Enantioselective total synthesis of (+)-vittatalactone

Article abstract of DOI:10.1002/ejoc.201100354

An enantioselective asymmetric total synthesis of (+)-vittatalactone has been accomplished employing enzymatic desymmetrization approach to create two methyl chiral centres. Other key steps involved are Wittig reaction, Evan's asym metric alkylation, hydroboration, TEMPO-BAIB-mediated selective oxidation of 1, 3-diol and lactonization mediated by p-toluenesulfonyl chloride. The total synthesis was achieved by a linear synthetic sequence with an overall yield of 11.8%.

Full text of DOI:10.1002/ejoc.201100354

FULL PAPER
DOI: 10.1002/ejoc.201100354
Enantioselective Total Synthesis of (+)-Vittatalactone
Jhillu S. Yadav,*[a,b] Nagendra Nath Yadav,[a] T. Srinivasa Rao,[a] B. V. Subba Reddy,[a] and
Ahmad Al Khazim Al Ghamdi[c]
Keywords: Natural products / Synthetic methods / Enzyme catalysis / Wittig reactions / Hydroboration / Alkylation /
Pheromones / Vittatalactone / Lactones
An enantioselective asymmetric total synthesis of (+)-vittata-
lactone has been accomplished employing enzymatic desym-
metrization approach to create two methyl chiral centres.
Other key steps involved are Wittig reaction, Evan’s asym-
metric alkylation, hydroboration, TEMPO-BAIB-mediated
selective oxidation of 1,3-diol and lactonization mediated by
p-toluenesulfonyl chloride. The total synthesis was achieved
by a linear synthetic sequence with an overall yield of 11.8%.
synthesis of (+)-1 has been reported by Breit et al. by the
o-DPPB-directed allylic substitution and by Schneider et al.
by using the [Ir(cod)L]BArF catalyst for the hydrogenation
reaction.[5b,5c] We herein report an alternative enantioselec-
tive total synthesis of (+)-1 by using Evan’s alkylation and
hydroborane oxidation of the E-enal to generate the three
chiral centres out of the five stereogenic centres in good
diastereoselectivity.
Introduction
Natural products derived from polydeoxypropionates are
known to exhibit various biological activities.[1–3] (+)-Vittata-
lactone (1), a structurally unique pheromone containing
five stereogenic centers was first identified by Morris and
Francke et al. in 2005 from the pheromone mixture secreted
by the feeding male striped cucumber beetles, Acalymma
vittatum.[4] The structural features of (+)-vittatalactone in-
cludes the presence of trideoxypropionate unit and β-
lactone units. Recently, Breit et al. have assigned the relative
and absolute configuration of natural (+)-1 and its stereo-
isomers 2a, 2b (see Figure 1).[5a,5b]
Results and Discussion
The retrosynthetic approach for (+)-1 is depicted in
Scheme 1 where the target molecule (+)-1 can easily be envi-
sioned from the diol 3 having all the required five chiral
centres. Further, compound 3 could be obtained by a se-
quence of reactions such as Wittig reaction, DIBAL-H re-
duction, hydroboration and oxidation with alkaline hydro-
gen peroxide from compound 4 having the required three
chiral centres. Then compound 4 can in turn be obtained
from the known compound 5 via 11 by means of Wittig
reaction followed by stereoselective Evan’s alkylation.
Figure 1. Chemical structures of (+)-vittatalactone (1) and its
stereoisomers 2a, 2b.
Our continuing interest in the total synthesis of various
biologically active natural products and the inherent bio-
logical activity of (+)-1 encouraged us to explore the syn-
thesis of this molecule. More recently, enantioselective total
[a] Organic Chemistry Division I, Indian Institute of Chemical
Technology (CSIR),
Hyderabad 500007, India
Fax: +91-40-27160512
E-mail: yadavpub@iict.res.in
[b] Bee Research Chair – College of Food and Agriculture Science,
King Saudi University,
Scheme 1. Retrosynthetic analysis of (+)-vittatalactone (1).
P. O. Box 2455, Riyadh 11451, Saudi Arabia
[c] Engineer Abdullah Baqshan for Bee Research, King Saudi
University,
Our synthesis began with the known precursor 5 that has
two chiral centres already in place. Compound 5 was syn-
thesized in four steps starting from cis-4,6-dimethylcy-
Saudi Arabia
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J. S. Yadav et al.
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clohexan-1,3-dione following a well-reported protocol.[6] and after separation by column chromatography).[12] The
Accordingly, cis-diketone was converted into the diacid by analytical data of the diol 3 was found to be identical to
periodate oxidation.[7] LiAlH4 reduction of the diacid in the prepared one by an alternative method (by oxidation,
THF at room temperature gave the meso-diol in 98% yield. C2-Wittig reaction, DIBAL-H reduction, Sharpless asym-
Desymmetrization of meso-diol by using porcine pancreatic metric epoxidation and Gillman’s opening of chiral epox-
lipase (PPL) and vinyl acetate in THF at ambient condi- ide).[5b] The di-hydroxy groups of diol 3 were protected as
tions furnished the mono acetate 5 in 47% yield and at their acetonide followed by the deprotection of silyl ether
least 95% ee along with the meso-diacetate.[8] It is note- on the other terminal with TBAF in THF afforded com-
worthy to mention that the meso-diacetate obtained was pound 13 in 93% yield in two steps. Oxidation of com-
again converted back to the meso-diol by treatment with pound 13 with IBX in DMSO furnished the corresponding
CH3ONa in methanol in quantitative yield for further uti- aldehyde for the envisioned Wittig reaction. Interestingly,
lilations. Mono acetate 5 in hand was protected as its silyl the Wittig olefination using the unstable ylide Ph3=CMe2
ether using TBSCl and imidazole in dichloromethane and provided only poor yield (Ͻ 35%) towards the formation of
then treated with CH3ONa in methanol to furnish the de- the corresponding olefin as a result olefination of aldehyde
sired terminal alcohol 6. Subsequently, oxidation of alcohol with stable ylide was performed, i.e. Ph3P=C(CH3)CO2Et
6 followed by two-carbon atoms extension by means of Wit- to furnish the corresponding α,β-unsaturated ester 14 in
tig reaction gave the α,β-unsaturated ester 7 in 86% yield Ͼ 85% yield from alcohol 13.[11] Reduction of the double
in overall two steps. Subsequent reduction of the double bond using NiCl2·6H2O and NaBH4 in MeOH gave the sat-
bond with NaBH4 in the presence of NiCl2·6H2O in MeOH urated ester 15 in 92% yield. Then treatment of compound
afforded the saturated ester 8,[9] in 96% yield which was 15 with LiAlH4 followed by tosylation and further re-
then hydrolyzed under basic conditions to furnish the corre- duction furnished the required compound 16 in 82% yields
sponding carboxylic acid 9 in 93% yield. Coupling of acid in overall 3 steps. Deprotection of acetonide 16 under acidic
9 with the Evan’s chiral oxazolidinone using piavloyl chlo- condition furnished the 1,3-diol 17 in 92% yield for which
ride in presence of triethylamine and LiCl furnished the re- the analytical data was in comparison with the data re-
quired compound 10 in 93% yield.[10] Diastereoselective ported in the literature.[13] Selective oxidation of 1,3-diol 17
methylation of the Na-enolate of compound 10 with MeI using TEMPO-BAIB afforded the β-hydroxy aldehyde,
furnished the desired compound 11 in 91% yield and in which was used as such in the next step without further
Ͼ 97:3[5c] which was confirmed by 1H NMR, and then sub- purification for the oxidation of β-hydroxy aldehyde under
jected to NaBH4 in MeOH to obtain the desired primary Pinniks conditions (NaClO2, NaH2PO4·2H2O) and fur-
alcohol 4 having a new additional chiral centre in 92% yield nished the β-hydroxy acid 18 in 76% yield.[14] The NMR
(Scheme 2).
(1H and 13C) analysis and optical rotation [α]D = –7.6 of 18
Scheme 2. Synthesis of alcohol 4.
Next, alcohol 4 was subjected to oxidation using IBX in
DMSO followed by C3-Wittig reaction to afford the α,β-
unsaturated ester 12 (E-isomer) as a sole product in 86%
over two steps.[11]
The ester 12 was then reduced to give the corresponding
aldehyde and the latter subjected to hydroboration followed
by oxidation to obtain the diol 3 in 72% yield with all the
five chiral centres in place along with 14% of the another
1
diastereoisomer (overall yield 86%, dr, 84:16 by H NMR Scheme 3. Synthesis of (+)-vittatalactone (1).
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Eur. J. Org. Chem. 2011, 4603–4608

Enantioselective Total Synthesis of (+)-Vittatalactone
were in good agreement with literature value.[13] Eventual
lactonization of β-hydroxy acid with p-toluenesulfonyl chlo-
ride in pyridine finally furnished the target natural product,
(+)-vittatalactone in 78% yield (Scheme 3).
of the reaction as indicated by TLC, the mixture was quenched
with saturated aqueous NH4Cl and extracted with CH2Cl2
(3ϫ50 mL). The combined organic layers were washed with brine,
dried with Na2SO4 and concentrated under reduced pressure to
furnish crude acetate. To the above mixture in MeOH (80 mL) was
added sodium methoxide (2.3 g, 43.05 mmol) at room temperature.
Then the mixture was stirred for 1 h at room temperature and con-
centrated under reduced pressure. The residue was then quenched
by the addition of saturated NH4Cl and extracted with EtOAc
(3ϫ100 mL). The combined organic layers were washed with
water, brine, dried with Na2SO4 and concentrated in vacuo. The
resulting crude product was purified by silica gel column
chromatography (1:9 EtOAc/hexane) to give the product as a color-
less oil 6 in (6.77 g, 96%) yield. [α]D = +0.9 (c = 1.2, CHCl3). IR
Conclusions
In conclusion, we have accomplished the total synthesis
of (+)-vittatalactone in enantioselective manner employing
enzymatic desymmetrization of meso-diol, Wittig reaction,
hydroboration/oxidation of E-enal, TEMPO-BAIB-medi-
ated selective oxidation and lactonization of β-hydroxy acid
as key steps. The synthesis follows linear synthetic sequence
with an overall yield of 11.8%.
(KBr): ν = 3348, 2954, 2928, 2857, 1466, 1252, 1097, 837, 775 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 3.32–3.50 (m, 4 H), 1.60–1.77
(m, 2 H), 1.36–1.50 (m, 2 H), 0.93 (d, J = 6.7 Hz, 3 H), 0.90 (d, J
= 6.7 Hz, 3 H), 0.89 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 68.2, 67.9, 37.2, 33.1, 25.8, 18.2, 17.7, 17.6, –5.4 ppm.
Experimental Section
Ethyl (2E,4S,6R)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4,6-dimeth-
General: All reactions were carried out under inert atmosphere of
argon or nitrogen using standard syringe, septa, and cannula tech-
niques unless otherwise mentioned. Commercial reagents were used
without further purification. All solvents were purified by standard
techniques. Infrared (IR) spectra were recorded on a Perkin–Elmer
683 spectrometer using NaCl optics. Spectra were calibrated
against the polystyrene absorption at 1610 cm–1. Samples were
scanned neat, in KBr wafers or in chloroform as a thin film. 1H
NMR spectra were recorded in CDCl3 on Bruker 300, Varian
Unity 500 NMR spectrometer. 13C NMR spectra were recorded at
75 MHz in CDCl3 using tetramethylsilane as a reference standard.
Column chromatography was performed using silica gel (60–
120 mesh) and the column was usually eluted with a mixture of
ethyl acetate/petroleum ether. Visualization of the spots on TLC
plates was achieved either by exposure to iodine vapor or UV light
or by dipping the plates to ethanolic anisaldehyde/sulfuric acid/
acetic acid or into phosphomolybdic acid/sulfuric acid solution and
heating the plates at 120 °C. Mass spectra were obtained on a Fin-
nigan MAT1020B or micromass VG 70-70H spectrometer op-
erating at 70 eV using a direct inlet system. Optical rotations were
recorded on Perkin–Elmer 241 polarimeter in 1.0 dm, 1.0 mL cells.
yl-2-heptenoate (7): To
a stirred solution of IBX (11.43 g,
40.8 mmol) in DMSO (30 mL) at 25 °C, was added slowly dropwise
a solution of alcohol 6 (6.7 g, 27.2 mmol) in CH2Cl2 (80 mL). The
resulting mixture was stirred at 25 °C for 3 h. The solid was filtered
and washed with diethyl ether. The filtrate was washed with satu-
rated aqueous NaHCO3 solution, water, brine and dried with
Na2SO4. The solvent was removed under reduced pressure to fur-
nish crude aldehyde. To the above crude mixture (4.94 g,
29.07 mmol) in CH2Cl2 (150 mL) was added (ethoxycarbonylme-
thylene)triphenylphosphorane (17.03 g, 48.96 mmol) and resulting
mixture was stirred for 12 hours at room temperature. The reaction
mixture was concentrated under reduced pressure and purified on
silica gel chromatography (5% EtOAc/hexane) to afford the unsatu-
rated ester 7 (7.3 g, 86%) as a colourless liquid. [α]D = +17.9 (c =
1.0, CHCl ). IR (KBr): ν = 2957, 2859, 1722, 1652, 1465, 1367,
˜
3
1259, 1180, 1094, 1042, 840, 775 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 6.76 (dd, J = 15.8, 8.3 Hz, 1 H), 5.75 (d, J = 15.8 Hz,
1 H), 4.17 (q, J = 14.3, 6.7 Hz, 2 H), 3.37 (dd, J = 5.2, 1.5 Hz, 2
H), 2.32–2.51 (m, 1 H), 1.44–1.67 (m, 2 H), 1.29 (t, J = 6.7 Hz, 3
H), 1.06–1.15 (m, 1 H), 1.06 (d, J = 6.7 Hz, 3 H), 0.89 (s, 9 H),
0.86 (d, J = 6.7 Hz, 3 H), 0.03 (s, 6 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 166.7, 154.3, 119.7, 68.3, 60.0, 39.8, 34.1, 33.3, 25.8,
20.4, 18.2, 16.5, 14.2, –5.4 ppm. MS (ESI): m/z = 337 [M +
Na]+. HRMS: calcd. for C17H34NaO3Si [M + Na]+ 337.2174; found
337.2174.
(2S,4R)-5-Hydroxy-2,4-dimethylpentyl Acetate (5): To a stirred
solution of meso-diol (4.0 g, 22.9 mmol) in THF (130 mL) and
water (170 μL) was added PPL (11.6 g) and vinyl acetate at room
temperature. The reaction mixture was stirred for 6 h at room tem-
perature. After complete conversion of the starting material (as
indicated by TLC), the reaction mixture was filtered off through a
pad of Celite, washed with ethyl acetate, dried with Na2SO4, con-
centrated in vacuo and purified by chromatography on silica gel
(1:5, EtOAc/hexane) to afford the monoacetate 5 (2.47 g, 47%) as a
colorless liquid. [α]D = +9.8 (c = 0.6, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 3.97 (dd, J = 10.5, 5.2 Hz, 1 H), 3.85 (dd, J = 10.5,
6.7 Hz, 1 H), 3.49 (dd, J = 10.5, 6.0 Hz, 1 H), 3.42 (dd, J = 10.5,
6.0 Hz, 1 H), 2.05 (s, 3H), 1.82–1.96 (m, 1 H), 1.64–1.78 (m, 1 H),
1.43 (br., 1 H), 1.39–1.49 (m, 1 H), 1.15–1.30 (m, 1 H), 0.96 (d, J
= 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 171.3, 69.1, 67.9, 37.2, 32.9, 29.9, 20.9, 17.8,
17.2 ppm.
Ethyl (4R,6R)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4,6-dimethyl-
heptanoate (8): To a cooled (0 °C) solution of 7 (7.2 g, 22.9 mmol)
and NiCl2·6H2O (1.08 g, 4.58 mmol) in MeOH (100 mL), was
added NaBH4 (2.0 g, 54.96 mmol) in small portions to the solution.
During addition of NaBH4, the reaction temperature was main-
tained at 0 °C. After complete addition of NaBH4, the reaction
mixture was stirred for 1 h at room temperature and the resulting
black precipitate was filtered and then washed with MeOH. The
solvent was removed under reduced pressure and then diluted with
water (100 mL) and extracted with ethyl acetate (3ϫ100 mL). The
combined organic layers were washed with water, brine and dried
with anhydrous Na2SO4. Removal of solvent under reduced pres-
sure followed by purification on silica gel column chromatography
(2S,4R)-5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4-dimethylpentan- using ethyl acetate/hexane (5% EtOAc/hexane) gave the product 8
1-ol (6): To a cold (0 °C) solution of alcohol 4 (5.0 g, 28.7 mmol) (6.9 g, 96% yield) as a colorless oil. [α]D = +3.8 (c = 1.2, CHCl3).
in dry CH2Cl2 (80 mL) was added imidazole (3.9 g, 57.4 mmol) and IR (KBr): ν = 2956, 1738, 1636, 1253, 1094, 772, 570 cm–1. 1H
˜
tert-butyldimethylsilyl chloride (5.16 g, 34.44 mmol). The resulting
mixture was stirred at room temperature for 3 h. After completion
NMR (300 MHz, CDCl3): δ = 4.10 (q, J = 14.3, 6.7 Hz, 2 H), 3.41
(dd, J = 9.8, 6.0 Hz, 1 H), 3.33 (dd, J = 9.8, 6.0 Hz, 1 H), 2.18–
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2.34 (m, 2 H), 1.28–1.75 (m, 6 H), 1.26 (t, J = 6.7 Hz, 3 H), 0.90
(d, J = 6.0 Hz, 3 H), 0.89 (s, 9 H), 0.87 (d, J = 6.0 Hz, 3 H), 0.02
(s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 174.0, 68.2, 60.1,
40.7, 33.0, 31.8, 31.5, 29.6, 25.9, 20.0, 18.2, 17.3, 14.2, –5.4 ppm.
MS (ESI): m/z = 339 [M + Na]+. HRMS: calcd. for C17H36NaO3Si
[M + Na]+ 339.2331; found 339.2321.
ethyl acetate and hexane (1:19) to afford the product 11 as a color-
less liquid (3.73 g, 91%). [α]D = +41.6 (c = 1.3, CHCl3). IR (KBr):
ν = 2956, 2928, 2857, 1783, 1699, 1460, 1385, 1351, 1249, 1208,
˜
1
1096, 839, 774, 700 cm–1. H NMR (300 MHz, CDCl3): δ = 7.17–
7.37 (m, 5 H), 4.55–4.68 (m, 1 H), 4.08–4.22 (m, 2 H), 377–3.93
(m, 1 H), 3.22–3.47 (m, 3 H), 2.70 (dd, J = 12.8, 9.8 Hz, 1 H),
1.25–1.98 (m, 5 H), 1.20 (d, J = 6.7 Hz, 3 H), 0.96–1.12 (m, 1 H),
0.89 (s, 9 H), 0.88 (d, J = 6.7 Hz, 6 H), 0.03 (s, 6 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 177.2, 152.9, 135.2, 129.4, 128.8, 127.2, 68.3,
65.9, 55.2, 41.2, 40.4, 37.8, 35.2, 33.0, 28.1, 25.9, 20.7, 18.5, 18.3,
17.4, –5.3 ppm. MS (ESI): m/z = 484 [M + Na]+. HRMS: calcd.
for C26H43NaO4Si [M + Na]+ 484.2859; found 484.2875.
(4R,6R)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-4,6-dimethylheptan-
oic Acid (9): LiOH·H2O (2.7 g, 64.5 mmol) was added portion wise
to a cooled solution (0 °C) of ester 8 (6.8 g, 21.5 mmol) in 80 mL of
CH3OH/H2O (3:1) and the stirring was continued for 2 h at room
temperature. The reaction mixture was then concentrated in vacuo
and the residue was diluted with EtOAc (80 mL) and washed with
saturated aqueous NH4Cl and extracted with EtOAc (3ϫ50 mL).
The combined organic layers were washed with brine, dried with
Na2SO4 and concentrated under reduced pressure. Removal of sol-
vent followed by column chromatography using 20% EtOAc/hex-
ane afforded the acid 9 (5.7 g, 93% yield) as a colorless liquid.
(2S,4R,6R)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4,6-trimethyl-
heptan-1-ol (4): To a stirred solution of 11 (5.0 g, 10.8 mmol) in
MeOH (40 mL) at 0 °C was added NaBH4 portion wise (1.23 g,
32.4 mmol). The reaction mixture was allowed to stir for 1 hour at
same temperature and then quenched with saturated aqueous
NH4Cl. The solvent was removed under reduced pressure and the
resulting residue was diluted with water and extracted with EtOAc
[α]D = +5.0 (c = 0.7, CHCl ). IR (KBr): ν = 2956, 2930, 2858,
˜
3
1711, 1464, 1414, 1253, 1094, 938, 839, 775, 667 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 3.30–3.45 (m, 2 H), 2.24–2.42 (m, 2 H), (3 ϫ 100 mL). The combined organic layers were dried with
1.06–1.78 (m, 6 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.89 (s, 9 H), 0.88 (d,
Na2SO4 and concentrated under reduced pressure and the crude
product was purified by silica gel column chromatography (10%,
J = 6.7 Hz, 3 H), 0.03 (s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 180.2, 68.1, 40.6, 33.0, 31.5, 31.2, 29.6, 25.9, 19.9, 18.3, 17.4, EtOAc/hexane) to afford the pure product 4 (2.86 g, 92%) as a
–5.3 ppm. MS (ESI): m/z = 311 [M + Na]+. HRMS: calcd. for
viscous liquid. [α]D = –5.8 (c = 1.0, CHCl ). IR (KBr): ν = 3351,
˜
3
C15H32NaO3Si [M + Na]+ 311.2018; found 311.2028.
2956, 2928, 2858, 1465, 1383, 1253, 1098, 1040, 838, 775, 667 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.29–3.55 (m, 4 H), 2.60 (s, 1
H), 0.96–1.88 (m, 7 H), 0.93 (d, J = 7.5 Hz, 3 H), 0.90 (d, J =
6.7 Hz, 3 H), 0.89 (s, 9 H), 0.88 (d, J = 6.7 Hz, 3 H), 0.03 (s, 6 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 68.1, 67.9, 41.2, 41.0, 33.0,
27.6, 25.9, 21.0, 18.3, 17.9, 17.5, –5.3 ppm. MS (ESI): m/z = 289
[M + H]+. HRMS: calcd. for C16H36NaO2Si [M + Na]+ 311.2382;
found 311.2398.
(4S)-4-Benzyl-3-{(4R,6R)-7-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-4,6-
dimethylheptanoyl}-1,3-oxazolan-2-one (10): To a stirred solution of
acid 9 (5.6 g, 19.4 mmol) in THF (100 mL) at –20 °C was added
Et3N (6.74 mL, 48.5 mmol) followed by PivCl (2.4 mL, 19.4 mmol).
After stirring for 1 h at –20 °C, LiCl (1.23 g, 29.1 mmol) followed
by (S)-oxazolidinone (3.77 g, 21.34 mmol) were added to it at the
same temperature. The stirring was continued for 1 h at –20 °C and
then 2 h at 0 °C. It was then quenched with saturated NH4Cl solu-
tion (50 mL) and extracted with ethyl acetate (2 ϫ 80 mL). The
combined organic layers were washed with brine (30 mL), dried
with anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatog-
raphy using ethyl acetate and hexane (1:16) to gave 10 (8.0 g, 93%)
Ethyl (2E,4S,6R,8R)-9-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4,6,8-
tetramethyl-2-nonenoate (12): The procedure was same as to that
described for the preparation of 7. The alcohol 4 (600 mg,
2.08 mmol), was treated with IBX (874 mg, 3.12 mmol) followed by
ethyl 2-(triphenylphosphoranylidene)propanoate (1.5 g, 4.16 mmol)
to give the product 12 (661 mg, 86%) as a colorless liquid. [α]D
=
as a viscous liquid. [α]D = +38.8 (c = 1.0, CHCl ). IR (KBr): ν =
+23.5 (c = 1.0, CHCl ). IR (KBr): ν = 2957, 2928, 2858, 1713,
˜
˜
3
3
1
2954, 2928, 2857, 1784, 1700, 1461, 1386, 1353, 1251, 1208, 1093,
1649, 1462, 1371, 1257, 1098, 839, 775 cm–1. H NMR (300 MHz,
1
839, 772, 701, 591 cm–1. H NMR (300 MHz, CDCl3): δ = 7.15– CDCl3): δ = 6.44 (d, J = 10.5 Hz, 1 H), 4.17 (q, J = 14.3, 7.5 Hz,
7.38 (m, 5 H), 4.54–4.67 (m, 1 H), 4.09–4.23 (m, 2 H), 3.43 (dd, J
= 9.8, 5.2 Hz, 1 H), 3.25–3.40 (m, 2 H), 2.78–3.03 (m, 2 H), 2.69
(dd, J = 13.5, 9.8 Hz, 1 H), 1.08–1.80 (m, 6 H), 0.95 (d, J = 6.0 Hz,
3 H), 0.89 (s, 9 H), 0.88 (d, J = 6.7 Hz, 3 H), 0.03 (s, 6 H) ppm.
2 H), 3.29–3.43 (m, 2 H), 2.52–2.70 (m, 1 H), 1.84 (s, 3 H), 1.02–
1.75 (m, 9 H), 0.99 (d, J = 6.0 Hz, 3 H), 0.89 (s, 9 H), 0.85 (d, J =
6.0 Hz, 3 H), 0.84 (d, J = 6.7 Hz, 3 H), 0.02 (s, 6 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 168.3, 148.0, 126.2, 68.1, 60.2, 44.2,
13C NMR (CDCl3, 75 MHz): δ = 173.6, 153.3, 135.3, 129.3, 128.8, 41.4, 32.9, 30.7, 28.1, 25.9, 20.6, 20.4, 18.2, 17.3, 14.2, 12.4,
127.2, 68.2, 66.0, 55.1, 40.8, 37.8, 33.1, 33.0, 30.8, 29.7, 25.9, 20.0, –5.4 ppm. MS (ESI): m/z = 393 [M + Na]+. HRMS: calcd. for
18.3, 17.4, –5.3 ppm. MS (ESI): m/z = 470 [M + Na]+. HRMS:
C21H43O3Si [M + H]+ 371.2981; found 371.2977.
calcd. for C25H41NNaO4Si [M + Na]+ 470.2702; found 470.2714.
(2S,3R,4S,6S,8R)-9-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2,4,6,8-tet-
ramethylnonane-1,3-diol (3): To a cooled (–78 °C) solution of 12
(650 mg, 1.75 mmol) in dry CH2Cl2 (10 mL), DIBAL-H (1.3 mL,
1.75 mmol, 20% solution in toluene) was added slowly over 15 min.
(4S)-4-Benzyl-3-{(2S,4S,6R)-7-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-
2,4,6-trimethylheptanoyl}-1,3-oxazolan-2-one (11): To a stirred solu-
tion of 10 (4.0 g, 8.9 mmol) in dry THF (80 mL) at –78 °C,
NaHMDS (1 m solution in THF, 13.35 mL, 13.35 mmol) was The resulting mixture was allowed to stir for 30 min at –78 °C,
added slowly dropwise with stirring under nitrogen atmosphere. Af- before being quenched with sodium potassium tartarate solution
ter stirring at –78 °C for 30 min, MeI (1.56 mL, 26.7 mmol) was (10 mL). The mixture was then stirred at room temperature until it
added dropwise to the reaction mixture and then stirring was con-
tinued for another 2 h at –78 °C. Then the mixture was quenched
with saturated NH4Cl (50 mL) and warmed to room temperature
and then extracted with ethyl acetate (2ϫ100 mL). The combined
organic extracts were washed with brine (50 mL), dried with anhy-
drous Na2SO4 and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography using
becomes clear solution. The aqueous layer was extracted with
CH2Cl2 (3ϫ20 mL). The combined organic layers were concen-
trated in vacuo and then purified the residue by flash column
chromatography (1:4, EtOAc/hexane) to furnish the crude alde-
hyde. To a cooled (0 °C) solution of aldehyde in dry THF (15 mL)
was added borane–dimethyl sulfide complex (2 m solution in THF,
4.8 mL, 9.6 mmol) dropwise and the resulting mixture was stirred
4606
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4603–4608

Enantioselective Total Synthesis of (+)-Vittatalactone
at room temperature for 3 h. After complete conversion of the
starting material as indicated by TLC, the mixture was cooled to
0 °C, and then treated with 15% NaOH solution (48 mL) followed
by 30% H2O2 (24 mL) solution. The resulting mixture was warmed
to room temperature and then allowed to stir for 3 h. The mixture
was quenched with NaHCO3 solution and extracted with EtOAc
(3ϫ20 mL). Removal of solvent followed by purification on silica
gel column chromatography (15% ethyl acetate/hexane) gave the
desired product 3 (435 mg, 72%) along with undesired diastereoiso-
mer (84 mg, 14%) as a viscous liquid. [α]D = +4.2 (c = 1.0, CHCl3).
HRMS: calcd. for C21H38NaO4 [M + Na]+ 377.2667; found
377.2653.
Ethyl (4R,6S,8S)-2,4,6-Trimethyl-8-[(4R,5S)-2,2,5-trimethyl-1,3-di-
oxan-4-yl]nonanoate (15): The procedure was same as to that used
for the preparation of 8. The unsaturated ester 14 (280 mg,
0.79 mmol) was treated with NiCl2·6H2O (38 mg, 0.16 mmol) and
NaBH4 (72 mg, 1.9 mmol) to give the saturated ester 15 (258 mg,
92%) as a viscous liquid. 1H NMR (300 MHz, CDCl3): δ = 4.15
(q, J = 14.3, 6.7 Hz, 2 H), 3.63 (dd, J = 11.3, 5.2 Hz, 1 H), 3.33–
3.49 (m, 2 H), 2.38–2.56 (m, 1 H), 1.63–1.87 (m, 3 H), 1.39–1.61
(m, 3 H), 1.19–139 (m, 3 H), 1.37 (s, 3 H), 1.31 (s, 3 H), 1.26 (t, J
= 6.7 Hz, 3 H), 1.12 (dd, J = 6.7, 5.2 Hz, 3 H), 0.89–1.08 (m, 1 H),
0.87 (d, J = 6.7 Hz, 3 H), 0.84 (d, J = 6.7 Hz, 3 H), 0.82 (d, J =
6.7 Hz, 3 H), 0.70 (d, J = 6.7 Hz, 3 H) ppm. MS (ESI): m/z = 379
[M + Na]+. HRMS: calcd. for C21H40NaO4 [M + Na]+ 379.2824;
found 379.2840.
IR (KBr): ν = 3405, 2958, 2927, 1707, 1461, 1380, 1253, 1092, 1032,
˜
1
838, 775 cm–1. H NMR (300 MHz, CDCl3): δ = 3.55–3.74 (m, 2
H), 3.29–3.50 (m, 3 H), 0.94–1.89 (m, 8 H), 0.90 (s, 9 H), 0.88 (d,
J = 6.7 Hz, 6 H), 0.86 (d, J = 6.7 Hz, 3 H), 0.81 (d, J = 6.7 Hz, 3
H), 0.03 (s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 79.5, 68.9,
68.0, 41.4, 41.2, 37.4, 33.0, 31.9, 27.3, 25.9, 20.8, 18.3, 17.9, 13.4,
12.8, –5.3 ppm. MS (ESI): m/z = 369 [M + Na]+. HRMS: calcd.
for C19H43O3Si [M + H]+ 347.2981; found 347.2971.
(4R,5S)-2,2,5-Trimethyl-4-[(1S,3S,5S)-1,3,5,7-tetramethyloctyl]-1,3-
dioxane (16): To a stirred suspension of LiAlH4 (51 mg, 1.3 mmol)
in dry THF (10 mL) at –10 °C was added a solution of 15 (240 mg,
0.67 mmol) in dry THF (10 mL) in dropwise manner. The resulting
mixture was allowed to stir for 10 min at same temperature and
then quenched with saturated aqueous Na2SO4 solution. The pre-
cipitate formed was filtered and washed with ethyl acetate. The
combined organic extracts were dried with Na2SO4 and concen-
trated under reduced pressure and the crude product was used for
next step without any further purification. To this crude alcohol in
dry CH2Cl2 were added triethylamine (203 mg, 0.28 mL,
2.0 mmol), p-toluenesulfonyl chloride (254 mg, 1.34 mmol), and
DMAP (16 mg, 134 μmol). The resulting solution was stirred for
3.0 h. After complete conversion as confirmed by TLC, the mixture
was quenched with NH4Cl solution and extracted with EtOAc
(3ϫ20 mL). Removal of solvent followed by purification on silica
gel column chromatography (10% ethyl acetate/hexane) gave the
pure tosyl derivative. To a stirred suspension of LiAlH4 (51 mg,
1.3 mmol) in dry THF (10 mL) at –10 °C was added a solution of
tosyl derivative in dry THF (10 mL). The resulting mixture was
allowed to stir for overnight at room temperature. It was then
quenched with dropwise addition of saturated aqueous Na2SO4.
The precipitate formed was filtered and washed with ethyl acetate.
The combined organic extracts were dried with Na2SO4 and con-
centrated under reduced pressure and the residue was purified by
silica gel column chromatography (5% ethyl acetate/hexane) to af-
ford compound 16 (163 mg, 82% over three steps) as a viscous
(2R,4S,6S)-2,4-Dimethyl-6-[(4R,5S)-2,2,5-trimethyl-1,3-dioxan-4-
yl]heptan-1-ol (13): 2,2-Dimethoxypropane (0.5 mL, 3.45 mmol)
and CSA (54 mg, 0.23 mmol) were added successively to a solution
of diol 3 (400 mg, 1.15 mmol) in a 10 mL mixture of CH2Cl2/Et2O
(9:1). The resulting solution was stirred for 1 h at room temperature
and then quenched with saturated aqueous NaHCO3. The aqueous
layer was extracted with diethyl ether (4ϫ100 mL). The combined
organic layers were washed with brine, dried with Na2SO4 and con-
centrated in vacuo. The crude residue was dissolved in dry THF at
0 °C, and then 2.5 mL of TBAF (1 m in THF) was added. The
resulting mixture was allowed to stir at room temperature for 6 h.
It was then quenched with saturated NH4Cl solution (10 mL) and
extracted with ethyl acetate (2ϫ30 mL). The combined organic
layers were washed with brine (30 mL), dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The crude prod-
uct was purified by silica gel column chromatography using ethyl
acetate and hexane (1:9) to give the product 13 (292 mg, 93%) as
a viscous liquid. [α]D = +35.5 (c = 1.5, CHCl ). IR (KBr): ν = 3420,
˜
3
2957, 2873, 1630, 1459, 1379, 1265, 1199, 1052, 865, 519 cm–1. H
1
NMR (300 MHz, CDCl3): δ = 3.69 (dd, J = 11.3, 4.9 Hz, 1 H),
3.30–3.52 (m, 4 H), 1.42–1.91 (m, 4 H), 1.38 (s, 3 H), 1.33 (s, 3 H),
1.12–1.32 (m, 2 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.81–1.0 (m, 2 H),
0.87 (d, J = 6.7 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.71 (d, J =
6.7 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 97.9, 74.9,
68.5, 66.3, 41.6, 39.8, 32.9, 30.6, 29.8, 29.6, 26.6, 20.5, 18.9, 16.8,
13.7, 12.2 ppm. C16H32O3 (272.43): calcd. C 70.54, H 11.84; found
C 70.69, H 12.05.
liquid. [α]D = +23.8 (c = 1.0, CHCl ). IR (KBr): ν = 2955, 1460,
˜
3
1377, 1197, 1062, 1010, 866, 763 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 3.58–3.73 (m, 1 H), 3.34–3.52 (m, 2 H), 1.72–1.90 (m,
2 H), 1.44–1.71 (m, 4 H), 1.38 (s, 3 H), 1.34 (s, 3 H), 0.90–1.34 (m,
5 H), 0.79–0.90 (m, 15 H), 0.72 (d, J = 6.6 Hz,3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 97.9, 75.0, 66.4, 47.0, 46.1, 40.1, 30.7, 29.9,
29.7, 27.4, 26.7, 25.1, 23.5, 22.2, 20.5, 20.1, 18.9, 13.8, 12.2 ppm.
Ethyl (2E,4R,6S,8S)-2,4,6-Trimethyl-8-[(4R,5S)-2,2,5-trimethyl-1,3-
dioxan-4-yl]-2-nonenoate (14): The procedure was same as to that
used for the preparation of 12. The alcohol 13 (270 mg, 1.0 mmol),
was treated with IBX (420 mg, 1.5 mmol), followed by ethyl 2-(tri-
phenylphosphoranylidene)propanoate (724 mg, 2.0 mmol) to give
product 14 (307 mg, 87%) as a colorless liquid. [α]D = +2.1 (c = (2S,3R,4S,6S,8S)-2,4,6,8,10-Pentamethylundecane-1,3-diol (17): To
1.1, CHCl ). IR (KBr): ν = 2960, 2929, 2873, 1711, 1457, 1377, a stirred solution of 16 (150 mg, 0.50 mmol) in THF (10 mL) was
1H NMR added aqueous 2 n HCl (1.3 mL, 2.5 mmol) and the resulting mix-
˜
3
1268, 1202, 1153, 1100, 1059, 866, 753, 519 cm–1
.
(500 MHz, CDCl3): δ = 6.45 (d, J = 9.9 Hz, 1 H), 4.16 (q, J = 14.8,
6.9 Hz, 2 H), 3.63 (dd, J = 10.9, 4.9 Hz, 1 H), 3.42 (t, J = 10.9 Hz,
1 H), 3.34 (d, J = 9.9, 1.9 Hz, 1 H), 2.55–2.69 (m, 1 H), 1.85 (s, 3
ture was stirred for 5 h at 25 °C. It was then diluted with ethyl
acetate and extracted the aqueous layer twice with ethyl acetate
(2ϫ20 mL). The combined organic layers were washed with brine,
H), 1.69–1.83 (m, 1 H), 1.24–1.44 (m, 5 H), 1.33 (s, 3 H), 1.31 (s, dried with Na2SO4 and evaporated the solvent under reduced pres-
3 H), 1.3 (t, J = 7.9 Hz, 3 H), 1.09–1.21 (m, 1 H), 0.99 (d, J =
6.9 Hz, 3 H), 0.83 (d, J = 5.9 Hz, 6 H), 0.70 (d, J = 5.9 Hz, 3 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 168.2, 148.0, 126.1, 97.9,
75.1, 66.3, 60.2, 44.9, 40.9, 30.7, 30.6, 29.8, 29.6, 27.3, 20.2, 19.5,
18.8, 14.2, 13.4, 12.4, 12.1 ppm. MS (ESI): m/z = 377 [M + Na]+.
sure. The resulting crude product was purified by column
chromatography (1:4, EtOAc/hexane) to afford the diol 17 (118 mg,
92%) as a viscous liquid. [α]D = –4.6 (c = 0.9, CHCl3). IR (KBr):
ν = 3367, 2957, 2917, 1461, 1378, 1151, 1070, 1026, 979, 624 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 3.56–3.75 (m, 2 H), 3.43 (dd, J
Eur. J. Org. Chem. 2011, 4603–4608
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4607

J. S. Yadav et al.
FULL PAPER
= 9.0, 2.2 Hz, 1 H), 2.68–2.83 (br., 1 H), 2.22–2.50 (br., 1 H), 0.91–
1.98 (m, 11 H), 0.88 (d, J = 6.0 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 3
H), 0.84 (d, J = 6.0 Hz, 6 H), 0.84 (d, J = 6.7 Hz, 3 H), 0.81 (d, J
= 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 79.4, 68.9,
46.4, 45.8, 41.3, 37.5, 31.9, 27.5, 27.0, 25.1, 23.8, 21.9, 20.5, 13.4,
12.8 ppm. MS (ESI): m/z = 281 [M + Na]+.
authors acknowledge the partial support by the King Saud Univer-
sity for Global Research Network for Organic Synthesis (GRNOS).
[1]
a) M. C. Liu, T. E. Hermann, J. Biol. Chem. 1978, 253, 5892;
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(2R,3R,4S,6S,8S)-3-Hydroxy-2,4,6,8,10-pentamethylundecanoic
Acid (18): To a stirred solution of diol 17 (100 mg, 0.38 mmol) in
CH2Cl2 (5 mL) at room temperature were added bis(acetoxy)iodo-
benzene (BAIB, 137 mg, 0.42 mmol), and 2,2,6,6-tetramethylpiper-
idine-1-oxyl (TEMPO, 6 mg, 0.038 mmol) sequentially. After com-
pletion of the reaction, a solution of saturated aqueous Na2S2O3
followed by Et2O (25 mL) was added. The separated organic phase
was washed with saturated aqueous NaHCO3 solution followed by
brine and then dried with anhydrous Na2SO4. Removal of solvent
gave the crude product which was used in the next step without
purification. To a stirred solution of the above hydroxy aldehyde
in a mixture of tert-butanol and water in 3:1 ratio at 0 °C were
added NaH2PO4 (55 mg, 0.45 mmol) followed by 2-methyl-2-but-
ene (66 μL, 0.57 mmol) and the resulting mixture was allowed it to
stir for 5 min. Then NaClO2 (42 mg, 0.45 mmol) was added and
the stirring was continued at 0 °C. After completion of the reaction,
the solvent was evaporated under reduced pressure and the residue
was diluted with EtOAc. The organic layer was washed once with
brine and dried with Na2SO4 and concentrated to give the crude
residue which was purified by column chromatography (petroleum
ether/EtOAc, 1:1) to afford the pure β-hydroxy acid 18 in good
[2]
a) J. Berger, L. M. Jampolsky, M. W. Goldberg, Arch. Biochem.
1949, 22, 476; b) W. Keller-Schierlein, Helv. Chim. Acta 1967,
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yield (78 mg, 76% yield). [α]D = –8.4 (c = 0.8, CHCl3). IR (KBr):
[4]
[5]
B. D. Morris, R. R. Smyth, S. P. Foster, M. P. Hoffmann, W. L.
Roelofs, S. Franke, W. Francke, J. Nat. Prod. 2005, 68, 26.
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1
ν = 3423, 2956, 1716, 1460, 1378, 1203, 979, 618 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 3.64 (dd, J = 8.6, 3.0 Hz, 1 H), 2.65 (dq,
J = 8.4, 7.1 Hz, 1 H), 1.38–1.79 (m, 6 H), 0.91–1.35 (m, 4 H), 1.18
(d, J = 6.9 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.5 Hz,
3 H), 0.85 (d, J = 6.6 Hz, 6 H), 0.83 (d, J = 6.6 Hz, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 181.4, 74.9, 46.3, 45.6, 43.5, 41.3,
31.2, 27.4, 26.9, 25.1, 23.7, 21.9, 20.5, 20.4, 14.0, 12.9 ppm. MS
(ESI): m/z = 295 [M + Na]+.
[6]
[7]
a) J. J. Miller, P. L. De Benneville, J. Org. Chem. 1957, 22, 1268;
b) G. Stork, V. Nair, J. Am. Chem. Soc. 1979, 101, 1315.
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2489.
(+)-Vittatalactone (1b): To a stirred solution of β-hydroxy acid 18
(50 mg, 0.18 mmol) in dry pyridine (1 mL) at 0 °C was added p-
toluenesulfonyl chloride (102 mg, 0.54 mmol) and the resulting
mixture was stirred at 0 °C for 10 h and then placed in the freezer
(–20 °C) for 24 h. After complete conversion as indicated by TLC,
the mixture was partitioned between water and ether (3ϫ8 mL),
and the combined organic extracts were washed with brine
(15 mL), dried with Na2SO4, and concentrated in vacuo. The re-
sulting crude product was purified by flash chromatography (pen-
tane/diethyl ether, 9:1) to the target β-lactone 1 (35 mg, 78%) as a
[8] a) K. Tsuji, Y. Terao, K. Achiwa, Tetrahedron Lett. 1989, 30,
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2551; f) the enantiomeric excess has been determined by the
comparison of [α]D rotation with the value reported in the lit-
erature, see ref.[8d,8e]
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colorless liquid. [α]D = +1.1 (c = 1.3, CH Cl ). IR (KBr): ν = 2957,
˜
2
2
2922, 1827, 1643, 1461, 1381, 1124, 983, 867 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 3.82 (dd, J = 8.1, 4.1 Hz, 1 H), 3.22 (qd,
J = 7.5, 4.1 Hz, 1 H), 1.76–1.95 (m, 1 H), 1.49–1.72 (m, 3 H), 1.39
(d, J = 7.5 Hz, 3 H), 0.93–1.31 (m, 6 H), 1.02 (d, J = 6.6 Hz, 3 H),
0.90 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H), 0.84 (d, J =
6.6 Hz, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 171.9, 83.6,
48.7, 45.8, 45.0, 39.6, 34.6, 27.5, 27.1, 25.0, 23.8, 21.6, 20.6, 15.6,
12.7 ppm. MS (ESI): m/z = 526 [2M + NH4]+. HRMS: calcd. for
C16H31O2 [M + H]+ 255.2324; found 255.2330.
Acknowledgments
Received: March 13, 2011
Published Online: June 21, 2011
N. N. Y. and T. S. R. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for the award of fellowships. The
4608
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4603–4608