Enantioselective total synthesis of (+)- and (-)-vittatalactone

Article abstract of DOI:10.1055/s-0031-1290155

The asymmetric total synthesis of both enantiomers of (+)- and (-)-vittatalactone has been achieved using a desymmetrization strategy to create three methyl chiral centers. The key steps in these total syntheses are Myers asymmetric alkylation, copper-cat

Full text of DOI:10.1055/s-0031-1290155

628
PAPER
Enantioselective Total Synthesis of (+)- and (–)-Vittatalactone
E
nantiosel
h
e
ctive Total
i
Synthe
l
sis of
(
+
l
)- and
u
(–)-VittatalactoneSingh Yadav,*a,b Eedubilli Srinivas,a Chinta Krinda Suresh Kumar,a Ahmad Al Khazim Al Ghamdib
a
Natural Product Chemistry, Organic Chemistry Division-I, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27100387; E-mail: yadavpub@iict.res.in
Engineer Abdullah Baqshan for Bee Research, King Saud University, Riyadh, Saudi Arabia
b
Received 4 November 2011; revised 6 December 2011
of vittatalactone have been reported: as key steps, the
method of Breit and coworkers involved an o-diphe-
nylphosphinobenzoic acid (o-DPPB) directed allylic sub-
stitution,2 whilst that of Schneider et al. utilized an
Abstract: The asymmetric total synthesis of both enantiomers of
(+)- and (–)-vittatalactone has been achieved using a desymmetriza-
tion strategy to create three methyl chiral centers. The key steps in
these total syntheses are Myers asymmetric alkylation, copper-
catalyzed
alkylation,
2,2,6,6-tetramethyl-1-piperidinyloxyl– iridium-catalyzed hydrogenation.6 Our group previously
(diacetoxyiodo)benzene [TEMPO–PhI(OAc2)] promoted oxidation
and p-toluenesulfonyl chloride mediated lactonization. The prod-
ucts are obtained in good overall yields employing linear synthetic
sequences.
accomplished the total synthesis of (+)-vittatalactone by
using an enzymatic desymmetrization approach.7 We
herein report the total synthesis of both enantiomers of
vittatalactone, (+)-1a and (–)-1b, by exploiting our previ-
ously developed desymmetrization strategy.
Key words: vittatalactone, desymmetrization, Myers asymmetric
alkylation, copper-catalyzed alkylation, lactonization
Our retrosynthetic strategy is shown in Scheme 1 in which
both enantiomers could be easily obtained from the com-
mon intermediate 5 by utilizing the appropriate chiral bo-
ron reagent.
Polydeoxypropionates are an important class of biologi-
cally active molecules and the development of methods
for their synthesis has led to the discovery of new strate-
gies. The use and application of pheromones is expected
to grow more rapidly and widely in the coming years be-
cause of increasing concerns of consumers about residual
chemicals from agricultural products. The chemical syn-
theses of such compounds will ensure ample supplies and
facilitate their practical use in agriculture and forestry.
Vittatalactone, a structurally unique pheromone, was iso-
lated from the striped cucumber beetle, Acalymma vit-
tatum by Francke1 and coworkers in 2005. It contains a
novel trans-configured b-lactone moiety and an all syn-
configured tetramethyl substituted alkyl chain as structur-
al features. Breit et al.2 have assigned the relative and ab-
solute configurations of natural (+)-1a and unnatural (–)-
1b3 vittatalactones through total synthesis.
The synthesis of (+)-vittatalactone started from the known
triol 3a8 which was readily obtained from 5 using a de-
symmetrization approach. Protection of the 1,3-diol moi-
ety was accomplished using 2,2-dimethoxypropane
[Me2C(OMe)2]9 and a catalytic amount of p-toluene-
sulfonic acid in dichloromethane at 0 °C to afford 6a in
85% yield. The primary hydroxy group in 6a was convert-
ed into the corresponding iodide to give 7a10 in 94% yield
using triphenylphosphine, imidazole and iodine in toluene
at room temperature. Next, iodide 7a was treated with the
enolate derived from the N-propionyl-(S,S)-pseudoephe-
drine, according to the protocol described by Myers,11 to
give compound 2a in a good 82% yield as a single diaste-
reomer. Reductive cleavage of the chiral auxiliary using
lithium amidotrihydroborate (LAB), prepared in situ from
lithium diisopropylamide and borane monoammoniate
(BH3·NH3), furnished alcohol 8a in 92% yield. The hy-
droxy group in 8a was converted into the corresponding
iodide as described above, and then treated with isopropyl-
magnesium chloride12 in the presence of copper(I) cya-
nide to give the desired intermediate 9a (Scheme 2).
O
(–)-vittatalactone (1b)
O
(+)-vittatalactone (1a)
O
O
Figure 1 Structures of (+)- and (–)-vittatalactone
Debenzylation of compound 9a was achieved by using
palladium hydroxide13 to afford the secondary alcohol
10a in 92% yield. This was converted into the correspond-
ing xanthate14 11a using lithium hexamethyldisilazide,
carbon disulfide and methyl iodide in THF (86%) and
then subjected to Barton–McCombie conditions15 [tribu-
tylstannane (Bu3SnH), catalytic 2,2¢-azobis(isobutyroni-
trile)] to afford the deoxygenated product 12a in 89%
yield. Acetonide deprotection16 of 12a was carried out un-
der acidic conditions to give the required diol 13a in 86%
yield. The 1,3-diol functionality of 13a was selectively
oxidized using 2,2,6,6-tetramethyl-1-piperidinyloxyl
(TEMPO) and (diacetoxyiodo)benzene [PhI(OAc)2]17 in
In continuation of our research on synthetic phero-
mones,4,5 and our ongoing studies on the synthesis of bio-
logically
active
molecules
by
exploiting
desymmetrization strategies, the interesting structural fea-
tures and biological activity of vittatalactone have attract-
ed our attention toward its synthesis. Two total syntheses
SYNTHESIS 2012, 44, 628–634
x
x
.x
x
.2
0
1
2
Advanced online publication: 25.01.2012
DOI: 10.1055/s-0031-1290155; Art ID: Z104311SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Total Synthesis of (+)- and (–)-Vittatalactone
629
acetonitrile–water to give the corresponding b-hydroxy Unless otherwise mentioned, all the reactions were carried out un-
der an inert atmosphere of Ar or N2 using standard syringe, septa
acid which was used directly in the next step without pu-
rification. Lactonization2 of the b-hydroxy acid was car-
and cannula techniques. Commercial reagents were used without
further purification. All solvents were purified by standard tech-
ried out with p-toluenesulfonyl chloride in pyridine to
niques. Optical rotations were obtained with a Jasco DIP-360 digital
afford (+)-vittatalactone (1a) in 61% yield over the two
polarimeter. Infrared (IR) spectra were recorded with a Perkin-
steps. The H and 13C NMR spectra and optical rotation
1
Elmer 683 spectrometer with NaCl optics. Samples were scanned
([a]D25 +3.0) were in good agreement with the literature.
neat, as KBr discs or in CHCl3 as thin films. NMR spectra were re-
corded in CDCl3 using Bruker 300 or Varian Unity 500 NMR spec-
trometers. Column chromatographic separations were carried out
on silica gel (ACME, 60–120 mesh). Mass spectra were obtained on
Finnigan MAT1020B or Micromass VG 70-70H spectrometers op-
erating at 70 eV using a direct inlet system. Analytical data for the
Similarly, the enantiomer (–)-1b was prepared from
known triol 3b as depicted in Scheme 3, by following the
same series of reactions as described for the synthesis of
(+)-vittatalactone (1a). Unnatural (–)-vittatalactone (1b)
was obtained in good yield and the optical rotation compounds shown in Scheme 2 are provided below. The optical ro-
([a]D25 –2.5) was in agreement with that reported.
tations for the series of compounds listed in Scheme 3 are included
for comparison. Melting points were determined using a Barnstead
electrothermal melting point apparatus and are uncorrected.
In conclusion, we have demonstrated the application of
our previously developed desymmetrization strategy for
the synthesis of both enantiomers of vittatalactone. The
approach adopted here demonstrates a synthetic applica-
tion for the construction of polyketide motifs. The key
steps in the synthesis are Myers asymmetric alkylation,
copper-catalyzed alkylation, selective oxidation and p-
toluenesulfonyl chloride mediated lactonization which
were utilized successfully to complete the total synthesis
(2S,3S,4S)-3-(Benzyloxy)-2-methyl-4-[(4S,5S)-2,2,5-trimethyl-
1,3-dioxan-4-yl]pentan-1-ol (6a)
To a stirred soln of triol 3a (4.0 g, 13.51 mmol) in anhyd CH2Cl2
were added 2,2-dimethoxypropane [Me2C(OMe)2] (2.5 mL, 20.26
mmol) and recrystallized PTSA (cat.) at 0 °C. The mixture was
stirred at r.t. for 5 h. After complete consumption of the starting ma-
terial (as monitored by TLC), the mixture was quenched with sat. aq
NaHCO3 soln. The organic layer was separated and the aq layer ex-
of (+)- and (–)-vittatalactone in linear synthetic sequences tracted with CH2Cl2 (2 × 40 mL). The combined organic layer was
dried over anhyd Na2SO4, evaporated and the residue purified by
with overall yields of 18.4% and 18.1%, respectively.
silica gel column chromatography (10% EtOAc–hexane) to afford
the protected triol 6a (3.9 g, 85%) as a white crystalline solid.
O
(–)-1b
O
(+)-1a
O
O
O
O
Me
N
OH
Me
N
OH
O
OBn
O
O
OBn
O
2b
2a
OH
OH
OH OH OBn
OH OH OBn
3b
3a
O
O
HO
HO
OBn
4b
4a
OBn
(+)-Ipc2BH
(–)-Ipc2BH
O
5
OBn
Scheme 1 Retrosynthesis of (+)- and (–)-vittatalactone
© Thieme Stuttgart · New York
Synthesis 2012, 44, 628–634

630
J. S. Yadav et al.
PAPER
6a: [a]D25 +28.2 (c 2, CHCl3); mp 96–97 °C. 6b: [a]D25 –32.5 (c 1,
CHCl3); mp 96–97 °C.
7a: [a]D25 –1.9 (c 1.05, CHCl3); 7b: [a]D25 +2.0 (c 1, CHCl3); mp
52–53 °C.
IR (KBr): 3483, 2926, 2878, 1460, 1381, 1064, 755, 698 cm–1.
IR (KBr): 2970, 2877, 1459, 1379, 1064, 732, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.73 (d, J = 6.6 Hz, 3 H), 0.87 (d,
J = 6.9 Hz, 3 H), 1.20 (d, J = 7.1 Hz, 3 H), 1.34 (s, 6 H), 1.79–2.05
(m, 3 H), 2.60 (s, 1 H), 3.41–3.50 (m, 2 H), 3.53 (dd, J = 7.1, 11.1
Hz, 1 H), 3.65 (dd, J = 6.2, 11.3 Hz, 1 H), 3.86 (d, J = 10.5 Hz, 2
H), 4.64 (q, J = 14.9 Hz, 2 H), 7.23–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 9.8, 12.4, 16.3, 19.4, 29.7, 30.2,
36.0, 37.4, 64.2, 66.1, 73.3, 75.4, 85.5, 97.9, 126.9, 127.5, 128.4,
138.3.
1H NMR (300 MHz, CDCl3): d = 0.71 (d, J = 6.6 Hz, 3 H), 0.89 (d,
J = 6.6 Hz, 3 H), 1.24 (d, J = 6.6 Hz, 3 H), 1.33 (d, J = 5.6 Hz, 6
H), 1.78–1.96 (m, 2 H), 2.00–2.13 (m, 1 H), 3.04 (t, J = 10.0 Hz, 1
H), 3.41 (dd, J = 7.1, 11.1 Hz, 3 H), 3.64 (dd, J = 5.0, 11.5 Hz, 1 H),
3.80 (d, J = 10.3 Hz, 1 H), 4.61 (q, J = 12.8 Hz, 2 H), 7.20–7.33 (m,
5 H).
13C NMR (75 MHz, CDCl3): d = 9.8, 10.3, 12.4, 19.4, 29.7, 30.2,
36.9, 39.3, 66.1, 73.3, 74.8, 83.3, 97.9, 126.8, 127.3, 128.2.
MS (ESI): m/z = 337 [M + H]+.
MS (ESI): m/z = 469 [M + Na]+.
HRMS (ESI-MS): m/z [M + Na]+ calcd for C20H32O4Na: 359.2198;
HRMS (ESI-MS): m/z [M + Na]+ calcd for C20H31O3INa: 469.1215;
found: 359.2201.
found: 469.1201.
(4S,5S)-4-[(2S,3R,4R)-3-(Benzyloxy)-5-iodo-4-methylpentan-2-
yl]-2,2,5-trimethyl-1,3-dioxane (7a)
(2R,4S,5S,6S)-5-(Benzyloxy)-N-[(1S,2S)-1-hydroxy-1-phenyl-
propan-2-yl]-N,2,4-trimethyl-6-[(4S,5S)-2,2,5-trimethyl-1,3-di-
oxan-4-yl]heptanamide (2a)
To a stirred soln of alcohol 6a (3.0 g, 8.92 mmol) in anhyd toluene
(25 mL) was added Ph3P (3.04 g, 11.6 mmol) followed by I2 (4.53
g, 17.8 mmol) and imidazole (1.21 g, 17.8 mmol) at 0 °C. The mix-
ture was allowed to warm to r.t., stirred for 3 h, then quenched with
sat. aq Na2S2O3 soln and diluted with EtOAc (20 mL). The aq layer
was extracted with EtOAc (2 × 30 mL) and the combined organic
layer washed with brine (20 mL), dried over anhyd Na2SO4 and fil-
tered. Evaporation of the solvent under vacuum gave a crude resi-
due which was purified by silica gel column chromatography (5%
EtOAc–hexane) to afford 7a (3.7 g, 94%) as a yellow solid.
LiCl (2.16 g, 50.4 mmol) was placed in a round-bottomed flask and
flame-dried for 30 min under high vacuum and then allowed to cool
to r.t. under an Ar atm. THF (18 mL) was added and the mixture
cooled to –78 °C, then diisopropylamine (4.05 mL, 28.9 mmol) was
added followed by n-BuLi (16.8 mL, 26.9 mmol, 1.6 M in hexanes)
and the resulting soln stirred for 10 min. The mixture was warmed
to 0 °C for 10 min before again being cooled to –78 °C. Next, a soln
of N-propionyl-(S,S)–pseudoephedrine (14a) (3.12 g, 14.12 mmol)
in THF (20 mL) was added and the mixture stirred at –78 °C for 1
h, warmed to 0 °C for 10 min and then to r.t. for a further 10 min.
Ph3P, I2
imidazole, toluene
OH
OH
I
Me2C(OMe)2, PTSA
OH OH OBn
O
O
OBn
6a
0 °C to r.t., 94%
O
O
OBn
7a
CH2Cl2, 0 °C to r.t.
85%
3a
Me
N
OH
LDA, LiCl
THF, –78 °C
OH
LDA, BH3⋅NH3
O
O
OBn
O
O
O
OBn
14a, 82%
0 °C, THF, 92%
2a
8a
(i) Ph3P, I2
imidazole, toluene
0 °C to r.t., 94%
LiHMDS, CS2
MeI, THF
Pd(OH)2
EtOAc, 92%
–78 °C, 86%
(ii) i-PrMgCl, CuCN
THF, r.t., 88%
O
O
OBn
9a
O
O
OH
10a
Bu3SnH, AIBN
benzene
2 M HCl
THF, 86%
reflux, 89%
O
O
O
O
O
S
12a
S
11a
Me
(i) TEMPO, PhI(OAc)2
MeCN–H2O (4:1)
O
N
OH Me
14a
(ii) p-TsCl, pyridine
61%
OH OH
O
O
13a
1a
Scheme 2 Synthesis of (+)-vittatalactone
Synthesis 2012, 44, 628–634
© Thieme Stuttgart · New York

PAPER
Enantioselective Total Synthesis of (+)- and (–)-Vittatalactone
631
Ph3P, I2
imidazole, toluene
OH
OH
I
Me2C(OMe)2, PTSA
0 °C to r.t., 94%
OH OH OBn
O
O
OBn
6b
O
O
OBn
7b
CH2Cl2, 0 °C to r.t.
85%
3b
Me
N
OH
LDA, LiCl
THF, –78 °C
OH
LDA, BH3⋅NH3
O
O
OBn
O
O
O
OBn
14b, 82%
0 °C, THF, 92%
2b
8b
(i) Ph3P, I2
imidazole, toluene
0 °C to r.t., 94%
LiHMDS, CS2
MeI, THF
Pd(OH)2
EtOAc, 92%
–78 °C, 86%
(ii) i-PrMgCl, CuCN
THF, r.t., 88%
O
O
OBn
9b
O
O
OH
10b
Bu3SnH, AIBN
benzene
2 M HCl
THF, 86%
reflux, 89%
O
O
O
O
O
S
12b
S
11b
Me
(i) TEMPO, PhI(OAc)2
MeCN–H2O (4:1)
O
N
OH Me
14b
(ii) p-TsCl, pyridine
61%
OH OH
O
O
13b
1b
Scheme 3 Synthesis of (–)-vittatalactone
After cooling to 0 °C, a soln of iodide 7a (1.5 g, 3.36 mmol) in THF
(15 mL) was added and the mixture stirred overnight. Sat. aq NH4Cl
soln was added to quench the reaction, the organic layer separated
and the aq layer extracted with EtOAc (2 × 30 mL). The combined
organic layer was washed with brine (30 mL), dried over anhyd
Na2SO4, filtered and concentrated under vacuum. The residue was
purified by silica gel column chromatography (30% EtOAc–hex-
ane) to afford the title compound 2a (1.5 g, 82%) as a yellow liquid.
(2R,4S,5S,6S)-5-(Benzyloxy)-2,4-dimethyl-6-[(4S,5S)-2,2,5-tri-
methyl-1,3-dioxan-4-yl]heptan-1-ol (8a)
To a stirred soln of diisopropylamine (5.1 mL, 36.27 mmol) in an-
hyd THF (25 mL) at –78 °C was added n-BuLi (21.3 mL, 34.14
mmol, 1.6 M in hexanes) and the resulting soln stirred for 5 min at
–78 °C. The soln was warmed to 0 °C for 10 min, and then r.t. for 5
min and cooled to 0 °C. Solid BH3·NH3 complex (1.16 g, 37.55
mmol) was added to the soln which resulted in vigorous gas evolu-
tion. After 10 min at 0 °C, the soln was warmed to r.t. and stirred for
an additional 10 min and then again cooled to 0 °C. A soln of amide
2a (2.3 g, 4.26 mmol) in THF (20 mL) was added and the mixture
allowed to warm to r.t. overnight. Sat. aq NH4Cl soln was added to
quench the reaction and the aq layer was extracted with EtOAc
(2 × 30 mL). The combined organic layer was washed with brine
(30 mL), dried over anhyd Na2SO4, filtered and concentrated under
vacuum. The residue was purified by silica gel column chromatog-
raphy (15% EtOAc–hexane) to afford 8a (1.49 g, 92%) as a colour-
less liquid.
2a: [a]D25 +50.0 (c 0.75, CHCl3); 2b: [a]D25 –47.5 (c 0.4, CHCl3).
IR (KBr): 3419, 2925, 2856, 1756, 1455, 1381, 1017, 757, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.74 (d, J = 6.0 Hz, 3 H), 0.87 (s,
3 H), 1.07 (d, J = 6.0 Hz, 4 H), 1.13 (d, J = 6.0 Hz, 3 H), 1.25 (t,
J = 15.1 Hz, 4 H), 1.33 (d, J = 9.0 Hz, 6 H), 1.64 (s, 1 H), 1.82–1.99
(m, 3 H), 2.68 (s, 1 H), 2.85 (d, J = 6.0 Hz, 3 H), 3.28 (q, J = 9.0 Hz,
1 H), 3.39–3.50 (m, 1 H), 3.64 (dd, J = 6.0, 12.0 Hz, 1 H), 3.83 (d,
J = 12.0 Hz, 1 H), 4.08 (t, J = 6.0 Hz, 1 H), 4.54–4.63 (m, 2 H),
7.21–7.35 (m, 10 H).
8a: [a]D25 +30.2 (c 0.9, CHCl3); 8b: [a]D25 –29.0 (c 1, CHCl3).
IR (KBr): 3449, 2926, 2875, 1459, 1379, 1061, 735, 697 cm–1.
13C NMR (75 MHz, CDCl3): d = 9.0, 12.2, 14.1, 15.3, 18.0, 18.5,
19.3, 26.8, 29.7, 30.0, 32.6, 33.5, 36.5, 57.8, 60.1, 66.0, 73.3, 74.7,
75.8, 84.2, 84.5, 97.7, 125.9, 126.6, 126.9, 127.2, 128.0, 128.4,
139.2, 142.3, 178.3.
MS (ESI): m/z = 540 [M + H]+.
HRMS (ESI-MS): m/z [M + H]+ calcd for C33H50O5N: 540.3688;
1H NMR (300 MHz, CDCl3): d = 0.71 (d, J = 6.7 Hz, 3 H), 0.83 (d,
J = 6.7 Hz, 3 H), 0.97 (d, J = 6.7 Hz, 3 H), 1.07 (d, J = 6.7 Hz, 3 H),
1.12–1.20 (m, 1 H), 1.33 (d, J = 5.2 Hz, 7 H), 1.38–1.48 (m, 1 H),
1.64–1.73 (m, 1 H), 1.78–1.91 (m, 3 H), 3.29 (dd, J = 9.8, 11.3 Hz,
1 H), 3.36 (t, J = 10.5 Hz, 1 H), 3.44 (t, J = 21.9 Hz, 1 H), 3.53 (dd,
J = 4.5, 10.5 Hz, 1 H), 3.63 (dd, J = 5.2, 11.3 Hz, 1 H), 3.84 (d,
J = 11.3 Hz, 1 H), 4.60 (q, J = 12.0 Hz, 2 H), 7.27–7.33 (m, 5 H).
found: 540.3703.
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J. S. Yadav et al.
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13C NMR (75 MHz, CDCl3): d = 9.6, 12.5, 18.5, 18.6, 19.5, 29.7,
29.9, 30.3, 32.8, 33.0, 33.3, 36.6, 66.2, 67.2, 73.5, 74.8, 84.4, 98.0,
126.9, 127.2, 128.2, 139.4.
HRMS (ESI-MS): m/z [M + Na]+ calcd for C26H44O3Na: 427.3188;
found: 427.3176.
(2S,3S,4S,6S)-4,6,8-Trimethyl-2-[(4S,5S)-2,2,5-trimethyl-1,3-
dioxan-4-yl]nonan-3-ol (10a)
MS (ESI): m/z = 401 [M + Na]+.
HRMS (ESI-MS): m/z [M + Na]+ calcd for C23H38O4Na: 401.2667;
To a soln of 9a (1.4 g, 3.46 mmol) in EtOAc (14 mL) under an Ar
atm was added Pd(OH)2 (486 mg, 20 wt% on C). The mixture was
stirred under an H2 atm at 50 psi for 8 h at 23 °C. The catalyst was
removed by elution with EtOAc through a short pad of Celite. The
eluent was concentrated under vacuum and the residue purified by
silica gel column chromatography (5% EtOAc–hexane) to afford al-
cohol 10a (1.0 g, 92%) as a colorless liquid.
found: 401.2675.
(4S,5S)-4-[(2S,3S,4S,6S)-3-(Benzyloxy)-4,6,8-trimethylnonan-
2-yl]-2,2,5-trimethyl-1,3-dioxane (9a)
Intermediate iodide: To a stirred soln of alcohol 8a (2.4 g, 6.35
mmol) in anhyd toluene (20 mL) was added Ph3P (2.16 g, 8.25
mmol) followed by I2 (3.22 g, 12.69 mmol) and imidazole (0.87 g,
12.69 mmol) at 0 °C. The reaction mixture was allowed to warm to
r.t., stirred for 3 h, then quenched with sat. aq Na2S2O3 soln and di-
luted with EtOAc (20 mL). The aq layer was extracted with EtOAc
(2 × 30 mL) and the combined organic layer washed with brine
(30 mL), dried over anhyd Na2SO4 and filtered. Evaporation of the
solvent under vacuum gave a crude residue which was purified by
silica gel column chromatography (6% EtOAc–hexane) to afford
the corresponding iodide (2.92 g, 94%) as a light yellow liquid.
10a: [a]D25 –33.6 (c 0.55, CHCl3); 10b: [a]D25 +33.0 (c 0.5, CHCl3).
IR (KBr): 3520, 2953, 1460, 1379, 1159, 1060, 864, 520 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.72 (d, J = 6.6 Hz, 3 H), 0.84 (d,
J = 6.4 Hz, 7 H), 0.89 (d, J = 6.4 Hz, 7 H), 1.02 (d, J = 6.9 Hz, 3 H),
1.07–1.18 (m, 1 H), 1.36 (s, 3 H), 1.46 (s, 3 H), 1.54–1.71 (m, 4 H),
1.84–1.97 (m, 2 H), 2.60 (d, J = 7.9 Hz, 1 H), 3.10 (q, J = 4.9 Hz,
1 H), 3.49 (t, J = 22.4 Hz, 1 H), 3.67 (dd, J = 6.4, 11.3 Hz, 1 H),
3.88 (d, J = 12.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 11.1, 11.9, 16.7, 19.0, 21.2, 21.6,
24.0, 25.2, 28.0, 29.7, 30.3, 33.4, 33.9, 40.8, 41.3, 45.6, 66.3, 75.3,
80.4.
Iodide a: [a]D25 +15.0 (c 0.7, CHCl3); iodide b: [a]D25 –20.5 (c 1,
CHCl3).
IR (KBr): 2960, 2858, 1457, 1376, 1193, 1064, 734, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.73 (d, J = 6.6 Hz, 3 H), 0.87 (d,
J = 6.6 Hz, 3 H), 1.00 (d, J = 5.8 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H),
1.32 (d, J = 9.0 Hz, 6 H), 1.23–1.39 (m, 3 H), 1.71–1.95 (m, 3 H),
3.15 (dd, J = 4.7, 9.4 Hz, 1 H), 3.23–3.32 (m, 2 H), 3.44 (t,
J = 11.1 Hz, 1 H), 3.63 (dd, J = 6.2, 11.3 Hz, 1 H), 3.86 (d, J = 10.5
Hz, 1 H), 4.60 (s, 2 H), 7.19–7.34 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 9.6, 12.5, 18.5, 18.6, 19.5, 29.7,
29.9, 30.3, 32.8, 33.0, 33.3, 36.6, 66.2, 73.5, 74.8, 84.4, 98.0, 126.9,
127.2, 128.2, 139.4.
MS (ESI): m/z = 337 [M + Na]+.
HRMS (ESI-MS): m/z [M + Na]+ calcd for C19H38O3Na: 337.2718;
found: 337.2716.
S-Methyl O-{(2R,3S,4S,6S)-4,6,8-trimethyl-2-[(4S,5S)-2,2,5-tri-
methyl-1,3-dioxan-4-yl]nonan-3-yl} carbonodithioate (11a)
LiHMDS (3.75 mL, 3.98 mmol, 1.06 M in THF) was added drop-
wise to a stirred soln of alcohol 10a (250 mg, 0.79 mmol) in THF (4
mL) at –78 °C under an Ar atm and the resulting mixture stirred for
30 min. CS2 (0.48 mL, 7.96 mmol) was added at –78 °C after which
the mixture was allowed to warm to 0 °C and stirred for 1 h before
being cooled to –78 °C. MeI (0.24 mL, 3.98 mmol) was added at
–78 °C and the mixture was allowed to warm to r.t. and stirred for 3
h. Sat. aq NH4Cl soln was added to quench the reaction and the aq
layer was extracted with EtOAc (2 × 10 mL). The combined organic
layer was washed with brine (10 mL), dried over anhyd Na2SO4, fil-
tered and concentrated under vacuum. The residue was purified by
silica gel column chromatography (3% EtOAc–hexane) to afford
xanthate 11a (278 mg, 86%) as a yellow liquid.
11a: [a]D25 –15.2 (c 0.75, CHCl3); 11b: [a]D25 +18.2 (c 0.35,
CHCl3).
IR (KBr): 2857, 1633, 1460, 1226, 1049, 867, 763 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.71 (d, J = 5.9 Hz, 3 H), 0.83 (d,
J = 6.9 Hz, 3 H), 0.87–0.92 (m, 9 H), 0.96 (d, J = 6.9 Hz, 4 H),
1.05–1.15 (m, 2 H), 1.27 (d, J = 4.9 Hz, 6 H), 1.30–1.37 (m, 1 H),
1.51–1.58 (m, 1 H), 1.60–1.70 (m, 1 H), 1.74–1.84 (m, 1 H), 1.95–
2.04 (m, 1 H), 2.09 (m, 1 H), 2.54 (s, 3 H), 3.39 (d, J = 9.8 Hz, 1 H),
3.43 (t, J = 10.8 Hz, 1 H), 3.62 (dd, J = 4.9, 5.9 Hz, 1 H), 5.83 (m,
1 H).
MS (ESI): m/z = 511 [M + Na]+.
HRMS (ESI-MS): m/z [M + H]+ calcd for C23H38O3I: 489.1865;
found: 489.1858.
9a: To a round-bottomed flask containing activated Mg turnings
(1.79 g, 74.93 mmol) was added 2-chloropropane (5.5 mL, 59.94
mmol) in THF (14.5 mL). The mixture was heated to reflux for ca.
30 min until the conversion into isopropylmagnesium chloride was
complete. The freshly prepared isopropylmagnesium chloride (19
mL, 74.9 mmol) was added dropwise to a stirred soln of the iodide
a (1.9 g, 3.89 mmol) and CuCN (0.348 g, 3.89 mmol) in THF (20
mL). The mixture was stirred for 1 h at r.t. and then quenched with
sat. aq NH4Cl soln. The organic layer was separated and the aq layer
extracted with EtOAc (2 × 20 mL). The combined organic layer was
washed with brine (30 mL), dried over anhyd Na2SO4, filtered and
concentrated under vacuum. The residue was purified by silica gel
column chromatography (4% EtOAc–hexane) to afford 9a (1.39 g,
88%) as a colorless liquid.
9a: [a]D25 +17.6 (c 0.65, CHCl3); 9b: [a]D25 –20.0 (c 1, CHCl3).
IR (KBr): 2957, 2873, 1459, 1378, 1197, 1065, 733, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.71 (d, J = 6.7 Hz, 3 H), 0.83 (t,
J = 12.8 Hz, 7 H), 0.86–0.91 (m, 6 H), 1.03 (d, J = 6.7 Hz, 3 H),
1.15–1.27 (m, 3 H), 1.33 (d, J = 6.0 Hz, 6 H), 1.47–1.58 (m, 1 H),
1.60–1.72 (m, 1 H), 1.76–1.91 (m, 3 H), 3.30 (d, J = 9.6 Hz, 1 H),
3.44 (t, J = 11.3 Hz, 1 H), 3.63 (dd, J = 6.2, 11.3 Hz, 1 H), 3.84 (d,
J = 10.3 Hz, 1 H), 4.59 (q, J = 15.4 Hz, 2 H), 7.25–7.32 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 9.2, 12.3, 17.4, 18.6, 18.8, 21.1,
21.5, 24.1, 25.2, 27.6, 29.5, 30.0, 32.8, 35.4, 38.4, 45.2, 66.0, 72.9,
88.2, 98.2.
MS (ESI): m/z = 427 [M + Na]+.
HRMS (ESI-MS): m/z [M + Na]+ calcd for C21H40O3S2Na:
427.2316; found: 427.2308.
13C NMR (75 MHz, CDCl3): d = 9.5, 12.4, 18.2, 19.4, 21.1, 21.5,
25.1, 27.6, 29.8, 30.2, 32.3, 36.4, 37.7, 45.2, 66.2, 73.5, 74.6, 74.7,
84.4, 97.9, 126.8, 127.0, 128.1, 139.5.
(4R,5S)-2,2,5-Trimethyl-4-[(2S,4S,6S)-4,6,8-trimethylnonan-2-
yl]-1,3-dioxane (12a)
To a stirred soln of xanthate 11a (300 mg, 0.74 mmol) in anhyd ben-
zene (10 mL) at 80 °C were added Bu3SnH (0.4 mL, 1.49 mmol) fol-
MS (ESI): m/z = 427 [M + Na]+.
Synthesis 2012, 44, 628–634
© Thieme Stuttgart · New York

PAPER
Enantioselective Total Synthesis of (+)- and (–)-Vittatalactone
633
lowed by a catalytic amount of AIBN (7.0 mg, 0.037 mmol) and the
mixture heated at reflux temperature for 4 h. The solvent was
removed under vacuum, the residue treated with aq KF soln (2 × 10
mL) (200 mg KF dissolved in 10 mL H2O) and extracted with
EtOAc (2 × 10 mL). The combined organic layer was dried over an-
hyd Na2SO4, filtered and concentrated under vacuum. The residue
was then purified by silica gel column chromatography (3%
EtOAc–hexane) to afford 12a (198 mg, 89%) as a colorless liquid.
12a: [a]D25 +19.5 (c 0.75, CHCl3); 12b: [a]D25 –21.3 (c 0.2, CHCl3).
IR (KBr): 2957, 2857, 1461, 1377, 1262, 1104, 1062, 805, 519 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.64 (d, J = 6.7 Hz, 3 H), 0.73–
0.83 (m, 17 H), 0.84–0.93 (m, 1 H), 0.95–1.11 (m, 2 H), 1.25 (s, 3
H), 1.31 (s, 3 H), 1.37–1.61 (m, 4 H), 1.65–1.82 (m, 2 H), 3.29–3.42
(m, 2 H), 3.58 (dd, J = 4.5, 11.3 Hz, 1 H).
1a: [a]D25 +3.0 (c 1.5, CHCl3); 1b: [a]D25 –2.5 (c 1.5, CHCl3).
IR (KBr): 2957, 2922, 1827, 1460, 1124, 867 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.84 (d, J = 6.6 Hz, 6 H), 0.87–
0.92 (m, 2 H), 0.88 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H),
1.02 (d, J = 6.6 Hz, 3 H), 0.99–1.05 (m, 1 H), 1.06–1.11 (m, 1 H),
1.13–1.28 (m, 2 H), 1.39 (d, J = 7.5 Hz, 3 H), 1.49–1.71 (m, 3 H),
1.78–1.93 (m, 1 H), 3.20 (qd, J = 7.5, 4.1 Hz, 1 H), 3.80 (dd, J = 8.1,
4.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 12.8, 15.7, 20.7, 20.9, 21.7, 23.8,
25.1, 27.2, 27.5, 34.7, 39.7, 45.0, 45.9, 48.8, 83.6, 172.0.
MS (ESI): m/z = 277 [M + Na]+.
HRMS (ESI-MS): m/z [M + Na]+ calcd for C16H30O2Na: 277.2143;
found: 277.2138.
13C NMR (75 MHz, CDCl3): d = 13.7, 18.9, 20.1, 20.5, 22.2, 23.5,
25.1, 26.7, 27.4, 29.7, 29.9, 30.7, 40.1, 46.2, 47.0, 66.4, 75.0, 97.9.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(2S,3R,4S,6S,8S)-2,4,6,8,10-Pentamethylundecane-1,3-diol
(13a)
To a stirred soln of 12a (112 mg, 0.375 mmol) in THF (1.5 mL) was Acknowledgment
added aq 2 M HCl (0.2 mL) and the resulting mixture stirred for 4
We thank the University Grants Commission (UGC), New Delhi,
h at r.t. The mixture was diluted with EtOAc (5 mL) and the aq layer
extracted with EtOAc (2 × 5 mL). The combined organic layer was
washed with brine (5 mL), dried over anhyd Na2SO4, filtered and
concentrated under vacuum. The residue was purified by silica gel
column chromatography (20% EtOAc–hexane) to afford 13a (83
mg, 86%) as a colorless liquid.
India, for the award of fellowships to E. Srinivas and Ch.
Suresh Kumar. The author acknowledges partial support by King
Saud University for the Global Research Network for Organic Syn-
thesis (GRNOS).
13a: [a]D25 –18.6 (c 1, CHCl3); 13b: [a]D25 +21.6 (c 0.6, CHCl3).
IR (KBr): 3373, 2957, 1461, 1377, 1026, 977 cm–1.
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© Thieme Stuttgart · New York