Concise formal synthesis of (S)-Gregatin B

Article abstract of DOI:10.3987/COM-05-10391

(S)-3-Acetyl-5-[(1E,3E)-1,3-hexadienyl]-4-hydroxy-5-methyl-2(5H)-furanone, known precursor for the synthesis of (S)-gregatin B, was synthesized in a fewer steps and higher overall yield starting from (R)-lactic acid.

Full text of DOI:10.3987/COM-05-10391

HETEROCYCLES, Vol. 65, No. 7, 2005
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HETEROCYCLES, Vol. 65, No. 7, 2005, pp. 1609 - 1614
Received, 7th March, 2005, Accepted, 27th April, 2005, Published online, 28th April, 2005
CONCISE FORMAL SYNTHESIS OF (S)-GREGATIN B
Keizo Matsuo,*a Masaru Kanayama,b Jin Yi Xu,a Rie Takeuchi,a
Keiji Nishiwaki,a and Yukihiro Asakab
a Faculty of Pharmaceutical sciences and b School of Science and
Engineering, Kinki University, 3-4-1 Kowakae, Higashiosaka,
Osaka 577-8502, Japan. e-mail: k-matsuo@phar.kindai.ac.jp
Abstract-(S)-3-Acetyl-5-[(1E,3E)-1,3-hexadienyl]-4-hydroxy-5-methyl-2(5H)-
furanone, known precursor for the synthesis of (S)-gregatin B, was synthesized
in a fewer steps and higher overall yield starting from (R)-lactic acid.
(S)-Gregatins A, B1 and (R)-aspertetronins A, B2 were isolated from Cephalosporium gregatum and
Aspergillus panamensis, respectively, as antimicrobial metabolites and phytotoxic substances.3 They are
regarded as the derivatives of 3-acyltetronic acid which possesses the same side chain at C5, although the
chirality is different (Figure 1). On the synthetic research of these compounds, only one report for the
synthesis of (S)-gregatin B appeared in 1984,4 but the multi-steps were required and the total yield was
relatively low.
R
O
R
O
CH3O
CH3O
O
O
t
t
[(R)-Aspertetronin A]
R=COCH=CHCH3
R=COCH=CHCH3
[(S)-Gregatin A]
[(S)-Gregatin B]
R=COCH2CH(OH)CH3 [(R)-Aspertetronin B]
R=COCH3
Figure 1
In the course of our synthetic studies on biologically active natural products, which possess chiral
quaternary center accompanying with one oxygen function, we have synthesized (+)-ipomeamarone5 and
(-)-vertinolide6 by adapting the chiral self-reproduction method developed by Seebach et al.7
O
O
OH
OH
O
O
O
O
O
O
O
(+)-Ipomeamarone
(-)-Vertinolide
1
Figure 2

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HETEROCYCLES, Vol. 65, No. 7, 2005
In continuation of that line, we planned to synthesize (S)-3-acetyl-5-[(1E,3E)-1,3-hexadienyl]-4-hydroxy-
5-methyl- 2(5H)-furanone (1),4, 8 known precursor for the synthesis of (S)-gregatin B, in a fewer steps and
higher yield. Conversion of 1 to (S)-gregatin B using diazomethane in the presence of BF3-etherate
was reported by Takaiwa and Yamashita.4
For the synthesis of 1, (2R,5R)-2-(1,1-dimethylethyl)-5-methyl-1,3-dioxolan-4-one (2) 6, 7 was selected as
the starting material, which was readily derived from (R)-lactic acid9 and 2,2-dimethylpropanal. The
addition of the enolate derived from 2 to trans-2-hexenal occurred stereoselectively from α-side to give
the alcohol (3) as a 1:1 mixture of diastereomers concerning with the orientation of the hydroxyl group
(Scheme 1).
p-TsOH
conc. H2SO4
in pentane
1) LDA
2) trans-2-hexenal
O
COOH
H
O
O
O
O
O
CHO +
HO
(54%)
(87%)
H
OH
3
2
Scheme 1
In order to confirm the stereochemistry of the newly formed chiral center at C5 of 3, it was converted to
1
the enone (4) by oxidation with Dess-Martin periodinane.10 In the H-NMR spectrum of 4, no NOE was
observed between C2 methine proton and C5 methyl group (Scheme 2). This result indicates that the
stereochemistry at C5 is S.
O
O
O
O
O
O
O
Dess-Martin Oxd.
(72%)
H
OH
4
3
Scheme 2
Transformation of the allyl alcohol (3) to E,E-1,3-diene (5) was examined. After several fruitless trials
including, for example, mesylation of 3 and elimination with base or base treatment of the tosylhydrazone
of 4 (Bamford-Stevens reaction or Shapiro reaction), [2,3] sigmatropic rearrangement of the sulfenate of
3 to the sulfoxide and its thermal syn elimination11 were performed. Thus, the treatment of 3 with
2,4-dinitrophenylsulfenyl chloride in the presence of triethylamine gave the sulfenate, which rearranged
to form the sulfoxide, and the successive thermal syn elimination of the sulfoxide occurred to afford
exclusively E,E-5 in 76% yield. The required conformation for the syn elimination of the sulfoxide is
favorable to give the E,E-diene as shown below (Scheme 3).
For the construction of 3-acetyltetronic acid skeleton, the dioxolanone (5) was first treated with
magnesium methoxide to form the hydroxy ester (6) in 97% yield, which was successively acylated with
diketene in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine to provide the keto
diester (7) in 89% yield. The final condensation reaction of 7 was examined by the three different

HETEROCYCLES, Vol. 65, No. 7, 2005
1611
O
O
O
O
O
O
O
O
1) ArSCl, (C2H5)3N
2) heat
(76%)
O
O
S
OH
SAr
Ar
O2N
O
3
O
Ar
O
O
S
Ar=
NO2
O
E,E-5
Diox
5
CH2CH3
H
H
Scheme 3
methods, 1) triethylamine in acetone,4 2) tetrabutylammonium fluoride in THF,12 and 3) sodium
methoxide in methanol.13 Among them, the method 1 took long reaction time and resulted in lower yield.
On the other hand, the methods 2 and 3 worked well, in the shorter reaction time and higher yields, but in
the case of method 2, difficulties were observed in purification step using silica gel flash column
chromatography. The method 3 was the best, and the reaction completed within 30 min and the yield of
1
the desired compound (1) was 97% (Scheme 4). IR, H-NMR and MS spectral data were identical with
those of the reported racemic 1.8 Takaiwa and Yamashita have reported the transformation of 1 to
(S)-gregatin B and (S)-isogregatin B using diazomethane in the presence of BF3-etherate.4 Therefore, we
have completed the concise formal synthesis of (S)-gregatin B.
O
diketene
DMAP, (C2H5)3N
COOCH3
6
Mg(OCH3)2
O
O
O
COOCH3
CH3OH
(97%)
(89%)
HO
O
O
7
5
O
O
O
O
OCH3
OH
NaOCH3
ref. 4
+
CH3OH
(97%)
CH3O
(S)-Gregatin B
O
O
O
O
O
(S)-Isogregatin B
1
Scheme 4
In conclusion, we synthesized (S)-3-acetyl-5-[(1E,3E)-1,3-hexadienyl]-4-hydroxy-5-methyl-2(5H)-
furanone (1), known precursor for the synthesis of (S)-gregatin B, in 6 steps and 30% overall yield
starting from (R)-lactic acid (the reported method4: 12 steps and 0.83% overall yield starting from
(S)-tetrahydro-2-methyl-5-oxo-2-furancarboxylic acid14).
EXPERIMENTAL

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HETEROCYCLES, Vol. 65, No. 7, 2005
IR spectra were measured with a Hitachi 260-30 or JASCO FT/IR-460 plus infrared spectrophotometer.
1H-NMR spectra were recorded on a JEOL JNM-GSX270 (270 MHz) or JEOL JNM-ECA500 (500 MHz)
spectrometer using tetramethylsilane as the internal standard. MS and high-resolution MS spectra
(HRMS) were measured with a JEOL JMS-700TKM instrument at 70 eV. Optical rotation was measured
with JASCO DIP-370 polarimeter.
(2R,5S)-2-tert-Butyl-5-(1-hydroxy-2-hexenyl)-5-methyl-1,3-dioxolan-4-one (3)
A solution of 2 (4.13 g, 15.3 mmol) in THF (20 mL) was added dropwise under stirring to a THF solution
of LDA [prepared from diisopropylamine (4.43 mL, 31.6 mmol), n-C4H9Li (19.4 mL, 30.9 mmol, 1.59 M
hexane solution, and THF (160 mL)] at -78 ℃, and the mixture was stirred for 45 min. To the obtained
solution was added dropwise under stirring a solution of trans-2-hexenal (4.40 g, 37.7 mmol) in THF (16
mL) at that temperature, and the mixture was stirred for 55 min at -78 ℃. After the mixture was warmed
up to rt, half saturated NH4Cl solution was added and the mixture was extracted with ether. The combined
organic layer was washed with brine and dried over anhydrous Na2SO4. Removal of the solvent under
reduced pressure gave an oil which was purified by SiO2 flash column chromatography
(hexane:ether=4:1) to give 3 (5.64 g, 87%) as a pale yellow oil. IR (neat): 3480, 1793, 1670 cm-1.
1H-NMR (CDCl3) δ: 0.88 (3H, m, CH3), 0.95 (9H, s, C(CH3)3), 1.37 (3H, s, CH2CH3), 1.40-1.45 (2H, m,
CH2CH3), 1.92 (1H, br s, OH), 2.01-2.11 (2H, m, =CHCH2), 4.20-4.25 (1H, m, CHOH), 5.41 (1H, s,
OCHO), 5.56-5.84 (2H, m, CH=CH). MS (m/z): 158, 125, 87, 70, 57, 43.
(2R,5S)-2-tert-Butyl-5-(2-hexenoyl)-5-methyl-1,3-dioxolan-4-one (4)
A solution of 3 (4.70 g, 18.5 mmol) in CH2Cl2 (18.2 mL) was added dropwise under stirring to the
solution of Dess- Martin periodinane (15 wt % in CH2Cl2, 55.8 mL, 26.8 mmol) and the solution was
heated under reflux for 1.5 h. After cooling down, the mixture was diluted with ether (107 mL) and
saturated NaHCO3 (107 mL) solution containing Na2SO3 (26.75 g), and stirred for 5 min. After separation
of the layers, the water layer was extracted with ether. The combined organic layer was washed with
saturated NaHCO3 solution, water, and brine, successively, and dried over anhydrous Na2SO4. Removal
of the solvent under reduced pressure gave an oil which was purified by SiO2 flash column
chromatography (hexane:ether=2:1) to afford 4 (3.35 g, 72%) as a pale yellow oil. IR (neat): 1797, 1704,
1626 cm-1. 1H-NMR (CDCl3) δ: 0.95 (3H, t, J=7.0 Hz, CH2CH3), 1.00 (9H, s, C(CH3)3), 1.52 (2H, sextet,
J=7.0 Hz, CH2CH3), 1.66 (3H, s, CH3), 2.21-2.29 (2H, m, CH2CH2CH3), 5.21 (1H, s, OCHO), 6.55 (1H,
dt, J=15.3, 1.65 Hz, CH=CHCH2), 7.16 (1H, dt, J=15.3, 7.0 Hz, CH=CHCH2). HRMS (m/z) Calcd for
C14H22O4: 254.1518. Found: 254.1526.
(2R,5S)-2-tert-Butyl-5-[(1E,3E)-1,3-hexadienyl]-5-methyl-1,3-dioxolan-4-one (5)
To a solution 3 (5.00 g, 19.5 mmol) in CH2Cl2 (176 mL) were added under stirring (C2H5)3N (7.1 mL,
50.7 mmol) and 2,4-dinitrobenzenesulfenyl chloride (10.98 g, 46.8 mmol) and the mixture was heated
under reflux for 3 h. After cooling down to rt, pentane was added to form precipitates, which were
removed by filtration. The filtrate was concentrated under reduced pressure to give an oil which was
purified by SiO2 flash column chromatography (hexane:ether=79:1) to afford 5 (3.53 g, 76%) as a pale

HETEROCYCLES, Vol. 65, No. 7, 2005
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yellow oil. IR (neat): 1793, 1670 cm-1. 1H-NMR (CDCl3) δ: 0.98 (9H, s, C(CH3)3), 1.05 (3H, t, J=7.0 Hz,
CH2CH3), 1.52 (3H, s, CH3), 2.06-2.17 (2H, m, =CHCH2), 5.14 (1H, s, OCHO), 5.52 (1H, d, J=15.5 Hz,
CH=CH-CH=CH2), 5.84 (1H, dt, J=15.5, 6.5 Hz, CH=CHCH2), 6.03 (1H, tdd, J=15.5, 10.5, 2.0 Hz,
=CH-CH=CHCH2), 6.30 (1H, dd, J=15.5, 10.5 Hz, CH=CH-CH=CHCH2). [α]D26: -77.85o (c=0.009,
CH3OH). HRMS (m/z) Calcd for C14H22O3: 238.1569. Found: 238.1577. Anal. Calcd for C14H22O3: C,
70.56; H, 9.31. Found: C, 70.69; H, 9.25.
(S)-(3E,5E)-Methyl 2-hydroxy-2-methyl-3,5-octadienoate (6)
To a solution of Mg(OCH3)2 in CH3OH [prepared from Mg (460 mg, 18.9 mg atom), CH3OH (10 mL),
and small amount of CCl4] was added dropwise under stirring a solution of 5 (1.50 g, 6.3 mmol) in THF
at 0 ℃. The reaction mixture was stirred and warmed gradually up to rt over a period of 25 min and then
the stirring was continued for 1.5 h at 30 ℃. After addition of saturated NH4Cl solution, the mixture was
extracted with AcOC2H5. The organic layer was washed with brine and dried over anhydrous Na2SO4.
Removal of the solvent under reduced pressure gave 6 (1.12 g, 97%) as a colorless oil. IR (neat): 3510,
1
1738, 1657 cm-1. H-NMR (CDCl3) δ: 1.00 (3H, t, J=7.4 Hz, CH2CH3), 1.50 (3H, s, CH3), 2.11 (2H, m,
=CHCH2), 3.78 (3H, s, COOCH3), 5.69 (1H, d, J=15.3 Hz, CH=CH-CH=), 5.79 (1H, dt, J=15.3, 6.5 Hz,
CH=CHCH2), 6.03 (1H, tdd, J=15.3, 10.3, 2.0 Hz, CH=CHCH=CH), 6.38 (1H, dd, J=15.3, 10.5 Hz,
CH=CHCH=). [α]D26: -11.53o (c=0.011, CH3OH). HRMS (m/z) Calcd for C10H16O3: 184.1099. Found:
184.1100.
(S)-Methyl 2-(3-oxobutanoyloxy)-2-methyl-(3E,5E)-3,5-octadienoate (7)
To a solution of 6 (787 mg, 4.3 mmol) and DMAP (47 mg 0.34 mmol) in ether (17.5 mL) was added
dropwise diketene (0.43 mL, 5.7 mmol) at rt under stirring and then the mixture was stirred for 50 min at
rt. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by
SiO2 flash column chromatography (hexane:ether=4:1) to afford 7 (1.02 g, 89%) as a colorless oil. IR
1
(neat): 1747, 1722, 1655 cm-1. H-NMR (CDCl3) δ: 1.01 (3H, t, J=7.5 Hz, CH2CH3), 1.71 (3H, s, CH3),
2.01-2.14 (2H, m, =CHCH2), 2.29 (3H, s, CH3), 3.47 (2H, s, COCH2CO), 3.74 (3H, s, COOCH3), 5.82
(1H, d, J=15.5 Hz, CH=CHCH=), 5.84 (1H, dt, J=15.5, 6.5 Hz, CH=CHCH2), 6.03 (1H, tdd, J=15.5, 10.3,
2.0 Hz, CH=CHCH=), 6.31 (1H, dd, J=15.5, 10.3 Hz, CH=CHCH=). [α]D26: -30.55o (c=0.013, CH3OH).
HRMS (m/z) Calcd for C14H20O5: 268.1311. Found: 268.1325.
(S)-3-Acetyl-5-[(1E,3E)-1,3-hexadienyl]-4-hydroxy-5-methyl-2(5H)-furanone (1)
To a solution of NaOCH3 [prepared from Na (14 mg, 0.61 mg atom) and CH3OH (1 mL)] was added
under stirring a solution of 7 (109.6 mg, 0.41 mmol) in CH3OH (3 mL) over a period of 10 min and then
the reaction mixture was heated under reflux for 30 min. After concentration of the mixture under reduced
pressure, to the residue was added 2N HCl (1.5 mL). The mixture was salted out and extracted with
CHCl3. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. Removal
of the solvent under reduced pressure gave 1 (93.4 mg, 97%) as a pale yellow oil. IR (neat): 1768, 1696,
1662, 1614 cm-1. 1H-NMR (CDCl3) δ: 1.00 (3H, t, J=7.4 Hz, CH2CH3), 1.58 (3H, s, CH3), 2.06-2.16 (2H,
m, =CHCH2), 2.54 (3H, s, COCH3), 5.60 (1H, d, J=15.3 Hz, CH=CHCH=), 5.84 (1H, dt, J=15.3, 6.5 Hz,

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CH=CHCH2), 5.96-6.05 (1H, m, CH=CHCH=), 6.37 (1H, dd, J=15.3, 10.1 Hz, CH=CHCH=), 11.16 (1H,
br s, OH). [α]D24: -128.46o (c=0.011, CHCl3). HRMS (m/z) Calcd for C13H16O4: 236.1049. Found:
236.1045.
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