Total synthesis of the marine polypropionates, siphonarienal, siphonarienone, and pectinatone

Article abstract of DOI:10.1016/j.tetasy.2009.08.021

The synthesis of the marine natural products, siphonarienal, siphonarienone, and pectinatone is described employing desymmetrization strategy to create three consecutive stereogenic centers. The key intermediate 7 was made by asymmetric hydroboration of t

Full text of DOI:10.1016/j.tetasy.2009.08.021

Tetrahedron: Asymmetry 20 (2009) 2205–2210
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of the marine polypropionates, siphonarienal,
siphonarienone, and pectinatone
*
Gowravaram Sabitha , Peddabuddi Gopal, Jhillu S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2009
Accepted 20 August 2009
Available online 26 September 2009
The synthesis of the marine natural products, siphonarienal, siphonarienone, and pectinatone is described
employing desymmetrization strategy to create three consecutive stereogenic centers. The key intermedi-
ate 7 was made by asymmetric hydroboration of the known meso-olefin using (ꢀ)-IPC2BH followed by PCC
and Baeyer-Villiger oxidation reactions.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
H
Marine mollusks of the genus Siphonaria are a rich source of poly-
propionates,1 polyether antibiotics,2 and macrolides.3 Natural prod-
ucts derived from marine mollusks have gained interest due to their
bio-active secondary metabolites1,4 and their unusual structures.
Siphanarienes 1 and 2 and pectinatone 3 are marine polypropionate
natural products produced from the genus Siphonaria such as
Siphonariea grisea5 and Siphonaria pectinata,6 respectively, collected
from the intertidal region of the Mediterranean sea and Atlantic
ocean. The members of this class all contain an alternating 1,3-syn
arrangement of methyl substituents in their respective aliphatic
chains connected through an olefinic linker to a more polar oxy-
gen-containing group.7 This structural motif offers a significant
challenge for asymmetric synthesis. They are active against Gram-
positive bacteria (Staphylococcus aureus and Bacillus subtilis), yeast
(Candida albicans and Saccharomyces cervisiae), and several human
cancer cell lines.5b,8 The structures of 1–3 were established on the
basis of their spectroscopic data and X-ray diffraction analysis.5a,9
Most of the reports which have appeared for the synthesis of
these compounds mainly used iterative alkylations or diastereose-
lective aldol reactions.10–12 Other methods include the iterative
application of CuI-Tol-BINAP-catalyzed asymmetric conjugative
addition13 and Zr-catalyzed asymmetric carboalumination.14 Herein,
we report the synthesis of polypropionates 1–3 (Fig. 1) utilizing
desymmetrization strategy to set the stereochemistry of the trim-
ethylnonyl unit.
O
O
2
1
O
O
OH
3
Figure 1.
pound 2 could be prepared directly from 5, which in turn could
be prepared from 6. Compound 6 is accessible from the known pre-
cursor 7.
Our synthesis began with the known precursor 7.15 Accordingly,
allylation of 7 with allyl bromide in the presence of LHMDS in
anhydrous THF at ꢀ78 °C gave compound 8 in 94% yield. Reductive
ring opening of 8 with LAH in anhydrous THF gave triol 6 in 90%
yield. The 1,3-diol of 6 was protected as acetonide 9 using 2,2-
dimethoxypropane and a catalytic amount of CSA, in CH2Cl2/Et2O
followed by protection of the primary hydroxyl group as its benzyl
ether 10. Next, the acetonide group was hydrolyzed to yield diol 11
and the primary hydroxyl group was selectively tosylated with
TsCl, Et3N, and DMAP in CH2Cl2 to furnish monotosylate 12 fol-
lowed by reductive cleavage16 (LiAlH4, THF, 80%) of the sulfonate
leading to the formation of 13. The secondary hydroxyl group
was converted into the xanthate ester and reduced to give com-
pound 15. Oxidative removal of the PMB group using DDQ yielded
alcohol 16, which was converted to the xanthate and reduced to
provide compound 18. Debenzylation and reduction of the termi-
nal olefin were successfully achieved in one-pot using Pd/C and
H2, in HPLC grade EtOAc to give alcohol 19, which on oxidation
using IBX provided the corresponding aldehyde 5 (Scheme 2).
2. Results and discussion
The retrosynthesis is depicted in Scheme 1. Compound 1 and 3
could be obtained from 4, which could be derived from 5. Com-
* Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.021

2206
G. Sabitha et al. / Tetrahedron: Asymmetry 20 (2009) 2205–2210
phenyl-k5-phosphanylidene)-3-pentanone in refluxing anhydrous
benzene to give siphonarienone 2 in 56% yield.
EtO
1
3
To prepare target compounds 1 and 3, aldehyde 5 was subjected
to a Wittig reaction using ethyl 2-(1,1,1-triphenyl-k5-phosphany-
lidene)propanoate in refluxing anhydrous benzene to give ester
4. The ester was reduced to allylic alcohol 20 and further oxidized
to afford siphonarienal 1. Whereas treatment of ester 4 with
O
4
2
HO
i
OHC
N-methoxy, N-methyl ammonium chloride, and PrMgCl, in anhy-
5
PMBO
OH OH
drous THF, at ꢀ20 to 0 °C afforded Weinreb amide 21 in 71% yield,
which on treatment with ethyl 2-methyl-3-oxopentanoate 2217
followed by cyclization of the resulting b,d-diketo ester 23 with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in refluxing toluene18
gave the target molecule, pectinatone 3 (Scheme 3).
6
O
O
O
O
ref 15f
HO
(6S)-alcohol
O
OPMB
meso-olefin
OPMB
OPMB
PPh3
7
O
5
Scheme 1. Retrosynthetic analysis.
dry benzene, reflux,
2
O
56%.
E:Z; 19:1
Br
LHMDS,
O
O
LiAlH4,
anhydrous THF,
(a) dry benzene, reflux,
O
O
0 oC - 25 oC,
90%.
anhydrous THF,
O
O
-78 oC, 94%.
EtO
OPMB
OPMB
PPh3
7
8
IBX/DMSO
72%.
O
5
1
2 h, 81%.
R
(a) 2,2-dimethoxypropane
CSA, CH2Cl2:Et2O, 93%.
(b) DIBAL-H,
anhydrous CH2Cl2,
-78 oC-r.t, 72%.
4: R = CO2Et
E:Z; 19:1
20: R = CH2OH
HO
RO
(b) NaH, Bn-Br,
anhydrous THF,
reflux, 92%.
PMBO
OH OH
PMBO
O
O
HN(MeO)Me·HCI,
2eq iPrMgCI, THF,
22,
OMe
6
9: R = H
anhydrous THF,
N
4
10: R = Bn
Me
-20 °C-0 °C, 71%
LDA
O
21
(a) LiAlH4,
(a) 2M HCl, THF/H2O
25 oC, 90%
anhydrous THF,
0 oC - 25 oC, 80%.
BnO
DBU,
(b) CS2, MeI, NaH,
anhydrous THF,
0 oC - 25 oC, 89%.
EtO
(b) TsCl, DMAP,
anhydrous CH2Cl2,
anhydrous Toluene,
O
OH OR
PMB
3
O
O
O
reflux, 30%.
11: R = H
12: R = Ts
Et3N, 92%.
23
Scheme 3.
n-Bu3SnH, AIBN,
BnO
BnO
Most of the previous syntheses involved three steps for the gen-
Toluene, reflux
91%.
eration of each additional stereogenic center with a stoichiometric
amount or even excesses of chiral carboxamides and related
reagents. Thus, the synthesis of target molecules 1–3 containing
three stereogenic centers typically requires approximately 10 steps
from readily available compounds. However, the present synthesis
utilizing desymmetrization strategy creates three consecutive ste-
reogenic centers in a single reaction to give an intermediate 6,
which is an attractive advantage over the reported methods.
PMBO
PMBO
OR
13: R = H
15
14: R = CS2Me
(a) DDQ, CH2Cl2,
pH 7 buffer (9:1)
n-Bu3SnH, AIBN,
0
oC-25 oC, 89%.
Toluene, reflux,
BnO
(b) CS2, MeI, NaH,
anhydrous THF,
92%.
OR
16: R = H
17: R = CS2Me
0
oC - 25 oC, 91%
3. Conclusions
We have achieved the total synthesis of siphonarienal, siphona-
rienone, and pectinatone using desymmetrization strategy to set
the asymmetric carbon centers.
(a) Pd/C, H2,
88%.
BnO
R
18
(b) IBX/DMSO
81%.
19: R = CH2OH
5: R = CHO
4. Experimental section
4.1. General
Scheme 2.
Aldehyde 5 was utilized for the synthesis of target molecules 1–3.
Aldehyde 5 was subjected to a Wittig reaction using 2-(1,1,1-tri-
Reactions were conducted under N2 in anhydrous solvents such
as CH2Cl2, THF, and EtOAc. All reactions were monitored by TLC

G. Sabitha et al. / Tetrahedron: Asymmetry 20 (2009) 2205–2210
2207
(silica-coated plates and visualizing under UV light). Light petro-
leum ether (bp 60–80 °C) was used. Yields refer to chromatograph-
ically and spectroscopically (1H, 13C NMR) homogeneous material.
Air-sensitive reagents were transferred by a syringe or double-
ended needle. Evaporation of solvents was performed at reduced
pressure on a Büchi rotary evaporator. 1H and 13C NMR spectra
of samples in CDCl3 were recorded on Varian FT-200 MHz (Gemini)
and Bruker UXNMR FT-300 MHz (Avance) spectrometers. Chemical
shifts (d) were reported relative to TMS (d = 0.0) as an internal
standard. Mass spectra were recorded in E1 conditions at 70 eV
on LC-MSD (Agilent technologies) spectrometers. All high-resolu-
tion spectra were recorded on QSTAR XL hybrid ms/ms system (Ap-
plied Biosystems/MDS sciex, foster city, USA), equipped with an ESI
source (IICT, Hyderabad). Column chromatography was performed
on silica gel (60–120 mesh) supplied by Acme Chemical Co., India.
TLC was performed on Merck 60 F-254 silica gel plates. Optical
rotations were measured with JASCO DIP-370 Polarimeter at 25 °C.
159.2, 135.6, 129.7, 129.4, 116.5, 113.8, 87.7, 75.7, 74.2, 65.1,
64.6, 55.0, 41.7, 37.6, 35.2, 32.5, 14.6, 11.5; HRMS (ESI): [M+Na]+
m/z calcd for C20H32O5Na: 375.2147, found: 375.2159 (+3.0804
ppm error).
4.1.3. (2R,3R,4R)-4-[(4R,5R)-5-Allyl-2,2-dimethyl-1,3-dioxan-4-
yl]-3-[(4-methoxybenzyl)oxy]-2-methylpentan-1-ol 9
2,2-Dimethoxypropane (25.9 mL, 213.0 mmol) and CSA (1.95 g,
42.61 mmol) were added successively to a solution of triol 6 (15 g,
42.61 mmol) in a mixture of CH2Cl2:Et2O (9:1) (150 mL). The solu-
tion was stirred for 1 h at room temperature and then quenched
with saturated aqueous NaHCO3 (30 mL). The aqueous layer was
extracted with ether (3 ꢁ 100 mL). The organic layers were washed
with brine, dried over Na2SO4 (1 g), and concentrated. The crude
compound was purified on column chromatography (1:3, EtOAc/
hexane) to afford the monoacetonide 9 (15.53 g, 93%) as a viscous
liquid. Rf = 0.37 (EtOAc/hexane, 1:3); ½a D25
¼ ꢀ39:5 (c 3.41, CHCl3);
ꢂ
IR (neat): mmax 3456, 2972, 2930, 1613, 1513, 1460, 1379, 1299,
4.1.1. 7-(4-Methoxybenzyloxy)-4(20-propen),6,8-diimethyl-
(1S,4S,5S,6S,7S,8R)-2,9-dioxabicyclo-[3.3.1]nonan-3-one 8
To a stirred solution of lactone 7 (16.5 g, 53.92 mmol) in
anhydrous THF (150 mL) at ꢀ78 °C under a nitrogen atmosphere,
was added LHMDS (70.09 mL, 70.09 mmol, 1.0 M) dropwise. After
one-hour stirring at ꢀ78 °C, allylbromide (neat 27.39 mL, 323.52
mmol) was added dropwise. The reaction mixture was stirred for
1 h at the same temperature and quenched with saturated aqueous
NH4Cl solution (30 mL) and extracted with ether (3 ꢁ 100 mL). The
organic extracts were washed with water and brine, and dried over
anhydrous Na2SO4 (2 g), concentrated in vacuo, and purified by
column chromatography (1:4, EtOAc/hexane) to afford allyl lactone
8 (17.53 g, 94%) as a white crystalline solid. Mp = 97–98 °C;
1247, 1198, 1038 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.19 (d,
;
J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.76–5.60 (m, 1H), 5.06–
4.96 (m, 2H), 4.54 (ABq, J = 10.7 Hz, 2H, ArH–CH2), 3.98 (dd,
J = 1.3, 10.0 Hz, 1H, CHaHb), 3.84 (dd, J = 3.0, 10.7 Hz, 1H, CH),
3.79 (s, 3H, OCH3), 3.74 (dd, J = 4.9, 11.5 Hz, 1H, CH), 3.53 (m, 2H,
CH2), 3.43 (dd, J = 2.2, 9.8 Hz, 1H, CHaHb), 2.67 (br s, 1H, OH),
2.13–1.72 (m, 5H, 3 ꢁ CH, allylic-CH2), 1.38 (s, 3H, CH3), 1.34 (s,
3H, CH3), 1.20 (d, J = 7.2 Hz, 3H, CH3), 0.87 (d, J = 7.0 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3) d 158.9, 134.8, 130.4, 128.4,
116.6, 113.6, 97.6, 84.8, 74.8, 71.3, 63.84, 63.78, 54.9, 37.1, 36.0,
34.4, 32.3, 29.3, 19.6, 16.1, 9.7; HRMS (ESI): [M+Na]+ m/z calcd
for C23H36O5Na: 415.2460, found: 415.2470 (+2.3014 ppm error).
Rf = 0.55 (EtOAc/hexane, 3:7); ½a D25
ꢂ
¼ ꢀ75 (c 1.3, CHCl3); IR (neat):
4.1.4. (4R,5R)-5-Allyl-4-(1R,2R,3R)-4-(benzyloxy)-2-[(4-
methoxybenzyl)oxy]-1,3-dimethylbutyl-2,2-dimethyl-1,3-
dioxane 10
mmax 2968, 1730, 1608, 1512, 1459, 1258, 1215 cmꢀ1
;
1H NMR
(300 MHz, CDCl3)
d 7.16 (d, J = 8.3 Hz, 2H, ArH), 6.82 (d,
J = 8.3 Hz, 2H, ArH), 5.70 (m, 1H), 5.35 (d, J = 2.2 Hz, 1H, CH),
5.16–5.04 (m, 2H), 4.60 (d, J = 11.3 Hz, 1H, CH), 4.38 (d,
J = 11.3 Hz, 1H, CH), 3.82 (d, J = 4.5 Hz, 1H, CH), 3.78 (s, 3H, CH3),
3.53 (t, J = 3.0 Hz, 1H, CH), 2.66–2.54 (m, 2H), 2.44 (dd, J = 3.0,
9.0 Hz, 1H, CH), 2.18 (m, 1H, CH), 2.0 (m, 1H, CH), 1.14 (d,
J = 6.8 Hz, 3H, CH3), 0.87 (d, J = 6.8 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d 169.5, 159.0, 135.3, 132.0, 129.0, 118.0, 113.5,
99.9, 78.6, 76.0, 72.6, 55.1, 40.3, 39.6, 37.6, 37.4, 13.4, 13.2; HRMS
(ESI): [M+Na]+ m/z calcd for C20H26O5Na: 369.1677, found:
369.1671 (ꢀ1.8797 ppm error).
To a stirred suspension of NaH (3.66 g, 76.53 mmol) in anhy-
drous THF (150 mL) under a nitrogen atmosphere was added
monoacetonide 9 (15.0 g, 38.26 mmol) in anhydrous THF (50 mL)
dropwise at 0 °C. The reaction mixture was allowed to warm to
25 °C and then heated at reflux for 1 h. It was then cooled to
25 °C, and benzyl bromide (5.0 mL, 42.09 mmol) was added
dropwise, refluxed for 3 h, and cooled to 0 °C. It was then quenched
with ice and extracted with ether (3 ꢁ 100 mL). The combined
extracts were washed with brine, dried over Na2SO4 (1 g), and
purified by column chromatography (1:9, EtOAc/hexane) to afford
10 (16.96 g, 92%) as a colorless oil. Rf = 0.41 (EtOAc/hexane, 1:9);
4.1.2. (2R,3R,4S,5R,6R)-2-Allyl-5-[(4-methoxybenzyl)oxy]-4,6-
dimethylheptane-1,3,7-triol 6
½
a 2D5
ꢂ
¼ ꢀ18:0 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.33–
7.20 (m, 5H, ArHH), 7.16 (d, J = 8.3 Hz, 2H, ArHH), 6.81 (d,
J = 8.3 Hz, 2H, ArHH), 5.65 (m, 1H), 5.06–4.91 (m, 2H), 4.51 (ABq,
J = 10.5, 17.3 Hz, 2H, ArH–CH2), 4.45 (s, 2H, ArH–CH2), 3.94 (m,
1H), 3.79 (s, 3H, CH3), 3.71 (dd, J = 4.5, 11.3 Hz, 1H, CH), 3.62 (dd,
J = 5.3, 9.0 Hz, 1H, CH), 3.48 (t, J = 10.5 Hz, 1H, CH), 3.38–3.27 (m,
2H), 2.14 (m, 1H, CH), 2.07–1.91 (m, 2H), 1.89–1.64 (m, 2H), 1.34
(s, 3H, CH3), 1.33 (s 3H, CH3), 1.10 (d, J = 6.8 Hz, 3H, CH3), 0.87 (d,
J = 6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 158.8, 138.7,
135.1, 129.3, 128.3, 128.2, 127.3, 127.2, 116.6, 113.6, 97.8, 82.8,
74.4, 73.0, 71.8, 71.6, 64.1, 55.1, 36.9, 35.9, 34.7, 32.4, 29.5, 19.7,
16.7, 9.9; HRMS (ESI): [M+Na]+ m/z calcd for C30H42O5Na:
505.2929, found: 505.2906 (ꢀ4.7390 ppm error).
To a stirred suspension of LiAlH4 (3.77 g, 99.42 mmol) in anhy-
drous THF (150 mL) at 0 °C was added dropwise a solution of allyl
lactone 8 (17.2 g, 49.71 mmol) in anhydrous THF (30 mL). The reac-
tion mixture was allowed to warm to 25 °C and stirred for 2 h. The
reaction mixture was then cooled to 0 °C and quenched by drop-
wise addition of saturated aqueous Na2SO4 (30 mL). The precipi-
tate formed was filtered and washed with ethyl acetate. The
combined organic extracts were dried over Na2SO4 (1 g) and con-
centrated under reduced pressure, and the crude product was puri-
fied by silica gel column chromatography (3:7, EtOAc/hexane) to
afford the pure product 6 (15.74 g, 90%) as a viscous liquid. Rf =
0.23 (EtOAc/hexane, 3:7); ½a D25
¼ þ6:0 (c 1.4, CHCl3); IR (neat): mmax
ꢂ
3412, 2967, 2929, 1613, 1514, 1461, 1301, 1249, 1176, 1034 cmꢀ1
;
4.1.5. (2R,3R,4S,5R,6R)-2-Allyl-7-(benzyloxy)-5-[(4-methoxy-
benzyl)oxy]-4,6-dimethylheptane-1,3-diol 11
1H NMR (200 MHz, CDCl3) d 7.22 (d, J = 8.0 Hz, 2H), 6.84 (d,
J = 8.8 Hz, 2H), 5.84–5.60 (m, 1H), 5.08–4.94 (m, 2H), 4.59 (ABq,
J = 15.3 Hz, 2H, ArH–CH2), 3.98–3.56 (m, 4H, CH), 3.80 (s, 3H,
CH3), 3.70 (dd, J = 2.9, 10.9 Hz, 1H, CH), 3.49 (dd, J = 2.9, 9.5 Hz,
1H, CH), 2.11–1.48 (m, 5H, allylic-CH2, 3 ꢁ CH), 1.14 (d, J = 7.3 Hz,
3H, CH3), 0.95 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) d
To a stirred solution of 10 (16 g, 33.19 mmol) in THF (120 mL)
was added aqueous 2 M HCl (83.0 mL, 165.97 mmol), and the
resulting reaction mixture was stirred for 5 h at 25 °C. It was di-
luted with EtOAc and the aqueous layer was extracted twice with
EtOAc (2 ꢁ 100 mL). The combined organic layers were washed

2208
G. Sabitha et al. / Tetrahedron: Asymmetry 20 (2009) 2205–2210
with brine, dried over anhydrous Na2SO4 (1 g), and the solvent
was evaporated under reduced pressure and purified by column
chromatography (1:3, EtOAc/hexane) to afford the diol 11
(13.2 g, 90%) as a viscous liquid. Rf = 0.48 (EtOAc/hexane, 2:3);
4.1.8. (1R,2S)-1-(1R,2R,3R)-4-(Benzyloxy)-2-[(4-methoxybenzyl)
oxy]-1,3-dimethylbutyl-2-methyl-4-pentenyl
(methylsulfanyl)methanethioate 14
To a solution of sodium hydride (1.0 g, 41.66 mmol) in anhy-
drous THF (30 mL) the alcohol 13 (8.8 g, 20.65 mmol) in anhydrous
THF (20 mL) was added at 0 °C and allowed to stir at room temper-
ature for 0.5 h. To this reaction mixture, carbon disulfide (3.73 mL,
61.97 mmol) and iodomethane (2.56 mL, 41.31 mmol) were added
at 0 °C. The mixture was stirred at room temperature for 2 h. After
completion of the reaction at 0 °C, it was quenched by the slow
addition of crushed ice. The mixture was raised to room tempera-
ture and separated, and the aqueous layer was washed with CH2Cl2
(2 ꢁ 100 mL). The combined organic extracts were dried (Na2SO4),
concentrated in vacuo, and purified by column chromatography
(1:14, EtOAc/hexane) to afford 14 (9.48 g, 89%). Rf = 0.62 (EtOAc/
½
a 2D5
ꢂ
¼ þ18:0 (c 1.15, CHCl3); IR (neat): mmax 3441, 2966, 2926,
1612, 1513, 1301, 1249, 1175, 1035 cmꢀ1 1H NMR (200 MHz,
;
CDCl3) d 7.30 (m, 5H, ArH), 7.10 (d, J = 8.8 Hz, 2H, ArH), 6.80 (d,
J = 8.1 Hz, 2H, ArH), 5.70 (m, 1H), 5.07–4.91 (m, 2H), 4.48 (s, 2H,
ArH–CH2), 4.47 (ABq, J = 10.2 Hz, 2H, ArH–CH2), 3.91 (m, 2H,
CH2), 3.79 (s, 3H, O–CH3), 3.67 (dd, 4.4, 8.8 Hz, 1H, CH), 3.62 (m,
1H), 3.52 (dd, J = 1.4, 9.5 Hz, 1H, CH), 3.44 (dd, J = 2.9, 8.8 Hz, 1H,
CH), 3.27 (br s, 1H, OH), 2.17–1.66 (m, 5H), 1.11 (d, J = 7.3 Hz,
3H, CH3), 0.99 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 159.4, 138.3, 135.9, 129.9, 129.3, 128.3, 127.6, 127.5, 116.6,
113.9, 86.8, 75.7, 74.6, 73.2, 72.0, 65.5, 54.9, 41.9, 36.7, 34.7,
32.9, 15.1, 12.1; HRMS (ESI): [M+Na]+ m/z calcd for C27H38O5Na:
465.2616, found: 465.2595 (ꢀ4.7165 ppm error).
hexane, 1:13); ½a D25
ꢂ
¼ þ2:3 (c 1.0, CHCl3); IR (neat): mmax 2969,
2924, 1612, 1513, 1457, 1300, 1241, 1172, 1048 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 7.27 (m, 5H, ArH), 7.18 (d, J = 8.5 Hz, 2H,
ArH), 6.79 (d, J = 8.6 Hz, 2H, ArH), 6.02 (dd, J = 3.9, 5.6 Hz, 1H,
CH), 5.67 (m, 1H), 5.06–4.90 (m, 2H), 4.60 (d, J = 10.5 Hz, 1H,
ArH–CHaHb), 4.44 (s, 2H, Ph–CH2), 4.43 (d, J = 10.2 Hz, 1H, ArH–
CHaHb), 3.78 (s, 3H, CH3), 3.55 (dd, J = 4.9, 8.8 Hz, 1H, CH), 3.41
(dd, J = 6.6, 9.0 Hz, 1H, Ph–CH2–O–CHaHb), 3.30 (dd, J = 4.7,
7.0 Hz, 1H, Ph–CH2–O–CHaHb), 2.53 (s, 3H, S–CH3), 2.24–2.09 (m,
3H, allylic-CH2, CH), 2.02–1.80 (m, 2H, 2 ꢁ CH), 1.09 (d, J = 6.9 Hz,
3H, CH3), 1.01 (d, J = 7.1 Hz, 3H, CH3), 0.93 (d, J = 6.7 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3) d 216.2, 158.9, 138.7, 136.3,
131.2, 129.0, 128.2, 127.4, 127.3, 116.6, 113.5, 86.8, 83.7, 73.9,
73.0, 72.2, 55.2, 38.3, 38.1, 36.9, 36.1, 18.7, 16.0, 14.7, 12.2; HRMS
(ESI): [M+Na]+ m/z calcd for C29H40O4NaS2: 539.2265, found:
539.2255 (ꢀ1.9907 ppm error).
4.1.6. (2R)-2-(1R,2S,3R,4R)-5-(Benzyloxy)-1-hydroxy-3-[(4-
methoxybenzyl)oxy]-2,4-dimethylpentyl-4-pentenyl 4-methyl-
1-benzenesulfonate 12
To a stirred solution of alcohol 11 (13 g, 29.41 mmol) in anhy-
drous Et3N (12.25 mL, 88.23 mmol) at 0 °C was added p-toluene-
sulfonylchloride (6.16 g, 32.35 mmol). After the reaction mixture
was stirred at 25 °C for 1.5 h, the reaction was quenched with
water (50 mL) and the resultant mixture was then extracted with
EtOAc (2 ꢁ 100 mL). The extracts were washed with brine
(30 mL), dried over anhydrous Na2SO4 (1 g), and concentrated in
vacuo. Purification of the residue by column chromatography
(1:9, EtOAc/hexane) afforded 12 (16.12 g, 92%) as a liquid. Rf = 0.4
(EtOAc/hexane, 1:4); 1H NMR (300 MHz, CDCl3) d 7.74 (d, J =
7.5 Hz, 2H, ArH), 7.29 (m, 5H, ArH), 7.25 (d, J = 7.5 Hz, 2H, ArH),
7.08 (d, J = 9.0 Hz, 2H, ArH), 6.79 (d, J = 8.3 Hz, 2H, ArH), 5.63 (m,
1H), 5.07–4.93 (m, 2H), 4.48 (s, 2H, Ph–CH2), 4.46 (ABq, J =
12.0 Hz, 2H, Ar–CH2), 4.12 (m, 2H, O–CH2), 3.79 (s, 3H, O–CH3),
3.72 (dd, J = 0.7, 9.0 Hz, 1H, Ph–CH2–O–CHaHb), 3.63 (dd, J = 4.5,
9.0 Hz, 1H, CH), 3.48 (dd, J = 1.5, 9.0 Hz, 1H, Ph–CH2–O–CHaHb),
3.43 (dd, J = 3.0, 8.3 Hz, 1H, CH), 3.37 (br s, 1H, OH), 2.40 (s, 3H,
CH3), 2.10–1.66 (m, 5H), 0.99 (d, J = 6.7 Hz, 3H, CH3), 0.97 (d,
J = 6.7 Hz, 3H, CH3).
4.1.9. (4S,6S,7S,8R)-9-(Benzyloxy)-7-[(4-methoxybenzyl)oxy]-
4,6,8-trimethyl-1-nonene 15
A
solution of 14 (9.2 g, 17.80 mmol), tributyltin hydride
(23.90 mL, 98.02 mmol), and AIBN (0.175 g, 1.06 mmol) in toluene
(130 mL) was heated at reflux for 1 h. The mixture was cooled, con-
centrated in vacuo, and purified by column chromatography (1:19,
EtOAc/hexane) to afford 15 (6.65 g, 91%) as an oil. Rf = 0.65 (EtOAc/
hexane, 1:19); ½a D25
ꢂ
¼ þ12:9 (c 1.0, CHCl3); IR (neat): mmax 2959,
2921, 1612, 1512, 1457, 1367, 1301, 1247, 1173, 1083 cmꢀ1
;
1H
4.1.7. (4S,5R,6S,7R,8R)-9-(Benzyloxy)-7-[(4-methoxybenzyl)-
oxy]-4,6,8-trimethyl-1-nonen-5-ol 13
NMR (200 MHz, CDCl3) d 7.28 (m, 5H, ArH), 7.14 (d, J = 8.0 Hz,
2H, ArH), 6.79 (d, J = 8.0 Hz, 2H, ArH), 5.72 (m, 1H), 5.08–4.88 (m,
2H), 4.45 (s, 2H, Ph–CH2), 4.43 (ABq, J = 5.8, Hz, 2H, ArH–CH2),
3.78 (s, 3H, CH3), 3.49 (d, J = 5.1 Hz, 2H, CH2), 3.16 (dd, J = 3.6,
7.3 Hz, 1H, CH), 2.20–1.20 (m, 7H), 1.01 (d, J = 7.3 Hz, 3H, CH3),
0.97 (d, J = 6.6 Hz, 3H, CH3), 0.89 (d, J = 5.8 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 158.9, 138.7, 137.2, 131.3, 129.0, 128.2, 127.5,
127.3, 115.6, 113.6, 86.0, 74.4, 73.0, 72.7, 55.1, 39.8, 37.8, 36.3,
32.6, 30.1, 20.8, 17.6, 15.6; HRMS (ESI): [M+Na]+ m/z calcd for
C27H38O3Na: 433.2718, found: 433.2709 (ꢀ2.2275 ppm error).
To a stirred suspension of LiAlH4 (2.04 g, 53.69 mmol) in anhy-
drous THF (10 mL) at 0 °C was added dropwise a solution of
tosylated compound 12 (16.0 g, 26.84 mmol) in anhydrous THF
(100 mL). The reaction mixture was refluxed for 1 h. It was then
cooled to 0 °C, diluted with ether, and quenched with the dropwise
addition of saturated aqueous Na2SO4 (50 mL). The solid material
was filtered and washed thoroughly with hot EtOAc (4 ꢁ 100 mL).
The combined organic layers were dried over anhydrous Na2SO4
(1 g). The solvent was removed under vacuo and the residue was
purified by column chromatography (1:14, EtOAc/hexane) to afford
the compound 13 (9.14 g, 80%) as a colorless liquid. Rf = 0.5 (EtOAc/
4.1.10. (2R,3S,4S,6S)-1-(Benzyloxy)-2,4,6-trimethyl-8-nonen-3-
ol 16
hexane, 2:23); ½a D25
¼ þ26:6 (c 1.15, CHCl3); IR (neat): mmax 3479,
ꢂ
2967, 2912, 1613, 1586, 1514, 1454, 1302, 1249, 1068, 1036 cmꢀ1
;
To a solution of 15 (6.2 g, 15.11 mmol) in CH2Cl2:H2O [10:1,
30 mL] was added dichlorodicyanoquinone (DDQ) (5.14 g, 22.67
mmol) at 0 °C. The solution was stirred for 2 h. After the reaction
was completed, the solution was filtered through a pad of Celite.
The Celite pad was washed with CH2Cl2 (3 ꢁ 50 mL). The combined
filtrate was concentrated, and purification by column chromatogra-
phy (1:4, EtOAc/hexane) provided 16 as a colorless liquid (3.9 g,
1H NMR (300 MHz, CDCl3) d 7.29 (m, 5H, ArH), 7.11 (d, J = 9.0 Hz,
2H, ArH), 6.79 (d, J = 8.3 Hz, 2H, ArH), 5.73 (m, 1H), 5.04–4.89 (m,
2H), 4.47 (s, 2H, ArH–CH2), 4.46 (ABq, J = 10.5 Hz, 2H, ArH–CH2),
3.78 (s, 3H, CH3), 3.65 (dd, J = 4.5, 8.3 Hz, 1H, CH), 3.55–3.49 (m,
2H, CH2), 3.45 (dd, J = 3.0, 8.3 Hz, 1H, CH), 2.07 (m, 2H, CH2), 1.94
(m, 1H, CH), 1.78–1.55 (m, 2H, 2 ꢁ CH), 1.06 (d, J = 6.8 Hz, 3H,
CH3), 0.99 (d, J = 6.8 Hz, 3H, CH3), 0.96 (d, J = 6.0 Hz, 3H, CH3); 13C
NMR (75 MHz, CDCl3) d 159.2, 138.4, 136.6, 129.3, 129.0, 128.3,
127.6, 127.4, 116.0, 113.7, 87.0, 75.5, 74.2, 73.0, 72.2, 55.1, 37.1,
36.6, 35.7, 34.4, 16.1, 15.0, 11.7; HRMS (ESI): [M+Na]+ m/z calcd for
C27H38O4Na: 449.2667, found: 449.2654 (ꢀ3.0711 ppm error).
89%). Rf = 0.3 (EtOAc/hexane, 1:9); ½a D25
ꢂ
¼ ꢀ25:0 (c 1.0, CHCl3); IR
(neat): mmax 3482, 2959, 2922, 1455, 1219, 1088, 988 cmꢀ1
;
1H
NMR (300 MHz, CDCl3) d 7.28 (m, 5H, ArH), 5.75 (m, 1H), 5.11–
4.89 (m, 2H), 4.50 (s, 2H, Ph–CH2), 3.60 (dd, J = 3.6, 8.8 Hz, 1H, Ph–
O–CHaHb), 3.43 (6.6, 8.8 Hz, 1H, Ph–O–CHaHb), 3.25 (m, 1H, CH),

G. Sabitha et al. / Tetrahedron: Asymmetry 20 (2009) 2205–2210
2209
3.10 (br s, 1H, OH), 2.15 (m, 1H, CH), 2.04–1.07 (m, 6H), 0.94 (d,
J = 6.6 Hz, 3H, CH3), 0.90 (d, J = 5.1 Hz, 3H, CH3), 0.89 (d, J = 6.6 Hz,
3H, CH3); 13C NMR (75 MHz, CDCl3) d 137.6, 137.4, 128.4, 127.7,
127.6, 115.6, 81.3, 75.5, 73.5, 39.8, 36.8, 35.3, 33.0, 30.1, 21.0, 17.2,
14.2; HRMS (ESI): [M+Na]+ m/z calcd for C19H30O2Na: 313.2143,
found: 313.2154 (+3.3517 ppm error).
4.1.14. (2S,4S,6S)-2,4,6-Trimethylnonanal 5
To an ice-cooled solution of 2-(iodooxy)benzoic acid (7.36 g,
27.27 mmol) in anhydrous DMSO (3.69 mL, 51.57 mmol) was
added a solution of alcohol 19 (1.6 g, 8.60 mmol) in anhydrous
CH2Cl2 (15 mL). The mixture was stirred at room temperature for
3 h and then filtered through a Celite pad and washed with Et2O
(2 ꢁ 10 mL). The combined organic filtrates were washed with
H2O (2 ꢁ 5 mL) and brine, dried over anhydrous Na2SO4 (1 g),
and concentrated in vacuo. The crude product was purified by sil-
ica gel column chromatography using (EtOAc/hexane, 1:200) to af-
ford aldehyde 5 (1.28 g, 81%) as a yellow liquid. Rf = 0.62 (EtOAc/
4.1.11. (1S,2S,4S)-1-[(1R)-2-(Benzyloxy)-1-methylethyl]-2,4-
dimethyl-6-heptenyl methylsulfanyl)methanethioate 17
To a solution of sodium hydride (0.65 g, 27.07 mmol) in anhy-
drous THF (20 mL), alcohol 16 (3.8 g, 13.1 mmol) in anhydrous
THF (10 mL) was added at 0 °C and allowed to stir at room temper-
ature for 0.5 h. To this reaction mixture, carbon disulfide (2.34 mL,
30.0 mmol) and iodomethane (1.61 mL, 20.0 mmol) were added at
0 °C. The mixture was stirred at room temperature for 2 h. After
completion of the reaction at 0 °C, it was quenched by the slow
addition of crushed ice. The mixture was raised to room tempera-
ture and separated, and the aqueous layer was washed with CH2Cl2
(2 ꢁ 50 mL). The combined organic extracts were dried (Na2SO4),
concentrated in vacuo, and purified by column chromatography
(1:14, EtOAc/hexane) to afford 17 (4.53 g, 91%) as a liquid.
hexane, 1:19);
½
a 2D5
ꢂ
¼ þ6:2 (c 0.26, CHCl3); 1H NMR (CDCl3
400 MHz) d 9.57 (d, J = 2.4 Hz, 1H, CHO), 2.55 (m, 1H, CH), 1.78
(m, 1H, CH), 1.62–1.46 (m, 2H, CH, CHaHb), 1.39–1.32 (m, 1H,
CH),1.32–0.92 (m, 6H, 3 ꢁ CH2, CHaHb), 1.10 (d, J = 7.2 Hz, 3H,
CH3), 0.88 (d, J = 6.4 Hz, 3H, CH3), 0.87 (t, J = 7.2 Hz, 3H, CH3),
0.84 (d, J = 6.4 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz) d 205.5,
45.1, 44.1, 38.9, 38.4, 29.7, 27.9, 20.4, 20.2, 19.9, 14.4, 14.3.
4.1.15. Siphonarienone, [(E,6S,8S,10S)-4,6,8,10-tetramethyl-4-
tridecen-3-one] 2
Rf = 0.42 (EtOAc/hexane, 1:12); ½a D25
¼ þ11:5 (c 1.1, CHCl3); IR
ꢂ
To a solution of 5 (0.1 g, 0.543 mmol) in anhydrous benzene
(8 mL) was added ethylcarbonylethylidenetriphenylphosphorane
(0.27 g, 0.776 mmol). The mixture was maintained at 80 °C for
3 h, and then the solvent was removed in vacuo. The residue was
purified by silica gel column chromatography (EtOAc/hexane,
1:30) to afford 2 (76.6 mg, 56%) as a colorless oil. Rf = 0.4 (100%
(neat): mmax 2963, 2923, 1455, 1375, 1223, 1098, 1049, 738,
697 cmꢀ1 1H NMR (CDCl3 300 MHz) d 7.27 (m, 5H, ArH), 5.79–
;
5.65 (m, 2H, db H, CH), 5.02–4.92 (m, 2H), 4.43 (s, 2H, Ph–CH2),
3.49 (dd, J = 4.3, 9.0 Hz, 1H, Ph–O–CHaHb), 3.24 (dd, J = 6.9, 9.0 Hz,
1H, Ph–O–CHaHb), 2.53 (s, 3H, CSS–CH3), 2.26 (m, 1H, CH), 2.08
(m, 2H, allylic-CH2), 1.76 (m, 1H, CH), 1.59 (m, 1H, CH), 1.42 (m,
1H, aliphatic-CHaHb), 1.08 (m, 1H, aliphatic-CHaHb), 1.03 (d,
J = 6.9 Hz, 3H, CH3), 0.96 (d, J = 6.7 Hz, 3H, CH3), 0.91 (d, J = 6.6 Hz,
3H, CH3); 13C NMR (CDCl3, 75 MHz) d 216.5, 138.4, 136.8, 128.2,
127.5, 127.3, 115.9, 89.8, 73.1, 72.0, 39.7, 38.0, 35.8, 32.8, 30.0,
hexane); ½a 2D5
ꢂ
¼ þ16:0 (c 1.2, CHCl3); IR (neat): mmax 2958, 1672,
1459, 1376 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 6.33 (d, J = 9.5 Hz,
1H), 2.75–2.58 (m, 1H, CH), 2.67 (q, J = 7.3 Hz, 2H, CH2), 1.80 (s,
3H, CH3), 1.55–1.4 (m, 3H), 1.4–1.25 (m, 3H), 1.24–1.13 (m, 2H),
1.13–1.04 (m, 2H), 1.09 (t, J = 7.3 Hz, 3H, CH3), 1.01 (d, J = 6.5 Hz,
3H, CH3), 0.88 (t, J = 7.3 Hz, 3H, CH3), 0.84 (d, J = 6.5 Hz, 3H, CH3),
0.81 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 202.9,
148.3, 135.4, 45.6, 44.7, 39.3, 31.2, 30.4, 29.6, 28.3, 20.7, 20.5,
19.9, 19.9, 14.4, 11.5, 9.0; MS(ESI): m/z = 270 [M+NH4]+.
20.8, 18.7, 16.8, 14.9; HRMS (ESI): [M+Na]+ m/z calcd for C21H32
O2NaS2: 403.1741, found: 403.1723 (ꢀ4.5733 ppm error).
-
4.1.12. (4S,6S,8S)-9-(benzyloxy)-4,6,8-trimethyl-1-nonene 18
A
solution of 17 (4.4 g, 17.80 mmol), tributyltin hydride
(15.54 mL, 63.76 mmol), and AIBN (0.113 g, 0.69 mmol) in anhy-
drous toluene (75 mL) was heated at reflux for 1 h. The mixture
was cooled, concentrated in vacuo, and purified by column chro-
matography (1:19, EtOAc/hexane) to afford 18 (2.91 g, 92%) as a
4.1.16. Ethyl (E,4S,6S,8S)-2,4,6,8-tetramethyl-2-undecenoate 4
To a solution of 5 (0.75 g, 0.14 mmol) in anhydrous benzene
(30 mL) was added ethoxycarbonylethylidenetriphenylphosphora-
ne (2.10 g, 5.82 mmol). The mixture was maintained at 80 °C for
3 h, and then the solvents were removed in vacuo. The residue
was purified by silica gel column chromatography (EtOAc/hexane,
1:40) to afford 4 (0.88 g, 81%) as a colorless oil. Rf = 0.4 (100% hex-
colorless liquid. Rf = 0.43 (EtOAc/hexane, 1:19); ½a D25
¼ þ2:9 (c
ꢂ
1.0, CHCl3); IR (neat): mmax 2956, 2915, 1455, 1372, 1102, 968,
736 cmꢀ1 1H NMR (CDCl3 200 MHz) d 7.27 (m, 5H, ArH), 5.72
;
(m, 1H), 5.42–4.84 (m, 2H), 4.45 (s, 2H, Ar–CH2), 3.23 (m, 2H,
CH2), 2.23–1.72 (m, 2H, CH2), 1.68–1.12 (m, 5H), 1.01–0.87 (m,
2H, CH2), 0.93 (d, J = 6.6 Hz, 3H, CH3), 0.86 (d, J = 6.6 Hz, 3H, CH3),
0.84 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz) d 138.8,
137.4, 128.2, 127.4, 127.3, 115.5, 75.9, 72.9, 44.5, 41.7, 40.8, 30.9,
29.9, 27.5, 20.8, 20.2, 18.3; HRMS (ESI): [M+Na]+ m/z calcd for
C19H30ONa: 297.2194, found: 297.2196 (+0.5533 ppm error).
ane); ½a 2D5
ꢂ
¼ þ26:5 (c 1, CHCl3); IR (neat): mmax 2958, 2924, 1713,
1268, 751 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 6.51 (dd, J = 1.1,
10.0 Hz, 1H), 4.19 (m, 2H, O–CH2), 2.62 (m, 1H, CH), 1.86 (d,
J = 1.3 Hz, 3H, CH3), 1.54–1.02 (m, 10H), 1.30 (t, J = 6.9 Hz, 3H,
CH3), 0.99 (d, J = 6.6 Hz, 3H, CH3), 0.88 (d, J = 6.7 Hz, 3H, CH3),
0.83 (t, J = 6.4 Hz, 3H, CH3), 0.81 (d, J = 6.6 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 168.4, 148.2, 126.2, 60.3, 45.5, 44.3, 39.3, 30.8,
29.7, 29.6, 28.1, 20.6, 20.4, 19.9, 14.4, 14.2, 12.4; HRMS (ESI):
[M+Na]+ m/z calcd for C17H32O2Na: 291.2300, found: 291.2312
(+4.1195 ppm error).
4.1.13. (2S,4S,6S)-2,4,6-Trimethylnonan-1-ol 19
A stirred solution of 18 (2.8 g 10.21 mmol) and 10% Pd/C (75 mg)
in anhydrous EtOAc (50 mL), was hydrogenated at 1 atm and room
temperature for 4 h. The reaction mixture was filtered through a Cel-
ite pad and the filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography (EtOAc/hex-
ane, 1:30) giving 19 (1.67 g, 88%) as a colorless liquid. Rf = 0.26
4.1.17. (E,4S,6S,8S)-2,4,6,8-Tetramethyl-2-undecen-1-ol 20
To a stirred solution of ester 4 (0.15 g, 0.56 mmol) in anhydrous
CH2Cl2 (10 mL) was added DIBAL-H (0.80 mL, 1.4 M, 1.12 mmol in
hexane) dropwise over a period of 5 min at ꢀ78 °C under N2 atmo-
sphere. After stirring for 2 h at room temperature anhydrous
MeOH (1 mL) was added at 0 °C, and the mixture was allowed to
warm to room temperature, saturated aqueous solution of sodium
potassium tartarate (5 mL) was added, and the resulting mixture
was stirred vigorously until the two layers were separated. The or-
ganic layer was separated and the aqueous layer was extracted
with additional CH2Cl2 (3 ꢁ 10 mL). The combined organic layers
(EtOAc/hexane, 1:19); ½a D25
ꢂ
¼ þ5:2 (c 0.3, CHCl3); IR (neat): mmax
3376, 2957, 2919, 1460, 1037, 771 cmꢀ1
;
1H NMR (CDCl3
300 MHz) d 3.52 (dd, J = 4.5, 9.8 Hz, 1H, HO–CHaHb), 3.35 (dd,
J = 6.7, 10.5 Hz, 1H, HO–CHaHb), 1.71 (m, 1H), 1.58 (m, 1H), 1.54–
0.97 (m, 9H), 0.92 (d, J = 6.7 Hz, 3H, CH3), 0.89 (t, J = 7.5 Hz, 3H,
CH3), 0.87 (d, J = 7.5 Hz, 3H, CH3), 0.84 (d, J = 6.7 Hz, 3H, CH3); 13C
NMR (CDCl3, 75 MHz) d 68.2, 45.1, 41.2, 38.7, 33.0, 29.7, 27.4, 20.9,
20.4, 19.9, 17.5, 14.4; MS(ESI): m/z = 204 [M+NH4]+.

2210
G. Sabitha et al. / Tetrahedron: Asymmetry 20 (2009) 2205–2210
were washed with H2O, brine solution, and dried over anhydrous
Na2SO4 (0.5 g). Removal of the solvent in vacuo and purification
by silica gel column chromatography using (EtOAc/hexane, 1:24)
to afford the alcohol 20 (0.91 g, 72% yield) as a liquid. Rf = 0.31
washed with EtOAc (2 ꢁ 5 mL), the combined organic layer was
dried over Na2SO4 (0.2 g) and concentrated in vacuo to afford crude
compound 23 (408 mg) as a liquid. Without further purification,
DBU was added (1.0 mL, 6.711 mmol) to a stirred solution of crude
compound 23 in anhydrous toluene and refluxed for 4 h. Toluene
was removed under reduced pressure, the residue was diluted with
CH2Cl2 (10 mL) and washed with water (3 mL). The aqueous layer
was again washed with CH2Cl2 (2 ꢁ 10 mL), the combined organic
layer was dried over Na2SO4 (0.2 g), concentrated in vacuo, and
purified by silica gel column chromatography (EtOAc/hexanes,
1:2) to give 1 (8.0 mg, 51% over two steps) as a solid. Mp = 126–
(EtOAc/hexane, 1:4); ½a D25
ꢂ
¼ þ9:4 (c 0.2, CHCl3); IR (neat): mmax
3355, 1457, 1158, 1011 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 5.13
(dd, J = 1.1, 9.4 Hz, 1H), 4.0 (s, 2H, CH2), 2.50 (m, 1H, CH), 1.69 (d,
J = 1.1 Hz, 3H, CH3), 1.55–0.95 (m, 10H), 0.93 (d, J = 6.6 Hz, 3H,
CH3), 0.88 (t, J = 6.7 Hz, 3H, CH3), 0.83 (d, J = 5.6 Hz, 3H, CH3),
0.81 (d, J = 6.4 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 133.2,
133.1, 69.2, 45.6, 44.9, 39.3, 29.7, 29.6, 27.8, 21.7, 20.5, 20.1,
20.0, 14.4, 13.8; MS(ESI): m/z = 249 [M+Na]+.
128 °C; Rf = 0.3 (EtOAc/hexane, 7:13); ½a D25
¼ þ60:5 (c 0.1, CHCl3);
ꢂ
IR (neat): mmax 3203, 2923, 2858, 1655, 1456, 1375, 1226 cmꢀ1
;
4.1.18. Siphonarienal [(E,4S,6S,8S)-2,4,6,8-tetramethyl-2-
undecenal] 1
1H NMR (400 MHz, CDCl3) d 5.36 (m, 1H, CH), 2.60 (m, 1H, CH),
2.03 (s, 3H, CH3), 1.97 (s, 3H, CH3), 1.87 (s, 3H, CH3), 1.50 (m,
2H), 1.41–0.78 (m, 8H), 0.92 (t, 3H, J = 6.4 Hz, CH3), 0.87 (d, 3H,
J = 6.0 Hz, CH3), 0.86 (d, 3H, J = 6.0 Hz, CH3), 0.81 (d, 3H,
J = 6.4 Hz, CH3); 13C NMR (75 MHz, CDCl3) d 165.3, 164.5, 159.7,
142.9, 126.2, 105.5, 98.6, 45.8, 44.8, 39.4, 30.5, 29.6, 28.3, 21.3,
20.2, 20.1, 19.9, 14.8, 14.4, 11.4, 8.4; MS(ESI): m/z = 352 [M+NH4]+.
To an ice-cooled solution of 2-(iodooxy)benzoic acid (107 mg,
0.397 mmol) in anhydrous DMSO (0.11 mL, 1.58 mmol) was added
a solution of alcohol 20 (60 mg, 0.265 mmol) in anhydrous CH2Cl2
(5 ml). The mixture was stirred at room temperature for 2 h, fil-
tered through a Celite pad, and washed with Et2O (2 ꢁ 5 mL). The
combined organic filtrates were washed with H2O (2 ꢁ 5 mL) and
brine, dried over anhydrous Na2SO4 (300 mg), and concentrated
in vacuo. The crude product was purified by silica gel column chro-
matography using (EtOAc/hexane, 1:30) to afford aldehyde 1
Acknowledgment
P.G. thanks CSIR, New Delhi, for the award of Fellowship.
(42 mg, 72%) as a liquid. Rf = 0.3 (100% hexane); ½a D25
ꢂ
¼ þ16:5 (c
1, CHCl3); IR (neat): mmax 2958, 2923, 1714, 1458, 1098 cmꢀ1
;
1H
References
NMR (300 MHz, CDCl3) d 9.39 (s, 1H, -CHO), 6.2 (qd, J = 1.3,
10.0 Hz, 1H), 2.83 (m, 1H), 1.78 (d, J = 1.1 Hz, 3H), 1.54–0.92 (m,
10H), 1.05 (d, J = 6.6 Hz, 3H, CH3), 0.88 (t, J = 6.7 Hz, 3H, CH3),
0.84 (d, J = 6.4 Hz, 3H, CH3), 0.81 (d, J = 6.6 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 195.6, 160.8, 138.0, 45.5, 44.2, 39.2, 31.2, 29.6,
28.2, 20.5, 20.3, 20.0, 19.9, 14.3, 9.3; MS(ESI): m/z = 242 [M+NH4]+.
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Perkin Trans 1 1990, 805–807.
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Galeyeva, Y.; Morr, M.; Laschat, S.; Baro, A.; Nimtz, M.; Sasse, F. Synthesis
2005, 2875–2880.
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1427.
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Tetrahedron Lett. 2004, 45, 6475; (c) Yadav, J. S.; Reddy, K. B.; Sabitha, G.
Tetrahedron 2008, 64, 1971; (d) Yadav, J. S.; Srinivas, R.; Sathaiah, K.
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4.1.19. N-1-Methoxy-N-1,2,4,6,8-pentamethyl-(E,4S,6S,8S)-2-
undecenamide 21
To a stirred solution of ester 4 (0.220 g, 0.82 mmol) and hydrox-
ylamine hydrochloride (0.24 g, 2.46 mmol) in anhydrous THF
i
(10 mL) was added PrMgCl (1.64 mL, 3.28 mmpl, 2 M solution in
THF) at ꢀ20 °C and allowed to stir for 1 h. The reaction mixture
was quenched by adding saturated aqueous NH4Cl (5 mL) and
washed with EtOAc (2 ꢁ 5 mL). The combined organic layer was
dried over Na2SO4 (0.3 g), concentrated in vacuo, and purified by
silica gel column chromatography (EtOAc/hexanes, 1:19) to give
21 (186 mg, 80%) as a liquid. Rf = 0.21 (EtOAc/hexane, 1:13);
½
a 2D5
ꢂ
¼ þ12:0 (c = 1, CHCl3); IR (neat): mmax 2923, 1624, 769 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 5.44 (qd, J = 1.7, 10.3 Hz, 1H), 3.38
(s, 3H, O–CH3), 2.61 (m, 1H, CH), 1.88 (s, 3H, N-CH3), 1.47 (m, 3H,
CH3), 1.37–0.93 (m, 10H), 0.99 (d, J = 6.7 Hz, 3H, CH3), 0.88 (t,
J = 6.7 Hz, 3H, CH3), 0.86 (d, J = 6.7 Hz, 3H, CH3), 0.82 (d,
J = 6.7 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) d 168.7, 141.7,
126.5, 45.6, 44.4, 39.1, 37.8, 30.2, 29.6, 29.5, 28.2, 28.8, 20.2,
20.1, 19.9, 14.3, 13.9; MS(ESI): m/z = 284 [M+H]+.
16. Li, W.-G.; Zhang, Z.-G.; Xiao, D.-M.; Zhang, X.-M. J. Org. Chem. 2000, 65, 3489.
17. Compound 19 was prepared independently as follows:
4.1.20. Pectinatone, (4-hydroxy-3,5-dimethyl-6-[(E,3S,5S,7S)-
1,3,5,7-tetramethyl-1-decenyl]-2H-2-pyranone) 3
O
A solution of 21 (140 mg, 0.494 mmol) in anhydrous THF (5 mL)
was added dropwise to a freshly prepared 1 M solution of LDA
(1.0 mL) in anhydrous THF at ꢀ20 °C and allowed to stir for
30 min at 0 °C, then a solution of 22 (0.234 g, 1.482 mmol) in anhy-
drous THF (5 mL) was added dropwise at 0 °C and allowed to stir
for a further 30 min at the same temperature. The reaction mixture
was quenched by adding saturated aqueous NH4Cl (6 mL) at 0 °C
and allowed to warm to rt. The aqueous layer was separated and
EtO
OEt
OEt
LHMDS,
Anhydrous THF,
O
O
O
2 h, 70%
22
18. Galeyevaa, Y.; Helbiga, S.; Morrb, M.; Sasseb, F.; Nimtzb, M.; Laschat, S.; Baroa,
A. Chem. Biodivers. 2006, 3, 935–941.