4 in the presence of iodine generated
the eventualpredominance of the desired product ( E)-
4,3 with an E:Z ratio >95:5. Treatment of (E)-4 with
AD-mix-b stereoselectively afforded cis-diol 5 in 92%
yield.4a The ee of 5 was determined as >95% by HPLC
analysis, while its configuration was anticipated to be
(1R,2R) according to the Sharpless model.4b This was
confirmed by converting 5 to compound 1 and compar-
ing its specific rotation to that reported for natural( R)-
1. Hydrogenolysis of 5 in ethylacetate over 10% Pd/C
furnished 6 in 70% yield5 (ee >93%), which was easily
converted into the corresponding methylether 7 in
99% yield. Its bromination with NBS in DMF,6a,b at
room temperature afforded monobromo compound 8
in 96% yield. Lithiation of 8 with n-BuLi and subsequent
reaction with ethylcholroformate gave ester 9 in 93%
yield. Finally, ester 9 on treatment with BBr3 directly
1
antifungalproperties. To the best of our knowledge,
the totalasymmetric synthesis of the titel compound
has not yet been reported. In order to study the
relationship between structure and activity of the
compound, we herein report the first enantiose-
lective synthesis from the easily available2 dimethyl
acetal 2.
HO
O
OH
O
1
Figure 1.
afforded 1 in 40% yield via demethylation and concom-
25
D
(c 0.1, CH3OH)} agreed well with that reported for
itant esterification.7 The rotation value of 1 {½aŠ ¼ À24
25
D
the absolute configuration of 5 as assigned above.
*
natural( R)-1 {½aŠ ¼ À20 (c 0.1, CH3OH)}, establishing
Corresponding author. Tel.: +86 (0)931 8912407; fax: +86 (0)931
8912582; e-mail: shexg@lzu.edu.cn
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.003

2232
W. Quan et al. / Tetrahedron: Asymmetry 16 (2005) 2231–2234
O
OMe
OMe
MeO
MeO
MeO
H
b
a
c
OMe
OMe
2
3
MeO
MeO
d
OMe
OMe
4
E-4
OH
MeO
MeO
MeO
MeO
f
e
OH
OH
OMe
6
OMe
5
MeO
HO
h
g
i
OMe
OMe
Br
OMe
7
OMe
8
O
OMe
CO2Et
OH
1
O
OMe
9
Scheme 1. Reagents and conditions: (a) 3 equiv Na, THF, rt, 24 h, 1.5 equiv n-BuBr, 0 ꢁC, 24 h then aqCH3COOH, reflux, 5 h, 85%; (b)
n-C6H13PPh3Br, n-BuLi, THF, 0 ꢁC, 96%; (c) hm, I2, hexane–ether = 3:2 v/v, 2 h, 99%; (d) AD-mix-b, MeSO2NH2, t-BuOH/H2O, 0 ꢁC, 24 h, 92%; (e)
10% Pd/C, CH3CO2Et, 70%; (f) NaH, CH3I, THF, 99%; (g) NBS, DMF, 96%; (h) n-BuLi, ClCO2Et, 93%; (i) excess BBr3, À78 ꢁC to rt, 24 h, 40%.
3. Conclusion
hol as eluant. Column chromatography was generally
performed on silica gel (200–300 meshes) eluting with
petroleum ether and ethyl acetate.
In summary, we have successfully achieved a highly
enantioselective synthesis of 1 in 18.4% overall yield
from the readily available dimethyl acetal 2. This syn-
thesis required only nine chemical operations. The abso-
lute stereochemistry was introduced by employing a
Sharpless AD reaction. Application of this sequence to
enantioselective synthesis of other types of more com-
plex natural products incorporating the corresponding
crucialdihydroisocoumarin core structures is currentyl
ongoing in our group.
4.2. 4-Butyl-3,5-dimethoxybenzaldehyde 3
To a suspension of the freshly cut sodium (0.276 g,
12 mmol) in anhydrous THF (30 mL), a solution of 2
(0.968 g, 4 mmol) in anhydrous THF (5 mL) was added
dropwise under a dry argon atmosphere. The mixture
was stirred at room temperature for 24 h, cooled to
0 ꢁC after which n-BuBr (0.816 g, 6 mmol) in anhydrous
THF (5 mL) was slowly added, and the resulting mixture
stirred for 24 h. The reaction was quenched by the
slow dropwise addition of H2O (10 mL) (caution!).
Subsequently the mixture was hydrolyzed (CH3COOH–
H2O = 5:1, 10 mL, reflux, 5 h) and extracted with ether.
The organic phase was washed with saturated aqueous
NaHCO3, dried, and evaporated. The residue was flash
chromatographed using petroleum ether and ethyl ace-
tate (50:1, v/v) to give compound 3 as a colorless oil,
which on standing gave a colorless solid (0.755 g, 85%).
4. Experimental
4.1. General
Melting points were measured on a Kofler apparatus
1
and are uncorrected. The H and 13C NMR data were
recorded in CDCl3 solution with a Varian Mercury
300 BB spectrometer. The chemicalshifts are reported
in ppm relative to TMS. The optical rotations were
determined with a JASCO J-20C polarimeter with
0.2 dm tube. The mass spectra were measured with EI
(70 eV) technique. HPLC analysis was performed on
Varian Dynamax SD-300 using chiralcel column
CDMPC (150 · 4.6 mmB) with hexane/isopropylaclo-
1
Mp 46–48 ꢁC. H NMR (300 MHz, CDCl3): d 0.89 (t,
J = 6.6 Hz, 3H), 1.31 (m, 2H), 1.33 (m, 2H), 2.64 (t,
J = 6.3 Hz, 2H), 3.81 (s, 6H), 6.98 (s, 2H), 9.82 (s, 1H);
13C NMR (75 MHz, CDCl3): d 13.8, 22.7, 23.0, 30.8,
55.5, 104.5, 127.0, 135.0, 158.3, 191.6. MS (EI): m/z 222
(M+, 21), 179 (100), 151 (26), 119 (27), 91 (44), 77 (31).

W. Quan et al. / Tetrahedron: Asymmetry 16 (2005) 2231–2234
2233
4.3. 2-Butyl-5-((E)-hept-1-enyl)-1,3-dimethoxybenzene
(E)-4
ture and atmospheric pressure. After neutralization
with solid Na2CO3, the catalyst was filtered off. The sol-
vent was distilled off and flash chromatographed using
petroleum ether and ethyl acetate (10:1, v/v) to afford
compound 6 as a white solid (200 mg, 70%). Mp 56–
To a solution of n-hexyltriphenylphosphonium bromide
(8.88 g, 20.82 mmol) in THF (40 mL), n-BuLi (3.30 M,
6.35 mL) was added dropwise and stirred for 30 min
under a stream of argon at 0 ꢁC. Compound 3 (4.20 g,
18.92 mmol) in THF (20 mL) was added dropwise to
the above solution at 0 ꢁC and stirred for 2 h at room
temperature. After quenching the reaction with brine,
it was extracted with ethylacetate and dried and evap-
orated. The residue was flash chromatographed using
petroleum ether and ethyl acetate (50:1, v/v) to give
an E:Z mixture 4 as a colorless oil (5.26 g, 96%). The
oilwas dissovled in hexane–ether (500 mL; v/v = 3:2)
and a couple of iodine crystals were added to the solu-
tion, which was exposed to sunlight for 1 h. After wash-
ing with aqueous sodium thiosulfate and water, the
solution was dried, and evaporated to dryness to give
(E)-4 as a colorless oil (5.25 g, 99%). 1H NMR
(300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3): d
0.89–0.93 (m, 6H), 1.34–1.55 (m, 10H), 2.20 (m, 2H),
2.61 (t, J = 7.2 Hz, 2H), 3.82 (s, 6H), 6.20 (m, 1H),
6.34 (d, J = 15.9 Hz, 1H) 6.54 (s, 2H); 13C NMR
(75 MHz, CDCl3): d 14.1, 22.6, 22.8, 29.1, 31.4, 31.6,
32.9, 55.6, 101.5, 118.6, 130.1, 130.4, 136.4, 158.3. MS
(EI): m/z 290 (M+, 25), 247 (100), 84 (44). HRMS calcd
for C19H31O2 (M+H): 291.2319. Found (M+H)+:
291.2314.
25
1
57 ꢁC. ½aŠ ¼ À12 (c 1.0, CH3OH, ee 93%); H NMR
D
(300 MHz, CDCl3): d 0.89–0.94 (m, 6H), 1.28–1.49
(m, 10H), 1.53 (m, 2H), 1.62 (s, 1H), 2.55
(dd, J = 13.5 Hz, 4.2 Hz, 1H), 2.57 (t, J = 6.9 Hz, 2H)
2.80 (dd, J = 13.5 Hz, 3.9 Hz, 1H), 3.79 (s, 6H), 3.80
(m, 1H), 6.39 (s, 2H); 13C NMR (75 MHz, CDCl3):
d 14.0, 22.5, 22.6, 22.9, 25.5, 31.6, 31.9, 36.9, 44.6,
55.7, 72.6, 104.8, 117.7, 137.0, 158.3. HRMS calcd
for C19H33O3 (M+H): 309.2424. Found (M+H)+:
309.2423.
4.6. (R)-2-Butyl-1,3-dimethoxy-5-(2-methoxyheptyl)-
benzene 7
To a solution of 6 (183 mg, 0.594 mmol) in THF
(20 mL) were added NaH (60%, 28.5 mg, 0.713 mmol)
and MeI (101 mg, 0.713 mmol) and the mixture stirred
under a stream of argon at room temperature for 12 h.
On completion of the reaction, water was added to the
solution. It was extracted with ether and the organic
extracts were washed with water, dried with anhydrous
Na2SO4, and the solvent evaporated. The residue was
flash chromatographed using petroleum ether and ethyl
acetate (25:1, v/v) to give compound 7 as a colorless oil
25
D
1
(189 mg, 99%). ½aŠ ¼ þ14 (c 1.0, CH3OH); H NMR
4.4. (1R,2R)-1-(4-Butyl-3,5-dimethoxyphenyl)heptane-
1,2-diol 5
(300 MHz, CDCl3): d 0.90 (t, J = 7.2 Hz, 3H), 0.93 (t,
J = 7.5 Hz, 3H), 1.30–1.68 (m, 12H), 2.61 (t,
J = 7.2 Hz, 2H), 2.65 (dd, J = 13.5 Hz, 6.0 Hz, 1H),
2.81 (dd, J = 13.5 Hz, 6.6 Hz, 1H), 3.34 (s, 3H), 3.38
(m, 1H), 3.81 (s, 6H), 6.40 (s, 2H); 13C NMR
(75 MHz, CDCl3): d 14.0, 22.5, 22.6, 22.8, 24.9, 31.7,
32.0, 33.6, 40.9, 55.7, 57.0, 82.4, 104.9, 117.3, 137.8,
158.0. HRMS calcd for C20H35O3 (M+H): 323.2581.
Found (M+H)+: 323.2576.
To a stirred solution of tert-BuOH (5 mL) and H2O
(5 mL), AD-mix-b (1.40 g) and MeSO2NH2 (95 mg)
were added and the mixture stirred at room tempera-
ture until both phases were clear, cooled to 0 ꢁC and
(E)-4 (0.290 g, 1.00 mmol) then added immediately
into it. The mixture was stirred vigorously at 0 ꢁC
and judged by TLC. The reaction was quenched at
0 ꢁC by addition of Na2SO3 (1.50 g), warmed to room
temperature and stirred for 0.5 h. The reaction mix-
ture was extracted with ethylacetate. The combined
organic layer was washed with a 2 N KOH solution,
water, and dried. The solvent was distilled off, and
the residue was flash chromatographed using petro-
leum ether and ethyl acetate (2:1, v/v) to afford the diol
4.7. (R)-2-Bromo-4-butyl-3,5-dimethoxy-1-(2-methoxy-
heptyl)benzene 8
To a solution of 7 (683 mg, 2.12 mmol) in dry DMF
(12 mL) was added NBS (378 mg, 2.12 mmol) and the
mixture stirred at room temperature for 24 h. The reac-
tion mixture was poured into ice water (50 mL) and
extracted with ethylacetate. The combined organic layer
was washed with brine and dried with anhydrous
Na2SO4. After column chromatography purification
using petroleum ether and ethyl acetate (25:1, v/v), the
5 as a white solid (0.298 g, 92%). Mp 84–86 ꢁC.
25
½aŠ ¼ À3.0 (c 1.0, CH3OH, ee 95%); 1H NMR
D
(300 MHz, CDCl3): d 0.83–0.93 (m, 6H), 1.25–1.48
(m, 12H), 2.40 (s, 1H), 2.61 (t, J = 7.2 Hz, 2H), 2.68
(s, 1H), 3.68 (m, 1H), 3.81 (s, 6H), 4.37 (d,
J = 6.0 Hz, 1H), 6.50 (s, 2H); 13C NMR (75 MHz,
CDCl3): d 14.0, 22.5, 22.8, 25.3, 31.4, 31.7, 32.6, 55.6,
75.8, 78.3, 102.1, 119.0, 139.8, 158.1. HRMS calcd for
C19H34O4Na (M+Na): 347.2193. Found (M+Na)+:
347.2191.
compound 8 was obtained as a colorless oil (814 mg,
25
D
96%). ½aŠ ¼ À4.0 (c 1.0, CH3OH); 1H NMR
(300 MHz, CDCl3): d 0.88 (t, J = 7.2 Hz, 3H), 0.92 (t,
J = 7.2 Hz, 3H), 1.27–1.54 (m, 12H), 2.63 (t,
J = 7.2 Hz, 2H), 2.82 (dd, J = 13.5 Hz, 6.0 Hz, 1H),
2.93 (dd, J = 13.5 Hz, 7.2 Hz, 1H), 3.32 (s, 3H), 3.46
(m, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 6.59 (s, 1H); 13C
NMR (75 MHz, CDCl3): d 13.9, 14.0, 22.6, 23.0, 24.4,
24.9, 32.0, 34.0, 41.4, 55.6, 57.3, 61.0, 80.5, 109.9,
110.9, 124.5, 137.3, 155.4, 157.2. HRMS calcd for
4.5. (R)-1-(4-Butyl-3,5-dimethoxyphenyl)heptan-2-ol 6
The diol 5 (300 mg, 0.926 mmol) was hydrogenated
using 10% Pd/C (30 mg) in dry ethylacetate (30 mL)
and two drops of 98% H2SO4 for 6 h at room tempera-
C20H37BrNO3
(M+NH4):
418.1951.
Found
(M+NH4)+: 418.1949.

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W. Quan et al. / Tetrahedron: Asymmetry 16 (2005) 2231–2234
4.8. Ethyl (R)-3-butyl-2,4-dimethoxy-6-(2-methoxy-
heptyl)benzoate 9
due flash chromatographed using petroleum ether and
ethylacetate (20:1, v/v) to give compound 1 as a color-
25
D
less solid (38 mg, 40%). Mp 148–149 ꢁC. ½aŠ ¼ À24 (c
25
D
To a solution of 8 (750 mg, 1.875 mmol) in dry THF
(10 mL), n-BuLi (2.60 M, 0.865 mL) was added drop-
wise under a stream of argon at À78 ꢁC. The resulting
reaction mixture was allowed to warm to 0 ꢁC gradually.
The reaction mixture was cooled to À78 ꢁC after 2 h,
after which ethylchol roformate (0.215 mL, 2.25 mmo)l
in THF (10 mL) was added to the above solution. The
resulting reaction mixture was allowed to warm to room
temperature gradually. The mixture was stirred until
TLC revealed the absence of 8. Brine was then added
to the reaction mixture, which was extracted with ethyl
acetate and the organic extract dried, and evaporated.
The residue was flash chromatographed using petroleum
0.1, CH3OH, ee 93%), lit.1 ½aŠ ¼ À20; 1H NMR
(300 MHz, CDCl3): d 0.89 (t, J = 6.9 Hz, 3H), 0.93 (t,
J = 7.2 Hz, 3H), 1.33 (m, 2H), 1.40 (m, 2H), 1.53 (m,
2H), 1.62 (m, 2H), 1.70 (m, 2H), 1.86 (m, 2H), 2.63 (t,
J = 7.5 Hz, 2H), 2.80 (m, 2H), 4.50 (m, 1H), 6.19 (s,
1H) 11.44 (s, 1H); 13C NMR (75 MHz, CDCl3): d
14.0, 22.2, 22.5, 22.8, 24.5, 30.9, 31.5, 32.9, 34.7, 79.3,
101.6, 105.9, 114.6, 138.3, 159.9, 162.2, 170.5. HRMS
calcd for C18H25O4 (MÀH): 305.1758. Found (MÀH)À:
305.1752.
Acknowledgements
ether and ethylacetate (30:1, v/v) to give the compound
25
9 as a colorless oil (687 mg, 93%). ½aŠ ¼ þ12 (c 1.02,
D
This work was supported by the SpecialDoctorialPro-
gram Funds of the Ministry of Education of China
(20040730008), A Hundred Talents Program of CAS,
NSFC (QT program), and NFSC (20372026).
CH3OH); 1H NMR (300 MHz, CDCl3): d 0.86 (t,
J = 6.9 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H), 1.16–1.53 (m,
12H), 1.37 (t, J = 6.9 Hz, 3H), 2.57 (t, J = 7.8 Hz, 2H),
2.64 (dd, J = 13.8 Hz, 5.7 Hz, 1H), 2.82 (dd,
J = 13.8 Hz, 7.2 Hz, 1H), 3.24 (s, 3H), 3.31 (m, 1H),
3.76 (s, 3H), 3.80 (s, 3H), 4.35 (q, J = 7.2 Hz, 2H),
6.53 (s, 1H); 13C NMR (75 MHz, CDCl3): d 13.9, 14.0,
14.2, 22.6, 23.1, 23.5, 24.9, 31.8, 31.9, 34.0, 38.4, 55.5,
57.2, 60.9, 62.6, 81.9, 108.6, 121.4, 122.8, 136.1, 156.3,
159.0, 168.6. HRMS calcd for C23H39O5 (M+H):
395.2792. Found (M+H)+: 395.2788.
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4.9. (R)-7-Butyl-6,8-dihydroxy-3-pentylisochroman-1-one
1
To a solution of BBr3 (0.87 mL, 9.39 mmol) in freshly
distilled CH2Cl2 (5 mL) at À78 ꢁC was added a solution
of 9 (122 mg, 0.313 mmol) dropwise in CH2Cl2 (3 mL).
The resulting reaction mixture was allowed to warm to
room temperature and stirred for 24 h. The reaction
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