Formal synthesis of pinolide via l-proline-catalyzed sequential α-aminooxylation, Horner-Wadsworth-Emmons olefination and Sharpless asymmetric dihydroxylation

Article abstract of DOI:10.1016/j.tetasy.2016.01.005

A convergent, formal enantioselective synthesis of pinolide, a new nonenolide, has been achieved with high enantiomeric purity (99% ee) starting from readily available raw materials. The main highlight of the synthetic strategy is the application of l-proline catalyzed sequential α-aminooxylation and Horner-Wadsworth-Emmons olefination of an aldehyde, Sharpless asymmetric dihydroxylation and Steglich esterification as the key steps for the construction of a key chiral intermediate of the target molecule.

Full text of DOI:10.1016/j.tetasy.2016.01.005

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Formal synthesis of pinolide via L-proline-catalyzed sequential
a-aminooxylation, Horner–Wadsworth–Emmons olefination
and Sharpless asymmetric dihydroxylation
⇑
Anil M. Shelke, Gurunath Suryavanshi
Chemical Engineering & Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent, formal enantioselective synthesis of pinolide, a new nonenolide, has been achieved with
high enantiomeric purity (99% ee) starting from readily available raw materials. The main highlight of
Received 19 December 2015
Accepted 7 January 2016
Available online xxxx
the synthetic strategy is the application of
L-proline catalyzed sequential a-aminooxylation and
Horner–Wadsworth–Emmons olefination of an aldehyde, Sharpless asymmetric dihydroxylation and
Steglich esterification as the key steps for the construction of a key chiral intermediate of the target
molecule.
Ó 2016 Elsevier Ltd. All rights reserved.
1
. Introduction
Pinolide 1, a naturally occurring nonenolide, was recently iso-
of being highly selective and reduces synthetic manipulations.5
Proline-catalyzed sequential transformation is an emerging area
of research in the organic synthesis of complex organic molecules,
which can be synthesized using a one-pot procedure.
lated from the liquid culture of CO-99 of Didymella pinodes together
with herbarumin I 3, herbarumin II 4 and 2-epi-herbarumin II 2
In continuation of our work on the sequential proline-catalyzed
synthesis of bioactive molecules, we herein report a simple and
1
6
(Fig. 1). The 10-membered, naturally occurring decanolides are
abundant substances that represent the core of many natural prod-
ucts. Many of these lactones have been found to display a wide
efficient asymmetric synthesis of pinolide 1 from readily available
2
starting materials via L-proline catalyzed sequential aminooxyla-
7
range of pharmacologically interesting features, such as antifungal,
antifeedant, antibacterial, herbicidal, antitumoral, plant growth
tion–olefination of n-valeraldehyde and Sharpless asymmetric
dihydroxylation reaction as the key chiral inducing steps (Schemes
2–4).
3
inhibition, and the inhibition of cholesterol biosynthesis. All
nonenolides shown in Figure 1 possess some common interesting
structural features, such as the olefinic function with a well-
defined geometry, as well as stereochemically pure hydroxyl
appendages, which make them challenging synthetic targets. In
the literature, there are two reports for the synthesis of pinolide
2
. Results and discussion
Our approach to the asymmetric synthesis of pinolide 1 is
shown in Scheme 1. We envisioned that the required ring closing
metathesis precursor 5 (Scheme 1) should, in turn, be accessible
from secondary alcohol fragment 6 and carboxylic acid fragment
4
4a
1.
Yadav et al. achieved the first total synthesis of pinolide 1,
in which the key steps involved are Barbier allylation, Yamaguchi
4
b
esterification and ring-closing metathesis. Recently Das et al.
7
via Steglich esterification. The secondary alcohol fragment 6
can be derived from n-valeraldehyde 10 via proline-catalyzed
sequential -aminooxylation and Horner–Wadsworth–Emmons
olefination while the acid fragment 7 from hex-5-enal 9 as the
starting material via -aminooxylation. Accordingly, the synthetic
reported an alternative approach for the synthesis of 1 using Jacob-
sen’s hydrolytic kinetic resolution, Yamaguchi esterification, and
intramolecular ring closing metathesis as the key steps. However,
the reported methods suffer from several disadvantages, such as
the use of chiral building blocks as starting materials, longer reac-
a
a
sequence began with the synthesis of alcohol fragment 6 from
commercially available n-valeraldehyde 10 (Scheme 2). Thus,
n-valeraldehyde 10 was subjected to
4
tion sequences, and low overall yields. Organocatalysis is a rapidly
growing research field in organic synthesis and has the advantages
a-aminooxylation with
nitrosobenzene as the oxygen source and
followed by in situ Horner–Wadsworth–Emmons olefination with
LiCl and DBU (Masamune–Roush protocol) to furnish crude
L
-proline at À20 °C,
⇑
Corresponding author. Tel.: +91 20 25902396; fax: +91 20 25902676.
E-mail address: gm.suryavanshi@ncl.res.in (G. Suryavanshi).
8
http://dx.doi.org/10.1016/j.tetasy.2016.01.005
957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
0
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A. M. Shelke, G. Suryavanshi / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
HO
HO
HO
HO
O
O
O
O
OH HO
OH HO
OH HO
OH
O
O
O
O
pinolide
1
2-epi-herbarumin II
2
herbarumin I
3
herbarumin II
4
Figure 1. Some naturally occurring small ring macrolides.
O
HO
HO
O
O
i
ii
H
OH
OTBS
O
O
OH
iv
OH
18
OH
OPMB
9
17
O
O
pinolide 1
5
iii
v
OTBS
OH
OPMB
OPMB
20
1
9
HO
O
O
OH
O
OH
O
OPMB
OPMB
6
7
7
Scheme 3. Reagents and conditions: (i) (a) PhNO,
À20 °C, 24 h then MeOH, NaBH , 20 min.; (b) CuSO
2 h, 87% (over two steps), 99% ee; (ii) TBSCl, imid., CH
D
-proline (20 mol %), CH
Á5H O (30 mol %), MeOH, 0 °C,
Cl , 0–25 °C, 2 h, 96%; (iii)
3
CN,
O
4
4
2
OH
1
2
2
H
O
OEt
PMB imidate, PTSA (cat), dry CH Cl , 0 °C to rt, 8 h, 90%; (iv) CSA, MeOH, 25 °C,
2
2
H
30 min, 63%; (v) TEMPO, PhI(OAc)
2
3 2
, CH CN/H O (4:1), 25 °C, 4 h, 86%.
O
10
8
9
ester 11 in 98% yield. The dihydroxylation of the
a,b-unsaturated
ester 11 was carried out under the Sharpless asymmetric dihydrox-
Scheme 1. Retrosynthetic plan for pinolide 1.
1
0
2 2 3 3 6 2 2
ylation conditions [(DHQ) PHAL, K CO , K Fe(CN) , MeSO NH ,
t-BuOH/H O (1:1), K OsO
ester 12 in 86% yield with a diastereomeric ratio of 3:1 (anti/syn).
Diol 12 was then protected as its acetonide (2,2-dimethoxy pro-
pane, catalytic camphorsulfonic acid) to afford acetonide 13 in
96% yield. The ester functionality in acetonide 13 was reduced with
2
2
4
Á2H O (0.2 mol %)] to give dihydroxylated
2
a
-aminooxy olefinic ester. Subsequent reduction of the crude
9
a
-aminooxy product with 30 mol % CuSO
-hydroxy ester 8 in 77% yield. The enantiomeric purity of
-hydroxy ester 8 was determined as 99% by chiral HPLC analysis.
4
2
Á5H O in MeOH yielded
1
1
the
c
c
Compound 8 upon silylation (TBSCl, imid.) gave
a,b-unsaturated
4
LiAlH to afford the corresponding alcohol 14 in 93% yield.
OR
TBSO
OH
H
OEt
iii
OEt
i
O
O
OH
12
O
8
, R = H
10
ii
1
1, R = TBS
O
OEt
OH
TBSO
TBSO
iv
v
vi
O
O
O
O
13
14
O
H
TBSO
RO
vii
O
O
O
O
15
1
6, R = TBS
viii
6
,
R = H
Scheme 2. Reagents and conditions: (i) (a) PhNO,
5 °C, 12 h, 77%, 99% ee; (ii) TBSCl, imid., CH Cl , 0–25 °C, 3 h, 98%; (iii) (DHQ)
dr = 3:1); (iv) 2,2 dimethoxypropane, cat. CSA, CH Cl , rt, 12 h, 96%; (v) LiAlH
5%; (viii) TBAF, THF, 0–25 °C, 2 h, 82%.
L
-proline (20 mol %), CH
3
CN, À20 °C, 24 h then triethyl phosphonoacetate, LiCl, DBU, 1 h; (b) CuSO
4
Á5H
2
O (30 mol %), MeOH,
2
(
7
2
2
2
PHAL, K
2
CO
3
3
, K Fe(CN)
6
, MeSO
2
NH
2
, t-BuOH/H
2
O (1:1), K
2
OsO
4
Á2H
2
O (0.2 mol %), 0 °C, 5 h, 86%,
+
À
2
2
4
, THF, 0–5 °C, 1 h, 93%; (vi) IBX, EtOAc, 80 °C, 2 h, 86%; (vii) Ph
3
P CH
3
I , n-BuLi, THF, 0 °C, 1 h,
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A. M. Shelke, G. Suryavanshi / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
HO
HO
HO
O
O
i
ref 4
O
OH
OPMB
O
O
OH
O
OPMB
O
O
O
6
7
pinolide 1
, 0–25 °C, 6 h, 88%.
5
Scheme 4. Reagents and conditions: (i) EDCIÁHCl, Et
3
N, DMAP, CH
2
Cl
2
Oxidation of alcohol 14 with IBX provided aldehyde 15 in 86%
yield, which was subsequently treated with iodomethyltriph-
enylphosphine in the presence of n-BuLi as a base to give terminal
olefin 16 in 75% yield. Finally, silyl deprotection in olefin 16 with
TBAF yielded the key alcohol fragment 6 in 82% yield (Scheme 2).
The physical constant, specific rotation value and spectroscopic
data of 6 were in complete agreement with the reported values.
Scheme 3 shows the synthetic sequence for acid fragment 7, which
starts from hex-5-enal 9. The conversion of hex-5-enal 9 to chiral
mentioned otherwise. HRMS data for new compounds were
recorded on a Thermo Scientific Q-Exactive, Accela 1250 pump.
IR spectra were recorded on a Perkin-Elmer model 683 B and
absorption is expressed in cm . Column chromatography was car-
ried out using silica gel of the selected particle size of 100–200
mesh or 230–400 mesh.
À1
4
4
.1.1. Ethyl(R,E)-4-hydroxyhept-2-enoate 8
To a solution of nitrosobenzene (5.5 g, 58.13 mmol) and L-pro-
line (1.33 g, 20 mol %) in CH CN (120 mL) was added n-valeralde-
3
hyde 10 (5.0 g, 58.13 mmol) at À20 °C. The reaction mixture was
stirred at the same temperature for 24 h, followed by the addition
of anhydrous LiCl (3.4 g, 87.19 mmol), triethyl phosphonoacetate
diol 17 proceeded via a sequence of reactions as follows: (i)
D-pro-
-aminooxylation12 of 9 followed by in situ reduc-
line catalyzed
tion with NaBH ; (ii) subsequent reduction of the crude aminoxy
product with 30 mol % CuSO O gave chiral diol 17 in 87% yield
Á5H
a
4
4
2
(
(
19.53 g, 87.19 mmol) and 1,8-diazabicyclo-[5.4.0]undec-7-ene
DBU) (8.8 g, 58.13 mmol). After stirring for 1 h, the reaction mix-
over two steps. The enantiomeric purity of chiral diol 17 was deter-
mined as 99% by its Mosher ester analysis. Selective silyl protection
of primary alcohol in diol 17 (TBSCl, imid.) gave mono-TBS pro-
tected alcohol 18 in 96% yield. Alcohol 18 upon subsequent PMB
ether formation using PMB-trichloroacetimidate (derived from
PMB-OH) and catalytic PTSA at 0 °C provided olefin 19 in 90% yield.
The TBS deprotection of olefin 19 with catalytic amount of cam-
phorsulfonic acid (CSA) yielded alcohol 20 in 63% yield. Finally, oxi-
ture was quenched with half saturated NH
ethyl acetate (200 mL). The combined organic layers were washed
with brine, dried over anhydrous Na SO , and concentrated under
reduced pressure to give a crude -aminooxy olefinic ester, which
was used directly for the next step without further purification. To
a well-stirred solution of crude -aminooxy olefinic ester in MeOH
50 ml) was added CuSO O (4.3 g, 30 mol %) at 25 °C. The reac-
4
Cl and extracted with
2
4
a
a
(
4
Á5H
2
dation of 20 [TEMPO, PhI(OAc)
6% yield (Scheme 3).
After the successful construction of both fragments, we carried
out the final coupling of key alcohol fragment 6 and acid fragment
N) to afford
2
] afforded the acid fragment 7 in
tion mixture was then allowed to stir for 12 h at this temperature.
After completion of the reaction (monitored by TLC), the solvent
was evaporated under reduced pressure to afford the crude
8
c
-hydroxy ester. The crude product was then purified by column
chromatography over silica gel using petroleum ether and ethyl
acetate (7:3) as eluents to afford -hydroxy ester 8 (7.7 g). Yield:
= À21.2 (c 1.0, CHCl ); IR (CHCl ):
1280, 1660, 1715, 2930, 3442 cm ; H NMR (200 MHz, CDCl ): d
.95 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H), 1.37–1.68 (m, 4H),
.83 (br s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.29 (m, 1H), 6.01 (dd,
7
using a Steglich esterification condition (EDCIÁHCl, Et
3
ring closing metathesis precursor 5 in 88% yield. Finally ring-clos-
ing metathesis of 5 and deprotection of the protecting groups (PMB
and acetonide), that are well described in the literature, gave the
c
2
5
7
7%; colorless liquid; [
a
]
D
3
3
À1
1
4
a
3
final product 1, thereby constituting a formal synthesis of 1
Scheme 4).
0
1
(
1
3
J = 15.5, 1.6 Hz, 1H), 6.92 (dd, J = 15.7, 5.0 Hz, 1H); C NMR
50 MHz, CDCl ): d 13.8, 14.2, 18.4, 38.6, 60.4, 70.8, 120.0, 150.3,
66.6; HRMS (m/z): calculated [M+Na] for C
found: 195.0995.
3
. Conclusion
(
1
3
+
9 3
H16NaO : 195.0997
In conclusion, a convergent, formal enantioselective synthesis
of pinolide 1 has been achieved. The strategy mainly comprises
of the -proline-catalyzed sequential -aminooxylation–Horner–
L
a
4
.1.2. Ethyl(R,E)-4-((tert-butyldimethylsilyl)oxy)hept-2-enoate 11
To a solution of -hydroxy ester 8 (6.4 g, 37.20 mmol) in anhy-
drous CH Cl (80 mL) were added imidazole (5.0 g, 74.4 mmol) and
Wadsworth–Emmons olefination reaction of n-valeraldehyde and
Sharpless asymmetric dihydroxylation as the key reactions for
the induction of chirality. The overall yields for both fragments,
alcohol fragment 6 and acid fragment 7, were calculated to be
c
2
2
TBSCl (6.6 g, 44.65 mmol) at 0 °C. The resultant mixture was
warmed to room temperature and stirred for 3 h. The reaction
3
0.6% and 40.7% respectively, with an excellent enantioselectivity
was immersed in an ice bath, and saturated aqueous NH
20 mL) was added. The layers were separated, the aqueous layer
was washed with CH Cl (220 mL) and the combined organic lay-
ers were dried over Na SO and concentrated under vacuum. The
4
Cl
of 99% ee. The operationally simple reactions with fewer steps,
high overall yields, requiring a relatively low amount of inexpen-
sive and non-toxic proline as the catalyst make this approach an
attractive and useful route. This methodology can be applied to
the synthesis of other members of decanolides as well.
(
2
2
2
4
crude residue was purified by column chromatography using pet-
roleum ether and ethyl acetate (9:1) as eluents to give TBS ether
2
5
1
CHCl
2
1 (10.42 g). Yield: 98%; pale yellow liquid; [
a]
D
= À15.2 (c 1.5,
À1
4
4
. Experimental
3
); IR (CHCl
3
, cm ) 1185, 1412, 1462, 1720, 2863, 2935,
1
965; H NMR (200 MHz, CDCl
0.89–0.92 (m, 12H), 1.30 (t, J = 6.6 Hz, 3H), 1.33–1.39 (m, 2H),
.49–1.54 (m, 2H), 4.16–4.23 (m, 2H), 4.28–4.32 (m, 1H), 5.94–
5.98 (dd, J = 15.7, 1.6 Hz, 1H), 6.90–6.94 (dd, J = 15.4, 4.7 Hz, 1H);
3
): d 0.03 (s, 3H), 0.06 (s, 3H),
.1. General
1
Solvents were purified and dried by standard procedures before
1
3
use. Optical rotations were measured using sodium D line on a
C NMR (50 MHz, CDCl
3
): d À4.9, À4.6, 14.0, 14.2, 18.10, 18.18,
1
13
JASCO-181 digital polarimeter. H NMR and C NMR spectra were
recorded on Brucker AC-200, 400 and 500 spectrometers unless
25.8, 39.5, 60.2, 71.4, 119.6, 151.1, 166.8; HRMS (m/z): calculated
+
[M+Na] for C15H30NaO Si: 309.1856 found: 309.1853.
3
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A. M. Shelke, G. Suryavanshi / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4
.1.3. Ethyl(2S,3S,4R)-4-((tert-butyldimethylsilyl)oxy)-2,3-
short pad of Celite and the Celite pad was washed with ethyl acet-
ate (30 mL). The organic layer was washed with water (50 mL),
brine (50 mL), and dried over Na SO . The residue obtained after
evaporation of the solvent afforded the crude aldehyde, which
was purified by column chromatography using petroleum ether/
ethyl acetate (9:1) as eluent to furnish aldehyde 15 (2.56 g). Yield:
dihydroxyheptanoate 12
To a mixture of K Fe(CN)
2.44 mmol), and (DHQ) -PHAL (135 mg, 1 mol %), in t-BuOH/H
1:1, 200 mL) cooled at 0 °C was added K OsO Á2H O (12 mg,
.2 mol %) followed by methanesulfonamide (1.66 g, 17.48 mmol).
3
6
(17.25 g, 52.44 mmol), K
2
CO
3
(7.23 g,
2
4
5
(
0
2
2
O
2
4
2
2
5
À1
After being stirred for 5 min at 0 °C, TBS protected ether 11 (5 g,
7.48 mmol) was added in one portion. The reaction mixture was
86%; colorless liquid; [
776, 1255, 1470, 1715, 2860, 2935, 2962; H NMR (200 MHz,
CDCl ): d 0.08 (s, 3H), 0.09 (s, 3H), 0.89–0.96 (m, 12H), 1.34–1.49
(m, 10H), 3.83–3.91 (m, 1H), 4.05–4.10 (dd, J = 4.0, 6.3 Hz, 1H),
4.34–4.38 (dd, J = 1.6, 6.6 Hz 1H), 9.77 (d, J = 3.2 Hz, 1H); 13
NMR (50 MHz, CDCl
): d À4.4, À4.1, 14.2, 18.0, 25.7, 25.9, 26.7,
27.0, 36.4, 71.5, 78.1, 82.6, 108.4, 117.2, 137.0; HRMS (m/z): calcu-
a
]
D
= À13.7 (c 1.0, CHCl
3 3
); IR (CHCl , cm )
1
1
stirred at 0 °C for 5 h and then the reaction was quenched with
solid sodium sulfite. Stirring was continued for an additional
3
4
5 min, and then the solution was extracted with EtOAc
C
(
3 Â 100 mL). The combined organic extracts were dried over
3
sodium sulfate and concentrated under vacuum. The crude residue
was then purified by column chromatography using petroleum
ether and ethyl acetate (85:15) as eluents to give diol 12 (4.73 g).
+
4
lated [M+Na] for C16H32NaO Si: 339.1968 found: 339.1967.
2
5
Yield: 86%; yellow gum; [
cm ) 775, 972, 1010, 1103, 1253, 1640, 1734, 2950, 3448;
a]
D
3
= À5.5 (c 1.6, CHCl ); IR (CHCl
3
,
4.1.7. tert-Butyl((R)-1-((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-
4-yl)butoxy)dimethylsilane 16
À1
1
H
NMR (200 MHz, CDCl
3
): d 0.10 (s, 6H), 0.90–0.95 (m, 12H), 1.30–
To a stirred solution of iodomethyltriphenylphosphine (5.13 g,
12.65 mmol) in THF (50 mL) was added n-BuLi (7.9 mL, 1.6 M,
12.65 mmol) dropwise at 0 °C. After 30 min, aldehyde 15 (2.0 g,
6.32 mmol) was added and the reaction mixture was allowed to
warm to room temperature over 15 min. The resultant mixture
1
3
.33 (t, J = 6.9 Hz, 3H), 1.38–1.47 (m, 2H), 2.29–2.63 (br s, 1H),
1
3
.15–3.33 (br s, 1H), 3.77–3.89 (m, 2H), 4.21–4.46 (m, 3H);
): d À4.9, À4.4, 14.1, 14.3, 17.0, 18.0, 25.8,
5.4, 35.8, 61.9, 70.1, 70.6, 72.7, 173.6; HRMS (m/z): calculated
C
NMR (50 MHz, CDCl
3
3
+
[
M+Na] for C15H32NaO
5
Si: 343.1911 found: 343.1907.
4
was quenched with saturated aqueous NH Cl, diluted with ethyl
acetate (25 mL). The combined organic layer was washed with
water and then brine. The organic layer was dried over anhydrous
4
2
.1.4. Ethyl(4S,5S)-5-((R)-1-((tert-butyldimethylsilyl)oxy)butyl)-
,2-dimethyl-1,3-dioxolane-4-carboxylate 13
2 4
Na SO , and concentrated under reduced pressure. The residue was
2 2
A solution of diol 12 (4.0 g, 12.5 mmol) in CH Cl (40 mL) was
purified by column chromatography using petroleum ether as elu-
25
treated with 2,2-dimethoxypropane (7.6 mL, 62.5 mmol) and CSA
290 mg, 10 mol %). The resulting solution was stirred at room
temperature for 12 h. After completion of the reaction (monitored
by TLC), the mixture was quenched by the addition of Et N (1 mL)
ent to give olefin 16 (1.49 g). Yield: 75%; colorless liquid; [
a
]
D
=
À1
(
+11.0 (c 1.0, CHCl
3 3
); IR (CHCl , cm ) 1100, 1260, 1470, 2935,
1
3
2960; H NMR (200 MHz, CDCl ): d 0.07 (s, 3H), 0.08 (s, 3H),
3
0.80–0.93 (m, 12H), 1.25–1.51 (m, 10H), 3.09–3.75 (m, 1H), 3.82–
3.89 (m, 1H), 4.35–4.42 (m, 1H), 5.16–5.22 (m, 1H), 5.32–5.42
and then concentrated under reduced pressure. The crude residue
was then purified by column chromatography using petroleum
ether and ethyl acetate (95:5) as eluents to give acetonide 13
1
3
(m, 1H), 5.78–5.95 (m, 1H); C NMR (50 MHz, CDCl
3
): d À4.4,
À4.1, 14.2, 18.1, 18.2, 25.9, 26.7, 27.0, 36.4, 71.5, 78.1, 82.6,
2
5
108.4, 117.2, 137.0; HRMS (m/z): calculated [M+Na]+ for
(
(
(
4.3 g). Yield: 96%; colorless liquid; [
a]
D
= +24.0 (c 1.2, CHCl
3
); IR
À1
1
CHCl
3
, cm ) 780, 1105, 1255, 1735, 2857, 2935, 2962; H NMR
17 3
C H34NaO Si: 337.2169 found: 337.2166.
200 MHz, CDCl
.29–1.53 (m, 13H), 3.78–3.89 (m, 1H), 4.16–4.46 (m, 4H);
NMR (50 MHz, CDCl
): d À4.3, À4.2, 14.1, 14.2, 18.1, 18.3, 25.4,
5.9, 26.7, 36.2, 61.2, 71.4, 74.9, 81.4, 110.0, 171.9; HRMS (m/z):
3
): d 0.07 (s, 3H), 0.08 (s, 3H), 0.89–0.95 (m, 12H),
1
3
1
C
4.1.8. (R)-1-((4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)
butan-1-ol 6
3
2
To a stirred solution of olefin 16 (1.3 g, 4.14 mmol) in THF
(20 mL) at 0 °C, TBAF (8.27 mL, 8.28 mmol, 1 M solution in THF)
was added dropwise. The mixture was allowed to stir at room tem-
perature over 2 h. The resultant mixture was quenched with water
and diluted with diethyl ether (5 mL). The organic layer was
washed with water and then with brine, respectively. The com-
+
5
calculated [M+Na] for C18H36NaO Si: 383.2224 found: 383.2222.
4
.1.5. ((4R,5S)-5-((R)-1-((tert-Butyldimethylsilyl)oxy)butyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methanol 14
To a stirred suspension of LiAlH (0.411 g, 11.11 mmol) in THF
4
(
(
40 mL) at 0 °C was added acetonide 13 (4 g, 11.11 mmol) in THF
40 mL). After 1 h of stirring at 0 °C, the reaction mixture was
2 4
bined organic layers were dried over anhydrous Na SO , and con-
centrated under reduced pressure. The residue was purified by
column chromatography over silica gel using petroleum ether/
ethyl acetate (9:1) as eluent to give alcohol 6 (678 mg). Yield:
quenched with H
H
and washed with hot ethyl acetate (80 mL), after which the filtrate
was concentrated under reduced pressure and purified by column
chromatography using petroleum ether and ethyl acetate (8:2) as
eluents to give alcohol 14 (3.2 g). Yield: 93%; colorless liquid;
2
O (1.8 mL), 15% aqueous NaOH (1.8 mL) and
2
O (5.0 mL). The precipitate was filtered through a Celite pad
2
5
À1
82%; colorless liquid; [
1105, 1254, 1380, 1466, 1640, 2865, 2960, 3455; H NMR
(200 MHz, CDCl ): d 0.87–0.95 (t, J = 7.1 Hz, 3H), 1.33–1.52 (m,
D 3 3
a] = +7.7 (c 1.0, CHCl ); IR (CHCl , cm )
1
3
10H), 2.08 (br s, 1H), 3.63 (dd, J = 3.8, 8.0 Hz, 1H),3.76–3.80 (m,
2
5
À1
[a
]
D
= À2.3 (c 1.0, CHCl
3
); IR (CHCl
3
, cm ) 1085, 1255, 1460,
): d 0.03 (s, 6H),
1H), 4.25–4.39 (m, 1H), 5.12–5.37, (m, 2H), 5.65–5.86 (m, 1H);
1
13
2
0
3
935, 2960, 3450; H NMR (200 MHz, CDCl
3
3
C NMR (100 MHz, CDCl ): d 13.8, 19.1, 26.9, 34.3, 70.1, 77.3,
+
.81–0.88 (m, 12H), 1.28–1.45 (m, 10H), 2.09 (br s, 1H), 3.49–
83.0, 108.7, 118.7, 136.4; HRMS (m/z): calculated [M+Na] for
20NaO : 223.1310 found: 223.1307.
.63 (m, 1H), 3.65–3.78 (m, 3H), 3.90–3.99 (m, 1H); 13C NMR
C
11
H
3
(
6
C
50 MHz, CDCl
3
): d À4.2, À4.1, 14.4, 17.2, 25.9, 27.1, 27.2, 36.9,
+
3.5, 73.1, 78.4, 79.6, 108.7; HRMS (m/z): calculated [M+Na] for
34NaO Si: 341.2119 found: 341.2116.
4.1.9. (S)-Hex-5-ene-1,2-diol 17
16
H
4
To a stirred, precooled (À20 °C) acetonitrile (100 mL) solution of
aldehyde
9 (5 g, 51.02 mmol) and nitrosobenzene (4.91 g,
4
.1.6. (4S,5S)-5-((R)-1-((tert-Butyldimethylsilyl)oxy)butyl)-2,2-
45.91 mmol) was added
mixture was allowed to stir at the same temperature for 24 h fol-
lowed by the addition of MeOH (20 mL) and NaBH (2.83 g,
76.53 mmol) to the reaction mixture, which was stirred for
20 min. After the addition of a phosphate buffer, the resulting
D-proline (1.17 g, 20 mol %). The reaction
dimethyl-1,3-dioxolane-4-carbaldehyde 15
To a stirred solution of alcohol 14 (3.0 g, 9.43 mmol) in (40 mL)
ethyl acetate was added IBX (5.28 g, 18.86 mmol) and refluxed for
4
2
h. After the reaction was complete (TLC), it was filtered through a
Please cite this article in press as: Shelke, A. M. ; Suryavanshi, G. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
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A. M. Shelke, G. Suryavanshi / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
mixture was extracted with EtOAc (3 Â 60 mL) and the combined
organic phases were dried over anhydrous Na SO and concen-
trated to give the crude aminooxy alcohol which was directly taken
up for the next step without purification.
CH
2
Cl
2
(3 Â 20 mL). The combined organic extracts were washed
SO
2
4
with water (3 Â 50 mL) and brine, dried over anhydrous Na
2
4
,
and concentrated under reduced pressure. Column chromatogra-
phy purification of the crude product using petroleum ether/EtOAc
(8:2) as eluent gave alcohol 20 (8.19 g). Yield: 63%; colorless liquid;
To a well-stirred solution of crude
a-aminooxy alcohol in MeOH
2
5
À1
(
50 ml) was added CuSO O (3.81 g, 30 mol %) at 0 °C. The reac-
4
Á5H
2
[a
]
D
= À34.0 (c 0.64, CHCl
3
); IR (CHCl
3
, cm ) 820, 915, 1035, 1250,
1
tion mixture was then allowed to stir for 12 h at this temperature.
After completion of the reaction (monitored by TLC), the solvent
was evaporated under reduced pressure to afford the crude diol.
The crude product was then purified by column chromatography
over silica gel using petroleum ether and ethyl acetate (7:3) as elu-
ents to afford pure diol 17 (5.1 g). Yield: 87%; colorless liquid;
1516, 1615, 1642, 2936, 3000, 3428; H NMR (200 MHz, CDCl
3
):d
1.49–1.80 (m, 2H), 2.08–2.18 (m, 2H), 3.50–3.78 (m, 3H), 3.81 (s,
3H), 4.50–4.62 (m, 2H), 4.95–5.07 (m, 2H), 5.71–5.91 (m, 1H);
1
3
C NMR (50 MHz, CDCl
63.5, 94.2, 117.8, 139.0; HRMS (m/z): calculated [M+Na] for
20NaO : 259.1310 found: 259.1308.
3
): d À4.5, 19.0, 26.6, 29.3, 32.3, 55.9,
+
C
14
H
3
2
5
À1
[
a
]
D
= À14.0 (c 0.5, CHCl
3
); IR (CHCl
954, 3430; H NMR (200 MHz, CDCl
.02–2.27 (m, 2H), 3.43 (m, 1H), 3.60–3.79 (m, 4H), 4.93–5.11
): d 29.9,
3
, cm ) 1097, 1420, 1645,
1
2
2
(
3
3
): d 1.41–1.59 (m, 2H),
4.1.13. (S)-2-((4-Methoxybenzyl)oxy)hex-5-enoic acid 7
To a solution of alcohol 20 (1.5 g, 6.35 mmol) in CH
3 2
CN/H O
m, 2H), 5.72–5.81 (m, 1H); 13C NMR (50 MHz, CDCl
3.4, 66.4, 72.7, 115.1, 138.5; HRMS (m/z): calculated [M+Na]
12NaO : 139.0735 found: 139.0733.
(4:1) were added in one portion bis-acetoxy iodobenzene (6.13,
19.05 mmol) and TEMPO (0.296 g, 1.90 mmol). The reaction mix-
ture was then allowed to stir at 25 °C for 4 h. After completion of
the reaction (monitored by TLC), the reaction mixture was
quenched by the addition of saturated solution of aq. ammonium
thiosulphate. The organic layer was separated, washed with brine,
and subjected to column chromatographic purification with petro-
leum ether/EtOAc (8:2 v/v) to afford acid 7. Yield: 86%; Yellow liq-
3
+
for C
6
H
2
4
.1.10. (S)-1-((tert-Butyldimethylsilyl)oxy)hex-5-en-2-ol 18
To a solution of diol 17 (4.5 g, 38.79 mmol) in anhydrous CH
2 2
Cl
(
(
100 mL) were added imidazole (5.27 g, 77.58 mmol) and TBSCl
6.9 g, 46.54 mmol) at 0 °C. The resultant mixture was warmed to
2
5
À1
room temperature and stirred for 3 h. The reaction was immersed
in an ice bath, and saturated aqueous NH Cl (20 mL) was added.
The layers were separated, the aqueous layer was washed with
uid; [
a
]
D
= À45.0 (c 0.3, CHCl
3
); IR (CHCl
3
, cm ) 772, 815, 916,
1
4
1100, 1235, 1460, 1610, 1720, 2850, 2923, 3440; H NMR
(200 MHz, CDCl ): 1.84–1.94 (m, 2H), 2.15–2.21 (m, 2H), 3.81 (s,
3
CH
Na
2
Cl
SO
2
(150 mL), and the combined organic layers were dried over
4
and concentrated under vacuum. The residue was purified
3H), 3.96 (t, J = 6.0 Hz, 1H), 4.38 (d, J = 11.0 Hz, 1H), 4.62 (d,
J = 11.0 Hz, 1H), 4.96–5.05 (m, 2H), 5.67–5.87 (m, 1H), 6.87 (d,
2
1
3
by column chromatography over silica gel using petroleum ether/
J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H); C NMR (100 MHz, CDCl
3
):
ethyl acetate (9:1) as eluent to give alcohol 18 (8.5 g). Yield:
d 29.2, 31.8, 55.2, 72.2, 113.8, 115.5, 129.1, 129.8, 137.2, 159.4,
25
À1
+
9
7
CDCl
6%; colorless liquid; [
82, 835, 1117, 1258, 2858, 2928, 3440; H NMR (200 MHz,
): d 0.10 (s, 6H), 0.82 (s, 9H), 1.49–1.56 (m, 2H), 1.74 (br s,
H), 1.97–2.04 (m, 2H), 3.44–3.68 (m, 3H), 4.88–4.97 (m, 2H),
a
]
D
= +7.3 (c 2.0, CHCl
3
); IR (CHCl
3
, cm
)
177.3; HRMS (m/z): calculated [M+Na] for
14 4
C H18NaO :
1
273.1103 found: 273.1102.
3
1
5
2
4.1.14. (R)-1-((4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
butyl(S)-2-((4-methoxybenzyl)oxy)hex-5-enoate 5
1
3
.63–5.77 (m, 1H); C NMR (50 MHz, CDCl
3
): d À4.3, 18.1, 25.9,
9.5, 33.1, 66.1, 72.3, 114.8, 138.1; HRMS (m/z): calculated [M
To a stirred solution of carboxylic acid 7 (500 mg, 2.0 mmol),
+
+Na] for C12
2
H26NaO Si: 253.1600 found: 253.1601.
EDCIÁHCl (613 mg 3.2 mmol), Et
3
N (0.86 ml, 6.0 mmol), and DMAP
cat.) in anhydrous CH Cl (25 mL) was added alcohol 6 (400 mg,
(
2
2
4
.1.11. (S)-tert-Butyl((2-((4-methoxybenzyl)oxy)hex-5-en-1-yl)-
2.0 mmol) and the reaction mixture was stirred for 12 h. After
completion of the reaction (monitored by TLC), it was quenched
oxy)dimethylsilane 19
To a cooled (0 °C) solution of alcohol 18 (6.0 g, 26.08 mmol) in
with H
2
O, and extracted with CH
2
Cl
2
. The combined organic layers
SO , and con-
dry CH
2
Cl
2
(80 mL) was added PMB imidate (14.70 g, 52.16 mmol)
were washed with brine, dried over anhydrous Na
2
4
followed by PTSA (catalytic amount) after which the reaction was
stirred at room temperature for 8 h. After completion of the reac-
tion, it was quenched with triethylamine, diluted with water
centrated under reduced pressure. The crude product was then
purified by column chromatography with petroleum ether/EtOAc
(9:1 v/v) to give bis-olefin ester 5 as a colorless liquid. Yield:
2
5
25
(
50 mL), and extracted into CH
2
Cl
2
(3 Â 50 mL). The combined
88%; Colorless liquid; [
a
3
]
D
= À16.5 (c 0.5, CHCl
3
) lit.[
a
]
D
= À16.5
À1
organic layers were washed with brine, dried over Na
2
SO , and
4
(c 0.5, CHCl ); IR (CHCl
3
, cm ) 1100, 1240, 1456, 1730, 2865,
1
concentrated in vacuo. The crude product was then purified by col-
umn chromatography on silica gel using petroleum ether/ethyl
acetate (9:1) as eluent to give compound 19 (8.19 g). Yield: 90%;
3
2925, 3458; H NMR (200 MHz, CDCl ): 0.92 (t, J = 8.0 Hz, 3H),
1.23–1.38 (m, 2H), 1.40 (s, 6H), 1.57–1.70 (m, 2H), 1.80–1.86 (m,
2H), 2.10–2.26 (m, 2H), 3.81 (s, 3H), 3.82 (dd, J = 2.0, 6.0 Hz, 1H),
3.91 (dd, J = 2.0, 6.0 Hz, 1H), 4.27–4.36 (m, 2H), 4.64 (dd, J = 1.0,
11.0 Hz, 1H), 4.95–5.02 (m, 2H), 5.21–5.29 (m, 2H), 5.40 (d,
J = 17.0 Hz, 1H), 5.72–5.88 (m, 2H), 6.88 (d, J = 9.0 Hz, 2 H), 7.29
2
5
À1
colorless liquid; [
1
6
a
]
D
= À21.8 (c 1.0, CHCl
3
); IR (CHCl
242, 1512, 1588, 1615; H NMR (200 MHz, CDCl ): d 0.06 (s,
H), 0.90 (s, 9H), 1.52–1.65 (m, 2H), 2.10–2.14 (m, 2H), 3.40–3.74
3
, cm )
1
3
1
3
(
m, 3H), 3.80 (s, 3H), 4.45 (d, J = 11.0 Hz, 1H), 4.60 (d, J = 11.0 Hz,
3
(d, J = 9.0 Hz, 2 H); C NMR (100 MHz, CDCl ): d 13.8, 18.4, 26.7,
1
7
2
1
C
H), 4.91–5.05 (m, 2H), 5.70–5.91 (m, 1H), 6.80–6.90 (m, 2H),
26.8, 29.4, 32.3, 33.1, 55.2, 71.8, 73.1, 73.2, 76.8, 76.2, 81.1,
1
3
.24–7.33 (m, 2H); C NMR (50 MHz, CDCl
5.9, 30.9, 55.2, 65.6, 71.9, 78.8, 113.6, 114.5, 129.7, 131.1, 132.8,
33.6, 138.7, 159.0; HRMS (m/z): calculated [M+Na] for
3
): d À5.4, À5.3, 18.2,
109.3, 113.6, 115.4, 118.8, 129.6, 129.8, 135.7, 137.3, 159.5,
+
172.2; HRMS (m/z): calculated [M+Na] for
25 6
C H36NaO :
+
455.2397 found: 455.2399.
20 3
H34NaO Si: 373.2175 found: 373.2173.
Acknowledgements
4
.1.12. (S)-2-((4-Methoxybenzyl)oxy)hex-5-en-1-ol 20
To a stirred solution of compound 19 (5.0 g, 14.28 mmol) in
A.M.S thanks UGC, New Delhi for the award of research fellow-
ships and SERB-DST (GAP302326), New Delhi for funds. The
authors are thankful to Dr. V.V. Ranade, Chair, Chemical Engineer-
ing and Process Development Division for his encouragement and
support.
MeOH (40 mL) was added (+)-camphor-10-sulfonic acid (6 mg,
4.28 mmol) at room temperature and the reaction mixture was
stirred for 30 min. After completion of the reaction (monitored
by TLC), H O (6 mL) was added and extraction was carried out with
1
2
Please cite this article in press as: Shelke, A. M. ; Suryavanshi, G. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
tetasy.2016.01.005

6
A. M. Shelke, G. Suryavanshi / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
6.
(a) Rawat, V.; Chouthaiwale, P. V.; Chavan, V. B.; Suryavanshi, G.; Sudalai, A.
Tetrahedron Lett. 2010, 51, 6565; (b) Kiran, I. N. C.; Reddy, R. S.; Suryavanshi, G.;
Sudalai, A. Tetrahedron Lett. 2011, 52, 438; (c) Devalankar, D. A.; Chouthaiwale,
P. V.; Sudalai, A. Tetrahedron: Asymmetry 2012, 23, 240; (d) Shelke, A. M.;
Rawat, V.; Sudalai, A.; Suryavanshi, G. RSC Adv. 2014, 4, 49770; (e) Kamble, R.
B.; Gadre, S. H.; Suryavanshi, G. Tetrahedron Lett. 2015, 56, 1263; (f) Shelke, A.
M.; Suryavanshi, G. Tetrahedron Lett. 2015, 56, 6207; (g) Shelke, A. M.; Rawat,
V.; Suryavanshi, G.; Sudalai, A. Tetrahedron: Asymmetry 2012, 23, 1534.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.01.
0
05.
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Please cite this article in press as: Shelke, A. M. ; Suryavanshi, G. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.
tetasy.2016.01.005