Stereoselective synthesis towards verbalactone and (+)-(3R,5R)-3-hydroxy-5- decanolide

Article abstract of DOI:10.1016/j.tetasy.2012.03.002

The stereoselective synthesis towards biologically active verbalactone and (+)-(3R,5R)-3-hydroxy-5-decanolide has been described. The key functionalities are derived from a chiral-auxiliary mediated acetate aldol addition, an oxa-Michael reaction and a 1,3-syn-reduction.

Full text of DOI:10.1016/j.tetasy.2012.03.002

Tetrahedron: Asymmetry 23 (2012) 381–387
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Tetrahedron: Asymmetry
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Stereoselective synthesis towards verbalactone and
(+)-(3R,5R)-3-hydroxy-5-decanolide
⇑
Akkaladevi Venkatesham, Ramisetti Srinivasa Rao, Kommu Nagaiah
Division of Organic and Biomolecular Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 067, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis towards biologically active verbalactone and (+)-(3R,5R)-3-hydroxy-
5-decanolide has been described. The key functionalities are derived from a chiral-auxiliary mediated
acetate aldol addition, an oxa-Michael reaction and a 1,3-syn-reduction.
Received 9 February 2012
Accepted 6 March 2012
Available online 2 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
the retrosynthetic route depicted in Scheme 1. We predicted that
both verbalactone 1 and (+)-(3R,5R)-3-hydroxy-5-decanolide 2
In recent years, greater than 10-membered C2-symmetric mac-
rocyclic lactone dimers with biological activity have attracted the
attention of both biologists and chemists. Representative examples
of these types of natural products include cyanolide A,1 malyngoli-
demer,2 tanikolide dimer,3 vermiculin4 and verbalactone 1 (Fig. 1).5
Among these, verbalactone 1 is the first example where a 1,7-diox-
acyclododecane moiety was reported as being the ring system of a
natural product and is obtained from the roots of Verbascum undul-
atum, a biennial plant of genus Verbascum that belongs to the
Schrophulariaceae family. Verbalactone 1 has exhibited interesting
antibacterial activity against various Gram-positive (MIC = 62.5
could be accessed from the key monomeric seco-acid, that is,
(3R,5R)-dihydroxy decanoic acid 3 by the hydrogenolysis of ben-
zylidene acetal acid 4, which in turn can be obtained from both
a,b-unsaturated ester 5 and b-hydroxy homoallylic ketone 9. Com-
pounds 5 and 9 could be synthesized from acetate aldol adduct 6,
which in turn could be prepared from an aldol reaction between
n-hexanal and the titanium enolate of N-acetyl-4-benzyl-thiazoli-
dinethione 7 (Scheme 1).
We started our synthesis (Scheme 2) with chiral auxiliary (R)-
4-benzyl-thiazolidine-2-thione 10, which was prepared from
commercially available
D-phenylalanine following the reported
lg/ml) and Gram-negative bacteria (MIC = 125
l
g/ml).5,6 This
procedure.10 (R)-4-Benzyl-thiazolidine-2-thione 10, upon treat-
ment with acetyl chloride in the presence of n-BuLi at ꢀ78 °C for
1 h, afforded N-acylated thiazolidinone 7 in 95% yield. Next, we
synthesized the key intermediate 6 via an aldol reaction between
n-hexanal 8 and titanium enolate of N-acetyl-4-benzyl-thiazolidin-
ethione 7.11 Consequently, the corresponding acetate aldol adducts
6 and 6a were obtained in 82% combined isolated yield and with
high diastereoselectivity (6/6a = syn:anti = 85:15). The more polar
major syn-diastereomer 6 was easily separated by flash column
chromatography in 69.7% isolated yield from the minor anti-
diastereomer 6a (12.3% isolated yield). The syn-aldol product 6
showed the characteristic 1H NMR chemical shift signals for the
macrocyclic lactone 1 is a symmetric dimer of a d-lactone, that
is, (+)-(3R,5R)-3-hydroxy-5-decanolide 2, which is a potent inhibi-
tor of the enzyme HMG-CoA reductase (Fig. 1).7 The NMR profile of
1 is very similar to the monomeric lactone of (3R,5R)-dihydroxy-
decanoic acid 3. The structure and absolute stereochemistry of
the lactones 1 and 2 were determined by spectroscopic methods
and chemical correlation. The interesting structural pattern and
potent antibacterial activity of verbalactone 1 and (+)-(3R,5R)-3-
hydroxy-5-decanolide 2 have prompted many synthetic chemists
to work towards their synthesis.8 In continuation of our efforts9 to-
wards the total synthesis of biologically active natural products,
we herein report the stereoselective synthesis of verbalactone 1
and (+)-(3R,5R)-3-hydroxy-5-decanolide 2.
a-protons at d 3.65 (dd, J = 17.9, 2.2 Hz, 1H) for the less shielded
proton and at d 3.13 (dd, J = 17.9, 8.6 Hz, 1H) for the more shielded
proton, along with other peaks in their respective positions. The
less polar minor anti-aldol product 6a showed 1H NMR chemical
2. Results and discussions
shift signals for the corresponding
a-protons at d 3.52–3.34 (m,
2H). Reductive cleavage12 of the chiral auxiliary moiety in 6 by
using DIBAL-H at ꢀ78 °C for 5 min afforded the aldehyde, which
upon two-carbon homologation using ethoxycarbonylmethylene-
triphenylphosphorane13 furnished the corresponding d-hydroxy
Our synthetic approach towards the synthesis of verbalactone 1
and (+)-(3R,5R)-3-hydroxy-5-decanolide 2 was envisioned through
a
,b-unsaturated esters 5 and 5a as an inseparable mixture (5/
⇑
Corresponding author. Fax: +91 40 27160387.
E-mail address: nagaiah@iict.res.in (K. Nagaiah).
5a:E/Z = 9/1 by 1H NMR) in 80% overall yield for the two steps.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.002

382
A. Venkatesham et al. / Tetrahedron: Asymmetry 23 (2012) 381–387
H3CO
H3CO
H3CO
O
O
O
O
O
O
H3C
O
O
O
O
O
OCH3
OCH3
O
O
O
O
O
CH3
O
O
OCH3
cyanolide A
vermiculin
R3
O
OH
R1
O
OH
O
R2
O
O
R2
O
R1
O
O
O
OH
valerolactone 2
O
R3
verbalactone 1
malyngolide dimer, if R1 = α-CH2OH
R2 = β-(CH2)8CH3
R3 = β-CH3
tanikolide dimer, if R1 = β-CH2OH
R2 = α-(CH2)10CH3
R3 = H
Figure 1.
Next, the mixture of 5 and 5a was subjected to the key intramo-
temperature afforded the corresponding b-hydroxy homoallylic
ketone 9 in 95% yield.17 The syn-selective reduction of b-hydroxy
homoallylic ketone 9 using diethylmethoxyborane in the solvent
system, THF/MeOH (4:1), at ꢀ78 °C for 30 min followed by the
addition of NaBH4 for 4 h afforded the required syn-1,3-diol 13
exclusively (syn/anti = 99:1, by 1H NMR) in 80% isolated yield,18
which was subsequently converted into the corresponding benzyl-
idine acetal 14 in 95% yield by treatment with benzylidine dimeth-
ylacetal and catalytic pyridinium para-toluenesulphonate (PPTS) in
CH2Cl2 for 12 h at room temperature. The ruthenium catalyzed oxi-
dative cleavage of the terminal olefin of 14 by using RuCl3/NaIO4 in
the solvent system CCl4/CH3CN/H2O (2:2:3) at room temperature
for 12 h under Sharpless’ conditions19 gave the desired carboxylic
lecular oxa-Michael reaction by using three portions of 1.1 equiv of
benzaldehyde and 0.1 equiv of potassium tert-butoxide at 0 °C in
dry THF to give the more stable major syn-1,3-benzylidene acetal
11 in 95% isolated yield.14 Basic hydrolysis of the ester group in
11 by using LiOH in THF/H2O furnished the corresponding acid 4
in 85% yield (Scheme 3).15
Alternatively, compound 4 can be prepared according to the
route depicted in Scheme 4. Transamidation16 of the b-hydroxy
amide with N,O-dimethylhydroxylamine hydrochloride and imid-
azole in CH2Cl2 for 12 h gave the corresponding Weinreb amide
12 in 92% yield. The addition of both allyl chloride and amide 12
in THF to a stirred solution of magnesium in THF at room
OH
O
O
O
O
OH
verbalactone 1
OH
OH
O
O
COOH
COOH
OH
4
3
OH
O
O
O
valerolactone 2
9
S
S
O
OH
O
N
OH
O
COOEt
H3C
N
S
+
S
H
n-hexanal 8
6
5
7
Ph
Ph
Scheme 1. Retrosynthetic strategy of verbalactone 1 and (+)-3(3R,5R)-3-hydroxy-5-decanolide 2.

A. Venkatesham et al. / Tetrahedron: Asymmetry 23 (2012) 381–387
383
S
S
O
HN
S
H3C
N
S
n-BuLi, THF, 0 °C
TiCl4, DIPEA
then CH3COCl
1 h, 95%
DCM, -78 °C, 82%
n-hexanal 8
10
7
Ph
Ph
S
OH
O
O
N
S
acetate anti-isomer 6a
OH
O
i.DIBAL-H -78 °C, 5 min
Ph
OEt
+
ii. Ph3P=CHCO2Et, CH2Cl2,
rt, 2 h, 80% (two steps)
5
S
OH
N
S
acetate syn-isomer 6
85 (syn): 15 (anti)
Ph
Scheme 2.
verbalactone 1 under the well established Yamaguchi macrolact-
onization conditions.21,8a–c In the final instance, the seco-acid 3
upon treatment with 4 M HCl in THF afforded (+)-(3R,5R)-3-hydro-
xy-5-decanolide 2 in 92% yield. The spectroscopic data of 2, includ-
ing the specific rotation, were in full agreement with the literature
(Scheme 5).5,7
Ph
O
O
O
PhCHO, t-BuOK, THF
5
COOEt
COOH
0 °C, 45 min, 95%
11
Ph
3. Conclusion
O
LiOH, THF-H2O (3:1)
In conclusion, we have described a simple, convenient and
efficient approach towards the synthesis of verbalactone 1 and
(+)-(3R,5R)-3-hydroxy-5-decanolide 2 involving a sequence of
reactions starting from N-acetyl-4-benzyl-thiazolidinethione 7.
This approach offers high stereoselectivity and uses readily
available starting, inexpensive material and simple experimental
conditions, which makes it a useful and attractive process.
0 °C to rt, 4h, 85%
4
Scheme 3.
acid 4 in 65% yield. The spectroscopic and specific rotation data of
this compound were in full agreement with the compound 4 pre-
pared in the synthetic route depicted in Scheme 3.
4. Experiments
Cleavage of benzylidine acetal 4 under hydrogenolysis by using
Pd/C in EtOAc resulted in the required seco-acid 3 in 80% yield.20
The seco-acid 3 was confirmed by its ESI-Ms spectrum, which
showed an m/z value at 227 [M+H]+. Thus we accomplished the
stereoselective synthesis of the well known precursor, seco-acid
3, which could be converted into the required natural dimeric
All solvents and reagents were used as received from the suppli-
ers. TLC was performed on Merck Kiesel gel 60, F254 plates with the
layer thickness of 0.25 mm. Column chromatography was
performed on silica gel (100–200 mesh) using a gradient of ethyl
acetate and hexane as the mobile phase. IR spectra were recorded
S
OH
O
OH
O
OH
O
MgCl
NH(Me)OMe·HCl
OCH3
N
S
N
imidazole, CH2Cl2
r.t., 12 h, 92%
THF, 0 °C
30 min., 95%
6
9
12
CH3
Ph
O
O
OH
OH
benzylidine
diethylmethoxy
borane
RuCl3/NaIO4
dimethylacetal
4
PPTS, CH2Cl2,
rt, 12 h, 95%
CCl4/CH3CN/H2O
rt, 12 h, 65%
THF:MeOH (4:1),
-78 °C, 5 h, 80%
13
14
Scheme 4.

384
A. Venkatesham et al. / Tetrahedron: Asymmetry 23 (2012) 381–387
OH
OH
O
O
O
ref. 21, 8a-c
O
OH
OH
O
Pd/C-H2, EtOAc
rt, 12 h, 80%
verbalactone 1
4
OH
OH
4M HCl, THF
12 h, 92%
3
O
O
(+)-(3R,5R)-3-hydroxy-5-decanolide 2
Scheme 5.
on a Perkin–Elmer RX-1 FT-IR system. 1H NMR spectroscopic data
were collected at 300, 400 and 500 MHz, while 13C NMR were re-
corded at 75, 100, 150 MHz. 1H NMR spectroscopic data are given
as chemical shifts in ppm followed by multiplicity (s–singlet; d–
doublet; t–triplet; q–quartet; m–multiplet), number of protons
and coupling constants. 13C NMR chemical shifts are expressed in
ppm. Optical rotations were measured with JASCO digital polarim-
eter. HRMS spectroscopic data were collected using an ORBITRAP
High Resolution Mass Spectrometer.
temperature and diluted with CH2Cl2 (60 mL). The organic layer
was separated and the aqueous layer was extracted with CH2Cl2
(2 ꢁ 60 mL). The combined organic extracts were washed with
80 mL of a half-saturated aq solution of NH4Cl (2 ꢁ 60 mL), water
(2 ꢁ 60 mL), brine (2 ꢁ 60 mL), dried over Na2SO4, filtered and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (100–200 mesh, eluent:
15–20% EtOAc in hexane) to afford the more polar major syn-dia-
stereomer (R)-1-((R)-4-Benzyl-2-thioxo-thiazolidin-3-yl)-3-hydro-
xy-octan-1one 6 (1.59 g, 69.7%) as a yellow oil along with less polar
minor anti-diastereomer, (S)-1-((R)-4-benzyl-2-thioxo-thiazolidin-
3-yl)-3-hydroxy-octan-1-one 6a (0.282 g, 12.3%), as a yellow oil.
4.1. (R)-1-(4-Benzyl-2-thioxo-thiazolidin-3-yl)ethanone 7
To a stirred solution of (R)-4-benzyl-thiazolidine-2-thione 10
(2.75 g, 13.2 mmol) in dry THF (30 mL) at 0 °C under a nitrogen
atmosphere was added slowly n-BuLi (6.3 mL, 15.7 mmol, 2.5 M)
and stirred for 30 min at the same temperature. Next, acetyl chlo-
ride (1.24 g, 15.7 mmol) was added slowly at 0 °C and stirred for
1 h. After completion of the reaction, the reaction mixture was
quenched with a saturated aq solution NH4Cl (15 mL). The organic
layer was separated and the aqueous layer was extracted with
EtOAc (3 ꢁ 25 mL). The combined organic layers were washed with
water (2 ꢁ 30 mL), brine (2 ꢁ 30 mL), dried over Na2SO4, filtered
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel (100–200 mesh,
eluent: 5% EtOAc in hexane) to afford (R)-1-(4-benzyl-2-thioxo-
thiazolidin-3-yl)-ethanone 7 (3.13 g, 95%) as bright yellow crystals.
4.2.1. syn-Diastereomer 6
½
a 2D5
ꢂ
¼ ꢀ72:6 (c 0.9, CHCl3); IR (KBR): mmax 3451, 3026, 2925,
2855, 1694, 1493, 1342, 1291, 1261, 1162, 1042, 746, 701 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.42–7.23 (m, 5H, Ar-H), 5.50–5.30
(m, 1H), 4.25–4.04 (m, 1H), 3.65 (dd, J = 17.9, 2.2 Hz, 1H), 3.41
(dd, J = 11.5, 7.2 Hz, 1H), 3.23 (dd, J = 13.0, 3.8 Hz, 1H), 3.13 (dd,
J = 17.9, 8.6 Hz, 1H), 3.06–2.97 (m, 1H), 2.90 (d, J = 11.5 Hz, 1H),
2.84–2.65 (br s, 1H, –OH), 1.67–1.41 (m, 3H), 1.40–1.22 (m, 5H),
0.89 (t, J = 6.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 201.37,
173.30, 136.37, 129.40, 128.89, 127.24, 68.29, 67.83, 45.87, 36.80,
36.31, 32.02, 31.69, 25.19, 22.56, 14.00; MASS (ESIMS): m/z 374
(M+Na)+.
½
a 2D5
ꢂ
¼ ꢀ210:0 (c 1.0, CHCl3); IR (KBR): mmax 2925, 1701, 1362,
4.2.2. anti-Diastereomer 6a
1215, 1018, 701 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.51–7.03
;
½
a 2D5
ꢂ
¼ ꢀ118:3 (c 1.08, CHCl3); IR (KBR):
2953, 2927, 2856, 1689, 1495, 1454, 1342, 1293, 1260, 1192, 1160,
1042, 892, 749, 702 cmꢀ1 1H NMR (400 MHz, CDCl3): d 7.46–7.20
mmax 3462, 3062, 3026,
(m, 5H, Ar-H), 5.37–5.29 (m, 1H), 3.36 (ddd, J = 11.3, 7.5, 0.9 Hz,
1H), 3.21 (dd, J = 13.2, 3.7 Hz, 1H), 3.02 (dd, J = 10.3, 0.9 Hz, 1H),
2.87 (d, J = 11.3 Hz, 1H), 2.78 (s, 3H); 13C NMR (75 MHz, CDCl3): d
201.51, 170.66, 136.45, 129.39, 128.85, 127.16, 68.15, 36.62,
31.76, 27.02; MASS (LCMS): m/z 274 (M+Na)+.
;
(m, 5H, Ar-H), 5.53–5.31 (m, 1H), 4.20–3.96 (m, 1H), 3.52–3.34 (m,
2H), 3.23 (dd, J = 13.1, 3.9 Hz, 1H), 3.05 (dd, J = 13.1, 10.4 Hz, 1H)
2.91 (d, J = 11.6 Hz, 1H), 1.76–1.44 (m, 4H), 1.43–1.16 (m, 5H),
0.90 (t, J = 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 201.44,
173.86, 136.32, 129.40, 128.91, 127.25, 68.44, 68.19, 45.44, 36.73,
36.53, 31.98, 31.70, 25.12, 22.56, 14.02; MASS (ESIMS): m/z 374
(M+Na)+.
4.2. (R)-1-((R)-4-Benzyl-2-thioxo-thiazolidin-3-yl)-3-hydroxy-
octan-1-one 6
To a stirred solution of (R)-1-(4-benzyl-2-thioxo-thiazolidin-3-
yl)-ethanone 7 (2.0 g, 7.96 mmol) in dry CH2Cl2 (51 mL) at 0 °C un-
der a nitrogen atmosphere was added dropwise TiCl4 (0.86 mL,
7.90 mmol) and stirred for 5 min. Next, a solution of DIPEA
(1.40 mL, 7.90 mmol) in dry CH2Cl2 (5 mL) was added via cannula.
The reaction mixture was cooled to ꢀ78 °C and continued to stir
for 30 min. Then a solution of n-hexanaldehyde 8 (1.17 mL,
9.56 mmol) in dry CH2Cl2 (15 mL) was transferred via cannula to
the reaction mixture, which was then stirred for 30 min at
ꢀ78 °C. After completion of the reaction, the reaction mixture
was quenched by the addition of a half-saturated solution of aq
NH4Cl (10 mL) while stirring and allowed to return to room
4.3. (R,E)-Ethyl 5-hydroxy-dec-2-enoate 5
To a stirred solution of (R)-1-((R)-4-benzyl-2-thioxo-thiazoli-
din-3-yl)-3-hydroxy-octan-1-one
6 (1.0 g, 4.67 mmol) in dry
CH2Cl2 (25 mL) at ꢀ78 °C under a nitrogen atmosphere was added
DIBAL-H (4.6 mL, 1.6 M in toluene, 6.54 mmol) dropwise. The
resulting mixture was stirred at ꢀ78 °C for 5 min. Then the reac-
tion mixture was quenched with a saturated sodium potassium
tartrate solution (10 mL) and allowed to return to room tempera-
ture and stirred for 2 h. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 ꢁ 10 mL). The

A. Venkatesham et al. / Tetrahedron: Asymmetry 23 (2012) 381–387
385
combined organic extracts were washed with water (1 ꢁ 20 mL),
brine (1 ꢁ 20 mL) and dried over anhydrous Na2SO4, filtered and
concentrated to afford the crude b-hydroxy aldehyde as a pale yel-
low oil, which was used in the next step without purification.
To a stirred solution of the crude b-hydroxy aldehyde in dry
CH2Cl2 (30 mL) at room temperature under a nitrogen atmosphere
was added ethoxycarbonylmethylene triphenylphosphorane
(2.47 g, 7.12 mmol) and stirred for 4 h. After completion of the
reaction, the solvent was removed under reduced pressure and
the residue was purified by flash column chromatography on silica
gel (100–200 mesh, eluent: 20% EtOAc in hexane) to afford (R,E)-
ethyl 5-hydroxy-dec-2-enoate 5 (0.487 g, 80% over two steps) as
layer was separated and the aqueous layer was extracted with
EtOAc (2 ꢁ 10 mL). The combined organic extracts were washed
with water (2 ꢁ 10 mL), brine (2 ꢁ 10 mL) and dried over anhy-
drous Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel (100–200 mesh, eluent: 30% EtOAc in hexane) to afford 2-
((4R,6R)-6-pentyl-2-phenyl-1,3-dioxan-4-yl)-acetic
acid
4
(0.387 g, 85%) as a colourless oil.
Alternatively, NaIO4 (0.854 g, 3.98 mmol) and RuCl3 (0.010 g,
0.049 mmol) were added successively to stirred solution
a
of (2R,4S,6R)-4-allyl-6-pentyl-2-phenyl-1,3-dioxane 14 (0.274 g
1.0 mmol) in a CCl4/CH3CN/H2O (2:2:4, 9 mL) mixture. The reaction
mixture was stirred for 12 h at room temperature. After comple-
tion of the reaction, the reaction mixture was diluted with CH2Cl2
(10 mL) and water (10 mL) and the resulting green heterogeneous
mixture was filtered over Celite to remove ruthenium salts. Next,
the organic layer was separated and the aqueous layer extracted
with CH2Cl2 (3 ꢁ 10 mL). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, filtered and concen-
trated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (60–120 mesh, eluent: 30%
EtOAc in hexane) to afford 2-((4R,6R)-6-pentyl-2-phenyl-1,3-diox-
a colourless oil. ½a D25
¼ ꢀ4:5 (c 0.9, CHCl3); IR (KBR): mmax 3448,
ꢂ
2929, 2860, 1715, 1653, 1462, 1369, 1316, 1267, 1122, 980,
771 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.03–6.82 (m, 1H), 5.86
;
(d, J = 15.6 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.79–3.63 (m, 1H),
2.50–2.20 (m, 2H), 1.72–1.54 (br s, 1H, –OH), 1.53–1.40 (m, 3H)
1.37–1.21 (m, 8H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 166.38, 146.25, 145.42, 123.60, 121.62, 71.22, 70.42,
60.22, 60.05, 40.10, 37.41, 37.00, 36.47, 31.66, 25.19, 22.52,
14.15, 13.93; MASS (ESIMS): m/z 237 (M+Na)+; HRMS (ESI): m/z
calcd for C12H22O3Na 237.1455. Found 237.1466.
an-4-yl)-acetic acid 4 (0.189 g, 65%) as a colourless oil. ½a D25
¼ þ5:8
ꢂ
4.4. Ethyl 2-((4R,6R)-6-pentyl-2-phenyl-1,3-dioxan-4-yl)-
acetate 11
(c 0.9, CHCl3); IR (KBR): mmax 3449, 2924, 2855, 1709, 1637, 1401,
1341, 1215, 1103, 760, 696 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
7.42 (d, J = 6.8 Hz, 2H), 7.35–7.20 (m, 3H), 5.50 (s, 1H), 4.33–4.18
(m, 1H), 3.86–3.73 (m, 1H), 2.75 (dd, J = 15.6, 6.8 Hz, 1H), 2.53
(dd, J = 15.6, 5.8 Hz, 1H), 1.75–1.60 (m, 2H), 1.54–1.40 (m, 3H),
1.40–1.27 (m, 5H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 175.93, 138.38, 128.66, 128.16, 126.06, 100.66, 76.58,
72.90, 40.72, 36.40, 35.76, 31.75, 24.65, 22.56, 14.0; MASS (ESIMS):
m/z 315 (M+Na)+; HRMS (ESI): m/z calcd for C17H24O4Na 315.1575.
Found 315.1572.
To a stirred solution of (R,E)-ethyl 5-hydroxy-dec-2-enoate 5
(0.450 g, 2.10 mmol) in dry THF (20 mL) at 0 °C under a nitrogen
atmosphere was added first
a portion of t-BuOK (0.078 g,
0.76 mmol) followed by benzaldehyde (0.078 mL, 0.76 mmol) and
the resulting mixture was stirred for 15 min. Then a second portion
of t-BuOK (0.078 g, 0.76 mmol) and benzaldehyde (0.078 mL,
0.76 mmol) was added, after 15 min, a third portion of t-BuOK
(0.078 g, 0.76 mmol) and benzaldehyde (0.078 mL, 0.76 mmol)
was added. The resulting mixture was stirred at 0 °C for 2 h. After
completion of the reaction, the reaction mixture was quenched
with a saturated aqueous NH4Cl solution (10 mL). The organic layer
was separated and the aqueous layer was extracted with EtOAc
(3 ꢁ 10 mL). The combined organic extracts were washed with
water (2 ꢁ 10 mL), brine (2 ꢁ 10 mL) and dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The res-
idue was purified by flash column chromatography on silica gel
(100–200 mesh, eluent: 8% EtOAc in hexane) to afford ethyl 2-
((4R,6R)-6-pentyl-2-phenyl-1,3-dioxan-4-yl)acetate 11 (0.639 g,
4.6. (R)-3-Hydroxy-N-methoxy-N-methyloctanamide 12
To a stirred solution of (R)-1-((R)-4-benzyl-2-thioxo-thiazoli-
din-3-yl)-3-hydroxy-octan-1one 6 (1.0 g, 2.84 mmol) in dry CH2Cl2
(15 mL) at room temperature under a nitrogen atmosphere was
added imidazole (0.965 g, 14.2 mmol) and Weinreb salt (0.822 g,
8.52 mmol) and continued to stir for 12 h at the same temperature.
After completion of the reaction, the reaction mixture was
quenched with a saturated aq solution of NH4Cl (5 mL). The organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (2 ꢁ 10 mL). The combined organic extracts were washed
with water (2 ꢁ 10 mL), brine (2 ꢁ 10 mL), dried over Na2SO4, fil-
tered and concentrated. The residue was purified by column chro-
matography on silica gel (100–200 mesh, eluent: 40% EtOAc in
hexane) to afford (R)-3-hydroxy-N-methoxy-N-methyloctanamide
95%) as a yellow oil. ½a D25
¼ þ85:0 (c 0.9, CHCl3); IR (KBR): mmax
ꢂ
3450, 2930, 2861, 1736, 1455, 1376, 1343, 1198, 1142, 1024,
; d 7.42 (d,
844, 756, 698 cmꢀ1 1H NMR (500 MHz, CDCl3):
J = 6.9 Hz, 2H), 7.34–7.22 (m, 3H), 5.50 (s, 1H), 4.30–4.20 (m, 1H),
4.14 (q, J = 6.9 Hz, 2H), 3.86–3.75 (m, 1H), 2.68 (dd, J = 15.6,
6.9 Hz, 1H), 2.45 (dd, J = 15.6, 5.8 Hz, 1H), 1.74–1.59 (m, 2H),
1.56–1.45 (m, 2H), 1.43–1.35 (m, 2H), 1.36–1.21 (m, 7H), 0.90 (t,
J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 170.80, 138.61,
128.52, 128.08, 126.02, 100.51, 76.58, 73.26, 60.53, 41.03, 36.54,
35.79, 31.74, 24.65, 22.55, 14.17, 14.00; MASS (ESIMS): m/z 343
(M+Na)+; HRMS (ESI): m/z calcd for C19H28O4Na 343.1885. Found
343.1896.
12 (0.532 g, 92%) as a pale yellow oil. ½a D25
¼ ꢀ29:2 (c 1.0, CHCl3);
ꢂ
IR (KBR): mmax 3463, 3421, 3395, 3365, 2956, 2929, 2858, 2378,
2310, 1643, 1458, 1419, 1388, 1214, 1179, 1125, 1043, 998, 754,
667 cmꢀ1 1H NMR (400 MHz, CDCl3): d 4.01–3.91 (s, 1H), 3.69 (s,
;
3H), 3.60–3.44 (br s, ,–OH, 1H), 3.17 (s, 3H), 2.59 (d, J = 16.8 Hz,
1H), 2.38 (dd, J = 16.8, 9.6 Hz, 1H), 1.58–1.28 (m, 8H), 0.90 (t,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 173.89, 67.82, 61.14,
38.11, 36.45, 31.72, 25.15, 22.53, 13.96; MASS (ESIMS): m/z 204
(M+H)+; HRMS (ESI): m/z calcd for C10H23O3N 204.1594. Found
204.1596.
4.5. 2-((2R,4R,6R)-6-Pentyl-2-phenyl-1,3-dioxan-4-yl)acetic acid
4
To a stirred solution of ethyl 2-((4R,6R)-6-pentyl-2-phenyl-1,3-
dioxan-4-yl)acetate 11 (0.5 g, 1.56 mmol) in THF/H2O (10 mL, 8:2)
at room temperature was added LiOHꢃH2O (0.098 g, 2.34 mmol)
and the resulting mixture was stirred for 12 h. After completion
of the reaction, the solvent was removed and the residue was trea-
ted with saturated aqueous NaHSO3 solution (10 mL). The organic
4.7. (R)-6-Hydroxyundec-1-en-4-one 9
To a stirred solution of Mg (0.144 g, 6.0 mmol) in dry THF
(10 mL) at room temperature under a nitrogen atmosphere was
added 1,2-dibromoethane (0.05 mL) and stirred for 10 min. Next,
a solution of (R)-3-hydroxy-N-methoxy-N-methyloctanamide 12

386
A. Venkatesham et al. / Tetrahedron: Asymmetry 23 (2012) 381–387
(0.406 g, 2.0 mmol) and allyl chloride (0.406 mL, 5.0 mmol) in dry
THF (15 mL) were added carefully over a period of 1 h. The reaction
mixture was stirred for an additional 1 h at room temperature.
After completion of the reaction, the reaction mixture was
quenched with a satd aq NH4Cl solution (10 mL). The organic layer
was separated and the aqueous layer extracted with EtOAc
(2 ꢁ 30 mL). The combined organic layers were washed with brine
(2 ꢁ 30 mL) and dried over Na2SO4, filtered and concentrated. The
residue was purified by column chromatography on silica gel
(100–200 mesh, eluent: 5% EtOAc in hexane) to give (R)-6-
4.10. (3R,5R)-3,5-Dihydroxydecanoic acid 3
To a stirred solution of 2-((4R,6R)-6-pentyl-2-phenyl-1,3-diox-
an-4-yl)-acetic acid 4 (0.292 g, 1.00 mmol) in EtOAc (10 mL) was
added 10% Pd/C (0.029 g, 10 mol %). Next, the reaction mixture
was stirred under an H2 atmosphere for 6 h at room temperature.
After completion of the reaction, the catalyst was filtered on a
Celite pad and washed with EtOAc (2 ꢁ 10 mL). The combined
organic extracts were concentrated and the residue was purified
by flash column chromatography on silica gel (60–120 mesh, elu-
ent: 5% CHCl3 in MeOH) to afford (3R,5R)-3,5-dihydroxydecanoic
acid 3 (0.163 g, 80%) as a colourless oil, which was used immedi-
ately in the next step. MASS (ESIMS): m/z 227 (M+Na)+.
hydroxyundec-1-en-4-one
¼ ꢀ37:1 (c 0.48, CHCl3); IR (KBR): mmax 3562, 3543, 3396,
2955, 2929, 2858, 2310, 1710, 1640, 1457, 1417, 1394, 1377,
1337, 1127, 1074, 1039, 993, 919, 770 cmꢀ1 1H NMR (300 MHz,
9 (0.349 g, 95%) as a clear liquid.
½ ꢂ
a 2D5
;
CDCl3): d 6.01–5.79 (m, 1H), 5.29–5.05 (m, 2H), 4.15–3.95 (m,
1H), 3.20 (dt, J = 7.0, 1.2 Hz, 2H), 3.06–2.92 (br s, –OH , 1H),
2.72–2.44 (m, 2H), 1.54–1.27 (m, 8H), 0.89 (m, 3H); 13C NMR
(75 MHz, CDCl3): d 209.81, 129.94, 119.25, 67.54, 48.63, 48.39,
36.38, 31.70, 25.10, 22.55, 13.97; MASS (ESIMS): m/z 207 (M+Na)+.
4.11. (+)-(3R,5R)-Hydroxy-5-decanolide 2
To a stirred solution of (3R,5R)-3,5-dihydroxydecanoic acid 3
(0.081 g, 6.79 mmol) in THF (5 mL) was added 4 M HCl (1 mL)
and continued to stir for 4 h at room temperature. After completion
of the reaction, the reaction mixture was quenched with saturated
aqueous NaHCO3 solution (5 mL). The organic layer was separated
and the aqueous layer was extracted with EtOAc (3 ꢁ 5 mL). The
combined organic extracts were concentrated and the residue
was purified by flash column chromatography on silica gel (100–
200 mesh, eluent: 40% EtOAc in hexane) to afford (+)-(3R,5R)-3-
4.8. (4S,6R)-Undec-1-ene-4,6-diol 13
To
a stirred solution of (R)-6-hydroxyundec-1-en-4-one 9
(0.323 g, 1.76 mmol) in dry THF (14 mL) and dry MeOH (3.5 mL)
at ꢀ78 °C under argon was added a solution of methoxydiethylbo-
rane (1.94 mL, 1 M solution in THF, 1.94 mmol) dropwise and the
resulting mixture was stirred for 30 min. Next, NaBH4 (0.066 g,
1.94 mmol) was added and the resulting mixture was allowed to
stir for 3 h. After completion of the reaction, the reaction mixture
was quenched with 1.9 mL of AcOH and then diluted with EtOAc
(20 mL). The organic layer was separated and the aqueous layer
was extracted with EtOAc (3 ꢁ 10 mL). The combined organic lay-
ers were washed with aq NaHCO3 (2 ꢁ 10 mL) and dried over
Na2SO4, filtered and concentrated. The residue was purified by col-
umn chromatography on silicagel (100–200 mesh, eluent: 35%
EtOAc in hexane) to afford (4S,6R)-undec-1-ene-4,6-diol 13
Hydroxy-5-decanolide
2
(0.068 g, 92%) as
a
colourless oil.
½
a 2D5
ꢂ
¼ þ25:2 (c 0.9, CHCl3); lit.7e
½ ꢂ
a 2D5
¼ þ22:0 (c 0.5, CHCl3); IR
(KBR): mmax 3425, 2925, 2856, 1715, 1631, 1257, 1073, 764, 564,
402 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.78–4.61 (m, 1H), 4.46–
;
4.34 (m, 1H), 2.74 (dd, J = 17.3, 4.5 Hz, 1H), 2.67-2.57 (ddd, 17.3,
3.0, 1.5, 1H), 2.03–1.91 (dddd, J = 14.3, 5.2, 3.0, 1.5 Hz, 1H), 1.80–
1.72 (m, 1H), 1.66–1.46 (m, 2H), 1.45–1.24 (m, 6H), 0.89 (t,
J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 170.85, 75.97, 62.65,
38.58, 35.85, 35.43, 31.52, 24.49, 22.48, 13.96; MASS (ESIMS): m/
z 209 (M+Na)+; HRMS (ESI): m/z calcd for C10H18O3Na 209.1149,
Found 209.1153.
(0.261 g, 80%) as a colourless liquid. ½a D25
¼ þ3:4 (c 0.37, CHCl3);
ꢂ
Acknowledgements
1H NMR (300 MHz, CDCl3): d 5.91–5.71 (m, 1H), 5.19–5.06 (m,
2H), 3.98–3.74 (m, 2H), 3.48–2.74 (br s, –OH, 2H), 2.33–2.16 (m,
2H), 1.63 (dt, 1H), 1.56–1.27 (m, 9H), 0.89 (t, J = 6.7 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 134.29, 118.20, 72.94, 71.97, 42.53,
42.27, 38.04, 31.80, 25.00, 22.59, 14.00; MASS (ESIMS): m/z 209
(M+Na)+; HRMS (ESI): m/z calcd for C11H23O2, 187.1692. Found
187.1694.
A.V. thanks the UGC, New Delhi for the award of fellowship and
the Director, IICT.
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