Stereoselective syntheses of siphonarienal and siphonarienone

Article abstract of DOI:10.1016/j.tetasy.2015.07.001

Abstract The asymmetric total synthesis of marine polypropionate natural products siphonarienal and siphonarienone has been achieved from a common precursor 3. The key transformations of this synthesis are the diastereoselective oxidative kinetic resoluti

Full text of DOI:10.1016/j.tetasy.2015.07.001

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective syntheses of siphonarienal and siphonarienone
Supriya Ghanty a,b, Chinta Krinda Suresh Kumar a, B. V. Subba Reddy a,
⇑
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
b An Associate Institution of University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric total synthesis of marine polypropionate natural products siphonarienal and
siphonarienone has been achieved from a common precursor 3. The key transformations of this synthesis
are the diastereoselective oxidative kinetic resolution, Wittig olefination, Grignard reaction, and Evans
asymmetric alkylation for the installation of a third stereogenic center of the target molecules from
commercially available starting materials.
Received 23 April 2015
Accepted 3 July 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
H
Polypropionate containing natural products are an important
class of biologically active molecules and efforts for the discovery
of new strategies are still continuing. Siphonarienal 1, siphonar-
ienone 2, and pectinatone can be isolated from the marine
mollusks genus Siphonaria, such as Siphonaria grisea and Siphonaria
pectinate, respectively (Fig. 1).1 These compounds are active against
Gram-positive bacteria, yeast, and various human cancer cell
lines.2 The structures of 1 and 2 were characterized by X-ray
diffraction analysis and chemical correlations.3 The members of
this class of natural products contain a (2S,4S,6S)-trimethylnonane
segment that is connected through an olefinic linker to a more
polar oxygen containing group (Fig. 1).
O
O
siphonarienal
1
2
siphonarienone
O
O
O
OH
OH
siphonarienolone
OH
pectinatone
OR
OH
COOH
However, many of the earlier syntheses of these compounds
employed either iterative alkylation or a diastereoselective aldol
reaction.4 Other methods include the Zr-catalyzed asymmetric
carboalumination,5 iterative application of CuI-Tol-BINAP-catalyzed
asymmetric conjugate addition,6 Burgess’s Ir-catalyzed hydrogena-
tion,7 and Feringa’s Josiphos-catalyzed conjugate addition8 by
employing a desymmetrization strategy, which involves the asym-
metric hydroboration of a known meso-olefin using (À)-IPC2BH
(diisopinocamphenyl-borane), PCC (@pyridinium chlorochromate),
and Baeyer–Villiger oxidation reaction to set the stereochemistry
of the trimethylnonyl unit,9 and desymmetrization of meso-diol
using Lipase-AK and vinyl acetate conditions.10 However, herein
we describe the utilization of a diastereoselective oxidative kinetic
resolution using glucose oxidase from Aspergillus niger and an
Evans asymmetric alkylation, which is an attractive method for
the installation of methyl centers.
TMC-151A
R = β-mannosyl
Figure 1. Representative examples of deoxypolypropionates.
2. Results and discussion
Our retrosynthetic plan for the synthesis of siphonarienal 1 and
siphonarienone 2 is depicted in Scheme 1. The synthesis of 1 and 2
could be achieved by the functional group transformation of a key
intermediate 3. Compound 3 can be accessed from alcohol 13 via
simple oxidation and Wittig olefination. Intermediate 13 was
expected to be synthesized from 6 in a stereoselective manner
involving a Wittig reaction, Evans asymmetric alkylation and
Grignard reaction. Compound 6 can in turn be synthesized from
the commercially available (R)-methyl 3-hydroxy-2-methyl
propionate involving simple protection, oxidation and Wittig
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
http://dx.doi.org/10.1016/j.tetasy.2015.07.001
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ghanty, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.001

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S. Ghanty et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 1
H
Product distribution in the oxidative kinetic resolution of alcohol 5 by glucose oxidase
enzyme
O
1
2
EtO
Time (h)
Yield of
Yield of
acid 7 (%)
Yield of
aldehyde (%)
alcohol 6a (%)
O
3
1.0
2.0
3.0
5.0
35
48
70
80
30
46
20
17
10
<5
<5
O
Traces
a
Yield refers to pure products after chromatography.
TBDPSO
OH
TBDPSO
OH
6
13
over two steps. Chemoselective reduction of the olefinic bond with
Pd/C in EtOAc afforded the saturated ester 9 in 96% yield, which
was then hydrolyzed under basic conditions to furnish the corre-
sponding carboxylic acid 10 in 93% yield. The coupling of 10 with
Evans’ chiral oxazolidinone using pivaloyl chloride in the presence
of Et3N and LiCl gave the required compound 11 in 93% yield.
Methylation of the Na-enolate of 11 with MeI gave the desired
compound 12 with a diastereoselectivity of 97:3,15 which was
confirmed by 1H NMR. Treatment of compound 12 with NaBH4 in
MeOH gave the chiral alcohol 13 in 92% yield with three stere-
ogenic centers (Scheme 3). The primary alcohol 13 was converted
into tosylate using TsCl, Et3N followed by Grignard reaction with
EtMgBr in THF at À20 °C in the presence of a catalytic amount of
Li2CuCl4 to furnish product 14 in 85% yield.16
TBDPSO
O
O
Scheme 1. Retrosynthetic analysis of siphonarienal 1 and siphonarienone 2.
olefination, reduction, and diastereoselective oxidative kinetic
resolution using glucose oxidase from Aspergillus niger.
The synthesis of siphonarienal 1 and siphonarienone 2 started
from the known precursor 4, which is available in three steps from
the commercially available (R)-methyl 3-hydroxy-2-methylpropi-
onate.11 Ester 4 was transformed into alcohol 5 (as a 1:1 diastere-
omeric mixture) in 88% yield (Scheme 2).12 In an earlier report, the
selective oxidation of the alcohol was performed using whole cells
Gluconobacter oxydans.13 This procedure was cumbersome and
requires a microbiologist to grow the cells, which are not commer-
cially available. Since the reaction is apparently catalyzed by
glucose oxidase, we performed the oxidation with commercially
available glucose oxidase derived from Aspergillus niger. The
oxidation proceeds selectively to give the aldehyde, which
spontaneously oxidizes into carboxylic acid 7 during the reaction.
At the end of the reaction, the desired alcohol 6 was obtained in
48% yield.
Deprotection of the silyl group in compound 14 using TBAF in
THF gave the primary alcohol 15 in 95% yield. Oxidation of alcohol
15 provided the required aldehyde, which was then subjected to
C3 Wittig olefination with (1-carbethoxyethylidene)-triph-
enylphosphorane to give the a,b-unsaturated ester 3 [(E)-isomer],
as the major product in 88% yield over two steps,17 which is a com-
mon precursor for the synthesis of two natural products 1 and 2.
Partial reduction of unsaturated ester 3 with DIBAL-H at À78 °C
provided directly the target molecule siphonarienal 1. For the
synthesis of siphonarienone 2, the
a,b-unsaturated ester 3 was
directly converted into the corresponding Weinreb amide using
MeNHOMeÁHCl and i-PrMgCl, which upon treatment with
EtMgBr in THF provided the siphonarienone in 80% yield over
two steps (Scheme 4). Spectroscopic data of both natural products
1 and 2 were in good agreement with those reported in the
literature.4d,6,9,18
For our synthetic exercise, we required chiral precursor 6.
Therefore, the oxidation was stopped after a 2 h interval. Chiral
alcohol
6
is known in the literature.13a,14 and its absolute
stereochemistry was confirmed by comparing its specific rotation
with an authentic sample. The undesired acid 7 can be converted
back into alcohol 5 using the literature procedure13a (Table 1).
Subsequent oxidation of alcohol 6 followed by chain elongation
by C2 Wittig olefination with (ethoxycarbonylmethylene)triph-
3. Conclusion
In conclusion we have demonstrated the asymmetric total
syntheses of siphonarienal and siphonarienone from commercially
available starting materials. The key transformations of these
syntheses are the Wittig olefination, diastereoselective oxidative
kinetic resolution using Glucose oxidase derived from Aspergillus
niger, Evans asymmetric alkylation, and Grignard reaction. This
approach further illustrates the application of oxidative kinetic
resolution for the synthesis of deoxypolypropionate units. Further
work is currently in progress to synthesize the other members of
this family.
enylphosphorane gave the
a,b-unsaturated ester 8 in 86% yield
TBDPSO
O
HO
O
i
ref 11
O
O
4
ii
TBDPSO
OH
O
TBDPSO
OH
4. Experimental
4.1. General
6
5
TBDPSO
OH
Reagents and solvents were obtained from commercial sources
and dried prior to use. Glucose Oxidase from Aspergillus niger was
purchased from Sigma Aldrich. All reactions were performed in
oven dried glassware under an inert atmosphere of nitrogen. All
reactions were monitored by thin-layer chromatography (TLC)
using UV light as visualizing agent and/or by exposure to Iodine
TBDPSO
+
+
O
H
7
Scheme 2. Kinetic resolution of alcohol 5. Reagents and conditions: (i) (a) Mg,
MeOH, rt, 12 h; (b) LAH, Et2O, 0–25 °C, 2 h; (ii) glucose oxidase, phosphate buffer
pH = 8, DCM, 25 °C, 2 h.
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S. Ghanty et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
i
ii
TBDPSO
TBDPSO
OH
TBDPSO
OEt
O
8
6
iv
iii
TBDPSO
OH
OEt
O
O
O
9
10
Ph
N
Ph
v
O
O
TBDPSO
TBDPSO
N
O
O
O
12
11
vi
TBDPSO
OH
13
Scheme 3. Synthesis of alcohol 13. Reagents and conditions: (i) (a) TPAP, NMO, CH2Cl2, 0.5 h; (b) Ph3PCHCO2Et, C6H6, 80 °C, 12 h; (ii) Pd/C, H2, AcOEt, 2 h; (iii) LiOHÁH2O,
MeOH/H2O (4:1) 2 h; (iv) (R)-4-benzyl-oxazolidin-2-one, Piv-Cl, Et3N, LiCl, THF, À20 to 0 °C, 3 h; (v) NaHMDS, MeI, À78 °C, THF; (vi) NaBH4, MeOH, 0–25 °C.
4.1.1. (S,E)-Ethyl 5-((tert-butyldiphenylsilyl)oxy)-2,4-dimethyl-
pent-2-enoate 4
i
TBDPSO
OH
TBDPSO
Compound 4 was synthesized by using the procedures reported
14
13
in Ref. 11. [
a]
D
25 = À2.6 (c 1.1, CHCl3). 1H NMR (CDCl3, 300 MHz): d
7.61–7.55 (m, 4H), 7.38–7.28 (m, 6H), 6.52 (dd, J = 1.4, 9.9 Hz, 1H),
4.15–4.07 (m, 2H), 3.50–3.45 (m, 2H), 2.71–2.63 (m, 1H), 1.73 (d,
J = 1.4 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.97 (s, 9H), 0.96 (d,
J = 6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 168.2, 144.4, 135.6,
133.6, 129.6, 127.6, 67.7, 60.4, 36.1, 26.8, 19.2, 16.3, 14.3, 12.6;
iii
ii
HO
15
H
O
IR (KBr):
m 3050, 2859, 2858, 1716, 1680, 1509, 1465, 1428,
iv
v
1267, 1083, 740, 701 cmÀ1; HRMS (m/z) calcd for C25H34O3NaSi:
1
2
433.21694; found: 433.21747.
EtO2C
3
4.1.2. (2R,4S)-5-(tert-Butyldiphenylsilyl)oxy)-2,4-dimethylpental-
1-ol 6
O
At first, magnesium turnings (2.92 g, 122.0 mmol) were added
to the unsaturated ester 4 (5 gm, 12.2 mmol) in anhydrous
MeOH (100 mL). Gas evolution was observed after 25 min of stir-
ring and after four hours, all of the magnesium turnings were dis-
solved and a white precipitate had formed. Next, the reaction
mixture was cooled to 0 °C and dilute HCl (200 mL, 2.5 M) was
added to dissolve the solid, which was followed by extraction with
diethyl ether (3 Â 150 mL). The combined ether extracts were
washed with sat. NaHCO3 (50 mL) and brine (50 mL), then dried
over MgSO4 and concentrated in vacuo and purified on silica gel
chromatography (EtOAc/Hexane, 1:19) of the crude product to
afford a mixture of methyl and ethyl esters, which were taken up
in anhydrous diethyl ether (30 mL) and reduced immediately with
LAH (1.4 g, 36.6 mmol) in anhydrous ether (30 mL) at 0 °C. After
2 h of stirring, the mixture was diluted with ether (50 mL) and
quenched by the slow addition of a saturated aq Na2SO4 solution
(15 mL). When the effervescence subsided, the reaction mixture
was filtered through a pad of Celite and washed with hot ethyl
acetate (60 mL). The filtrate was evaporated in vacuo and the resi-
due was purified by column chromatography (EtOAc/Hexane, 1:3)
to furnish compound 5 (2 isomer, 3.97 g, 88% over 2 steps) as a col-
orless liquid. To a stirred solution of alcohol 5 (3.97 g, 10.74 mmol)
in DCM (30 mL), phosphate buffer (25 ml, pH = 8, 0.1 M) and
800 mg of glucose oxidase enzyme were added at 25 °C. The bio-
transformations were monitored periodically by TLC analysis.
Scheme 4. Synthesis of siphonarienal
1 and siphonarienone 2. Reagents and
conditions: (i) (a) TsCl, DCM, Et3N, DMAP; (b) EtMgBr, Li2CuCl4, THF, À20 °C; (ii)
TBAF, THF, 2 h; (iii) (a) TPAP, NMO, CH2Cl2, 0.5 h; (b) Ph3PC(Me)CO2Et, C6H6, 80 °C;
(iv) DIBAL-H, CH2Cl2, À78 °C; (v) (a) MeNHOMeÁHCl, i-PrMgCl, THF, À20 °C, 1.5 h;
(b) EtMgBr, THF, rt, 45 min.
vapors and/or by spraying with p-anisaldehyde/H2SO4 reagent fol-
lowed by heating at ca. 60 °C. Column chromatographic separa-
tions were carried out on silica gel (60–120 mesh) and flash
chromatographic separations were carried out using 230–400
mesh silica gel using a mixture of ethyl acetate–hexane as eluent.
Infrared spectra were recorded on Perkin–Elmer FT-IR 240-c
spectrophotometer using KBr optics. NMR spectra were recorded
in CDCl3 on Bruker NMR instrument operating at 1H NMR
(300 MHz) and 13C NMR (75 MHz). Chemical shifts (d) are quoted
in parts per million and are internally referenced (0.0 ppm for
TMS for 1H NMR and 77.0 ppm for 13C NMR). Coupling constants
(J) are quoted in Hertz. The following abbreviations are used to
designate signal multiplicity: s = singlet, d = doublet, dd = doublet
of doublet, t = triplet, q = quartet, m = multiplet and br = broad.
Mass spectra were recorded on Micromass VG-7070H for EI and
VG Autospec M for FABMS. Optical rotations of the products were
recorded on Digipol-781 M6U Polarimeter.
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S. Ghanty et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
After two hours, the aqueous phase was extracted with DCM
(3 Â 50 mL). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
Column chromatographic separation on silica gel (Hexane/EtOAc,
washed with saturated aq NH4Cl solution and extracted with
EtOAc (3 Â 20 mL). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated under reduced pres-
sure. Removal of solvent followed by column chromatography
(EtOAc/hexane, 1:5) to afford the acid 10 (1.23 g, 93% yield) as a
3:1) afforded pure compound 6 (1.91 g, 48% yield). [
a]
25 = +1.75
D
(c 0.25, CHCl3); Lit [
a]
25 = +1.8 (c 0.23, CHCl3); 1H NMR (CDCl3,
colorless liquid. [a]
25 = +8.0 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
D
300 MHz): d 7.71–7.60 (m, 4H), 7.48–7.34 (m, 6H), 3.56–3.30 (m,
4H), 1.80–1.56 (m, 2H), 1.51–1.39 (m, 2H), 1.06 (s, 9H), 0.95 (d,
J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,75 MHz):
d 135.5, 133.8, 129.4, 127.5, 68.6, 67.9, 37.1, 32.9, 26.8, 17.8,
300 MHz): d 7.71–7.62 (m, 4H), 7.45–7.34 (m, 6H), 3.53–3.37 (m,
2H), 2.41–2.22 (m, 2H), 1.80–1.30 (m, 6H), 1.05 (s, 9H), 0.92 (d,
J = 6.6 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 180.4, 135.6, 134.0, 129.8, 127.5, 68.8, 40.7, 33.1, 31.6, 31.3,
17.3; IR (KBr)
m
3455, 2931, 2856, 1110, 1091, 702 cmÀ1; HRMS
29.6, 26.9, 19.8, 19.3; IR (KBr):
1246, 1101, 912, 830, 768 cmÀ1
25H36O3NaSi: 435.23314; found 435.23238.
m
2956, 2926, 2860, 1710, 1495,
(m/z) calcd for C23H34O2NaSi: 393.22203; found: 393.22189.
;
HRMS (ESI): calcd for
C
4.1.3. (4R,6S,E)-Ethyl 7-((tert-butyldiphenyl silyl)oxy)-4,6-dime-
thylhept-2-enoate 8
4.1.6. (R)-4-Benzyl-3-((4S,6S)-7-((tert-butyl diphenylsilyl)oxy)-4,
6-dimethyl heptanoyl)oxazolidin-2-one 11
To a stirred solution of alcohol 6 (1.50 g, 4.05 mmol) and
activated powder 4 Å molecular sieves (2 g) in anhydrous
CH2Cl2 (40 ml) at 0 °C were added tetrapropylammonium
perruthenate(VII), (70 mg, 0.2 mmol) and 4-methylmorpholine-
N-oxide (700 mg, 6 mmol). The reaction mixture was stirred
under argon for 30 min and filtered through a short pad of silica
eluting with ethyl acetate to yield the aldehyde. To this crude
aldehyde in benzene (20 mL) was added the stabilized
ylide Ph3PCHCO2CH2CH3 (2.10 g, 6.0 mmol) and the reaction
mixture was stirred overnight at 80 °C temperature. The reaction
mixture was then concentrated under reduced pressure and
purified on silica gel chromatography (EtOAc/Hexane, 1:19) to
afford the unsaturated ester 8 (1.51 g, 86% over two steps) as a
To a stirred solution of acid 10 (1.20 g, 2.91 mmol) in THF
(15 mL) at À20 °C was added Et3N (0.9 mL, 7.3 mmol) followed
by PivCl (0.4 mL, 2.91 mmol) under a nitrogen atmosphere. After
stirring for 1 h at À20 °C, LiCl (183 mg, 4.37 mmol) followed by
(R)-1,3-oxazolidin-2-one (560 g, 3.2 mmol) were added at the
same temperature. The stirring was continued for 1 h at À20 °C
and then 2 h at 0 °C. It was then quenched with saturated NH4Cl
solution (10 mL) and extracted with ethyl acetate (3 Â 25 mL).
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatogra-
phy using ethyl acetate and hexane (1:16) to give 11 (1.54 g, 93%)
colorless liquid. [
a]
D
25 = +25.5 (c 1.0, CHCl3); 1H NMR (CDCl3,
as a pale yellow liquid. [a]
25 = +40.0 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
300 MHz): d 7.70–7.62 (m, 4H), 7.46–7.32 (m, 6H), 6.80 (dd,
J = 15.7, 8.3 Hz, 1H), 5.78 (d, J = 15.7 Hz, 1H), 4.19 (q, J = 7.2 Hz,
2H), 3.50–3.40 (m, 2H), 2.46–2.30 (m, 1H), 1.74–1.48 (m, 3H),
1.29 (t, J = 7.2 Hz, 3H), 1.05 (s, 9H), 1.02 (d, J = 6.6 Hz, 3H), 0.89
(d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 166.8, 154.4,
135.6, 133.9, 129.5, 119.7, 68.9, 60.1, 39.8, 34.1, 33.3, 26.8, 20.4,
300 MHz): d 7.71–7.63 (m, 4H), 7.45–7.16 (m, 11H), 4.72–4.60 (m,
1H), 4.24–4.11 (m, 2H), 3.91–3.83 (m, 1H), 3.52 (dd, J = 5.3, 9.6 Hz,
1H), 3.41 (dd, J = 6.6, 9.8 Hz, 1H), 3.29 (dd, J = 3.2, 13.4 Hz, 1H),
304–2.78 (m, 2H), 2.72 (dd, J = 9.6, 13.2 Hz, 1H), 1.86–1.33 (m,
4H), 1.30–1.21 (m, 2H), 1.05 (s, 9H), 0.95 (d, J = 6.8 Hz, 3H), 0.88
(d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 173.6, 153.3,
135.6, 133.9, 129.4, 128.9, 127.5, 127.3, 68.8, 66.0, 55.1, 40.9,
19.2, 16.7, 14.2; IR (KBr):
1264, 1108, 1047, 821, 704, 506 cmÀ1; HRMS (m/z) calcd for
27H38O3NaSi: 461.24824; found: 461.24742.
m 2928, 2856, 1725, 1664, 1464, 1374,
37.8, 33.2, 33.0, 30.9, 29.6, 26.8, 19.9, 19.3, 17.6; IR (KBr):
2925, 2855, 1783, 1698, 1457, 1385, 1352, 1273, 1195, 1106,
770, 702 cmÀ1
HRMS (ESI): calcd for C35H45NO4Si Na:
m
C
;
4.1.4. (4S,6S)-Ethyl 7-((tert-butyldiphenylsilyl)oxy)-4,6-dimethyl-
heptanoate 9
594.30101; found 594.29941.
To a stirred solution of compound 8 (1.50 g, 3.42 mmol) in
AcOEt (10 mL) was added Pd/C (10%, 20 mg) and subjected to
hydrogenation under atmospheric pressure using H2-filled balloon.
The reaction was monitored by TLC. After complete consumption
of the starting material, the reaction mixture was filtered through
a pad of Celite and the filtrate was concentrated in vacuo and
purified on silica gel chromatography (EtOAc/Hexane, 1:19) to
afford the saturated ester 9 (1.44 g, 96% yield) as colorless liquid.
4.1.7. (R)-4-Benzyl-3-((2R,4R,6S)-7-((tert-butyldiphenylsilyl)oxy)-
2,4,6-trimethyl heptanoyl)oxazolidin-2-one 12
A flame dried 100 mL round bottom flask was charged with 11
(1.5 g, 2.63 mmol) and 25 mL anhydrous THF. The solution was
cooled to À78 °C, NaHMDS (1 M solution in THF, 4.0 mL, 4.0 mmol)
was added dropwise with stirring under a nitrogen atmosphere.
After 30 min of stirring, MeI (0.33 mL, 5.26 mmol) was added drop-
wise to the reaction mixture and then stirring was continued for
another 2 h at À78 °C. The mixture was then quenched with satu-
rated NH4Cl (15 mL), warmed to room temperature, and then
extracted with ethyl acetate (3 Â 50 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography using ethyl acetate
and hexane (1:19) to afford product 12 (1.43 g, 93%) as colorless
[a]
25 = +5.4 (c = 1.0 in CHCl3); 1H NMR (CDCl3, 300 MHz):
D
d 7.70–7.62 (m, 4H), 7.46–7.34 (m, 6H), 4.11 (q, J = 7.2 Hz, 2H),
3.55–3.37 (m, 2H), 2.36–2.18 (m, 2H), 1.80–1.62 (m, 2H),
1.53–1.32 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H), 1.05 (s, 9H), 0.92 (d,
J = 6.7 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d 174.0, 135.6, 129.4, 127.5, 68.8, 60.1, 40.7, 33.0, 31.8, 31.5,
29.6, 26.8, 19.9, 17.5, 14.2; IR (KBr):
m 2928, 2856, 1738, 1464,
1430, 1372, 1254, 1107, 1054, 703, 612, 507 cmÀ1; HRMS (m/z)
liquid. [a]
25 = +42.8 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d
D
calcd for C27H40O3NaSi: 463.26389; found: 463.26295.
7.71–7.62 (m, 4H), 7.45–7.18 (m, 11H), 4.67–4.60 (m, 1H), 4.14
(d, J = 5.3 Hz, 2H), 3.91–3.83 (m, 1H), 3.50 (dd, J = 5.3, 9.7 Hz, 1H),
3.41 (dd, J = 6.6, 9.6 Hz, 1H), 3.24 (dd, J = 3.2, 13.3 Hz, 1H), 2.75
(dd, J = 9.6, 13.5 Hz, 1H), 1.95–1.77 (m, 3H), 1.50–1.32 (m, 3H),
1.20 (d, J = 6.7 Hz, 3H), 1.05 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.83
(d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 177.2, 152.9,
135.6, 134.0, 129.4, 128.8, 127.5, 127.3, 69.1, 65.9, 55.2, 41.5,
40.5, 37.8, 35.3, 33.0, 29.7, 28.1, 26.8, 20.5, 19.3, 18.7, 17.6; IR
4.1.5. (4S,6S)-7-((tert-Butyldiphenylsilyl)oxy)-4,6-dimethylhep-
tanoic acid 10
To a stirred solution of ester 9 (1.40 g, 3.18 mmol) in 25 mL of
CH3OH/H2O (4:1) was added portion wise LiOHÁH2O (400 mg,
9.60 mmol) at 0 °C after which stirring was continued for 2 h at
room temperature. The reaction mixture was then concentrated
in vacuo and the residue was diluted with EtOAc (20 mL) and
(KBr):
m 2957, 2923, 2853, 1783, 1699, 1460, 1385, 1351, 1218,
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S. Ghanty et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
1109, 772, 703, 613 cmÀ1; HRMS (ESI): calcd for C36H47NO4SiNa:
608.31666; found 608.31370.
chromatography using ethyl acetate/hexane mixture (1:9) to yield
compound 15 (313 mg, 95% yield) as a colorless oil. [
a
]
25 = À12.0 (c
D
1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 3.50 (dd, J = 5.3, 10.6 Hz,
1H), 3.34 (dd, J = 6.8, 10.6 Hz, 1H), 1.78–1.64 (m, 2H), 1.62–1.43 (m,
2H), 1.40–1.10 (m, 6H), 0.92 (d, J = 6.8 Hz, 3H), 0.90–0.82 (m, 10H);
13C NMR (CDCl3, 75 MHz): d 68.2, 45.1, 41.2, 38.8, 33.0, 29.7, 27.5,
4.1.8. (2R,4S,6S)-7-((tert-Butyldiphenylsilyl)oxy)-2,4,6-trimethyl-
heptan-1-ol 13
To a stirred solution of 12 (1.4 g, 2.4 mmol) in MeOH (10 mL)
was added NaBH4 portionwise (274 mg, 7.2 mmol) at 0 °C. The
reaction mixture was allowed to stir for 1 h at the same tempera-
ture 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 (3 Â 30 mL).
The combined organic layers were dried over Na2SO4 and concen-
trated under reduced pressure, after which the crude product was
purified by silica gel column chromatography (EtOAc/hexane, 1:9)
to afford pure product 13 (910 mg, 92%) as a viscous liquid.
20.9, 20.4, 19.9, 17.5, 14.4; IR (KBr):
m
.
3449, 2955, 2919, 2857,
HRMS (ESI): calcd for
1637, 1457, 1371, 1101, 760 cmÀ1
C12H26ONa: 209.18813; found 209.18890.
4.1.11. (4S,6S,8S,E)-Ethyl 2,4,6,8-tetramethyl undec-2-enoate 3
To a stirred solution of alcohol 15 (300 mg, 1.61 mmol) and
activated powder 4 Å molecular sieves (800 mg) in anhydrous
CH2Cl2 (15 ml) at 0 °C were added tetrapropyl ammonium
perruthenate(VII), (28 mg, 0.08 mmol) and 4-methylmorpholine-
N-oxide (283 mg, 2.4 mmol). The mixture was stirred under argon
for 30 min and then filtered through a short pad of silica eluting
with ethyl acetate to yield the aldehyde. To this crude aldehyde
in benzene (10 mL) was added the stabilized ylide
Ph3PC(Me)CO2CH2CH3 [(1-carbethoxyethylidene)-triphenylphos-
phorane] (875 mg, 2.14 mmol) and resulting mixture was stirred
overnight at 80 °C. The reaction mixture was concentrated under
reduced pressure and purified on silica gel chromatography (3%
EtOAc/hexane) to afford the unsaturated ester 3 (378 mg, 88% over
[
a
]
25 = À6.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.70–
D
7.63 (m, 4H), 7.45–7.34 (m, 6H), 3.54–3.45 (m, 2H), 3.44–3.30
(m, 2H), 1.79–1.64 (m, 2H), 1.41–1.18 (m, 5H), 1.05 (s, 9H), 0.93
(d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d 135.6, 134.0, 129.5, 127.6, 68.7, 68.2,
41.8, 41.2, 33.2, 27.7, 26.9, 21.0, 18.1, 17.6, 16.5. IR (KBr):
m 3019,
2957, 2928, 2857, 1466, 1428, 1364, 1216, 1109, 1033, 823, 771,
667 cmÀ1. HRMS (ESI): calcd for C26H40O2SiNa: 435.26898; found
435.27008.
two steps) as a colorless liquid. [a]
25 = +18.1 (c 0.9, CHCl3); 1H NMR
D
4.1.9. tert-Butyldiphenyl(((2S,4S,6S)-2,4,6-trimethylnonyl)oxy)
silane 14
(CDCl3, 300 MHz): d 6.45 (d, J = 10.2 Hz, 1H) 4.28–4.11 (m, 2H),
2.68–2.53 (m, 1H), 1.84 (s, 3H), 1.54–1.14 (m, 10H), 0.99 (d,
J = 6.6 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.86–0.76 (m, 9H); 13C
NMR (CDCl3, 75 MHz): d 168.3, 148.0, 126.2, 60.2, 45.5, 44.3,
A solution of alcohol 13 (0.9 g, 2.18 mmol) in dry CH2Cl2
(15 mL) and dry triethylamine (0.4 mL, 2.6 mmol) was cooled at
0 °C, after which was added p-toluenesulfonyl chloride (414 mg,
2.18 mmol). The resulting mixture was stirred at room tempera-
ture for 3 h. After complete conversion as confirmed by TLC, the
mixture was quenched with NH4Cl solution and then extracted
with EtOAc (3 Â 15 mL). Removal of the solvent followed by purifi-
cation on silica gel column chromatography (ethyl acetate/hexane,
1:19) gave the pure tosyl derivative. To a stirred solution of acti-
vated Mg-turnings (178 mg, 7.4 mmol) in anhydrous diethyl ether
(6 mL), ethyl bromide (0.6 mL, 7.63 mmol) was added slowly. After
the complete addition, the mixture was then heated at reflux
(ꢀ30 min) until initiation of the reaction. After disappearance of
the metal, this solution was transferred via a cannula to a solution
containing tosylate (1.166 g, 2.06 mmol) in dry diethyl ether
(20 mL) at À20 °C under a nitrogen atmosphere. To this mixture,
a solution of Li2CuCl4 (0.1 M in tetrahydrofuran, 0.2 mL, 0.2 mmol)
was slowly added. The resulting mixture was stirred vigorously
overnight at room temperature and then quenched with saturated
aqueous NH4Cl (10 mL) at 0 °C and then extracted with diethyl
ether (3 Â 20 mL). Removal of the solvent under reduced pressure
followed by column chromatography (Pentane:Et2O, 5:1) gave
39.3, 30.8, 29.6, 28.1, 20.5, 20.4, 19.9, 14.3, 14.2, 12.4; IR (KBr):
3453, 2958, 2925, 1711, 1648, 1460, 1378, 1102, 1035, 760,
667 cmÀ1
HRMS (ESI) calcd for C17H32O2 268.23968; found
268.23968.
m
;
4.1.12. (4S,6S,8S,E)-2,4,6,8-Tetramethyl-2-undecenal (siphonar-
ienal) 1
To a cooled (À78 °C) solution of 3 (185 mg, 0.69 mmol) in dry
CH2Cl2 (5 mL), DIBAL-H (0.75 mL, 0.75 mmol, 20% solution in
toluene) was added slowly. The resulting mixture was allowed to
stir for 30 min at À78 °C. The reaction was quenched with sat.
solution of sodium potassium tartarate (5 mL). The reaction
mixture was then stirred vigorously at room temperature until a
clear biphasic separation was observed. The aqueous layer was
extracted with CH2Cl2 (3 Â 10 mL) and the combined organic
layers were concentrated in vacuo. Purification of the residue by
column chromatography (EtOAc/hexane, 1:30) gave siphonarienal
1 (247 mg, 80%) as a colorless liquid. [
a]
25 = +16.1 (c 1.1, CHCl3).
D
Lit. [a
]
D
30 = +16.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 9.39
(s, 1H), 6.23 (d, J = 9.8 Hz, 1H), 2.92–2.75 (m, 1H), 1.77 (s, 3H),
1.55–1.10 (m, 7H), 1.05 (d, J = 6.0 Hz, 3H), 0.95–0.77 (m, 12H);
13C NMR (CDCl3, 75 MHz): d 195.5, 160.7, 137.9, 45.6, 44.2, 39.2,
product 14 as a colorless liquid (786 mg, 85% yield). [
a
]
25 = À7.0
D
(c 1.07, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.68–7.54 (m, 4H),
7.40–7.25 (m, 6H), 3.45–3.29 (m, 2H), 1.85–1.75 (m, 1H),
1.72–1.60 (m, 2H), 1.44–1.09 (m, 6H), 0.98 (s, 9H), 0.91 (d,
J = 6.4 Hz, 3H), 0.89–0.84 (m, 5H), 0.82 (d, J = 6.6 Hz, 3H), 0.76 (d,
J = 6.3 Hz, 3H) 13C NMR (CDCl3, 75 MHz): d 135.6, 134.0, 129.5,
127.5, 69.4, 43.2, 41.3, 40.4, 33.1, 32.4, 32.2, 27.5, 27.3, 26.9,
32.2, 29.6, 28.2, 20.5, 20.3, 20.0, 19.9, 14.3, 9.3; IR (neat):
m 2956,
2925, 2910, 2871, 2705, 1691, 1644, 1457, 1378, 1008, 807 cmÀ1
;
MS (ESI): m/z = 225 (M+H)+.
4.1.13. [(6S,8S,10S,E)-4,6,8,10-Tetramethyl tridec-4-3-one] (sipho-
narienone) 2
20.6, 19.9, 19.7, 19.3, 17.8, 16.6. IR (KBr):
m 2958, 2928, 2857,
1464, 1428, 1380, 1363, 1219, 1110, 824, 772, 703, 614 cmÀ1
HRMS (ESI): calcd for C28H45OSi: 425.32396; found 425.32340.
.
To a stirred solution of 3 (185 mg, 0.69 mmol) and N,O-
dimethylhydroxylamineÁhydrochloride (MeONHMeÁHCl) (202 mg,
i
2.07 mmol) in dry THF (5 mL) at À20 °C was added PrMgCl solu-
4.1.10. (2S,4S,6S)-2,4,6-Trimethylnonan-1-ol 15
tion (2 M solution in THF, 1.15 mL, 3.0 mmol) slowly. After 1.5 h,
the reaction was quenched satd NH4Cl solution and the aqueous
layer was extracted with Et2O (3 Â 10 mL). The combined organic
extracts were washed with brine, dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. Without further purifi-
cation, a solution of Weinreb amide containing residue was used
To a stirred solution of 14 (750 mg, 1.77 mmol) in dry THF
(15 mL), was added TBAF (1 M solution in THF, 5.3 mL, 5.3 mmol)
under a nitrogen atmosphere. The resulting reaction mixture was
stirred for 5 h and then concentrated under reduced pressure.
The crude product was purified by silica gel column
Please cite this article in press as: Ghanty, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.001

6
S. Ghanty et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3. Garson, M. J.; Small, C.; Skelton, B. W.; Thinapong, P.; White, A. H. J. Chem. Soc.,
Perkin Trans. 1 1990, 805–807.
for the next step. To a stirred solution of this in dry THF (5 mL) was
added EtMgBr (3 M solution in Et2O, 1.15 mL, 3.45 mmol) at 0 °C
under a nitrogen atmosphere. The reaction mixture was stirred
for 45 min at room temperature. After completion of the reaction,
it was quenched with satd NH4Cl solution. The aqueous layer was
extracted with Et2O (3 Â 10 mL), and the combined organic
extracts were washed with brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The resulting residue was
purified by column chromatography (ethyl acetate/hexane, 1:30)
gave the siphonarienone (2) (139 mg, 80%) as a colorless oil.
4. (a) Birkbeck, A. A.; Enders, D. Tetrahedron Lett. 1998, 39, 7823–7826; (b) Abiko,
A.; Masamune, S. Tetrahedron Lett. 1996, 37, 1081–1084; (c) Galeyeva, Y.; Morr,
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Calter, M. A.; Liao, W.; Struss, J. A. J. Org. Chem. 2001, 66, 7500–7504.
5. Magnin, L. M.; Tan, Z.; Liang, B.; Negishi, E. Org. Lett. 2004, 6, 1425–1427.
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7. (a) Zhou, J.; Burgess, K. Angew. Chem., Int. Ed. 2007, 46, 1129–1131; (b) Zhou, J.;
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8. Wang, S.-Y.; Lum, T.-K.; Ji, S.-J.; Loh, T.-P. Adv. Synth. Catal. 2008, 350,
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[a] a]
25 = +22.4 (c 1.0, CHCl3); Lit. [ 30 = +26.4 (c 1.5, CHCl3); 1H
9. Sabitha, G.; Gopal, P.; Yadav, J. Tetrahedron: Asymmetry 2009, 20, 2205–2210.
10. (a) Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 66, 493–502; (b) Wang, Y. F.;
Chen, C. S.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1984, 106, 3695–3696; (c)
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D
D
NMR (CDCl3, 300 MHz): d 6.34 (dd, J = 9.6, 1.2 Hz, 1H), 2.75–2.64
(m, 3H), 1.80 (s, 3H), 1.54–1.15 (m, 10H), 1.10 (t, J = 7.3 Hz, 3H),
1.0 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H), 0.83 (d, J = 6.4 Hz,
3H), 0.81 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 202.8,
148.2, 135.3, 45.5, 44.5, 39.3, 31.2, 30.3, 29.6, 28.2, 20.7, 20.4,
19.9, 14.4, 11.5, 8.9; IR (neat):
m 3451, 2960, 2940, 2871, 2844,
1700, 1650, 1450, 1360, 1250, 1050, 790 cmÀ1
; MS (ESI):
m/z = 253 (M+H)+.
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S.G and CHSK thank the CSIR-New Delhi, India, for the award
of fellowships. Authors thank Dr. Nitin W. Fadnavis,
Biotransformation Laboratory, Indian Institute of Chemical
Technology, Hyderabad for his helpful discussion on oxidative
kinetic resolution.
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Please cite this article in press as: Ghanty, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.001