Stereoselective total synthesis of dodoneine

Article abstract of DOI:10.1016/j.tetasy.2009.05.036

The stereoselective total synthesis of the naturally occurring bioactive dihydropyranone dodoneine has been achieved involving the Sharpless asymmetric epoxidation, 1,3-syn diastereoselective reduction and Grubb's ring-closing metathesis as key steps.

Full text of DOI:10.1016/j.tetasy.2009.05.036

Tetrahedron: Asymmetry 20 (2009) 1536–1540
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of dodoneine q
*
Biswanath Das , Kanaparthy Suneel, Gandham Satyalakshmi, Duddukuri Nandan Kumar
Organic Chemistry Division-1, 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:
The stereoselective total synthesis of the naturally occurring bioactive dihydropyranone dodoneine has
been achieved involving the Sharpless asymmetric epoxidation, 1,3-syn diastereoselective reduction
and Grubb’s ring-closing metathesis as key steps.
Received 12 May 2009
Accepted 29 May 2009
Available online 24 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
epoxide with Red-Al formed the 1,3-diol 10, which was converted
into a di-TBS ether by treatment with TBS-Cl and subsequently into
Naturally occurring 5,6-dihydropyran 2-ones possess various
important biological properties including antifungal, antibacterial
and cytotoxic activities.1 Dodoneine [(R)-6-[(S)-2-hydroxyl-4-(4-
hydroxyphenyl)butyl]-5,6-dihydropyran-2-one] 1, a member of
this group, has recently been isolated from Tapinanthus dodoneifo-
lius, a parasitic medicinal plant that grows on the Sheanut trees in
Loumbila, West Africa.2 The structure of 1 was determined from
spectroscopic data and X-ray diffraction analysis of a crystalline
derivative. The compound exhibits a releasing effect on precon-
stricted rat aortic rings. Considering the structure as well as activ-
ity we were interested in its synthesis. While our work on the
synthesis of 1 was in progress two synthetic works on the molecule
have recently appeared.3 Herein we report our alternative ap-
proach for the stereoselective synthesis of 1.
mono-TBS ether 11 by reaction with PTSA. Swern oxidation of 11
yielded aldehyde 4, which was treated with allyl magnesium bro-
mide to provide a diastereomeric mixture (syn:anti 42:58 by 1H
NMR analysis) of a homoallylic alcohol 12, which in turn was oxi-
dized with Dess–Martin periodinane reagent to form allyl ketone
13. At this stage the diastereoselective reduction of this ketone to
prepare syn-1,3-diol derivative was studied. The best result was ob-
tained with LiAlH4–LiI at ꢀ100 °C to form the product with a ratio of
syn- and anti-isomers of 94:6, as determined by chiral HPLC.5
The selectivity was less (syn:anti, 4:1) when the reaction was car-
ried out at ꢀ78 °C. Reduction with DIBAL-H was also less impressive.
The syn-diol derivative 3 was separated by column chromatography
and its structure determined from spectroscopic (IR, 1H NMR and
MS) analysis. From a minor amount of 3, the deprotection of the
TBS ether with TBAF and subsequent formation of the acetonide A
with 2,2-DMP confirmedthe syn-stereoselectivity of 3. The structure
of A (with cis-stereochemistry) was determined from its spectro-
scopic data, especially the 13C NMR values which appear at d 20.7
and 30.6for two methylgroups of the acetonidemoiety.6 The alcohol
3 underwent acylation with acrolyl chloride to produce the diene es-
ter 2. In the intramolecular metathesis reaction,7 in the presence of
5 mol % Grubbs’ catalyst of the 1st generation (B), compound 2
2. Results and discussion
Retrosynthetic analysis (Scheme 1) suggests that compound 1
can be obtained from the intermediate 2 (by Grubbs’ ring-closing
metathesis) which can be prepared from the homoallylic alcohol 3
(byacylationwithacryloylchloride). Compound3 canin turnbe pre-
pared from allylic alcohol 6 by Sharpless asymmetric epoxidation
followed by reduction, protection, oxidation and allylation. Com-
pound 6 can easily be obtained from 4-hydroxy benzaldehyde 7.
We initiated our synthesis with 7 by converting it into a benzyl
ether, followedby2C-Wittighomologationwith(carboethoxymeth-
ylene) triphenyl phosphorane and reduction of the resulting ester
with LiAlH4 to form alcohol 8 (Scheme 2). Swern oxidation of 8 and
2C-Wittig homologation produced ester 9. Reduction of 9 with DI-
BAL-H afforded the unsaturated alcohol 6 which underwent epoxi-
dation under Sharpless asymmetric epoxidation conditions4 using
(+)-DIPT to furnish epoxy alcohol 5. The reductive opening of this
yielded the
a-b-unsaturated lactone 14. The cleavage of the TBS
and benzyl groups of 14 with TiCl4 furnished the compound 1, which
was purified by column chromatography. The physical and spectro-
scopic properties of the compound were identical to those reported
for natural dodoneine.2
20.7 ppm
Me
30.6 ppm
Me
PCy3
Ru
99.8
Cl
Cl
H
ppm
O
O
Ph
PCy3
q
Part 29 in the series, ‘Synthetic studies on natural products’.
BnO
Grubbs' Catalyst (1st generation)
* Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
A
B
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.036

B. Das et al. / Tetrahedron: Asymmetry 20 (2009) 1536–1540
1537
O
O
OH
O
OTBS O
OH
OTBS
HO
BnO
BnO
1
2
3
OTBS
CHO
CHO
OH
OH
O
BnO
BnO
BnO
HO
4
5
6
7
Scheme 1.
CHO
COOEt
OH
OH
i, ii, iii
iv, v
vi
vii
BnO
HO
BnO
BnO
7
5
8
9
6
OH
OTBS
OTBS
OH
OH
OH
viii
xi
O
ix, v
BnO
BnO
BnO
BnO
10
11
Y
X
OTBS
O
OTBS
CHO
xiii
xii
xiv
12
BnO
13
BnO
a) X=OH, Y=H b) Y=OH, X=H
O
4
O
OTBS OH
OTBS
O
O
OTBS
xvi
xvii
xv
1
BnO
BnO
BnO
3
14
2
Scheme 2. Reagents and conditions: (i) NaH, BnBr, THF, 0 °C to rt, 4 h, 82%; (ii) PPh3CHCOOEt, CH2Cl2, rt, 6 h, 80%; (iii) LiBH4, H2O, Et2O, 0 °C, 24 h, 91%; (iv) (COCl)2, DMSO,
Et3N, CH2Cl2, ꢀ78 °C, 0.5 h, 82%; (v) PPh3CHCOOEt, CH2Cl2, rt, 24 h, 81%; (vi) DIBAL-H, CH2Cl2, ꢀ78 °C to ꢀ10 °C, 0.5 h, 79%; (vii) Ti(iOPr)4 (1.0 equiv), (+)-DIPT (1.1 equiv),
TBHP (2.5 equiv), CH2Cl2, ꢀ20 °C, 12 h, 92%; (viii) Red-Al (3.0 equiv), THF, 0 °C, 0.5 h, 82%; (ix) TBSCl, imidazole, DMF, rt, 12 h, 88%; (x) PTSA(0.05 equiv), MeOH, 0 °C, 81%; (xi)
(COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 0.5 h, 82%; (xii) CH2@CHCH2MgBr, Et2O, 0 °C, 1 h, 74%; (xii) DMP, NaHCO3, CH2Cl2, 0 °C to rt, 1 h, 88%; (xiv) LiAlH4–LiI, Et2O, ꢀ100 °C,
30 min 94%; (xv) acryloyl chloride, Et3N, 0 °C to rt, 30 min 96%; (xvi). Grubbs’ first generation catalyst, CH2Cl2, 50 °C, 24 h, 85%; (xvii). TiCl4, DCM, 0 °C, 89%.
3. Conclusion
on Merck Silica Gel 60 F254 plates. Column chromatography was
carried out using silica gel 60–120 mesh (Qingdao Marine Chemi-
cal, China). NMR spectra were recorded on Gemini 200 MHz spec-
trometer with tetramethylsilane as internal standard using CDCl3.
The chemical shifts are expressed as d values in parts per million
(ppm) and the coupling constants (J) are given in hertz (Hz). Yields
were of purified compounds and were not optimized. Optical rota-
tions were measured with JASCO DIP 300 digital polarimeter at
25 °C.
In conclusion, the asymmetric total synthesis of dodoneine has
been accomplished by using a Sharpless asymmetric epoxidation, a
1,3-syn-diasteroselective reduction and Grubb’s metathesis as key
steps.
4. Experimental
4.1. General
4.1.1. 4-(Benzyloxy)benzaldehyde
To a stirred suspension of NaH (3.77 g, 163.91 mmol) in THF
(70 mL) a solution of 7 (10 g, 81.96 mmol) in THF (20 mL) was
added dropwise at 0 °C under a nitrogen atmosphere. After stirring
for 15 min, benzyl bromide (90.16 mmol, 10.7 mL) was added and
the reaction mixture was stirred overnight. The reaction mixture
was quenched with saturated aq NH4Cl (50 mL) at 0 °C and
extracted with ethylacetate (3 ꢁ 50 mL). The combined organic
All commercially available reagents were used directly without
further purification unless otherwise stated. The solvents used
were all of AR grade and were distilled under a positive pressure
of dry nitrogen atmosphere where necessary. All reactions were
performed in pre-dried apparatus under a nitrogen atmosphere
unless otherwise stated. The progress of the reactions was moni-
tored by analytical thin-layer chromatography (TLC) performed

1538
B. Das et al. / Tetrahedron: Asymmetry 20 (2009) 1536–1540
extracts were washed with brine, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography (ethyl acetate/hexane, 5:5) to af-
ford pure 4-(benzyloxy) benzaldehyde (14.24 g, 82%) as a white
purified by column chromatography (ethyl acetate/hexane, 2:8) to
afford pure 9 (0.850 g, 81%) as a yellow solid. IR (neat): 1715, 1601,
1511, 1455, 1249 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 7.49–7.30
.
(5H, m), 7.09 (2H, d, J = 8.0 Hz), 6.99–6.87 (3H, m), 5.82 (1H, d,
J = 16.0 Hz), 5.00 (2H, s), 4.15 (2H, q, J = 7.0 Hz), 2.68 (2H, t,
J = 7.0 Hz), 2.50–2.41 (2H, m), 1.22 (3H, t, J = 7.0 Hz). 13C NMR
(50 MHz, CDCl3): d = 166.3, 157.3, 148.0, 133.1, 129.4, 128.2,
127.6, 127.1 114.5, 114.1, 69.9, 60.0, 33.8, 33.2, 13.8. ESIMS: m/z
311 [M+H]+. Anal. Calcd for C20H20O2: C, 77.42; H, 7.10. Found: C,
77.39; H, 6.99.
solid. IR (neat): 3423, 1739, 1686, 1506, 1255 cmꢀ1 1H NMR
.
(200 MHz, CDCl3): d = 7.83 (2H, d, J = 8.0 Hz), 7.50–7.32 (5H, m),
7.06 (2H, d, J = 8.0 Hz), 5.16 (2H, s). 13C NMR (50 MHz, CDCl3):
d = 190.6, 164.8, 137.2, 132.4, 130.1, 128.8, 128.2, 127.5, 115.0,
70.2. ESIMS: m/z 213 [M+H]+. Anal. Calcd for C14H12O2: C, 79.25;
H, 5.66. Found: C, 79.17; H, 5.61.
4.1.2. (E)-Ethyl 3-(4-(benzyloxy)phenyl) acrylate
4.1.6. (E)-5-(4-(Benzyloxy) phenyl) pent-2-en-1-ol
To a stirred solution of 4-(benzyloxy) benzaldehyde (5.0 g,
23.58 mmol) in dry CH2Cl2 (50 mL) ethyl (triphenyl phosphorny-
lidene) acetate (13.3 g, 38.21 mmol) was added and the mixture
was stirred at ambient temperature for 8 h. It was then concen-
trated in vacuo. The residue on purification by column chromatog-
raphy (ethyl acetate/hexane, 2:8) afforded pure (E)-ethyl 3-(4-
(benzyloxy) phenyl) acrylate (5.32 g, 80%) as a colourless solid. IR
To a solution of 9 (0.850 g, 2.74 mmol) in dry CH2Cl2 (10 mL)
cooled to ꢀ78 °C DIBAL-H (1.4 M, 4.9 mL, 6.85 mmol) was added
dropwise and the mixture was stirred at that temperature for
1 h. The reaction mixture was then quenched by slow addition of
dry methanol (10 mL) and was brought to room temperature. Sat-
urated aq sodium potassium tartrate solution (10 mL) was added
to the reaction mixture and stirred until two layers separated
(2 h). Dichloromethane was evaporated under reduced pressure
and the remaining aq layer was extracted with EtOAc
(2 ꢁ 50 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification of the residue by column chromatography (ethyl ace-
tate/hexane, 3:7) afforded pure 6 (0.580 g, 79%) as a yellow solid.
(neat): 1712, 1632, 1570, 1509, 1249 cmꢀ1 1H NMR (200 MHz,
.
CDCl3): d = 7.64 (1H, d, J = 16.0 Hz), 7.49–7.30 (5H, m), 6.95 (2H,
d, J = 8.0 Hz), 6.31 (1H, d, J = 16.0 Hz), 5.08 (2H, s), 4.22 (2H, q,
J = 7.0 Hz), 1.32 (3H, t, J = 7.0 Hz). 13C NMR (50 MHz, CDCl3):
d = 167.2, 160.8, 144.9, 136.2, 129.9, 128.2, 128.0, 127.0, 116.2,
115.0, 70.2, 60.1, 13.3. ESIMS: m/z 283 [M+H]+. Anal. Calcd for
C18H18O3: C, 76.60; H, 6.38. Found: C, 76.55; H, 6.32.
IR (neat): 3386, 1606, 1510, 1455, 1241 cmꢀ1 1H NMR (200 MHz,
.
CDCl3): d = 7.49–7.26 (5H, m), 7.09 (2H, d, J = 8.0 Hz), 6.90 (2H, d,
J = 8.0 Hz), 5.70–5.61 (2H, m), 5.01 (2H, s), 4.02 (2H, d, J = 6.0 Hz),
2.60 (2H, t, J = 7.0 Hz), 2.32–2.22 (2H, m), 2.11 (1H, br s). 13C
NMR (50 MHz, CDCl3): d = 156.8, 137.2, 134.1, 132.2, 129.7,
129.3, 128.5, 127.8 127.2, 114.5, 70.0, 63.2, 34.8, 34.3. ESIMS: m/z
269 [M+H]+. Anal. Calcd for C18H20O2: C, 80.60; H, 7.46. Found: C,
80.52; H, 7.41.
4.1.3. 3-(4-(Benzyloxy)phenyl)propan-1-ol
To a solution of (E)-ethyl 3-(4-(benzyloxy) phenyl) acrylate (2 g,
7.0 mmol) in dry THF (20 mL) at 0 °C LiBH4 (0.446 g, 21.23 mmol)
was added with stirring under nitrogen atmosphere and the stir-
ring was continued for 36 h at room temperature. The reaction
mixture was quenched with saturated NH4Cl solution (20 mL) at
0 °C and extracted with EtOAc (2 ꢁ 50 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography (ethyl acetate/hexane, 3:7) to af-
ford pure 8 (1.561 g, 91%) as a colourless crystalline solid. IR
4.1.7. ((2S,3S)-3-(4-(Benzyloxy) phenethyl) oxiran-2-yl)
methanol
To a suspension of the powder of activated 4 Å (0.116 g) molec-
ular sieves in dry CH2Cl2 (10 mL) Ti (OiPr)4 (2.16 mmol, 0.6 mL) and
(+)-DIPT (2.38 mmol, 0.5 mL) were added sequentially at ꢀ20 °C.
After stirring for 30 min allylic alcohol (0.580 g, 2.16 mmol) in
dry CH2Cl2 (8 mL) was added and stirring was continued for an-
other 30 min at the same temperature. Then TBHP (5.4 mmol,
1.5 mL) was added and after stirring for another 3 h at the same
temperature, the reaction mixture was quenched by addition of
water (10 mL). It was allowed to remain at room temperature by
stirring for 30 min. After re-cooling at 0 °C, an aq solution of NaOH
(30% W/V, 10 mL, saturated with brine) was added to it and the
mixture was stirred at 0 °C for 1 h. The solvent was removed under
reduced pressure and the residue was extracted with ether
(3 ꢁ 10 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (ethyl ace-
tate/hexane, 4:6) to afford pure 5 (0.565 g, 92%) as a colourless so-
(neat): 3324, 1608, 1510, 1242 cmꢀ1 1H NMR (200 MHz, CDCl3):
.
d = 7.40–7.22 (5H, m), 7.08 (2H, d, J = 8.0 Hz), 6.87 (2H, d,
J = 8.0 Hz), 4.88 (2H, s), 3.59 (2H, t, J = 7.0 Hz), 3.00 (1H, br s),
2.59 (2H, t, J = 7.0 Hz), 1.85–1.72 (2H, m).13C NMR (50 MHz,
CDCl3): d = 156.5, 137.2, 134.0, 129.0, 128.2, 127.8, 127.1, 114.1,
69.8, 61.1, 34.0, 20.2. ESIMS: m/z 243 [M+H]+. Anal. Calcd for
C16H18O2: C, 79.34; H, 7.44. Found: C, 79.28; H, 7.39.
4.1.4. 3-(4-(Benzyloxy) phenyl) propanal
To a solution of oxaloyl chloride (9.69 mmol, 0.8 mL) in dry
CH2Cl2 (15 mL) at ꢀ78 °C, DMSO (20.6 mmol, 1.4 mL) was added
dropwise with stirring under nitrogen atmosphere. After 15 min.
compound 8 (1.561 g, 6.4 mmol) was added into the reaction mix-
ture and subsequently after stirring for 0.5 h at ꢀ78 °C, Et3N
(32.2 mmol, 4.5 mL) was added and the mixture was stirred for an-
other 0.5 h at ꢀ78 °C and then for 0.5 h at 0 °C. The reaction mix-
ture was quenched with saturated NH4Cl solution (20 mL) at 0 °C
and extracted with EtOAc (2 ꢁ 50 mL). The combined organic ex-
tracts were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. The aldehyde, thus obtained (0.813 g,
82%), was used directly after flash column chromatography for
the next reaction.
lid. ½a 2D5
ꢂ
¼ ꢀ5:4 (c 0.5, CHCl3). IR (neat): 3418, 1608, 1510,
1239 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d = 7.68–7.50 (5H, m),
7.30 (2H, d, J = 8.0 Hz), 7.11 (2H, d, J = 8.0 Hz), 5.25 (2H, s), 4.02
(1H, dd, J = 12.0, 2.0 Hz), 3.73 (1H, dd, J = 12.0, 3.0 Hz), 3.17 (1H,
m), 3.02 (1H, m), 2.99–2.81 (2H, m), 2.11–2.01 (2H, m). 13C NMR
(50 MHz, CDCl3): d = 157.1, 137.2, 133.5, 129.8, 128.4, 127.9,
127.7, 114.9, 70.0, 61.8, 58.8, 55.2, 33.5, 31.2. ESIMS: m/z
285[M+H]+. Anal. Calcd for C18H20O3: C, 76.06; H, 7.04. Found: C,
76.14; H, 7.01.
4.1.5. (E)-Ethyl 5-(4-(benzyloxy) phenyl) pent-2-enoate
To a solution of aldehyde (0.813 g, 3.38 mmol) in dry CH2Cl2
(10 mL) ethyl (triphenyl phosphornylidene) acetate (1.76 g,
5.0 mmol) was added and the mixture was stirred at ambient tem-
perature for 8 h. It was concentrated in vacuo and the residue was
4.1.8. (S)-5-(4-(Benzyloxy) phenyl) pentane-1,3-diol
To a stirred solution of 5 (0.565 g, 1.98 mmol) in dry THF (8 mL)
under a N2 atmosphere at 0 °C was added Red-Al solution in

B. Das et al. / Tetrahedron: Asymmetry 20 (2009) 1536–1540
1539
toluene (1.8 mL, 5.9 mmol of 70% w/w) and the reaction mixture
was stirred at room temperature for 2 h. The reaction mixture
was quenched with saturated aq NH4Cl (10 mL) solution and then
extracted with EtOAc (30 mL). The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography
(ethyl acetate/hexane, 5:5) to afford pure 10 (0.466 g, 82%) as a col-
for 0.5 h at 0 °C. The reaction mixture was quenched with satu-
rated NH4Cl solution (10 mL) at 0 °C and extracted with EtOAc
(2 ꢁ 10 mL). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo.
The aldehyde 4 thus obtained (0.163 g, 82%) was used directly after
flash column chromatography for the next reaction.
ourless solid. ½a D25
ꢂ
¼ ꢀ1:4 (c 0.5, CHCl3). IR (neat): 3330, 1611,
4.1.12. (S)-8-(4-(Benzyloxy) phenyl)-6-(tert-butyldimethyl-
silyloxy) oct-1-en-4-ol
1512, 1455, 1247 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d = 7.66–7.51
(5H, m), 7.28 (2H, d, J = 8.0 Hz), 7.10 (2H, d, J = 8.0 Hz), 5.21 (2H,
s), 4.14–3.92 (3H, m), 2.92–2.74 (2H, m), 2.68 (2H, br s), 2.01–
1.90 (2H, m). 13C NMR (50 MHz, CDCl3): d = 157.2, 137.8, 134.1,
129.0, 128.3, 127.3, 127.1, 114.8, 71.4, 70.0, 61.2, 39.2, 38.5, 31.0.
ESIMS: m/z 287 [M+H]+. Anal. Calcd for C18H22O3: C, 75.52; H,
7.69. Found: C, 75.41; H, 7.65.
To a solution of aldehyde 4 (0.163 g, 0.4 mmol) in dry ether
(4 mL) at 0 °C allyl magnesium bromide (0.2 mL, 1.63 mmol) was
added slowly with stirring under nitrogen atmosphere. After
10 min. the reaction mixture was quenched with saturated NH4Cl
(5 mL) and was extracted with EtOAc (2 ꢁ 10 mL). The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuo. Purification of the residue by
column chromatography (ethyl acetate/hexane, 2:8) afforded pure
12 (0.133 g, 74%) as a viscous liquid.
4.1.9. (S)-5-(4-(Benzyloxy)phenethyl)-2,2,3,3,9,9,10,10-
octamethyl-4,8-dioxa-3,9-disilaundecane
Imidazole (0.443 g, 6.5 mmol) and TBDMS-Cl (0.490 g,
3.25 mmol) were added sequentially to a solution of 10 (0.466 g,
1.62 mmol) in dry DMF (6 mL) at 0 °C. After stirring for 5 min,
DMAP (catalytic amount) was added to the reaction mixture and
stirring was continued for 12 h at room temperature. The reaction
mixture was quenched with saturated aq NH4Cl solution (10 mL)
and extracted with EtOAc (3 ꢁ 10 mL). The combined organic ex-
tracts were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification of the residue by column chro-
matography (ethyl acetate/hexane, 1:9) afforded pure di-TBS com-
4.1.13. (S)-8-(4-(Benzyloxy) phenyl)-6-(tert-butyldimethyl-
silyloxy) oct-1-en-4-one
To a solution 12 (0.133 g, 0.3 mmol) in dry CH2Cl2 (3 mL) were
added NaHCO3 (0.05 g, 0.6 mmol) and DMP (256 mg, 0.6 mmol) at
0 °C. The reaction mixture was stirred for 30 min while warming to
room temperature. A portion of aq Na2S2O3 solution (5 mL) was
added to quench the reaction and the aq layer was extracted with
EtOAc (2 ꢁ 10 mL). The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (ethyl acetate/
hexane, 1:9) to afford pure 13 (0.116 g, 88%) as a viscous liquid.
pound (0.736 g, 88%) as a viscous solid. ½a D25
¼ þ7:0 (c 0.5, CHCl3).
ꢂ
IR (neat): 1611, 1511, 1465, 1250 cmꢀ1. 1H NMR (200 MHz, CDCl3):
d = 7.68–7.51 (5H, m), 7.32 (2H, d, J = 8.0 Hz), 7.10 (2H, d,
J = 8.0 Hz), 5.23 (2H, s), 4.05 (1H, m), 3.92–3.85 (2H, m), 2.84–
2.71 (2H, m), 2.03–1.89 (4H, m), 1.05 (18H, s), 0.24 (6H, s), 0.18
(6H, m). 13C NMR (50 MHz, CDCl3): d = 157.4, 137.0, 135.1, 129.7,
129.0, 128.1, 128.0, 115.1, 70.2, 69.5, 60.2, 40.5, 40.0, 31.1, 25.2,
17.7, ꢀ4.2, ꢀ5.0. ESIMS: m/z 487 [M+H]+. Anal. Calcd for
C30H50O3Si2: C, 70.04; H, 9.73. Found: C, 70.23; H, 9.70.
½
a 2D5
ꢂ
¼ þ1:8 (c 0.6, CHCl3). IR (neat): 1716, 1612, 1511, 1479,
1245 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 7.62–7.50 (5H, m), 7.29
.
(2H, d, J = 8.0 Hz), 7.10 (2H, d, J = 8.0 Hz), 6.05 (1H, m), 5.38–5.25
(2H, m), 5.22 (2H, s), 4.28–4.13 (2H, m), 4.06–3.95 (4H, m), 2.82–
2.71 (2H, m). 13C NMR (50 MHz, CDCl3): d = 207.5, 157.0, 136.2,
135.0, 130.3, 129.5, 129.1, 130.7, 126.5, 119.9, 115.1, 70.2, 69.4,
49.9, 39.6, 30.0, 25.8, 19.2, ꢀ4.5. ESIMS: m/z 439 [M+H]+. Anal. Calcd
for C27H38O3Si: C, 73.97; H, 8.68. Found: C, 73.84; H, 8.62.
4.1.10. (S)-5-(4-(Benzyloxy) phenyl)-3-(tert-butyldimethyl-
silyloxy) pentan-1-ol
4.1.14. (4R,6S)-8-(4-(Benzyloxy) phenyl)-6-(tert-
A solution of di-TBS compound (0.736 g, 1.431 mmol) in MeOH
(5 mL) was treated with PTSA (0.013 g, 0.07 mmol) at 0 °C. After
stirring for 20 min the reaction mixture was quenched with satu-
rated aq NaHCO3. The solvent was removed in vacuo and the resi-
due was extracted with EtOAc (2 ꢁ 20 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4
and concentrated in vacuo. The remaining mass was purified by
column chromatography (ethyl acetate/hexane, 2:8) to afford pure
butyldimethylsilyloxy)oct-1-en-4-ol
To a stirred solution of ketone 13 (0.116 g, 0.26 mmol) in ether
(3 mL) was added LiI (0.354 g, 2.64 mmol) and the resulting mix-
ture was stirred at ꢀ40 °C for 5 min. The mixture was cooled to
ꢀ78 °C, and LiAlH4 (0.100 g, 2.64 mmol) was added. The mixture
was stirred for 30 min and quenched with aq 10% potassium so-
dium tartrate solution (5 mL). The layers were separated and the
aq layer was extracted with ether (2 ꢁ 10 mL). The combined or-
ganic extracts were washed with brine, dried over anhydrous
Na2SO4 and concentrated in vacuo. The remaining mass was puri-
fied by column chromatography (ethyl acetate/hexane, 2:8) to af-
11 (0.463 g, 81%) as a viscous liquid. ½a D25
ꢂ
¼ ꢀ33:0 (c 0.6, CHCl3). IR
(neat): 3444, 1613, 1510, 1459, 1243 cmꢀ1
.
1H NMR (200 MHz,
CDCl3): d = 7.68–7.53 (5H, m), 7.30 (2H, d, J = 8.0 Hz), 7.12 (2H, d,
J = 8.0 Hz), 5.23 (2H, s), 4.18 (1H, m), 4.05 (1H, m), 3.94 (1H, m),
2.81–2.74 (2H, m), 2.08–1.98 (4H, m), 1.07 (9H, s), 0.29 (6H, s).
13C NMR (50 MHz, CDCl3): d = 158.0, 137.3, 131.7, 129.5, 128.9,
128.2, 128.0, 115.1, 71.1, 70.2, 60.0, 39.1, 38.1, 29.5, 27.0, 17.6,
ꢀ4.3. ESIMS: m/z 400[M+H]+. Anal. Calcd for C24H36O3Si: C,
72.00; H, 9.00. Found: C, 71.87; H, 8.94.
ford pure 3 (0.109 g, 94%) as a viscous liquid. ½a D25
ꢂ
¼ ꢀ0:1 (c 0.6,
CHCl3). IR (neat): 3456, 1611, 1511, 1461, 1245 cmꢀ1
.
1H NMR
(200 MHz, CDCl3): d = 7.40–7.22 (5H, m), 7.03 (2H, d, J = 8.0 Hz),
6.82 (2H, d, J = 8.0 Hz), 5.76 (1H, m), 5.13–5.05 (2H, m), 5.01 (2H,
s), 3.94 (1H, m), 3.75 (1H, m), 2.61–2.50 (2H, m), 2.21–2.15 (2H,
m), 1.87–1.72 (2H, m), 1.65–1.56 (2H, m), 0.92 (9H, s), 0.06 (6H,
s). 13C NMR (50 MHz, CDCl3): d = 157.5, 137.9, 136.1, 134.7,
129.8, 129.0, 128.1, 127.8, 118.0, 114.9, 72.6, 70.2, 68.1, 42.9,
40.0, 31.5, 26.4, 18.1, ꢀ3.2, ꢀ4.4. ESIMS: m/z 441 [M+H]+. Anal.
Calcd for C27H40O3Si: C, 73.64; H, 9.09. Found: C, 73.50; H, 9.01.
4.1.11. (S)-5-(4-(Benzyloxy) phenyl)-3-(tert-butyldimethyl-
silyloxy) pentanal
To a solution of oxaloyl chloride (0.06 mL, 0.75 mmol) in dry
CH2Cl2 (4 mL) at ꢀ78 °C, DMSO (0.1 mL, 1.6 mmol) was added
dropwise with stirring under nitrogen atmosphere. After 15 min
compound 8 (0.200 g, 0.5 mmol) was added to the reaction mix-
ture. After stirring for 0.5 h at ꢀ78 °C, Et3N (0.3 mL) was added
and the mixture was stirred for another 0.5 h at ꢀ78 °C and then
4.1.15. (4R,6S)-8-(4-(Benzyloxy)phenyl)-6-(tert-butyldimethyl-
silyloxy)oct-1-en-4-yl acrylate
To a stirred solution of 3 (0.050 g, 0.11 mmol) in dry CH2Cl2
(2 mL) were added acryloyl chloride (0.02 g, 0.22 mmol) and Et3N

1540
B. Das et al. / Tetrahedron: Asymmetry 20 (2009) 1536–1540
(0.057 g, 0.56 mmol) at 0 °C. The reaction mixture was allowed to
warm to room temperature and stirred for 3 h. The mixture was di-
luted with water (3 mL) and extracted into CH2Cl2 (2 ꢁ 10 mL).The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuo. The gummy mass
was purified by column chromatography (ethyl acetate/hexane,
with stirring under a N2 atmosphere. After 2 h the reaction mixture
was quenched with saturated ammonium chloride solution (3 mL)
and extracted with EtOAc (2 ꢁ 10 mL). The combined organic ex-
tracts were washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification of the residue by column chro-
matography (ethyl acetate/hexane, 3:7) afforded pure (3S,5R)-1-
(4-(benzyloxy) phenyl)oct-7-ene-3,5-diol (0.035 g, 95%) as a vis-
cous liquid which was used directly for the acetonide protection
reaction.
1:9) to afford pure
¼ ꢀ2:0 (c 0.25, CHCl3). IR (neat): 3431, 1724, 1611, 1511,
1242 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 7.50–7.31 (5H, m),
2 (0.053 g, 96%) as a colourless solid.
½ ꢂ
a 2D5
.
7.12 (2H, d, J = 8.0 Hz), 6.91 (2H, d, J = 8.0 Hz), 6.40 (1H, m), 6.14
(1H, m), 5.89–5.68 (2H, m), 5.21–5.03 (3H, m), 5.02 (2H, s), 3.80
(1H, m), 2.70–2.51 (2H, m), 2.48–2.31 (2H, m), 1.94–1.70 (4H,
m), 0.92 (9H, s), 0.04 (6H, s). 13C NMR (50 MHz, CDCl3): d = 165.2,
157.1, 137.4, 134.8, 133.6, 131.0, 130.7, 129.0, 128.9, 128.2,
127.8, 127.4, 118.1, 114.5, 71.4, 70.2, 69.0, 41.1, 38.9, 29.9, 26.0,
18.2, -3.8. ESIMS: m/z 495[M+H]+. Anal. Calcd for C30H42O4Si: C,
72.87; H, 8.50. Found: C, 72.75; H, 8.43.
4.1.19. (4R,6S)-4-Allyl-6-(4-(benzyloxy)phenethyl)-2,2-
dimethyl-1,3-dioxane
To a stirred solution of (3S,5R)-1-(4-(benzyloxy) phenyl)oct-7-
ene-3,5-diol (0.035 g, 0.1 mmol) in dry DCM (2 mL) 2,2-dimethoxy
propane (0.02 mL, 0.12 mmol) was added at 0 °C. Then CSA
(0.01 mmol) was added with stirring under a N2 atmosphere. After
stirring for further 2 h, the reaction mixture was quenched with
saturated aq NaHCO3 solution (3 mL) and extracted with EtOAc
(2 ꢁ 10 mL). The combined organic layer was washed with water
and brine dried over Na2SO4 and concentrated. The crude residue
was purified by column chromatography (ethyl acetate/hexane,
4.1.16. (R)-6-((S)-4-(4-(Benzyloxy)phenyl)-2-(tert-
butyldimethylsilyloxy)butyl)-5,6-dihydro-2H-pyran-2-one
To
a stirred solution of Grubbs’ catalyst (1st generation,
5 mol %) in dry CH2Cl2 (1 mL) at 55 °C was added compound 2
(0.053 g, 0.10 mmol) dissolved in CH2Cl2 (2 mL). The resulting mix-
ture was heated for 12 h. After completion of the reaction, the con-
tents were cooled and the solvent was removed under reduced
pressure to yield a crude product, which was purified by silica
gel column chromatography (ethyl acetate/hexane, 2:8) to afford
pure 14 (0.042 g, 85%) as a colourless solid. 1H NMR (200 MHz,
CDCl3): d = 7.46–7.24 (7H, m), 7.05 (1H, m), 6.84 (2H, d,
J = 8.0 Hz), 6.02 (1H, d, J = 10.0 Hz), 5.04 (2H, s), 4.58 (1H, m),
4.12 (1H, m), 2.68–2.52 (2H, m), 2.38–2.29 (2H, m), 1.96–1.61
(4H, m), 0.86 (9H, s), 0.05 (6H, s). ESIMS: m/z 467[M+H]+. Anal.
Calcd for C28H38O4Si: C, 72.10; H, 8.16. Found: C, 72.28; H, 8.11.
1:9) to afford pure A (0.034 g, 89%) as a yellow solid. ½a D25
ꢂ
¼ ꢀ7:1
(c 0.15, CHCl3) IR (neat): 1611, 1510, 1379, 1238 cmꢀ1 1H NMR
.
(200 MHz, CDCl3): d = 7.43–7.21 (5H, m), 7.02 (2H, d, J = 8.0 Hz),
6.82 (2H, d, J = 8.0 Hz), 5.74 (1H, m), 5.06 (2H, m), 5.02 (2H, s),
3.82–3.63 (2H, m), 2.71–2.52 (2H, m), 2.25 (1H, m), 2.11(1H, m),
1.75 (1H, m), 1.60 (1H, m), 1.48–1.28 (2H, m), 1.32 (6H, s). 13C
NMR (50 MHz, CDCl3): d = 157.2, 137.2, 134.5, 134.2, 129.5,
128.6, 127.8, 127.2, 117.1, 114.5, 98.8, 70.1, 68.9, 67.5, 40.8, 38.2,
36.2, 30.1, 30.0, 20.0. HRMS: m/z 367.2285 [M+H]+ (Calcd for
C24H31O3: 367.2273).
Acknowledgements
4.1.17. (R)-6-((S)-2-Hydroxy-4-(4-hydroxyphenyl) butyl)-5,6-
dihydro-2H-pyran-2-one
The authors thank CSIR and UGC, New Delhi for financial
assistance.
To a stirred solution of 14 (0.042 g, 0.09 mmol) in dry CH2Cl2
(2 mL) under a N2 atmosphere at 0 °C TiCl4 (0.02 mL, 0.19 mmol,)
was added and the reaction mixture was stirred at room tempera-
ture for 1 h. The reaction mixture was quenched with saturated aq
NaHCO3 solution (5 mL) and then extracted with CHCl3 (2 ꢁ 5 mL).
The combined organic layer was washed with water and brine and
dried over Na2SO4. The mixture was concentrated and the crude res-
iduewaspurifiedbycolumnchromatography(ethylacetate/hexane,
References
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Tetrahedron 1994, 50, 171.
3:7) toafford pure 1 (0.021 g, 89%) as a colourlesssolid. ½a D25
¼ þ39:3
ꢂ
(c 0.35, CHCl3) {lit.2
½
a 2D5
ꢂ
¼ þ40:2 (c 0.4, CHCl3)}, IR (neat): 3417,
1700, 1513, 1454, 1258 cmꢀ1 1H NMR (200 MHz, CDCl3): d = 7.01
.
(2H, d, J = 8.0 Hz), 6.82 (1H, m), 6.70 (2H, d, J = 8.0 Hz), 5.95 (1H, d,
J = 10.0 Hz), 4.84 (1H, br s), 4.61 (1H, m), 3.99 (1H, m), 3.82 (1H, br
s), 2.71–2.51 (2H, m), 2.37–2.22 (2H, m), 2.00–1.66 (4H, m). 13C
NMR (50 MHz, CDCl3): d = 163.8, 154.6, 145.2, 145.0, 133.6, 129.5,
129.2, 129.0, 120.5, 115.0, 75.2, 66.1, 42.4, 39.6, 36.2, 30.5. HRMS:
m/z 285.1111 [M+Na]+ (Calcd for C15H18O4Na: 285.1102).
5. Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett. 1988, 29, 5419.
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4.1.18. (3S,5R)-1-(4-(Benzyloxy) phenyl) oct-7-ene-3,5-diol
To a stirred solution of 3 (0.050 g, 0.11 mmol) in dry THF (2 mL)
at 0 °C, TBAF (0.03 mL, 0.1 mmol, 1 M in THF solution) was added