Synthesis of (+)-(3R,5R)-3-hydroxy-5-decanolide and massoialactone, and formal synthesis of verbalactone

Article abstract of DOI:10.1080/00397910802055294

Total synthesis of (3R, 5R)-(+)-3-hydroxy-5-decanolide (1) and massoialactone (2), and formal synthesis of verbalactone (3), have been reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802055294

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Synthesis of (+)-(3R,5R)-3-
Hydroxy-5-decanolide and
Massoialactone, and Formal
Synthesis of Verbalactone
Gowravaram Sabitha a , V. Bhaskar a & J. S. Yadav a
a Organic Division I, Indian Institute of Chemical
Technology, Hyderabad, India
Published online: 09 Sep 2008.
To cite this article: Gowravaram Sabitha , V. Bhaskar & J. S. Yadav (2008) Synthesis
of (+)-(3R,5R)-3-Hydroxy-5-decanolide and Massoialactone, and Formal Synthesis
of Verbalactone, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:18, 3129-3141
To link to this article: http://dx.doi.org/10.1080/00397910802055294
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Synthetic Communications1, 38: 3129–3141, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802055294
Synthesis of (+)-(3R,5R)-3-Hydroxy-5-
decanolide and Massoialactone, and Formal
Synthesis of Verbalactone
Gowravaram Sabitha, V. Bhaskar, and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad, India
Abstract: Total synthesis of (3R, 5R)-(þ)-3-hydroxy-5-decanolide (1) and
massoialactone (2), and formal synthesis of verbalactone (3), have been reported.
Keywords: Dimer, formal synthesis, d-lactones, total synthesis
INTRODUCTION
Mevinic acids such as compactin and mevinolin that contain a b-hydroxy
lactone system stimulated a great deal of interest. Despite its rather sim-
ple structure, the lactone moiety of the mevinic acids has proved to be
essential for the biological activity of such compounds.[1] For these rea-
sons, many efforts have been made to discover and synthesize numerous
very potent and selective HMG-CoA reductase inhibitors in which the
lactone moiety has been attached to simpler fragments, and in some
cases, such analogs have proven to be more effective than the natural
mevinic acids.[2] b-Hydroxy and a, b-unsaturated d-lactone moieties are
present in a number of bioactive natural products such as (ꢀ)-callystatin
A[3] and (þ)-discodermolide.[4] (þ)-(3R, 5R)-3-Hydroxy-5-decanolide 1 is
a potent inhibitor of the enzyme HMG-CoA reductase.[5]
[6]
Massoialactone 2 is an alkyl lactone derived from the bark of the
Massoia tree (Cryptocaria massoia), which is found throughout Malaysia,
though the compound can also be found as a component of cane sugar
Received February 19, 2008.
Address correspondence to Gowravaram Sabitha, Organic Division I, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail:
gowravaramsr@yahoo.com
3129

3130
G. Sabitha, V. Bhaskar, and J. S. Yadav
molasses, cured tobacco, and the essential oil of sweet osmanthus
(Osmanthus fragrans). Once widely used as a natural coconut flavoring,
natural massoialactone has been largely superseded by a synthetic alter-
native because the extraction process is expensive and the tree is killed
during the process of removing the bark. Therefore, over the years, this
molecule has received considerable interest, and many racemic[7–11] and
[22]
enantioselective[12–21] syntheses have been reported. Verbalactone 3
is a macrocyclic dimer lactone isolated from the roots of verbascum
undulatum and exhibits antibacterial activity. This macrocyclic lactone
is a symmetrical dimer of the lactone 1. Only three synthetic proce-
dures[23–25] for the construction of this dimer have been reported so far.
Still, the synthesis of these compounds in an optically pure form has
turned out to be challenging, and it was always achieved in several steps
either by means of asymmetric reactions or starting from optically active
natural products. On account of such intriguing biological importance,
we are particularly interested in the synthesis of naturally occurring
b-hydroxy and a, b-unsaturated d-lactones such as (3R, 5R)-(þ)-3-
hydroxy-5-decanolide 1, massoialactone 2, and verbalactone 3 (Scheme 1).
The synthesis of 1 started with the known 2, 3-epoxychloride 5
(Scheme 2). The 2, 3-epoxychloride 5 was directly converted into an alky-
lated chiral acetylenic carbinol 6 in 80% yield in one pot by subjecting
it to a base-induced opening with Li metal in liquid NH3 in tetrahydro-
furan (THF), and the resulting alkynol without isolation was treated with
1-bromopropane at ꢀ33ꢁC for 6 h. The spectral data of compound 6 was
in good agreement with the assigned structure. The secondary hydroxyl
of 6 was protected as silyl ether 7 in 90% yield using tertiarybutyldiphe-
nylsilyl chloride (TBDPSCl) and imidazole in CH2Cl2 at room tempera-
ture. Next, hydrogenation of triple-bond compound 7 with 10% Pd=C in
EtOAc at room temperature for 4 h yielded a saturated compound 8 in
90% yield followed by deprotection of the THP group using pyridinium
Scheme 1. Retrosynthetic plan for (3R,5R)-(þ)-3-hydroxy-5-decanolide,
massoialactone, and verabalactone.

Synthesis of Decanolide, Massoialactone, and Verbalactone
3131
Scheme 2. Reagents and conditions: (a) Li=liq NH3, ferric nitrate (catalyst), dry
ꢁ
ꢁ
THF, compound 5, ꢀ33 C, 2 h, then propyl bromide, ꢀ33 C, 6 h, 80%; (b)
ꢁ
TBDPSCl, imidazole, DCM, 0 C–rt, 1 h, 90%; (c) 10% Pd=C, EtOAc, H2, rt,
ꢁ
4 h, 90%; (d) PPTS, methanol, rt, 2 h, 86%; (e) IBX, DMSO, DCM, 0 C–rt,
ꢁ
3 h, 80%; (f) anhyd. SnCl2, N2CHCOOEt, DCM, 0 C–rt, 6 h, 75%; (g) TBAF,
THF, 1 h, 90%; (h) catecholborane, dry THF, ꢀ10 ꢁC, 4 h, 92%; (i) 2,
2-DMP, PPTS, dry acetone, 85%.
paratoluenesulfonate in methanol and oxidation with iodoxbenzoic acid
in DMSO afforded aldehyde 10. Treatment of aldehyde 10 with ethyl
diazoacetate in the presence of a catalytic amount of tin(II) chloride in
CH2Cl2 at room temperature led to the formation of b-keto ester 11 in
75% yield. Selective deprotection of TBDPS ether group was done using
TBAF in THF at rt to produce d–hydroxy-b-ketoester 12 in 90% yield.
The stereoselective reduction of d–hydroxy-b-ketoester 12 to the corre-
sponding syn-1, 3-diol 13 was achieved using catecholborane (3.0 eq.) in
ꢁ
THF at ꢀ10 C in 92% yield with high diastereoselectivity (syn: anti,
99:1). To confirm the relative configuration of syn-1, 3-diol as well as to
protect the diol function required for the following reaction, syn diol 13
was transformed into the corresponding acetonide derivative 4 using 2,
2-DMP and PPTS in dry acetone in 85% yield. The 13C NMR chemical
shifts of the two methyl groups in the acetonide part in 4 exhibited peaks
at d19.6 and 30.0 and the quaternary carbon at d 99.0, indicating that the

3132
G. Sabitha, V. Bhaskar, and J. S. Yadav
Scheme 3. Reagents and conditions: (a) 3 N NaOH, MeOH, rt, 1 h, pH 2.0, 80%;
(b) benzene, p- TSA, 12 h, 64%.
two hydroxy groups are in a 1, 3-syn orientation.[26] In contrast, in the acet-
onide derivative prepared from a minor reduction product, signals were
found at almost the same values, namely, d 24.9 and 25.0, and the quatern-
ary carbon at d100.2, which were characteristic for the methyl groups in
the acetonide part of 1, 3-anti diol moiety. The key intermediate 4 served
as the divergent point for both natural products. With the protected ester
readily in hand, the final drive was to synthesize two molecules 1 and 2.
Thus, under hydrolysis conditions using 3 N NaOH in MeOH at rt
maintining pH at 2.0 for 1 h, intermediate 4 yielded (3R,5R)-(þ)-
3-hydroxy-5-decanolide 1 in 80% yield. Accordingly, treatment of inter-
mediate 4 with p TSA in benzene at rt for 12 h gave massoialactone 2 in
64% yield. The spectral data (1H, 13C NMR) and optical rotation values
[[a]D25: þ22.0 (c 0.5, CHCl3), [a]D25: ꢀ113.0 (c1.0, CHCl3)] lactones 1
and 2 are in good agreement with the reported compounds (Scheme 3).
Next, our goal was to synthesize verbalactone 3. Thus, the intermedi-
ate 4 was converted into the required dihydroxycarboxylic acid 15 in two
steps. Accordingly, hydrolysis of intermediate 4 using 4 N NaOH in
EtOH at rt maintaining pH at 6.0 for 1 h furnished carboxylic acid 14
in 78% yield by keeping the protecting group intact (Scheme 4). The
physical and spectroscopic data of 14 were identical to the reported
values, [a]D25: þ 3.6 (c 0.2, CHCl3) and [lit.[25] [a ]D25: þ 3.4 (c 0.15,
CHCl3)]. Because the conversion of acid 14 to verbalactone 3 through
Scheme 4. Reagents and conditions: (a) 4 N NaOH, EtOH, rt, 1 h, pH 6.0, 78%.

Synthesis of Decanolide, Massoialactone, and Verbalactone
3133
15 has already been reported in the literature, the present sequence herein
constitutes a formal synthesis of verbalactone 3 (Scheme 4).
EXPERIMENTAL
Reactions were conducted under a nitrogen atmosphere using anhydrous
solvents such as dichloromethane (DCM), THF, CCl4, benzene, and
EtOAc. All reactions were monitored by thin-layer chromatography
(TLC) using silica-coated plates and visualizing under UV light. Light pet-
roleum of the distillation range 60–80 ꢁC was used. Yields refer to chroma-
tographically and spectroscopically (1H, 13C) homogeneous material.
Air-sensitive reagents were transferred by syringe or with a double-ended
needle. Evaporation of solvents was performed at reduced pressure, using
a Buchi rotary evaporator. 1H NMR spectra were recorded on Varian FT
200-MHz (Gemini) and Bruker UXNMR FT 300-MHz (Avance) instru-
ments in CDCl3. Chemical shift values were reported in parts per million
(d) relative to tetramethylsilane (d 0.0) as an internal standard. Mass
spectra were recorded under electron impact at 70 eV on LC-MSD
(Agilent Technologies). Column chromatography was performed on sil-
ica-gel (60–120 mesh) supplied by Acme Chemical Co., India. TLS was
performed on Merck 60 F-254 silica-gel plates. Optical rotations were
ꢁ
measured with a Jasco DIP-370 polarimeter at 20 C.
(3S)-1-(Tetrahydro-2H-2-pyranyloxy)-4-octyn-3-ol (6)
To freshly distilled ammonia (200 mL) in a 500-mL, two-necked, round
bottom flask fitted with a cold finger condenser, a catalytic amount of
ferric nitrate (100 mg) was added, followed by lithium metal (2.87 g,
ꢁ
410.9 mmol) in fractions at –33 C. The resulting gray suspension was
stirred for 30 min. To this, epoxychloride 5 (15.0 g, 68.49 mmol) in
dry tetrahydrofuran (30 mL) was added over aꢁ period of 10 min. The
reaction mixture was then stirred for 2 h at –33 C, and propyl bromide
(12.6 g, 102.7 mmol) in dry tetrahydrofuran (50 mL) was added drop-
wise to the reaction mixture and stirred for another 6 h at the same tem-
perature. The reaction mixture was quenched with solid NH4Cl (12 g),
and then excess ammonia was allowed to evaporate. The residue was
dissolved in water, and the residue was filtered through a small pad
of Celite1. The filtrate was extracted with ethyl acetate (4 ꢂ 100 ml).
The organic layers were combined, washed once with water (1 ꢂ 100 ml)
ml) and brine (80 ml), and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified by
column chromatography (pet. Ether–EtOAc 8:2) to afford the 6 as a

3134
G. Sabitha, V. Bhaskar, and J. S. Yadav
slightly yellow liquid (12.5 g, 80.5%). [a]D25: ꢀ13.6 (c1.0, CHCl3);
1H NMR (CDCl3, 300 MHz): d 0.89 (t, J ¼ 7.5 Hz, 3H), 1.37–2.10
(m, 10H), 2.18 (td, J ¼ 7.5, 2.2 Hz, 2H), 3.44–3.59 (m, 1H), d 3.63–3.74
(m, 1H), 3.76–3.95 (m, 1H), 4.07 (td, J ¼ 9.0, 3.7 Hz, 1H), 4.48–4.65 (m,
2H); 13C NMR (75 MHz, CDCl3): d 98.7, 85.3, 80.7, 64.6, 62.0, 61.2,
37.2, 30.4, 25.2, 22.0, 20.6, 19.2, 13.7; IR (neat): 3422, 2933, 2870, 2250,
1277, 1202, 1120, 1067, 1029, 754 cmꢀ1; LCMS: m=z 249 (Mþ þ Na).
HRMS (ESI): m=z calcd. for C13H22O3 Na (Mþ þ Na): 249.1461; found:
249.1464.
tert-Butyl(diphenyl)((1S)-1-[2-(tetrahydro-2H-2-pyranyloxy)-
ethyl]-2-hexynyloxy)silane (7)
To a stirred solution of alcohol 6 (10.0 g, 44.2 mmol) and imidazole (6.0 g,
80.4 mmol) in dry DCM (70 mL), TBDPSCl (13.8 ml, 52.7 mmol) was
ꢁ
added portionwise at 0 C. The reaction mixture was stirred at the same
temperature for 1 h and then quenched with water (30 ml). The DCM
layer was separated, and the aqueous layer was extracted with additional
DCM (3 ꢂ 30 mL). Combined organic layers were washed with water
(2 ꢂ 50 ml), brine (2 ꢂ 50 ml) and solution and dried over anhydrous
Na2SO4. The solvent was removed in vacuo and the residue was purified
by silica-gel column chromatography (pet. ether–EtOAc 9:1) to afford 7
(18.5 g, 90% yield), as a colorless liquid. [a]D25: ꢀ32.0 (c0.5, CHCl3);
1H NMR (CDCl3, 300 MHz): d 0.87 (t, J ¼ 7.5 Hz, 3H), 1.06 (bs, 9H),
1.21–1.80 (m, 8H), 1.85–2.05 (m, 4H), 3.34–3.53 (m, 2H), 3.64–3.91 (m,
2H), 4.40 (t, J ¼ 3.7 Hz, 1H), 4.47–4.56 (m, 1H), 7.27–7.47 (m, 6H),
7.67 (dd, J ¼ 7.5, 1.5 Hz, 2H), 7.72 (dd, J ¼ 7.5, 1.5 Hz, 2H); 13C
NMR (100 MHz, CDCl3): d 136.0, 133.7, 129.5, 127.4, 98.6, 98.2, 85.6,
85.5, 81.2, 63.8, 38.9, 38.8, 30.5, 26.8, 25.4, 21.8, 20.6, 19.2, 13.4; IR
(neat): 3070, 2933, 2860, 2250, 1589, 1466, 1427, 1385, 1357, 1262,
1200, 1111, 1033, 983, 819, 739, 703 cmꢀ1; ESIMS: m=z 487 (Mþ þ Na);
HRMS (ESI): m=z calcd. for C29H40O3Si Na (Mþ þ Na): 487.2644;
found: 487.2661.
tert-Butyl(diphenyl)((1R)-1-[2-(tetrahydro-2H-2-
pyranyloxy)ethyl]hexyloxy)silane (8)
To a solution of 7 (10.0 g, 21.5 mmol) in anhyd. ethyl acetate (50 mL), a
catalytic amount of 10% Pd=C (1.5 g) was added, and the mixture was
stirred at room temperature under an H2 atmosphere for 4 h. Then, the
catalyst was filtered off and washed with ethyl acetate (3 ꢂ 50 ml), and
the filtrate was concentrated under reduced pressure and purified by

Synthesis of Decanolide, Massoialactone, and Verbalactone
3135
column chromatography (pet. ether–EtOAc 9:1) to afford 8 as a colorless
liquid (9.0 g, 90%). [d]D25: ꢀ3.4 (c 0.5, CHCl3); 1H NMR (CDCl3,
300 MHz): d 0.87 (t, J ¼ 7.5 Hz, 3H), 1.04 (bs, 9H), 1.08–1.63 (m, 10H),
1.73 (t, J ¼ 6.7 Hz, 2H), 3.27–3.45 (m, 2H), 3.63–3.77 (m, 2H), 3.78–3.93
(m, 1H), 4.40 (m, 1H), 7.28–7.41 (m, 6H), 7.65 (dd, J ¼ 7.5, 1.5 Hz, 4H);
13C NMR (75 MHz, CDCl3): d 134.7, 134.5, 129.4, 127.3, 98.6, 71.1, 64.2,
62.1, 36.7, 36.3, 31.8, 30.7, 27.0, 25.5, 24.4, 24.3, 22.5, 19.5, 13.9; IR
(neat): 2933, 2859, 1589, 1466, 1427, 1381, 1200, 1111, 1073, 1032,
704 cmꢀ1; LCMS: m=z 491 (Mþ þ Na); HRMS (ESI): m=z calcd. for
C29H44O3 Si Na (Mþ þ Na): 491.2957; found: 491.2937.
(3R)-3-[1-(tert-Butyl)-1, 1-diphenylsilyl]oxyoctan-1-ol (9)
To a stirred solution of compound 8 (7.0 g, 14.9 mmol) in methanol
(35 mL), a catalytic amount of pyridine p-toluenesulfonate (PPTS)
(0.8 g) was added. The reaction mixture was stirred at room temperature
for about 2 h, and methanol was removed under reduced pressure. The
crude residue was purified by silica-gel column chromatography to afford
9 (4.9 g, 86%) as a viscous liquid. [a]D25: ꢀ19.2 (c1.95, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 0.80 (t, J ¼ 7.5 Hz, 3H), 0.98–1.20 (m, 16H), 1.25–
1.68 (m, 3H), 1.73–1.86 (m, 2H), 3.55–3.67 (m, 2H), 3.68–3.80 (bs, 1H),
3.90 (q, J ¼ 6.7 Hz, 1H), 7.30–7.44 (m, 6H), 7.63–7.70 (m, 4H);
13C NMR (75 MHz, CDCl3): d 135.9, 134.8, 129.7, 127.5, 72.4, 59.8,
37.6, 36.2, 31.6, 27.0, 24.7, 22.4, 19.2, 13.9; IR (neat): 3381, 3069, 2930,
2857, 1587, 1466, 1427, 1382, 1108, 1051, 737, 702 cmꢀ1; LCMS: m=z
407 (Mþ þ Na); HRMS (ESI): m=z calcd. for C24H36O2Si Na (Mþ þ Na):
407.2382; found: 407.2362.
(8R)-8-[1-(tert-butyl)-1, 1-diphenylsilyl]oxytridecane-4, 6-dione (11)
To an ice-cooled solution of 2-iodoxybenzoic acid (5.1 g, 18.2 mmol) in
DMSO (6 mL, mmol), a solution of alcohol 9 (3.5 g, 9.1 mmol) in anhyd.
CH2Cl2 (20 mL) was added. The mixture was stirred at room temperature
for 3 h and then filtered through a Celite1 pad and washed with Et2O
(3 ꢂ 60 ml). The combined organic filtrates were washed with H2O
(2 ꢂ 20 ml) and brine (20 ml), dried (anhyd. Na2SO4), and concentrated
under vacuum at temperatures colder than 45 ꢁC. The crude product was
purified by column chromatography to afford aldehyde 10 as an unstable
viscous liquid (2.8 g, 80%), which was directly used for the next stage.
CH2Cl2 (10 mL) followed by ethyl diazoacetate (0.6 ml, 4.7 mmol)
were added with stirring at room temperature to anhydrous tin(II) chlor-
ide (0.075 g, 0.39 mmol). A few drops of compound 10 (1.5g, 3.9 mmol) in

3136
G. Sabitha, V. Bhaskar, and J. S. Yadav
dry CH2Cl2 slowly were added to this suspension. When nitrogen evol-
ution began, the remaining solution of compound was added dropwise
over 10 min. After nitrogen evolution had stopped (6 h), the reaction
was transferred to a separator funnel with saturated brine (NaCl,
20 mL) and extracted with diethyl ether (2 ꢂ 20 mL). The organic layers
were combined and dried over anhydrous Na2SO4. Solvent was removed
in vacuo, and residue was purified by silica-gel column chromatography
(pet. ether–EtOAc 9:1) to afford compound 11 (1.37 g, 75% yield) as a
25
viscous liquid. [a]D
:
ꢀ10.8 (c1.0, CHCl3); 1H NMR (CDCl3,
300 MHz): d 0.80 (t, J ¼ 7.5 Hz, 3H), 1.02 (bs, 9H), 1.08–1.21 (m, 4H),
1.22–1.31 (m, 4H), 1.35–1.44 (m, 3H), 2.61 (d, J ¼ 5.8 Hz, 2H), 3.24
(d, J ¼ 2.2 Hz, 2H), 4.02–4.23 (m, 3H), 7.31–7.43 (m, 6H), 7.59–7.67
(m, 4H); 13C NMR (75 MHz, CDCl3): d 203.0, 166.9, 135.8, 133.9,
129.6, 127.5, 91.1, 69.8, 61.1, 50.0, 42.7, 36.9, 31.5, 26.9, 24.4, 22.4,
14.0, 13.8; IR (neat): 2931, 2858, 1745, 1718, 1649, 1466, 1427, 1312,
1234, 1108, 1047, 738, 704 cmꢀ1; ESIMS: m=z 491 (Mþ þ Na); HRMS
(ESI): m=z calcd. for C28H40O4Si Na (Mþ þ Na): 491.2593; found:
491.2572.
(8R)-8-Hydroxytridecane-4, 6-dione (12)
To compound 11 (1.1 g, 2.35 mmol) in dry tetrahydrofuran (10 ml), tetra-
butyl ammonium fluoride (TBAF) (2.35 ml, 2.35 mmol, 1 M solution in
tetrahydrofuran) was added dropwise at 0 ꢁC, and the mixture was stirred
for 60 min. Water (2 mL) was added, and the mixture was extracted with
ethyl acetate (3 ꢂ 35 ml). The organic extracts were washed with brine
(2 ꢂ 20 ml) and dried over anhydrous Na2SO4. Evaporation of the solvent
afforded the product 12 (0.49 g, 90%), as a colorless liquid. [a]D25: ꢀ27.5
1
(c 0.5, CHCl3); H NMR (CDCl3, 300 MHz): d 0.90 (t, J ¼ 6.7 Hz, 3H),
1.21–1.5 (m, 11H), 2.54–2.74 (m, 2H), 3.41 (s, 2H), 3.96–4.09 (m, 1H),
4.19 (q, J ¼ 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 203.8, 166.8,
67.5, 61.4, 49.9, 49.6, 36.4, 31.6, 25.1, 22.5, 14.0, 13.9; IR (neat): 3439,
2929, 2860, 1740, 1713, 1462, 1408, 1372, 1315, 1237, 1153, 1031 cmꢀ1;
LCMS: m=z 253 (Mþ þ Na); HRMS (ESI): m=z calcd. for C12H22O4Na
(Mþ þ Na): 253.1415; found: 253.1422.
Ethyl (3R, 5R)-3, 5-Dihydroxydecanoate (13)
A solution of compound 12 (0.4 g, 1.7ꢁ4 mmol), in dry tetrahydrofuran
was chilled in an MeOH–ice bath (ꢀ10 C) and charged with freshly dis-
tilled catecholborane (0.66 mL, 5.22 mmol). After 4 h, the reaction mix-
ture was quenched by the addition of 1 mL of anhydrous MeOH and

Synthesis of Decanolide, Massoialactone, and Verbalactone
3137
2 mL of a saturated aqueous solution of sodium potassium tartarate. This
mixture was allowed to stir at room temperature for 2 h. The layers were
separated, and aqueous layer was extracted with ethyl acetate (3 ꢂ 30 ml).
The organic extracts were washed with brine (30 ml) and dried over
anhydrous Na2SO4, and the desired product was isolated by silica-gel
column chromatography (pet. ether–EtOAc 6:4) to afford the diol 13
(0.33 g, 82%) as a liquid. [a]D25: ꢀ9.8 (c 0.5, CHCl3); 1H NMR (CDCl3,
300 MHz): d 0.90 (t, J ¼ 6.7 Hz, 3H), 1.22–1.48 (m, 11H), 1.50–1.56 (m,
2H), 2.42–2.46 (m, 2H), 3.77–3.89 (m, 1H), 4.11–4.27 (m, 3H); 13C NMR
(75 MHz, CDCl3): d 172.5, 72.2, 69.1, 60.7, 42.0, 37.7, 31.7, 29.6, 24.9,
22.5, 14.1, 13.9; IR (neat): 3419, 2925, 2855, 1727, 1461, 1376, 1252,
1165, 1065 cmꢀ1; LCMS: m=z 255 (Mþ þ Na); HRMS (ESI): m=z calcd.
for C12H24O4Na (Mþ þ Na): 255.1566; found: 255.1573.
Ethyl 2-[(4R, 6R)-2, 2-Dimethyl-6-pentyl-1, 3-dioxan-4-yl]acetate (4)
To a solution of diol 13 (0.3 g, 1.3 mmol) in dry acetone (5 mL), 2,
2-dimethoxy propane (0.32 mL, 2.6 mmol) and a catalytic amount of
PPTS (pyridine p-toluenesulfonate) (0.01 mg) were added. The mixture
was stirred at ambient temperature for 3 h. Sodium bicarbonate (30 mg)
was added to neutralize pyridine p-toluenesulfonate and filtered.
Removal of solvent and purification by silica-gel column chromato-
graphy (pet. ether–EtOAc 8:2) afforded the acetonide 4 (0.3 g, 85%),
1
as a light yellow liquid. [a]D25: þ8.0 (c 0.25, CHCl3); H NMR (CDCl3,
300 MHz): d 0.89 (t, J ¼ 6.7 Hz, 3H), 1.20–1.46 (m, 13H), 2.24–2.40 (ddd,
J ¼ 5.4, 6.08, 6.04 Hz, 1H), 2.42–2.53 (m, 1H), 3.66–3.84 (m, 1H), 4.12 (q,
J ¼ 7.5 Hz, 2H), 4.17–4.30 (m, 1H); 13C NMR (75 MHz, CDCl3): d 170.9,
98.5, 68.7, 65.9, 60.3, 41.4, 36.4, 36.2, 31.7, 30.0, 24.5, 22.5, 19.6, 14.1,
13.9; IR (neat): 2987, 2932, 2862, 1739, 1461, 1377, 1261, 1223, 1197,
1168, 1130, 1023 cmꢀ1; LCMS: m=z 295 (Mþ þ Na); HRMS (ESI): m=z
calcd. for C15H28O4Na (Mþ þ Na): 295.1885; found: 295.1897.
2-[(4R, 6R)-2, 2-Dimethyl-6-pentyl-1, 3-dioxan-4-yl]aceticacid (14)
Acetonide ester 4 (0.20 g, 0.74 mmol) was dissolved in MeOH (2 mL)
and 4 N NaOH (1 mL) was added. The resulting mixture was left to stir
at rt for 1 h. The solvents were then removed under reduced pressure and
the crude product was redissolved with ethyl acetate. The PH of the
aqueous layer was adjusted to 6.0 with aqueous HCL (1 N), and the
aqueous phase was extracted with ethyl acetate (3 ꢂ 20 mL). The com-
bined organic phase was washed once with water (15 ml) and brine
(15 ml), dried over MgSO4, and concentrated under reduced pressure.

3138
G. Sabitha, V. Bhaskar, and J. S. Yadav
Purification by silica-gel column chromatography (pet. ether–EtOAc 6:4)
afforded the acid 14 (0.14 g, 78%), as a liquid. [a]D25: þ 3.6 (c 0.2,
CHCl3); NMR (CDCl3, 300 MHz): d 0.90 (t, J ¼ 7.0 Hz, 3H), 1.36 (s,
3H), 1.44 (s, 3H), 1.18–1.64 (m, 10H), 2.43 (dd, J ¼ 5.4, 15.7 Hz, 1H),
2.57 (dd, J ¼ 7.0, 16.4 Hz, 1H), 3.63–3.93 (m, 1H), 4.15–4.35 (m, 1H);
13C NMR (75 MHz, CDCl3): d 174.7, 99.1, 68.8, 65.9, 41.1, 36.2, 31.7,
30.0, 29.7, 24.5, 22.6, 19.7, 14.0; IR (neat): 3445, 2992, 2928, 2860,
1711, 1459, 1378, 1258, 1198, 1165, 1023 cmꢀ1; ESIMS: m=z 267
(Mþ þ Na); HRMS (ESI): m=z calcd. for C13H24O4Na (Mþ þ Na):
267.1572; found: 267.1569.
Massoialactone (2)
To a stirred solution of acetonide ester 4 (0.1g, 0.37 mmol) in benzene
(5 mL), a pinch of p-tolunesulfonic acid (PTSA) was added. The reaction
mixture was allowed to stir overnight at room temperature, and benzene
was removed in vacuum. The crude product was purified by column
chromatography (pet. ether–EtOAc 7:3) using silica-gel to give a lactone
2 (0.4 g, 64%) as a pale yellow liquid. [a]D25: ꢀ 113.0 (c1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d 0.91 (t, J ¼ 6.0 Hz, 3H), 1.22–1.46 (m,
6H), 1.47–1.70 (m, 1H), 1.71–1.87 (m, 1H), 2.27–2.35 (m, 2H), 4.33–4.44
(m, 1H), 5.99 (td, J ¼ 9.8, 2.2 Hz, 1H), 6.80–6.87 (m, 1H); 13C NMR
(75 MHz, CDCl3): 164.5, 145.0, 121.4, 78.0, 34.8, 31.5, 29.4, 24.5, 22.5,
14.0; IR (neat): 2933, 1725, 1039 cmꢀ1; ESIMS: 169 (Mþ þ H). HRMS
(ESI): m=z calcd. for C10H17O2 (Mþ þ H): 169.1228; found: 169.1232.
(3R, 5R)-(+)-3-Hydroxy-5-decanolide (1)
A stirred solution of compound 4 (0.10 g, 0.37 mmol) was dissolved in
MeOH (6 mL), then 3 N NaOH (0.6 mL) was added. The resulting
mixture was left to stir at rt for 1 h, followed by thin-layer chromato-
graphy (TLC). The solvents were then removed under reduced press-
ure, and the crude product was redissolved in ethyl acetate (25 ml).
The PH of the aqueous layer was adjusted to 2 with aqueous HCL
(1 N), and the aqueous phase was extracted with ethyl acetate
(3 ꢂ 20 mL). The combined organic phase was washed once with water
(10 ml), dried over MgSO4, and concentrated under reduced pressure.
Purification by silica-gel column chromatography (pet. ether–EtOAc
1:1) afforded the monomeric lactone 1 (0.055 g, 80%) as a colorless
1
liquid. [a]D25: þ 22.0 (c 0.5, CHCl3); HNMR (CDCl3, 200 MHz): d
0.90 (t, J ¼ 7.0 Hz, 3H), 1.20–1.43 (m, 6H), 1.67–1.73(m, 1H), 1.47–
1.77 (m, 2H), 1.95 (td, J ¼ 4.2, 14.5 Hz, 1H), 2.55–2.67 (m, 2H),

Synthesis of Decanolide, Massoialactone, and Verbalactone
3139
4.27–4.38 (m, 1H), 4.60–4.76 (m, 1H); 13C NMR (75 MHz, CDCl3): d
170.5, 76.0, 62.8, 38.8, 36.0, 35.3, 31.4, 24.2, 22.4, 14.0; IR (neat):
3482, 2928, 2861, 1716, 1460, 1386, 1255, 1065; ESIMS: m=z 187
(Mþ þ 1). HRMS (ESI): m=z calcd. for C10H18O3Na (Mþ þ Na):
209.1153; found: 209.1149.
ACKNOWLEDGMENT
V. B. thanks University Grants Commission, New Delhi, for the award
of fellowship.
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