Organocatalytic approach for short asymmetric synthesis of (r)-paraconyl alcohol: Application to the total syntheses of IM-2, SCB2, and a-factor γ-butyrolactone autoregulators

Article abstract of DOI:10.1021/acs.joc.8b00122

(R)-Paraconyl alcohol is found to be a key intermediate for the syntheses of many γ-butyrolactone autoregulators. The chiral auxiliary approach and enzymatic resolution are the two common strategies employed so far in the literature for the asymmetric syn

Full text of DOI:10.1021/acs.joc.8b00122

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Note
An Organocatalytic Approach for Short Asymmetric Synthesis
of (R)-Paraconyl Alcohol: Application to the Total Syntheses
of IM-2, SCB2 and A-Factor #-Butyrolactone Autoregulators
Abhijeet M Sarkale, Amit Kumar, and Chandrakumar Appayee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00122 • Publication Date (Web): 28 Feb 2018
Downloaded from http://pubs.acs.org on February 28, 2018
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The Journal of Organic Chemistry
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An Organocatalytic Approach for Short Asymmetric Synthesis of
(R)-Paraconyl Alcohol: Application to the Total Syntheses of IM-2,
SCB2 and A-Factor γ-Butyrolactone Autoregulators
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Abhijeet M. Sarkale, Amit Kumar and Chandrakumar Appayee*
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India
Supporting Information Placeholder
ABSTRACT: (R)-Paraconyl alcohol is found to be a key intermediate for the syntheses of many γ-butyrolactone autoregu-
lators. Chiral auxiliary approach and enzymatic resolution are the two common strategies employed so far in the litera-
ture for the asymmetric synthesis of (R)-paraconyl alcohol. Herein, we report a first organocatalytic approach for the
short asymmetric synthesis of (R)-paraconyl alcohol in four steps and single column purification. Asymmetric syntheses
of IM-2, SCB2 and A-factor γ-butyrolactone autoregulators were achieved from (R)-paraconyl alcohol in three steps.
Chiral γ-butyrolactones are the most common structur-
al motifs in wide variety of bioactive natural products
and pharmaceuticals.1 2,3-Disubstituted γ-butyrolactone
autoregulators have been isolated from Streptomyces spe-
cies that trigger production of commercially significant
antibiotics2 and pigments3. Fourteen such autoregulators
have been isolated and chemically identified so far.
Figure 1. γ-Butyrolactone autoregulators and (R)-paraconyl
Figure 2. Asymmetric synthesis of (R)-paraconyl alcohol 1.
alcohol 1.
Many synthetic methodologies have been developed for
the syntheses of A-factor5, virginiae butanolides6 and IM-
27,6c type natural products. (R)-Paraconyl alcohol 1 have
been considered as an important chiral intermediate for
the syntheses of most of these autoregulators5a,5c,6b,8 and
other bioactive molecules.9 Racemic synthesis of para-
Based on the functional groups and stereochemistry of
the side-chain, γ-butyrolactone autoregulators have been
classified as A-factor type (possessing 1 -keto group), vir-
giniae butanolide type (possessing 1 -(S)-hydroxyl group)
and IM-2 type (possessing 1 -(R)-hydroxyl group) auto-
regulators (Figure 1).4
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conyl alcohol and its application towards butyrolactone
Page 2 of 7
To achieve higher product ee for the α-
hydroxymethylation of methyl 4-oxobutanoate 4, we have
used the general procedure reported14d for the α-
hydroxymethylation of aldehydes by Hayashi et al. with
slight modification (reaction concentration was doubled
and NaCl was used as an additive). Accordingly, methyl 4-
oxobutanoate 4 was reacted with aqueous formaldehyde
in presence of (S)-diarylprolinol and NaCl in toluene and
autoregulators10 and other natural products11 were also
reported in the literature. Chiral auxiliary approach5a and
enzymatic resolution5c,12a,b are the two common strategies
have been so far reported in the literature for the asym-
metric synthesis12 of (R)-paraconyl alcohol 1 in seven
steps. Through chiral auxiliary approach, alcohol 1 was
obtained from oxazolidinone 2 in seven steps with 8%
overall yield (Figure 2).5a By lipase-mediated enzymatic
resolution, alcohol 1 was obtained from diester 3 in seven
steps with 9% overall yield and 83% ee.12a
1
2
3
4
5
6
7
8
methanol at
0
°C for
6
days. The crude α-
hydroxymethylated product was oxidized to carboxylic
acid 5 using Pinnick oxidation. As acid 5 was partially cy-
clized to (S)-paraconic acid 6 during work up conditions,
the crude reaction mixture was treated with 6 M HCl to
undergo complete cyclization. The crude (S)-paraconic
acid 6 was further reduced using BH3.Me2S to give (R)-
paraconyl alcohol 1 in 35% isolated yield and 95% ee after
silica gel column chromatography (Scheme 1). Enantio-
meric excess of alcohol 1 was determined by converting it
into chromophoric 4-tert-butylbenzoate derivative 7 (see
experimental section).
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In this paper, we report a first organocatalytic approach
for the asymmetric synthesis of (R)-paraconyl alcohol 1
starting from methyl 4-oxobutanoate 4 in four steps with
35% yield and 95% ee after single column chromatog-
raphy purification. We have also applied this methodolo-
gy for the asymmetric syntheses of IM-2, SCB2 and A-
factor γ-butyrolactone autoregulators in three steps.
Scheme 1. Asymmetric synthesis (R)-paraconyl alco-
hol 1
After achieving short synthesis of (R)-paraconyl alcohol
1, its application to the total syntheses of IM-2, SCB2 and
A-factor γ-butyrolactone autoregulators was explored.
Scheme 2. Synthesis TBS ether of IM-2 through acyla-
tion followed by reduction
For the synthesis of (R)-paraconyl alcohol 1, asymmetric
α-hydroxymethylation of aldehyde 4 using aqueous for-
maldehyde was conceived as a key step. Though chiral
amine catalyzed aldol reactions are one of the most stud-
ied carbon-carbon bond forming reactions in the past few
decades,13 use of formaldehyde as an aldehyde partner is
For the total synthesis of IM-2, initially, acylation fol-
lowed by reduction strategy was envisaged. Accordingly,
(R)-paraconyl alcohol 1 was subjected to silyl protection
to synthesize TBS ether 8 (95%) followed by acylation
using NaHMDS (sodium bis(trimethylsilyl)amide) and
°
butyryl chloride at –78 C to form ketone 9 in 87% yield.
less
explored
in
the
literature14.
Diastereoselective reduction of ketone 9 was studied with
reducing agents such as NaBH4, Zn(BH4)2 and
CeCl3.7H2O/NaBH4. Among them, CeCl3.7H2O/NaBH4
α-Hydroxymethylated aldehydes were found to be unsta-
ble for purification and hence further oxidized to carbox-
ylic acids using Pinnick oxidation.14b,c
°
(Luche reduction) in MeOH at –20 C was found to be
more effective to produce diastereomeric alcohols in 90%
isolated yield and 70:30 dr. The major diastereomeric al-
cohol 10 (63%) was purified by silica gel column chroma-
tography (Scheme 2).
Although L-proline successfully catalyzed aldol reaction
of methyl 4-oxobutanoate 4 with benzaldehydes,15 we
observed that the similar reaction with formaldehyde
failed to give aldol product. On the other hand, aldol re-
action of methyl 6-oxohexanoate with formaldehyde cata-
lyzed by (S)-diphenylprolinol trimethyl silyl ether has
been reported to give α-hydroxymethylated product with
>99% ee.14b Using the similar reaction conditions, we have
obtained only moderate (78% ee) enantioselectivity for
the α-hydroxymethylation of methyl 4-oxobutanoate 4.
Scheme 3. Synthesis of IM-2 and SCB2 through direct
aldol reaction
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The Journal of Organic Chemistry
for the short synthesis of (R)-paraconyl alcohol 1 shall also
1
2
be applied for the synthesis of other 2,3-disubstituted γ-
butyrolactone natural products.
3
4
5
Experimental section
General information
All reactions were carried out in the oven dried glassware
unless otherwise noted. Except as otherwise indicated, all
reactions were magnetically stirred and monitored by
thin-layer chromatography using Merck pre-coated silica
gel plates. Column chromatography was done with 60-120
mesh silica gel supplied by Merck. Commercially available
reagents and solvents were used without further purifica-
tion except as indicated below. Methanol, dichloro-
methane, and toluene (PhMe) were freshly distilled over
calcium hydride under an atmosphere of dry argon prior
to use. THF were freshly distilled over sodium under an
atmosphere of dry nitrogen prior to use. Organic solu-
tions were concentrated using a Heidolph rotary evapora-
tor. NMR spectra were recorded on a Bruker 500 MHz
spectrometer in chloroform-d. Chemical shifts (δ) are
reported in parts per million (ppm) relative to internal
standard (TMS, 0.00 ppm). Multiplicities are given as s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet)
and br (broad). Optical rotations were measured using a
Rudolph Research Analytical polarimeter. HPLC analysis
was performed by Agilent Technologies 1260 infinity in-
strument with an IA chiral column (25 cm) using the giv-
en conditions. Infrared spectra were taken on a Perki-
nElmer FTIR spectrometer. The HRMS data for all the
compounds were recorded (in positive ion mode) with
Waters Synapt-G2S ESI-Q-TOF Mass instrument.
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An alternative method for the synthesis of alcohol 10
was developed involving a direct aldol reaction of lactone
°
8 with NaHMDS16 and butyraldehyde at –78 C to rt to
obtain alcohol 10 in 70% yield with 67:33 dr. The major
diastereomeric alcohol 10 (47%) was purified by silica gel
column chromatography. TBS group in alcohol 10 was
conveniently deprotected using HCl in diethyl ether to
achieve IM-2 12 in 94% isolated yield (Scheme 3). Similar-
ly, lactone 8 was reacted with octan-1-al to form major
aldol product 11 (42%) that was subjected to HCl in dieth-
yl ether to generate SCB2 13 in 95% isolated yield.
Scheme 4. Synthesis of A-factor
(R)-4-(hydroxymethyl)dihydrofuran-2(3H)-one 1:
round-bottom flask equipped with magnetic stir bar was
charged with (S)-bis(3,5-
A
a
bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol (4.7
g, 9.0 mmol) and NaCl (8.7 g) under argon condition. The
flask was capped with a rubber septum, toluene (13.5 mL)
Acylation of lactone 8 using NaHMDS and acid chloride
1410f at –78 °C gave ketone 15 in 52% yield. Deprotection of
silyl group in 15 using tetrabutylammonium fluoride in
THF resulted in 70% isolated yield of A-factor 16 along
with its hemiketal form5d in 3:1 ratio (Scheme 4). Spectral
data of IM-2 12, SCB2 13 and A-factor 16 obtained are in
good agreement with that of reported in the literature.7
°
and methanol (1.5 mL) was added by syringe at 0 C. For-
maldehyde (6.7 mL of 37% aq. solution, 90.0 mmol) was
added to the vigorously stirring heterogeneous mixture.
This was allowed to stir for 15 min before distilled methyl
4-oxobutanoate 417 (3.14 mL, 30.0 mmol) was added. The
°
In conclusion, we have developed first organocatalytic
approach for a short asymmetric synthesis of (R)-
paraconyl alcohol 1 staring form methyl 4-oxobutanoate 4
in four steps with 35% isolated yield and 95% ee after sin-
gle column purification. (S)-Diaryl prolinol was used as a
catalyst for the asymmetric α-hydroxymethylation of me-
thyl 4-oxobutanoate 4 using aqueous formaldehyde. We
have also accomplished total synthesis of IM-2 12, a γ-
butyrolactone autoregulator through direct aldol reaction
in just three steps from (R)-paraconyl alcohol 1 with 42%
overall yield. Alternate method was developed through
acylation followed by reduction to obtain higher overall
yield (49%) but in four steps. We have also shown appli-
cation of (R)-paraconyl alcohol 1 for the asymmetric syn-
theses of SCB2 13 through direct aldol reaction and A-
factor 16 through acylation. Our synthetic methodology
reaction was stirred the mixture stirred at 0 C for 6 days
and then the solvent was removed in vacuo to afford a
colorless liquid.
The crude product was then dissolved in tert-butanol
(150 mL), 2-methyl-2-butene (31.9 mL, 300.0 mmol) was
added and allowed to stir. To the stirring solution was
added a solution of NaClO2 (10.84 g, 120.0 mmol) and
NaH2PO4·H2O (16.54 g, 120.0 mmol) in H2O (75 mL) and
the reaction was capped with a rubber septum with a
needle as outlet. The resulting biphasic solution was
stirred for 7 h at which point the tert-butanol was re-
moved in vacuo to afford an aqueous residue. The residue
was acidified with 10% HCl and saturated with sodium
chloride. The aqueous layer was then extracted with
EtOAc (3 × 100 mL), the organic extracts were dried with
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Page 4 of 7
Na2SO4 and the solvent was removed in vacuo to afford a
(S)-4-(((tert-
1
crude acid 5.
butyldimethylsilyl)oxy)methyl)dihydrofuran-2(3H)-
2
3
4
5
6
7
8
9
one 8
The crude product 5 was dissolved in THF (80 mL) and
H2O (20 mL) was added to it. The resulting solution was
To a solution of alcohol 1 (1.0 g, 8.6 mmol) in dichloro-
methane (69 mL) was added imidazole (1.17 g, 17.2 mmol)
and tert-butyldimethylsilyl chloride (TBSCl) (2.59 g, 17.2
mmol). The reaction mixture was stirred at room temper-
ature for 24 h and quenched by the slow addition of water
(35 mL). The organic phase was separated, dried (sodium
sulfate) and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel
[hexane:EtOAc (93:7)] to yield the title compound 8 as
colorless oil (1.88 g, 95% yield). Rf = 0.4 [hexane:EtOAc
(4:1)]; 1H NMR (500 MHz, CDCl3) δ 4.37 (t, J = 8.5 Hz, 1H),
4.19 (dd, J = 5.5, 9.0 Hz, 1H), 3.59–3.66 (m, 2H), 2.69–2.74
(m, 1H), 2.56 (dd, J = 9.0, 17.5 Hz, 1H), 2.38 (dd, J = 9.0, 17.5
°
stirred for 10 min at 0 C and then 6 M HCl (60 mL) was
added. The round-bottom flask was capped with rubber
septum and stirred at room temperature. After 24 h THF
was removed in vacuo and the aqueous layer was then
extracted with EtOAc (3 × 80 mL), the organic extracts
were dried with Na2SO4 and the solvent was removed in
vacuo to afford crude (S)-paraconic acid 6.
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Crude paraconic acid 6 was dissolved in dry THF (14.4
mL) and BH3·SMe2 (2 M solution in THF; 48 mL, 96
°
mmol) was added drop wise over 30 min at 0 C and
stirred for 7.5 h before quenching with MeOH (50 mL) at
0 °C. The volatiles were removed in vacuo (at 30 °C). More
MeOH (50 mL) was added and the mixture was again
concentrated in vacuo (repeated 2 times). The crude
product was purified by column chromatography on silica
gel [CH2Cl2:MeOH (97:3)] to yield the title compound 1 as
a clear liquid (1.22 g, 35% after 4 step). Rf = 0.4
[CH2Cl2:MeOH (9:1)]; 1H NMR (500 MHz, CDCl3) δ 4.41 (t,
J = 8.5 Hz, 1H), 4.22 (t, J = 8.5 Hz, 1H), 3.66–3.68 (m, 2H),
2.75–2.76 (m, 1H), 2.61 (dd, J = 9.0, 18.0 Hz, 1H), 2.39 (dd, J
= 5.5, 18.0 Hz, 1H), 2.31 (br, 1H), 13C NMR (125 MHz,
CDCl3) δ 177.9, 70.9, 62.9, 37.1, 30.9; IR (neat) ν 3394, 2919,
2880, 1750, 1418, 1389, 1179 cm−1; HRMS (ESI) m/z calcd for
C5H9O3 [M+H]+: 117.0546, found: 117.0566; [α]D24 = −41.4 (c
= 1.12, CHCl3 for 95% ee) [lit.5a, −42.4 (c = 6.8, CHCl3)].
13
Hz, 1H) 0.89 (s, 9H), 0.05 (s, 6H); C NMR (125 MHz,
CDCl3) δ 177.0, 70.5, 63.3, 37.3, 30.7, 25.8, 18.2, –5.5; IR
(neat) ν 2930, 2856, 1780, 1423, 1254, 1171, 1107, 837 cm−1;
HRMS (ESI) m/z calcd for C11H23O3Si [M+H]+: 231.1411,
found: 231.1399; [α]D25 = −19.8 (c = 2.4, CHCl3 for 95% ee).
General procedure for acylation reaction of lactone
8
To a solution of 8 (3.04 mmol) in dry THF (32 mL) un-
der
argon
at
–78
°C
was
added
sodium
bis(trimethylsilyl)amide (1.0 M in THF; 7.60 mL, 7.60
mmol) followed after 1.5 h delay by alkanoyl chloride (3.95
mmol), and the mixture stirred at –78 °C for 4 h. The reac-
tion mixture was quenched with a saturated aqueous
NH4Cl solution and extracted with diethyl ether (3 × 50).
The combined organic fractions were dried (sodium sul-
fate) and concentrated in vacuo.
(R)-(5-oxotetrahydrofuran-3-yl)methyl-4-(tert-
butyl)-benzoate 7
A solution of 4-tert-butylbenzoyl chloride (53 µL, 0.27
mmol) in CH2Cl2 (900 µL) was added dropwise to a stirred
solution of 1 (21 mg, 0.18 mmol), triethylamine (37 µL,
0.36 mmol) and DMAP (2.2 mg, 0.018 mmol) in CH2Cl2
(3R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-
butyryldihydrofuran-2(3H)-one 9
Following the above general procedure using butanoyl
chloride, compound 9 was obtained. The crude product
was purified by column chromatography on silica gel
[hexane:EtOAc (97:3)] to yield the title compound 9 as a
colorless oil (793 mg, 87%) Rf = 0.4 [hexane:EtOAc (9:1)];
1H NMR (500 MHz, CDCl3) δ 4.39 (t, J = 8.5 Hz 1H), 4.12 (t,
J = 8.0 Hz, 1H), 3.62–3.63 (m, 3H), 3.17–3.18 (m, 1H), 2.93
(dt, J = 7.0, 15.0 Hz, 1H), 2.60 (dt, J = 6.5, 15.0 Hz, 1H) 1.62–
1.66 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H) 0.88 (s, 9H), 0.04 (s,
°
(900 µL) at 0 C. The reaction was allowed to stir at the
same temperature for 30 minutes and then slowly raised
to room temperature. After stirring for overnight, the
reaction mixture was quenched with water (1 mL), acidi-
fied with 1 M HCl and extracted with CH2Cl2 (3×5 mL).
The organic layer were dried (Na2SO4) and concentrated
under reduced pressure to give crude ester, which was
further purified by column chromatography [hex-
ane:EtOAc (85:15)] resulting in the pure ester 7 (41 mg,
82% yield). Rf = 0.4 [hexane:EtOAc (3:2)]; HPLC analysis:
DAICEL CHIRALPAK IA, 4.6 × 250 mm (Hex/IPA = 80/20,
0.5 mL/min, 254 nm), tR (minor) = 17.5 min, tR (major) =
18.9 min, 95% ee; 1H NMR (500 MHz, CDCl3) δ 7.94 (d, J =
7.5 Hz, 2H), 7.47 (d, J = 7.5 Hz, 2H), 4.50 (t, J = 8.0 Hz,
1H), 4.40 (dd, J = 4.5, 11.5 Hz, 1H), 4.33 (dd, J = 6.5, 11.5 Hz,
1H), 4.26 (dd, J = 5.5, 8.5 Hz, 1H) 3.04 (m, 1H), 2.74 (dd, J =
9.0, 18.0 Hz, 1H ) 2.47 (dd, J = 6.0, 18.0 Hz, 1H ) 1.34 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 176.0, 166.3, 157.3, 129.5,
126.5, 125.6, 70.4, 64.8, 35.1, 34.7, 31.1; IR (neat) ν 2964,
1779, 1720, 1275, 1189, 775 cm−1; HRMS (ESI) m/z calcd for
C16H21O4 [M+H]+: 277.1434 found: 277.1441; [α]D24= −27.0
(c = 1.0, CHCl3 for 95% ee).
13
6H); C NMR (125 MHz, CDCl3) δ 202.7, 172.5, 69.2, 62.0,
54.7, 44.4, 39.4, 25.7, 18.2, 16.8, 13.5, −5.6; IR (neat) ν 2956,
2858, 1772, 1717, 1471, 1102, 834 cm−1; HRMS (ESI) m/z calcd
for C15H29O4Si [M+H]+: 301.1830, found: 301.1826; [α]D
=
27
−19.5 ( c = 3.3, CHCl3 for 95% ee).
(3R)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6-
methylheptanoyl)dihydrofuran-2(3H)-one 15
Following the above general procedure using alkanoyl
chloride 1410f, compound 15 was obtained. The crude
product was purified by column chromatography on silica
gel [hexane:EtOAc (98:2)] to yield the title compound 15
as a colorless oil (562 mg, 52%) Rf = 0.4 [hexane:EtOAc
(9:1)]; 1H NMR (500 MHz, CDCl3) δ 4.39 (t, J = 8.5 Hz 1H),
4.12 (dd, J = 6.5, 9.0 Hz, 1H), 3.62–3.65 (m, 3H), 3.16–3.20
(m, 1H), 2.95 (dt, J = 7.0, 18.0 Hz, 1H), 2.62 (dt, J = 7.5, 18.0
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Hz, 1H), 1.49–1.62 (m, 3H), 1.25–1.33 (m, 2H), 1.15–1.20 (m,
2H), 0.87 (t, J = 6.5 Hz, 15H), 0.05 (s, 6H); C NMR (125
= 8.0 Hz, 1H), 3.85 (m, 1H), 3.67 (m, 2H), 2.98 (br, 1H),
13
1
2
3
4
2.58–2.69 (m, 2H), 1.56–1.61 (m, 2H), 1.29 (br, 10H) 0.89 (s,
12H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 178.0, 71.2,
68.8, 62.7, 47.3, 40.6, 34.6, 31.8, 29.4, 29.2, 25.8, 25.6, 22.6,
18.2, 14.0, −5.6; IR (neat) ν 3451, 2954, 2856, 1754, 1464,
1253, 1105, 835 cm−1; HRMS (ESI) m/z calcd for C19H39O4Si
MHz, CDCl3) δ 202.7, 172.4, 69.2, 62.0, 54.7, 42.5, 39.4,
38.6, 27.8, 26.8, 25.7, 23.6, 22.5, 18.1, −5.6; IR (neat) ν 2954,
2858, 1774, 1718, 1471, 1105, 836 cm−1; HRMS (ESI) m/z calcd
24
for C19H37O4Si [M+H]+: 357.2456, found: 357.2451; [α]D
=
5
[M+H]+: 359.2613, found: 359.2633; [α]D = −14.6 (c = 1.0,
25
6
7
−16.4 ( c = 1.0, CHCl3 for 95% ee).
CHCl3 for 95% ee).
(3R,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-
8
butyryldihydrofuran-2(3H)-one 10
General procedure for Silyl group deprotection
9
To a solution of 9 (166 mg, 0.55 mmol) in methanol (5.5
mL) at −20 °C was added CeCl3.7H2O (309 mg, 0.83 mmol)
in a one portion followed by the addition of the NaBH4
(63 mg, 1.66 mmol). The reaction mixture was stirred at
−20 °C for 7 h, after which it was quenched with a saturat-
ed aqueous NH4Cl solution (5 mL) and 1 M HCl was add-
ed until the reaction mixture became clear. The mixture
was extracted with EtOAc (3 × 10 mL). The combined or-
ganic layer was washed with water and dried over anhy-
drous Na2SO4 and concentrated in vacuo. The crude prod-
uct was purified by column chromatography on silica gel
[hexane:EtOAc (93:7)] to yield the title compound 10 as a
colorless oil (105 mg, 63%).
To a solution of silyl ether (0.38 mmol) in THF (3.6
mL) at 0 C was added 1 M HCl in Et2O (3.12 mL, 3.12
mmol). The reaction mixture was allowed to warm up to
room temperature and stirred overnight. The solvent was
removed under reduced pressure.
°
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3R,4R)-3-((R)-1-hydroxybutyl)-4-
(hydroxymethyl)di-hydrofuran-2(3H)-one 12
Following the above general procedure, compound 12
was synthesized from 10. The crude product was purified
by column chromatography on silica gel [CH2Cl2:MeOH
(100:0 to 97:3)] to yield the title compound 12 as a color-
less liquid (68 mg, 94%). Rf = 0.4 [CH2Cl2:MeOH (9:1)]; 1H
NMR (500 MHz, CDCl3) δ 4.42 (t, J = 8.5 Hz, 1H), 3.96–
4.03 (m, 2H), 3.73 (dd, J = 5.0, 11.0 Hz, 1H), 3.64–3.68 (dd, J
= 6.5, 11.0 Hz, 1H), 2.80–3.30 (br, 2H), 2.72–2.84 (m, 1H)
2.64 (dd, J = 4.5, 9.0 Hz, 1H), 1.36–1.64 (m, 4H) 0.94 (t, J =
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.5, 70.6, 68.5,
62.9, 49.2, 40.1, 36.0, 19.1,13.9; IR (neat) ν 3383, 2959, 2874,
1748, 1382, 1181 cm−1; HRMS (ESI) m/z calcd for C9H17O4
[M+H]+: 189.1121, found: 189.1131; [α]D24= −3.1 (c = 2.0,
CHCl3 for 95% ee) [lit.7a, −6.7 (c = 0.89, CHCl3 for 99%
ee)].
General procedure for aldol reaction
To a solution of 8 (1.0 mmol) in dry THF (10 mL) under
argon
at
−78
°C
was
added
sodium
bis(trimethylsilyl)amide (1.0 M in THF; 2.5 mL, 2.5 mmol)
followed after 2 h delay by aldehyde (2.0 mmol). The reac-
tion mixture was allowed to reach rt and stirred for 12 h at
the same temperature. The reaction mixture was
quenched with a saturated aqueous NH4Cl solution (10
mL) and extracted with diethyl ether (3 × 10 mL). The
combined organic fractions were dried (sodium sulfate)
and concentrated in vacuo.
(3R,4R)-4-(hydroxymethyl)-3-((R)-1-
hydroxyoctyl)di-hydrofuran-2(3H)-one 13
(3R,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-
((R)-1-hydroxybutyl)dihydrofuran-2(3H)-one 10
Following the above general procedure, compound 13 was
synthesized from 11. The crude product was purified by
column chromatography on silica gel [CH2Cl2:MeOH
(100:0 to 98:2)] to yield the title compound 13 as a color-
less liquid (88 mg, 95%). Rf = 0.4 [CH2Cl2:MeOH (9:1)]; 1H
NMR (500 MHz, CDCl3) δ 4.41 (t, J = 8.5 Hz, 1H), 4.01 (m,
1H), 3.98 (t, J = 8.5 Hz, 1H), 3.75 (dd, J = 5.0, 10.0 Hz, 1H),
3.68 (dd, J = 6.5, 10.5 Hz, 1H), 2.95 (br, 1H), 2.73–2.81 (m,
1H), 2.65 (dd, J = 5.0, 9.5 Hz, 1H), 1.57–1.63 (m, 1H), 1.48–
1.55 (m, 2H) 1.25–1.35 (m, 10H), 0.88 (t, J = 6.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 177.2, 70.9, 68.4, 63.0, 49.0, 40.2,
34.0, 31.8, 29.4, 29.2, 25.8, 22.6, 14.1; IR (neat) ν 3418, 2922,
2852, 1742, 1464, 1181, 837 cm−1; HRMS (ESI) m/z calcd for
C13H25O4 [M+H]+: 245.1747, found: 245.1765; [α]D24 = −3.8 (c
= 1.0, CHCl3 for 95% ee).
Following the above general procedure using butanal,
compound 10 was synthesized. The crude product was
purified by column chromatography on silica gel [hex-
ane:EtOAc (93:7)] to yield the title compound 10 as a col-
1
orless oil (142 mg, 47%). Rf = 0.4 [hexane:EtOAc (4:1)]; H
NMR (500 MHz, CDCl3) δ 4.37 (t, J = 9.0 Hz, 1H), 4.03 (t, J
= 8.5 Hz, 1H), 3.86 (m, 1H), 3.67 (m, 2H), 3.00 (br, 1H),
2.58–2.68 (m, 2H), 1.41–1.64 (m, 4H) 0.94 (t, J = 7.5 Hz,
3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ 178.2, 70.9, 68.8, 62.7, 47.4, 40.5, 36.7, 25.8, 18.8, 18.2,
13.9, −5.5; IR (neat) ν 3463, 2956, 2858, 1757, 1471, 1253,
1174, 833 cm−1; HRMS (ESI) m/z calcd for C15H31O4Si
25
[M+H]+: 303.1986, found: 303.1979; [α]D = −16.2 (c = 3.1,
CHCl3 for 95% ee).
(3R)-4-(hydroxymethyl)-3-(6-
methylheptanoyl)dihydro-furan-2(3H)-one 16
(3R,4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-3-
((R)-1-hydroxyoctyl)dihydrofuran-2(3H)-one 11
A round-bottom flask was charged with compound 15
and tetra-n-butylammonium fluoride (1.0 M in tetrahy-
drofuran; 492 µL, 7.0 mmol) was added dropwise. The
reaction mixture was at room temperature for 24 h. The
reaction mixture was quenched with a saturated aqueous
NH4Cl solution (1 mL) and extracted with diethyl ether (2
× 10 mL). The combined organic fractions were dried (so-
Following the above general procedure using octanal,
compound 11 was synthesized. The crude product was
purified by column chromatography on silica gel [hex-
ane:EtOAc (95:5)] to yield the title compound 11 as a col-
1
orless oil (150 mg, 42%). Rf = 0.4 [hexane:EtOAc (4:1)]; H
NMR (500 MHz, CDCl3) δ 4.37 (t, J = 8.5 Hz, 1H), 4.03 (t, J
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The Journal of Organic Chemistry
Page 6 of 7
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dium sulfate) and concentrated in vacuo. The crude
1
2
3
4
5
6
7
8
product was purified by column chromatography on silica
gel [CH2Cl2:EtOAc (100:0 to 95:5)] to yield compound 16
(major) along with its hemiketal form5d in 3:1 ratio as a
colorless liquid (12 mg, 70%). Rf = 0.4 [CH2Cl2:EtOAc
J. Ferment. Bioeng. 1989, 68, 170–173.
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Yamane, K. Tetrahedron 1982, 38, 2919–2921. (d) Parsons, P. J.;
Lacrouts, P.; Buss, A. D. J. Chem. Soc., Chem. Commun. 1995,
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Iida, Y.; Kuribayashi, H.; Adachi, K.; Yoda, H.; Ao, M. Bioorg.
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1
1
(8:2)]; H NMR (500 MHz, CDCl3) H NMR (500 MHz,
CDCl3) δ 4.44 (dd, J = 8.5, 9.0 Hz 1H), 4.15 (dd, J = 6.5, 9.0
Hz, 1H), 3.67 (m, 3H), 3.21–3.27 (m, 1H), 2.97 (dt, J = 7.5,
18.0 Hz, 1H), 2.65 (dt, J = 7.5, 18.0 Hz, 1H), 1.63–1.57 (m,
2H), 1.56–1.50 (m, 1H), 1.29–1.34 (m, 2H), 1.17–1.20 (m, 2H),
0.86–0.87 (dd, J = 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3)
δ 202.9, 172.3, 69.0, 61.9, 55.0, 42.5, 39.2, 38.7, 27.8, 26.8,
23.5, 22.5; IR (neat) ν 3456, 2953, 2869, 1764, 1716, 1384, 1171
cm−1; HRMS (ESI) m/z calcd for C13H23O4 [M+H]+: 243.1591,
found: 243.1584; [α]D24= −8.1 (c = 1.0, CHCl3 for 95% ee)
[lit.5c, −13.1 (c = 1.18, CHCl3)].
9
10
11
12
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
1
Copies of H NMR and 13C NMR spectra of all products, and
HPLC chromatograms of 7 (PDF)
AUTHOR INFORMATION
Corresponding Author
(8) Mori, K. Tetrahedron 1983, 39, 3107–3109.
(9) Mattei, P.; Boehringer, M.; Di Giorgio, P.; Fischer, H.;
Hennig, M.; Huwyler, J.; Koçer, B.; Kuhn, B.; Loeffler, B. M.;
MacDonald, A.; Narquizian, R.; Rauber, E.; Sebokova, E.;
Sprecher, U. Bioorg. Med. Chem. Lett. 2010, 20, 1109–1113.
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Angew. Chem., Int. Ed. 2013, 52, 5305–5308. (b) Qureshi, Z.;
Weinstabl, H.; Suhartono, M.; Liu, H.; Thesmar, P.; Lautens, M.
Eur. J. Org. Chem. 2014, 2014, 4053–4069. (c) Crotti, A. E. M.;
Bronze-Uhle, E. S.; Nascimento, P. G. B. D.; Donate, P. M.;
Galembeck, S. E.; Vessecchi, R.; Lopes, N. P. J. Mass Spectrom.
2009, 44, 1733–1741. (d) Biswas, A.; Swarnkar, R. K.; Hussain, B.;
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Phys. Chem. B 2014, 118, 10035−10042. (e) Kakiuchi, S.; Yamada,
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*E-mail: a.chandra@iitgn.ac.in
ORCID
Chandrakumar Appayee: 0000-0003-1165-4918
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This paper is dedicated to Professor Srinivasan Chandra-
sekaran (Indian institute of Science, Bangalore) on the occa-
sion of his 72nd birthday. The authors are grateful to the
Indian Institute of Technology Gandhinagar for the facilities
and financial support.
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8
(16)
Other
bases
like
LiHMDS
(lithium
bis(trimethylsilyl)amide) in similar reaction conditions gave
60:40 dr and LDA (lithium diisopropylamide) resulted in traces
of product 10 along with complete decomposition of starting
compounds.
(17) Commercially available methyl 4-oxobutanoate 4 (CAS
Number: 13865−19−5) have been easily accessed following the
literature procedure, Ref: Gannett, P. M.; Nagel, D. L.; Reilly, P.
J.; Lawson, T.; Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, 1064–
1071.
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