Total synthesis of (+)-anamarine

Article abstract of DOI:10.1039/c2ob06940g

Total synthesis of (+)-anamarine a polyoxygenated δ-pyranone natural product was accomplished via cross-metathesis protocol starting from 3-butene-1-ol and glycidol. Other key features of this synthetic strategy include use of Sharpless asymmetric epoxida

Full text of DOI:10.1039/c2ob06940g

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PAPER
Total synthesis of (+)-anamarine†
Krishnammagari Suresh Kumar and Cirandur Suresh Reddy*
Received 18th November 2011, Accepted 14th January 2012
DOI: 10.1039/c2ob06940g
Total synthesis of (+)-anamarine a polyoxygenated δ-pyranone natural product was accomplished via
cross-metathesis protocol starting from 3-butene-1-ol and glycidol. Other key features of this synthetic
strategy include use of Sharpless asymmetric epoxidation, dihydroxylation, and deoxygenation-
isomerization through allene rearrangement.
could be made from the commercially available 3-butene-1-ol
and glycidol respectively by sequential reactions. Cross-metath-
esis reaction of 6 and 7 leads to the target compound.
Synthesis of alkene 6 was accomplished from 3-butenol 10.
Treatment of 10 with benzyl bromide afforded its benzylether 13
in 95% yield. Subsequently 13 was converted into racemic
epoxide 14 in 92% yield by epoxidation with m-CPBA.
Introduction
(+)-Anamarine (1) a member of the polyoxygenated δ-pyranone
(5,6-dihydro-2H-pyran-2-one) containing natural product family
was isolated from the flowers and leaves of an unclassified Peru-
vian Hyptis species.1 It is structurally similar to other members
of the polyhydroxy δ-pyranone family such as synargentolide A
(2), spicigerolide (3), synrotolide (4) and hyptolide (5). δ-Pyra-
none is an ubiquitous structural unit found in a number of bio-
active natural products of therapeutic significance. Natural
products and their analogues possessing this moiety exhibit a
number of pharmacological properties such as anti-cancer2 and
anti-leukemic3 activity, inhibits HIV protease,4 induce apopto-
sis5,6 and bioactivities in many other biological processes.7
As a result of their biological importance, several stereo-
selective synthetic approaches have been made for anamarine
1.8–11 The first synthesis which was accomplished from carbo-
hydrate obviously proved its absolute stereochemical configura-
The racemic terminal epoxide 14, on subjection to solvent free
hydrolytic kinetic resolution13 with (R,R)-(−)-N,N1-bis(3,5-di-
tert-butylsalicyclidene)-1,2-cyclohexanediaminocobalt
(III)
afforded the required isomer of the chiral epoxide 15 in 42%
yield. Reduction of 15 with LiAlH4 gave secondary alcohol 16
which was converted into TBDMS ether 17 in 98% yield by
silylation with TBDMSCl (Scheme 2). Selective reductive clea-
vage of benzyl ether function in 17 by lithium napthalenide led
to its primary alcohol 18 in 94% yields.14 The alcohol 18 on
tion.8a Recent approaches to (+)-anamarine
1 exploited
asymmetric dihydroxylation,10 asymmetric epoxidation11 and
aldol reaction.9 But all of them involved multiple steps and
afforded rather low yields.
Results and discussion
As a part of our work, on the synthesis of a novel biologically
active compounds,12 we have ventured into the total synthesis of
pharmacological active natural products. In this endeavour the
total synthesis of (+)-anamarine 1 is reported (Fig. 1).
Retrosynthetic analysis (Scheme 1) revealed that the target
compound 1 is made up of two units, olefine 6 and vinyl lactone
7. These two substrates olefine 6 and vinyl lactone 7 in turn
Department of Chemistry, Sri Venkateswara University, Tirupati 517
502, A.P., India.. E-mail: csrsvu@gmail.com; Fax: +91-877 2289555;
Tel: +91-9849694958
†Electronic supplementary information (ESI) available: Spectra of all
the compounds are given as supplementary information. See DOI:
10.1039/c2ob06940g
Fig. 1 Polyoxygenated δ-pyranones.
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subjection to Swern oxidation followed by addition of lithiated
ethylpropiolate gave to the hydroxy alkynoate 9 in 75% yield.
The PPh3-mediated allene type rearrangement of 9 resulted in
(E,E)-diene 8 in 71% yield.15 On stereo and regioselective asym-
metric hydroxylation of 816 via Sharpless asymmetric dihydroxy-
lation, using AD-mix-α the diol 20 was obtained in 90% yield
with a diastereomeric ratio of 90 : 10. The diol 20 was sub-
sequent converted into its acetonide 21 under standard con-
ditions. Chemoselective reduction of the ester 21 with DIBAL-H
at −30 °C afforded the required allylic alcohol 22 in 90% yield.
The requisite chiral epoxy alcohol 23 in 88% yield was obtained
at this stage via a Sharpless asymmetric epoxidation17 of 22
using (+)-DET. Conversion of epoxy alcohol 23 into the
target alkene18 6 was effected by initial conversion of 23 to its
iodo derivative 24 followed by instantaneous reductive elimin-
ation of the epoxy iodide from 24 by rapid addition of tert-butyl-
lithium in ether.
The other required component for accomplishing the final syn-
thesis of (+)-anamarine (1) is the vinyl lactone 7. It was syn-
thesized from the racemic glycidol 12. Treatment of 12 with p-
methoxybenzyl bromide gave its PMB derivative 25 in 92%
yield which was subjected to solvent free hydrolytic kinetic res-
olution19 with (S,S)-(–)-N,N1-bis(3,5-di-tert-butylsalicyclidene)-
1,2-cyclohexanediaminocobalt (III) to afford the chiral epoxide
26 in 42% yield. Simple opening of the epoxide ring in 26 with
the anion generated from ethyl propiolate in the presence of
BF3·OEt2 delivered quantitatively the known alkyne 2720 which
was subsequently converted into cis alkene 11 by Lindlar’s
reduction. The alkene ester 11 was cyclized with p-PTS in
benzene to obtain the pyran derivative 28. The PMB masked
hydroxyl group of the lactone 28 was released by its deprotection
using DDQ and the free alcohol 29 was subjected to Swern oxi-
dation followed by Wittig reaction with triphenyl phosphonium
methyl iodide to give the desired lactone intermediate 721
(Scheme 3).
The alkene 6 on cross-metathesis reaction with the vinyl
lactone 7 using second-generation Grubb’s ruthenium complex
as the catalyst (Catalyst A) affords the desired lactone 30 in
86% yield.11,22 In the cross-metathesis of 6 and 7 they were used
in 1 : 2 stoichiometric ratio to facilitate easy identification of the
product formed in the reaction from the substrates in TLC moni-
toring and also in the separation of the product. Removal of acet-
enoide and TBS protecting groups and acetylation of the
resulting tetrahydroxy derivative afforded (+)-anamarine 1 in
80% yield (Scheme 4). The spectral and specific rotation data of
the synthesized sample 1 are in complete agreement with that
reported in the literature.9–11
Scheme 1 Reterosynthetic analysis of anamarine 1.
Scheme 2 Reagents and conditions; (a) NaH, BnBr, TBAI, anhydrous THF, 0 °C to rt, 12 h, 95%; (b) m-CPBA, CH2Cl2, 0 °C, 2 h, 92%; (c) (R,R)-
Jocobsen’s catalyst, water, 36 h, 42%; (d) LiAlH4, THF, 0 °C to rt, 3 h, 95%; (e) TBDMSCl, Imidazole, CH2Cl2, 0 °C to rt, 3 h, 98%; (f) Li, Naptha-
lene, THF, −20 °C, 2 h, 94%; (g) (COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, 3 h; (h) Ethyl propiolate, LiHMDS, THF, −78 °C, 1 h, 75% (for two
t
steps); (i) PPh3, benzene, rt, 6 h, 71%; ( j) AD-mix-α, CH3SO2NH2, BuOH–H2O (1 : 1), 0 °C, 3 days, 90% (90 : 10); (k) 2,2-DMP, CSA (cat.),
CH2Cl2, 0 °C to rt, 1 h, 92%; (l) DIBAL-H, anhydrous CH2Cl2, −30 °C, 1 h, 90%; (m) (+)-DET, Ti(OiPr)4, TBHP, anhydrous CH2Cl2, −20 °C, 24 h,
88%; (n) PPh3, I2, CH2Cl2, 0 °C-reflux, 1 h; (o) tBuLi, THF, −90 °C, 20 min, 96%.
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silica gel. Light petroleum ether (bp 60–80 °C) was used. Yields
refer to chromatographically and spectroscopically (1H, 13C
NMR) homogeneous material. Air-sensitive reagents were trans-
ferred by syringe or double-ended needle. Evaporation of sol-
vents was performed at reduced pressure on a Buchi rotary
evaporator. IR spectra were recorded on Perkin–Elmer 683 spec-
trometer. Optical rotations were obtained on a Horiba 360 digital
1
polarimeter. H and 13C NMR spectra were recorded in CDCl3
solution on Brucker, Avance 300, 400, Varian Gemini 500 MHz.
Chemical shifts are reported in parts per million with respect to
the internal TMS. Mass spectra were recorded on VG micro-
mass-7070H (70 Ev).
Scheme 3 Reagents and conditions; (a) NaH, PMB-Br, TBAI, DMF,
20 h, 92%; (b) (S,S)-Jacobsen’s catalyst, water, 36 h, 42%; (c) Ethyl pro-
piolate, n-BuLi, BF3.OEt3, THF, −78 to 0 °C, 1 h, 99%; (d) Lindlar’s
catalyst, quinoline (cat), H2, Ethyl acetate, 2 h; (e) p-TSA (cat),
Benzene, 85% (for two steps); (f) DDQ, CH2Cl2:H2O (8 : 2), 3 h, 82%;
(g) (i) Dess–Martin periodinate, CH2Cl2, 0 °C to rt, 1 h; (ii) Triphenyl
phosphonium methyl iodide, n-BuLi, THF, −78 °C, 1 h, 70%.
1-(3-Butenyloxymethyl)benzene (13)
To a suspension of NaH (6.656 g, 277.354 mmol, 60% w/v dis-
persion in mineral oil) in anhydrous THF (300 mL) was added
drop wise
a
solution of 3-buten-1-ol 10 (10.000 g,
138.670 mmol) at 0 °C. To this reaction mixture TBAI (0.150 g)
and benzyl bromide (18.140 mL, 152.544 mmol) were added
and stirring was continued for 2 h at the same temperature and
overnight at room temperature. The reaction mixture was
quenched by small crushed ice flakes until a clear solution
(biphasic) had formed. The reaction mixture was extracted with
ether and the extract was washed with water (1 × 100 mL), brine
(1 × 100 mL) and dried over anhydrous Na2SO4. Evaporation of
the solvents followed by column chromatography (9.5 :
0.5 hexane : EtOAc) afforded the pure product 13 (27.38 g, 95%
yield) as a colourless liquid. IR (KBr): 3033, 2927, 2864, 1454,
1363, 1105, 739 cm−1 1H NMR (500 MHz, CDCl3): δ
;
7.32–7.20 (m, 5H), 5.86–5.76 (m, 1H), 5.08–5.00 (dd, J =
17.00, 10.01 Hz, 2H), 4.50 (s, 2H), 3.04–2.99 (m, 1H), 2.73 (t, J
= 4.86 Hz, 1H), 2.47 (dd, J = 4.86, 2.9 Hz, 1H), 1.91–1.85 (m,
1H), 1.77–1.71 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
138.37, 135.18, 128.28, 127.57, 127.47, 116.30, 72.82, 69.52,
34.18; GC-MS: 162 [M+]; Anal. Calcd for C11H14O: C, 81.44;
H, 8.70; found C, 81.40; H, 8.65.
Scheme 4 Reagents and conditions; (a) Catalyst A, anhydrous
CH2Cl2, reflux, 5 h, 86%; (b) 1 N HCl, MeOH–AcCN (1 : 1), 0 °C to rt,
8 h (c) Ac2O, TEA, DMAP, anhydrous CH2Cl2, 0 °C to rt, 0.5 h, 80%.
2-(2-(Benzyloxy)ethyl)oxirane (14)
Conclusion
Crude benzyl ether 13 (15.000 g, 92.592 mmol) was dissolved
in dry CH2Cl2 (300 mL) and the solution was cooled to 0 °C.
NaHCO3 was added (23.362 g), followed by m-CPBA
(45.333 g, 185.185 mmol, 70% w/w). The solution was stirred
for 16 h before being filtered through a pad of celite and concen-
trated under reduced pressure. The residue was then dissolved in
water (100 mL) and extracted with Et2O (3 × 50 mL). The com-
bined organic extracts were then washed with 3 M NaOH (3 ×
50 mL), followed by brine (50 mL), dried over Na2SO4 and
evaporated. Chromatography on silica gel (4 : 1 hexane : EtOAc),
gave 14, as a colourless oil (15.162 g, 92%). IR (KBr): 3031,
In conclusion, we have developed an efficient enantioselective
route for the synthesis of (+)-anamarine 1. The key steps in the
route feature a deoxygenative rearrangement of an alkynol, and a
highly enantio and diastereo controlled dihydroxylation, asym-
metric epoxidation and cross-metathesis.
Experimental section
General methods
Flasks were oven or flame dried and cooled in a desiccator. Dry
reactions were carried out under an atmosphere of Ar or N2.
Reagents and chemicals were purchased from Aldrich. All sol-
vents and reagents were purified by standard techniques. THF
was freshly distilled over Na-benzophenone ketyl. Crude pro-
ducts were purified by column chromatography on 100–200
2969, 2916, 2871, 1452, 1368, 1094, 738 cm−1 1H NMR
;
(500 MHz, CDCl3): δ 7.32–7.23 (m, 5H), 4.50 (s, 2H),
3.62–3.56 (m, 2H), 3.14–2.99 (m, 1H), 2.74 (dd, J = 5.84, 4.61
Hz, 1H), 2.47 (dd, J = 5.84, 2.92 Hz, 1H), 1.91–1.85 (m, 1H),
1.77–1.71 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 138.19,
128.34, 127.57, 126.82, 73.03, 66.97, 50.05, 47.06, 32.88;
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GC-MS: 178.10 [M+]; Anal. Calcd for C11H14O2: C, 74.13; H,
7.92. Found: C, 74.09; H, 7.88.
3H), 0.87 (m, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR
(75.468 MHz, CDCl3): δ 138.60, 128.35, 127.71, 127.51, 73.02,
67.32, 65.62, 39.65, 25.91, 24.17, 18.12, −4.38, −4.83; HRMS
for C17H30O2Si+Na calcd 317.1912; found 317.1910.
(R)-2-(2-(Benzyloxy)ethyl)oxirane (15)
A mixture of (R,R)-(−)-N,N1-Bis(3,5-di-tert-butylsalicyclidene)-
1,2-cyclohexanediaminocobalt (II) (0.240 g, 0.391 mmol)
toluene and AcOH (0.05 mL, 0.793 mmol) was stirred while
open to the air for 1 h at room temperature. The solvent was
removed under reduced pressure and the brown residue was
dried over high vacuum. The oxirane 14 (14 g, 78. 65 mmol)
was added in one portion, the stirred mixture was cooled in an
ice water bath. Water (0.780 mL, 43.261 mmol) was slowly
added and the temperature of the reaction mixture was main-
tained in such a way that it never rises more than 20 °C.
Addition was complete in 1 h. The ice bath was removed and the
reaction mixture was stirred for 36 h at room temperature and
purified by column chromatography to afford the (R)-epoxide 15
(S)-3-(tert-Butyldimethylsilyloxy)butan-1-ol (18)
To
a stirred solution of naphthalene powder (6.791 g,
53.060 mmol) in dry THF (100 mL) lithium metal (0.285 g,
40.816 mmol) was added. The mixture was stirred for 3 h at
room temperature then cooled to −20 °C and compound 17
(6.000 g, 20.408 mmol) was added and the reaction mixture was
stirred for 2 h. After completion of reaction, it was quenched
with saturated aqueous NH4Cl solution and extracted with ethyl
acetate (2 × 200 mL). The organic layer was washed with water,
followed by brine and dried over Na2SO4. Solvent was removed
under reduced pressure and purification by silica gel column
chromatography (eluent: EtOAc : petroleum ether
= 4 : 6)
(4 : 1 hexane : EtOAc) as a colourless oil (5.880 g, 42%); [α]D20
+15.8 (c 2.0, CHCl3).
=
afforded primary alcohol 18 (3.916 g, 94% yield) as a colourless
liquid. [α]2D0 = +30.4 (c 1.0, CHCl3); IR (KBr): 3456, 2923,
2852, 1218, 773 cm−1 1H NMR (300 MHz, CDCl3): δ
;
4.14–4.03 (m, 1H), 3.84–3.73 (m, 1H), 3.72–3.62 (m, 1H), 2.38
(br s, 1H), 1.81–1.68 (m, 1H), 1.67–1.54 (m, 1H), 1.19 (d, J =
6.04 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
(75.468 MHz, CDCl3): δ 68.21, 60.33, 40.43, 25.71, 23.35,
17.86, −4.43, −5.03; LC-MSD: 205 [M + H]+; Anal. Calcd for
[C10H24O2Si+1]: C, 58.77; H, 11.84; found C, 58.74; H, 11.79.
(S)-4-(Benzyloxy)butan-2-ol (16)
To a suspension of LAH (2.134 g, 56.179 mmol) in anhydrous
THF (50 mL) was added drop wise a solution of (R)-epoxide 15
(5.000 g, 28.089 mmol) in THF (30 mL) at 0 °C. The mixture
was stirred at room temperature for 1 h and then re-cooled to
0 °C. To the resultant mixture saturated solution of sodium
sulfate (6.440 mL) was added and stirred for 3 h and the mixture
was filtered through Celite. The filtrate was concentrated in
vacuo and the residue was chromatographed (eluent: EtOAc :
petroleum ether = 4 : 6) to afford secondary alcohol 16 (4.803 g,
95% yield). [α]2D0 = −3.1 (c 2.1, CHCl3); IR (KBr): 3414, 3032,
(S)-Ethyl 6-(tert-butyldimethylsilyloxy)-4-hydroxyhept-2-ynoate
(9)
To a cooled and stirred solution (−78 °C) of oxalyl chloride
(2.260 mL, 34.288 mmol) in CH2Cl2 (50 mL) was added
DMSO (4.890 mL, 68.576 mmol) drop wise under nitrogen
atmosphere. After 10 min a solution of alcohol 18 (3.500 g,
17.144 mmol) in CH2Cl2 (15 mL) was added in 5 min. The reac-
tion mixture was stirred for another 15 min and Et3N
(14.290 mL, 102.864 mmol) was added at same temperature.
After being stirred for 10 min at −78 °C, the cooling bath was
removed and water (30 mL) was added at room temperature. The
aqueous layer was extracted with CH2Cl2 (2 × 50 mL) and com-
bined organic layers were washed with brine (60 mL), dried over
anhydrous Na2SO4 and evaporated to furnish the aldehyde 19,
which was used for further reaction without any purification.
2969, 2870, 1452, 1367, 1094, 738 cm−1; H NMR (500 MHz,
1
CDCl3): δ 7.33–7.20 (m, 5H), 4.49 (s, 2 H), 3.99–3.92 (m, 1H),
3.69–3.63 (m, 1H), 3.62–3.56 (m, 1H), 2.63 (br s, 1H),
1.76–1.64 (m, 2H), 1.16 (d, J = 6.39 Hz, 3H); 13C NMR
(75.468 MHz, CDCl3): δ 137.80, 128.30, 127.56, 127.51, 73.11,
68.85, 67.19, 37.98, 23.19; GC-MS: 181 [M+]; Anal. Calcd for
C11H16O2: C, 73.30; H, 8.95; found C, 73.27; H, 8.92.
(S)-4-(Benzyloxy)butan-2-yloxy (tert-butyl)dimethylsilane (17)
To a solution of secondary alcohol 16 (4.500 g, 25.000 mmol)
cooled in ice-bath, imidazole (6.805 g, 100.000 mmol) in anhy-
drous CH2Cl2 (50 mL) was added a solution of TBDMSCl
(4.875 g, 32.510 mmol) in anhydrous CH2Cl2 (50 mL). The
mixture was stirred at room temperature for 2 h, then diluted
with water (50 mL) and extracted with ether (3 × 60 mL). The
combined organic extracts were washed with brine (50 mL) and
dried over anhydrous Na2SO4. After filtration and concentration
in vacuo, and the residue was purified by column chromato-
graphy (eluent: EtOAc : petroleum ether = 2 : 8) to give TBS
ether 17 (7.203 g) as colourless oil with 98% yield. [α]2D0 = +5 (c
1.0, CHCl3); IR (KBr): 3033, 2957, 2931, 2858, 1459, 1374,
To
a stirred solution of ethylpropiolate (2.120 mL,
22.280 mmol) in THF (70 mL), was added LiHMDS
(45.770 mL, 25.716 mmol, 1 M in toluene) at −78 °C and
stirred the solution at same temperature for 45 min. Then the
crude aldehyde (19) dissolved in freshly distilled dry THF
(50 mL) was added to the reaction mixture slowly over 15 min at
same temperature. It was stirred for another 30 min. Reaction
mixture was quenched with aqueous saturated NH4Cl at −78 °C
and diluted with water (75 mL). Then it was allowed to warm to
room temperature and stirred for 1 h. The two layers were separ-
ated and aqueous layer was extracted with Et2O (3 × 50 mL).
The combined organic fraction was dried over anhydrous
Na2SO4 and the solvent was evaporated in vacuo. The residue
upon column chromatography of the residue over silica gel using
1254, 1113, 835, 775 cm−1 1H NMR (300 MHz, CDCl3): δ
;
7.33–7.19 (m, 5H), 4.50–4.39 (m, 2H), 4.05–3.93 (m, 1H,),
3.58–3.42 (m, 2H), 1.72–1.61 (m, 2H), 1.13 (d, J = 6.04 Hz,
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1
1 : 9 EtOAc : petroleum ether yielded the hydroxy alkynoate 9
(3.871 g, 75%) as a light brownish oil. [α]2D0 = +23 (c 1.5,
CHCl3); IR (KBr): 3420, 2957, 2932, 2858, 2237, 1717, 1368,
1086, 834, 776 cm−1; H NMR (300 MHz, CDCl3): δ 6.96 (dd,
J = 15.86, 4.54 Hz, 1H), 6.12 (d, J = 15.86, 1H), 4.50–4.44 (m,
1H), 4.18 (q, J = 6.79 Hz, 2H), 3.91–3.89 (m, 1H), 3.62–3.53
(m, 1H), 1.30 (t, J = 6.80 Hz, 3H), 1.22 (d, J = 6.04 Hz, 3H),
0.91 (s, 9H), 0.089 (s, 3H), 0.085 (s, 3H); 13C NMR
(75.468 MHz, CDCl3): δ 166.25, 146.16, 121.25, 84.66, 71.61,
69.61, 60.42, 25.83, 21.35, 17.98, 14.19, −4.311, −4.539;
HRMS for C15H30O5Si + Na calcd 341.1864; found 341.1861.
1
1249, 838, 775 cm−1; H NMR (300 MHz, CDCl3): δ 4.61 (t, J
= 6.79 Hz, 1H), 4.22 (q, J = 6.79 Hz, 1H), 4.14–4.00 (m, 1H),
2.75 (br s, 1H), 2.02–1.90 (m, 1H), 1.88–1.76 (m, 1H), 1.32 (t, J
= 6.79 Hz, 3H), 1.22 (d, J = 6.04 Hz, 3H), 0.88 (s, 9H), 0.08 (s,
3H), 0.07 (s, 3H); 13C NMR (75.468 MHz, CDCl3): δ 153.37,
87.40, 67.49, 62.05, 61.00, 45.50, 25.74, 24.12, 17.86, 13.95,
−4.095, −4.998; HRMS for C15H28O4Si + Na calcd 323.1654;
found 323.1653.
(E)-Ethyl 3-((4S,5R)-5-((S)-1-(tert-butyldimethylsilyloxy)ethyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (21)
To the stirred solution of diol 20 (1.800 g, 5.687 mmol) in dry
CH2Cl2 (50 mL), was added 2,2-DMP (1.742 mL,
14.219 mmol) and CSA (cat.) at 0 °C under N2-atmosphere and
stirred for 1 h at room temperature. After completion of reaction,
the reaction mixture was quenched by addition of aqueous satu-
rated NaHCO3 solution at room temperature. The two layers
were separated and the aqueous layer was extracted with CH2Cl2
(3 × 100 mL). The combined CH2Cl2 layer was dried over anhy-
drous Na2SO4 and the solvent was evaporated in vacuo. The
residue upon silica gel chromatography using 1 : 9 EtOAc–pet-
roleum ether yielded the acetonide 21 (1.873 g, 92%) as a light
yellow oily liquid. [α]2D0 = −3 (c 0.66, CHCl3); IR (KBr): 2985,
2935, 2861, 1726, 1661, 1373, 1256, 1163, 1101, 1070, 835,
(S,2E,4E)-Ethyl 6-(tert-butyldimethylsilyloxy)hepta-2,4-dienoate
(8)
To a stirred solution of hydroxy alkynoate 9 (3.200 g,
10.624 mmol) dissolved in dry benzene (75 mL), was added
PPh3 (3.340 g, 12.759 mmol) at room temperature and stirred for
6 h under N2-atmosphere. Then to the reaction mixture, a little
excess MeI (1 mL) was added to remove the unreacted PPh3 in
form of +PPh3MeI− salt. The salt was removed by simple fil-
tration through a sintered funnel and washed with ether. The
combined filtrate was dried over anhydrous Na2SO4, solvent was
evaporated in vacuo and column chromatography over silica gel
using (0.5 : 9.5 ethylacetate–petroleum ether) afforded the diene
ester 8 (2.143 g, 71%) as a yellowish oil. [α]2D0 = +10 (c 0.9,
CHCl3); IR (KBr): 2957, 2932, 2859, 1723, 1660, 1368, 1258,
1
778 cm−1; H NMR (300 MHz, CDCl3): δ 6.95 (dd, J = 15.86,
4.53 Hz, 1H), 6.08 (d, J = 15.86, 1H), 4.53–4.85 (m, 1H), 4.17
(q, J = 6.79 Hz, 2H), 3.93–3.83 (m, 1H), 3.64–3.52 (m, 1H),
1.40 (s, 3H), 1.37 (s, 3H), 1.30 (t, J = 6.79 Hz, 3H), 1.22 (d, J =
6.04 Hz, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.086 (s, 3H); 13C
NMR (75.468 MHz, CDCl3): δ 166.23, 146.12, 121.22, 109.59,
84.60, 77.55, 69.556, 60.36, 27.00, 26.56, 25.76, 21.29, 17.92,
14.13, −4.364, −4.600; HRMS for C18H34O5Si + Na calcd
381.2073; found 381.2089.
1
835, 778 cm−1; H NMR (300 MHz, CDCl3): δ 7.22 (dd, J =
15.11, 11.33 Hz, 1H), 6.28 (dd, J = 15.11, 11.33 Hz, 1H), 6.07
(dd, J = 15.11, 4.53 Hz, 1H), 5.83 (d, J = 15.11 Hz, 1H),
4.44–4.33 (m, 1H), 4.17 (q, J = 6.79 Hz, 2H), 1.34–1.20 (m,
6H), 0.90 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR
(75.468 MHz, CDCl3): 166.23, 146.12, 131.13, 129.22, 119.08,
69.54, 60.36, 25.76, 21.28, 17.92, 14.13, −4.364, −4.600;
LC-MSD: 308.0 [M + Na]+; Anal. Calcd for C15H28O3Si+Na:
C, 63.33; H, 9.92; found C, 63.30; H, 9.90.
(E)-3-((4S,5R)-5-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (22)
(4S,5R,6S,E)-Ethyl-6-(tert-butyldimethylsilyloxy)-4,5-
dihydroxyhept-2-enoate (20)
To a stirred solution of acetonide protected (E)-α,β,-unsaturated
ester 21 (1.50 g, 4.189 mmol) dissolved in CH2Cl2 (30 mL),
was added DIBAL-H (1 M solution in hexane, 10.491 mL,
10.475 mmol) at –30 °C under N2 atmosphere. Then the reaction
mixture was stirred for 1 h at the same temperature. The reaction
mixture was quenched with saturated aqueous sodium potassium
tartrate (40 mL) at 0 °C and stirred for 6 h at room temperature.
Then the two layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic layer
was washed with brine, dried over anhydrous Na2SO4 and the
solvent was removed in vacuo. Crude product was purified
through silica gel chromatography (3 : 7 EtOAc–petroleum ether)
to afford allyl alcohol 22 (1.192 g, 90%) as an on oily liquid.
[α]2D0 = +6 (c 1.0, CHCl3); IR (KBr): 3423, 2929, 2857, 1462,
1372, 1251, 1083, 831, 774 cm−1; 1H NMR (500 MHz, CDCl3):
δ 5.95 (tt, J = 16.02, 5.01 Hz, 1H), 5.76 (dd, J = 16.02, 7.01 Hz,
1H), 4.38 (t, J = 7.01 Hz, 1H), 4.14 (d, J = 5.01 Hz, 2H),
3.92–3.87 (m, 1H), 3.54 (dd, J = 7.01, 6.01 Hz, 1H), 1.383 (s,
3H), 1.376 (s, 3H), 1.18 (d, J = 7.01 Hz, 3H), 0.90 (s, 9H), 0.08
(s, 6H); 13C NMR (75.468 MHz, CDCl3): δ 132.65, 129.80,
t
To a 1 : 1 mixture of BuOH (45 mL) and water (45 mL), was
added AD-mix-α (9.840 g, 1.400 g of AD-mix-α per mmol of
olefin) and methane sulphonamide (0.668 g, 7.010 mmol). The
mixture was stirred for 10–15 min to get clear solution. The reac-
tion bath was cooled to 0 °C and then diene ester 8 (2.000 g,
t
7.030 mmol) dissolved in minimum volume of BuOH (5 mL)
was added. The reaction mixture was stirred for 3 days at 0 °C
(at night, the reaction mixture was kept in freeze). Then the reac-
tion mixture was quenched with solid sodium sulphite (Na2SO3)
(15.000 g) at room temperature and stirred for another 30 min.
The reaction mixture was diluted with EtOAc and two layers
were separated. The aqueous layer was extracted with EtOAc (3
× 75 mL). The combined organic fraction was dried over anhy-
drous Na2SO4 and the solvent was evaporated in vacuo. The
residue upon column chromatography over silica gel using 2 : 8
EtOAc–petroleum ether as eluent yielded the diol ester 20
(2.001 g, 90%) as a light yellowish oil. [α]2D0 = +8.1 (c 1.2,
CHCl3); IR (KBr): 3480, 2951, 2933, 2859, 1462, 1373, 1254,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2647–2655 | 2651

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108.78, 84.92, 78.08, 68.86, 62.83, 27.05, 25.82, 20.94, 18.04,
−4.403, −4.512; HRMS for C16H32O4Si+Na calcd 339.1967;
found 339.1960.
2 : 8) afforded pure 6 (0.601 g, 96%) as a pale yellow liquid.
[α]2D0 = +7 (c 1.0, CHCl3); IR (KBr): 3467, 3032, 2926, 2864,
1
1454, 1363, 1105, 739 cm−1; H NMR (300 MHz, CDCl3): δ
5.94 (dddd, J = 17.20, 10.39, 5.66, Hz, 1 H), 5.34 (dd, J = 7.37,
1.51 Hz, 1 H), 5.10 (dd, J = 10.39, 1.51 Hz, 1 H), 4.05 (dd, J =
5.66, 5.47 Hz, 1 H), 3.82–3.58 (m, 3H), 2.7 (br s, 1H), 1.37 (s,
3H), 1.35 (s, 3H), 1.27 (d, J = 6.04, 3H), 0.91 (s, 9H), 0.12 (s,
6H); 13C NMR (75.468 MHz, CDCl3): δ 137.40, 114.30,
109.65, 84.42, 76.06, 71.96, 65.27, 26.66, 25.80, 20.84, 18.51,
−4.42, −4.576; HRMS for C16H32O4Si + Na calcd 339.6221;
found 339. 6197.
((2S,3R)-3-((4S,5R)-5-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)oxiran-2-yl)methanol (23)
In a two neck round-bottomed flask, was weighed 3 g of 4 A°
molecular sieves (dry powder) under N2 atmosphere and dry
CH2Cl2 (10 mL) was added and the mixture was then cooled to
–23 °C. To this cold suspension, was added Ti(OiPr)4 (0.190 g,
0.630 mmol) followed by D-(+)-diethyl tartrate (0.141 g,
0.790 mmol) and the mixture was stirred vigorously at –23 °C
for 45 min. Then allyl alcohol 22 (1.000 g, 3.162 mmol) dis-
solved in CH2Cl2 (15 mL) was added slowly at –23 °C, stirred
for 30 min and tert-butyl hydroperoxide (2 mL, 5.20 mmol) was
added to the reaction mixture being maintained at the same
temperature and stirred for 24 h. After completion of the reac-
tion, the reaction mixture was filtered through a celite pad,
washed with CH2Cl2 (3 × 20 mL). The filtrate was quenched by
addition of water (2 mL), 10% NaOH solution (0.66 mL), stirred
for 1 h at −5 °C. The filtrate was dried over anhydrous Na2SO4
and concentrated to give crude epoxy alcohol, which was
purified through silica gel chromatography (2 : 8 EtOAc–pet-
roleum ether) to afford epoxy alcohol 23 (0.920 g, 88%) as a
white solid. [α]2D0 = +20 (c 1.2, CHCl3); IR (KBr): 3413, 3031,
2-((4-Methoxybenzyloxy)methyl)oxirane (25)
A solution of glycidol 12 (5.000 g, 54.036 mmol) in DMF
(20 mL) was added to a stirred suspension of sodium hydride
(3.242 g, 60% dispersion in oil, 81.054 mmol) in DMF (50 mL)
at −20 °C. The resulting mixture was stirred until effervescence
ceased and then 4-methoxybenzyl chloride (9.386 mL,
75.651 mmol) and nBu4NI (20 mg, cat.) were added. The
mixture was allowed to warm to room temperature and stirred
overnight. The reaction was quenched with water and ether. The
layers were separated and the aqueous phase extracted three
times with Et2O. The combined organic extracts were washed
twice with cold water, once with brine, dried (MgSO4) and con-
centrated under reduced pressure. The crude product was
purified by silica gel column chromatography, eluting with
hexane–ethyl acetate (5 : 1) to provide PMB-ether 25 (9.644 g,
92%) as a clear, colourless oil. IR (KBr) 2999, 2838, 1514,
1249 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.23 (d, J = 8.50 Hz,
2H), 6.84 (d, J = 8.50 Hz, 2H), 4.54–4.44 (m, 2H), 3.80 (s, 3H),
3.66 (dd, J = 11.33, 3.21 Hz, 1H), 3.39 (dd, J = 11.33, 5.67 Hz,
1H), 3.15–3.07 (m, 1H), 2.75 (dd, J = 5.10, 4.15 Hz, 1H), 2.56
(dd, J = 5.10, 2.64 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
159.31, 129.92, 129.40, 113.83, 72.90, 70.54, 50.80, 55.22,
44.31; HRMS for C11H14O3 calcd 194.0943, found 194.0944.
2870, 1452, 1367, 1094, 738 cm−1 1H NMR (300 MHz,
;
CDCl3): δ 4.47–4.42 (dd, J = 7.55, 6.79 Hz, 1H), 4.36–4.47 (dd,
J = 8.31, 6.04 Hz, 1H), 4.00–3.60 (m, 3H), 3.21–3.01 (m, 2H),
1.41 (br s, 1H), 1.37 (s, 6H), 1.34 (d, J = 6.79 Hz, 3H), 0.90 (s,
9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (75.468 MHz,
CDCl3): δ 120.74, 88.85, 88.37, 71.96, 69.60, 60.97, 55. 71,
29.68, 27.08, 26.66, 25.80, 20.94, 14.11, −4.418, −4.578;
LC-MSD: 333.0 [M + H]+; Anal. Calcd for C16H32O5Si: C,
57.79; H, 9.70; found C, 57.75; H, 9.68.
(R)-1-((4S,5R)-5-((S)-1-(tert-Butyldimethylsilyloxy)ethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (6)
To an ice-bath cooled solution of epoxy alcohol 23 (0.700 g,
2.108 mmol), TPP (0.580 g, 2.213 mmol), I2 (0.273 g,
2.150 mmol), imidazole (0.286 g, 4.220 mmol) in anhydrous
CH2Cl2 (15 mL) was added. The reaction mixture was stirred at
0 °C later kept under reflux for 1 h, then diluted with water
(20 mL) and extracted with ether (3 × 8 mL). The combined
organic phases were washed with brine (20 mL) and dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The
residue was purified by column chromatography (eluent :
EtOAc : petroleum ether = 4 : 6) to give TBS ether 24 as colour-
less oil.
(R)-2-((4-Methoxybenzyloxy)methyl)oxirane (26)
A mixture of (S,S)-(–)-N,N1-Bis(3,5-di-tert-butylsalicyclidene)-
1,2-cyclohexanediaminocobalt (II) (0.140 g, 0.232 mmol)
toluene (1mL) and AcOH (0.027 mL, 0.464 mmol) was stirred
while open to the air for 1 h at room temperature. The solvent
was removed under reduced pressure and the brown residue was
dried over high vacuum. The (glycidol PMB-ether ( )25
(9.000 g, 46.391 mmol) was added in one portion, the stirred
mixture was cooled in an ice water bath. Water (0.459 mL,
25.515 mmol) was slowly added and the temperature of the reac-
tion mixture was maintained in such a way that it never rises
more than 20 °C. After 1 h addition was complete. The ice bath
was removed and the reaction mixture was stirred for 36 h. the
crude reaction mixture was purified by silica gel column chrom-
atography to afford the (R)-glycidol PMB–ether 26 (4 :
1 hexanes : EtOAc) as a colourless oil (3.781 g, 42%); other
characterization data were identical to those reported for the
compound. [α]D20 = +4.2 (c 0.95, CHCl3).
To a stirred suspension of iodide derivative 24 in dry THF
t
(5 mL) kept at −78 °C, BuLi in hexane (2.2 equ) was added
drop wise under N2 atmosphere. After 15 min the reaction
mixture was quenched with saturated NH4Cl solution (5 mL)
and extracted with diethyl ether (2 × 10 mL). The combined
organic extracts were washed with brine (2 × 10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue on
purification by column chromatography (ethyl acetate–hexane,
2652 | Org. Biomol. Chem., 2012, 10, 2647–2655
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(R)-Ethyl 5-hydroxy-6-(4-methoxybenzyloxy)hex-2-ynoate (27)
To −90 °C solution of ethyl propiolate (3.779 mL,
1H), 6.88 (d, J = 8.5 Hz, 1H), 6.32–6.09 (m, 1H), 5.59 (d, J =
12.16 Hz, 1H), 4.54–4.49 (m, 3H), 3.73 (s, 3H), 3.71 (dd, J =
12.27 Hz, 1H), 3.65 (m, H), 2.77–2.60 (m, 1H), 2.39–2.32 (m,
1H), 13C NMR (75.468 MHz, CDCl3): 163.86, 159.73, 144.53,
129.88, 129.86, 122.48, 114.85, 88.52, 74.29, 72.92, 55.84,
28.27; MS-EIMS: m/z 249 [M + H]+.
a
37.209 mmol) in THF (mL) was added dropwise n-BuLi
(14.910 mL of a 2.5 M solution in hexanes, 37.198 mmol).
After 20 min, BF3·Et2O (4.720 mL, 37.198 mmol) was added,
the mixture was brought to −78 °C, and stirred for 10 min. Sub-
sequently, a solution of (R)-glycidol PMB-ether 26 (2.410 g,
12.422 mmol) in THF (10 mL) was added dropwise, the result-
ing solution allowed to reach to 0 °C, and stirred for 30 min.
After addition of saturated NH4Cl solution, the organic layer was
separated, and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed (brine), dried (Na2SO4),
and concentrated in vacuo. The residue thus obtained was
purified by silica gel column chromatography (hexanes : EtOAc,
2 : 1 to 1 : 1) to give 3.589 g (99%) of ester 27 as a colourless
oil. [α]D20 = +15.8 (c 1.05, CHCl3); IR (KBr) 3421, 2956, 2931,
2858, 2237, 1717, 1464, 1368, 1250, 1143, 1074, 837,
(R)-6-(Hydroxymethyl)-5,6-dihydropyran-2-one (29)
DDQ (1.794 g, 7.903 mmol) was added to a stirred mixture of
28 (1.400 g, 5.645 mmol) in CH2Cl2 (15 mL) and H2O (3 mL)
at room temperature. After 3 h the reaction was quenched slowly
with saturated NaHCO3 (20 mL) followed by of H2O (40 mL)
and then extracted with CH2Cl2 (5 × 20 mL). The combined
organic layers were washed with saturated NaHCO3, water,
brine, dried (Na2SO4), and then concentrated to an yellow oil
that was purified by column chromatography (2 : 8 ethyl AcOEt–
1
776 cm−1; H NMR (300 MHz, CDCl3) δ 7.21 (d, J = 8.31 Hz,
pentane) to provide 29 a colourless oil (0.593 g 82%). [α]D20
=
2H), 6.84 (d, J = 8.31 Hz, 2H), 4.49 (s, 2H), 4.20 (q, J = 6.80
Hz, 2H), 4.02–4.00 (m, 1H), 3.81 (s, 3H), 3.59–3.40 (m, 2H),
2.57 (dd, J = 6.043, 2.26 Hz, 1H), 2.37 (br s, 1H), 1.32 (t, J =
6.80, Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 153.5,
129.7, 129.4, 113.9, 85.0, 74.8, 73.1, 72.2, 68.3, 61.9, 55.2,
23.7, 14.0; MS (ESI) calcd for C16H20NaO5 [M + Na]+: 315.1.
120.4 (c 0.4, CHCl3); IR (KBr) 3400, 2929, 1713, 1260, 1039,
1
816 cm−1; H NMR (300 MHz, CDCl3): δ 6.97–6.91 (m, 1H),
5.98 (dd, J = 2.26, 9.82 Hz, 1H), 4.57–4.47 (m, 1H), 3.87 (m, J
= 12.27 Hz, 1H), 3.71 (dd, J = 12.27 Hz, 1H), 3.48 (br s, 1H),
2.66–2.54 (m, 1H), 2.38–2.28 (m, 1H), 13C NMR (75.468 MHz,
CDCl3): 164.14, 145.57, 120.71, 78.41, 63.55, 25.17;
MS-EIMS: m/z 129 [M + H]+.
(R,Z)-Ethyl 5-hydroxy-6-(4-methoxybenzyloxy)hex-2-enoate (11)
Quinoline (10 μL) and Pd–CaCO3 poisoned with lead (Lindlar’s
catalyst, 5 wt%, 1 g) were added to a solution of 27 (2.00 g,
6.849 mmol) in AcOEt (20 mL). The mixture was shaken under
hydrogen (1–2 atm) until TLC showed complete conversion.
The suspension was filtered through a short pad of Celite. The
organic layer was washed with 2 N HCl (2 × 10 mL) and brine,
dried over MgSO4, and evaporated under reduced pressure.
Purification by chromatography with silica gel (hexane/AcOEt
9 : 1) gave 11 as colourless oil (1.853 g, 92%). [α]D20 = +56.0 (c
1.0, CHCl3); IR (KBr) 3319, 3032, 2957, 2931, 2858, 1725,
(R)-6-Vinyl-5,6-dihydropyran-2-one (7)
To a stirred solution of compound 29 (0.400 g, 3.120 mmol) in
CH2Cl2 (10 mL), Dess–Martin periodinate (1.456 g,
3.420 mmol) was added at 0 °C for 1 h. After completion of the
reaction, the reaction mixture was quenched with saturated
sodium thiosulfate solution (10 mL) and saturated aqueous
sodium bicarbonate solution (10 mL). The reaction mixture was
extracted with dichloromethane (5–7 mL), dried over anhydrous
Na2SO4 and concentrated at 30 °C in vacuo to afford the alde-
hyde. This was used directly in the next step without further
purification.
1
1458, 1374, 1254, 1112, 836, 776 cm−1; H NMR (300 MHz,
CDCl3): δ 7.20 (d, J = 8.31 Hz, 2H), 6.83 (d, J = 8.31 Hz, 2H),
6.42–6.31 (m, 1H), 5.85 (d, J = 12.09 Hz, 1H), 4.49 (s, 2H),
4.46 (s, 2H), 4.15 (q, J = 7.55 Hz, 2H), 3.93–3.83 (m, 1H), 3.80
(s, 3H), 3.51–3.30 (m, 2H), 2.90–2.61 (m, 2H), 1.57 (br s, 1H),
1.29 (t, J = 7.55 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
163.87, 159.72, 144.29, 129.84, 129.64, 122.44, 114.87, 78.52,
73.29, 72.32, 55.87, 31.87, 14.29.
To a stirred suspension of triphenyl phosphonium methyl
iodide (1.356 g, 3.359 mmol) in dry THF (5 mL) at −78 °C, n-
BuLi in hexane (1.6 M, 1.96 mL, 3.14 mmol) was added drop-
wise under N2 atmosphere and was allowed to reach room temp-
erature. After 45 min the reaction mixture was again cooled to
−78 °C and the aldehyde obtained above, dissolved in dry THF
(5 mL) was added drop wise and stirred for another 45 min. The
reaction mixture was quenched with saturated NH4Cl solution
(7 mL) at 0 °C and extracted with diethyl ether (2 × 15 mL). The
combined organic extracts were washed with brine (2 × 15 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue on purification by column chromatography (ethyl
acetate–hexane, 2 : 8) afforded pure (R)-5,6-dihydro-6-vinyl-
(R)-6-((4-Methoxybenzyloxy)methyl)-5,6-dihydropyran-2-one
(28)
To a stirred solution of compound 11 (1.850 g, 6.292 mmol) in
benzene was added a catalytic amount of p-TSA under an N2
atmosphere. After stirring for 3 h at room temperature, the reac-
tion mixture was quenched with solid NaHCO3 and filtered off,
the solvent was removed under reduced pressure and the residue
was purified by silica gel column chromatography to afford com-
pound 28 as a yellow liquid (1.357 g, 87%). [α]2D0 = +70.3 (c
0.6, CHCl3); IR (KBr) 3454, 2928, 1747, 1257, 1095,
pyran-2-one 7 (0.210 g, 70%) as a pale yellow liquid. [α]D20
+90.4 (c 0.7, CHCl3); IR (KBr): 1723, 1660, 1467, 1368, 1259,
=
−1
1157 cm
;
1H NMR (200 MHz, CDCl3): δ 6.84 (1H, m),
6.05–5.86 (2H, m), 5.40 (1H, dd, J = 12.0, 2.0 Hz), 5.29 (1H,
dd, J = 7.0, 2.0 Hz), 4.90 (1H, m), 2.51–2.38 (2H, m); 13C
NMR (50 MHz): δ 163.88, 144.53, 134.72, 121.48, 117.83,
1
831 cm−1; H NMR (300 MHz, CDCl3): δ 7.26 (d, J = 8.5 Hz,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2647–2655 | 2653

View Article Online
77.79, 29.26; ESIMS: m/z 125 [M + H]+; Anal. Calcd for
C7H8O2: C, 67.74; H, 6.45. Found: C, 67.65; H, 6.52.
1H), 6.05 (ddd, J = 1.7, 1.7, 9.9 Hz, 1H), 5.88–5.74 (m, 2H),
5.36 (dd, J = 5.2, 7.2 Hz, 1H), 5.30 (dd, J = 3.5, 7.2 Hz, 1H),
5.17 (dd, J = 3.5, 7.0 Hz,1H), 4.96 (m, 1H) 4.90 (dq, J = 6.4,
6.4 Hz, 1H), 2.45 (m, 2H), 2.11 (s, 3H, CH3), 2.07 (s, 3H, CH3),
2.06 (s, 3H, CH3), 2.03 (s, 3H, CH3), 1.17 (d, J = 6.4 Hz, 3H,
CH3). 13C NMR (75.468 MHz, CDCl3): δ 170.03, 169.87,
169.72, 169.50, 163.57, 144.51, 133.07, 125.53, 121.64, 75.95,
71.91, 71.51, 70.40, 67.50, 29.46, 21.05, 20.90, 20.84, 20.50,
15.89; HRMS for C20H26O10+Na: calcd 449.1423; found:
449.1434.
(R)-6-((R,E)-3-((4S,5R)-5-((S)-1-(tert-Butyldimethylsilyloxy)
ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxyprop-1-enyl)-
5,6-dihydro-2H-pyran-2-one (30)
A flame-dried round-bottomed flask was charged with alkene 6
(0.072 g, 0.230 mmol) and vinyl lactone
7 (0.057 g,
0.460 mmol) in CH2Cl2 (30 mL) and was added Grubb’s catalyst
(2nd generation, 0.19 g, 0.230 mmol) as a solid. The reaction
mixture was refluxed for 5 h to complete the reaction (by TLC)
and brought it to room temperature. The mixture was concen-
trated in vacuo and the residue, was purified by silica gel chrom-
atography using petroleum ether–EtOAc (9 : 1) to give 30
(0.081 g, 86% yield). [α]2D0 = + 10.1 (c 0.4, CHCl3); IR (KBr)
Acknowledgements
The
authors
express
their
grateful
thanks
to
Dr. S. Chandrasekhar, Scientist-G, Organic Chemistry Division-
I, Indian Institute of Chemical Technology, Hyderabad, India for
the scientific support. Also thankful to Prof. C.D. Reddy, Depart-
ment of Chemistry, Sri Venkateswara University, Tirupati for his
helpful discussions and the Council of Scientific and Industrial
Research Project (01/2347/09/EMR-II) CSIR, New Delhi, India
for providing financial support.
2925, 1739, 1374, 1023, 974 cm−1 1H NMR (400 MHz,
;
CDCl3): δ 6.87 (dt, J = 8.6, 3.8 Hz, 1H), 6.04 (d, J = 9.8 Hz,
1H), 5.87 (d, J = 15.5 Hz, 1H), 5.83 (d, J = 15.3 Hz, 1H), 4.95
(brs, 1H), 4.20 (brd, J = 2.3 Hz, 1H), 3.98 (dd, J = 6.3, 3.0 Hz,
1H), 3.86 (t, J = 6.8 Hz, 1H), 3.79 (dq, J = 12.2, 6.0 Hz, 1H),
2.54–2.34 (m, 2H), 1.41 (s, 3H), 1.36 (s, 3H), 1.21 (d, J = 5.9
Hz, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 163.76, 144.55, 131.42, 130.76, 121.63,
109.55, 81.61, 80.70, 77.06, 75.16, 70.53, 29.64, 27.66, 27.11,
25.86, 21.33, 17.98, −4.25, −4.39; HRMS for C21H36O6Si+Na:
calcd 435.2179; found: 435.2174.
References
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Synthesis of (+)-anamarine (1)
To a stirred solution of 30 (0.016 g, 0.040 mmol) in a mixture of
MeOH–water (9 : 1, 2 mL) was added p-PTS (0.005 g,
0.020 mmol) at room temperature, and the reaction mixture was
refluxed for 12 h. After completion of the reaction (TLC),
NaHCO3 (0.150 g) was added and the mixture was stirred for
5 min. It was filtered through a short pad of Celite and was
washed with CHCl3 (15 mL). The residue obtained after evapor-
ation of the solvent was purified by a short-path silica gel
column chromatography using EtOAc–MeOH (4 : 1) as eluent to
furnish the tetrol, which was used as such in the next step
without characterization.
To a precooled (0 °C) solution of the tetrol obtained above in
CH2Cl2 (1 mL) were added DMAP (0.001 g, 0.007 mmol) and
Et3N (0.055 mL, 0.400 mmol) followed by Ac2O (0.032 mL,
0.033 mmol) under argon atmosphere. The reaction mixture was
stirred at room temperature for 1 h. After completion of the reac-
tion (TLC), it was poured into cold water and extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed
with brine (5 mL) and dried over Na2SO4. Evaporation of
solvent followed by column chromatography of the resultant
residue using petroleum ether–EtOAc (1 : 1) as eluent furnished
(+)-anamarine 1 (0.010 g) in 80% yield as a white solid: mp =
107–109 °C; [α]2D0 = + 17.1 (c 0.3, CHCl3); lit.1 for natural ana-
marine, mp 110–112 °C; [α]D = +14.5 (c 0.06; CHCl3); lit.1 for
natural anamarine, [α]D = + 28.2 (c 0.52; CHCl3), value later
revised to + 18.8; lit.8 for synthetic (+)-anamarine, [α]D = +15.9
(c 0.8; CHCl3); IR (KBr) 2925, 1739, 1374, 1023, 974 cm−1; 1H
NMR (300 MHz, CDCl3): δ 6.88 (ddd, J = 3.5, 5.2, 9.9 Hz,
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16 For similar regioselective asymmetric dihydroxylation of distant olefinic
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22 Literature related to cross-metathesis reaction: G. Sabitha, N. Fatima,
P. Gopal, C. N. Reddy and J. S. Yadav, Tetrahedron: Asymmetry, 2009,
20, 184.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2647–2655 | 2655