Efficient total synthesis of sapinofuranone B

Article abstract of DOI:10.1021/jo048087k

(Chemical Equation Presented) An efficient enantioselective synthesis of sapinofuranone B (1) using Sharpless asymmetric dihydroxylation, Sonogashira coupling, and Wittig olefination as the key steps is described.

Full text of DOI:10.1021/jo048087k

Efficient Total Synthesis of
Sapinofuranone B
Pradeep Kumar,* S. Vasudeva Naidu, and Priti Gupta
Division of Organic Chemistry: Technology, National
Chemical Laboratory, Pune 411008, India
tripathi@dalton.ncl.res.in
Received October 28, 2004
FIGURE 1. Structures of sapinofuranones and L-factor.
A. strictum, was further confirmed by the catalytic
hydrogenation of the diene and by comparing the optical
rotations of the saturated product with that of L-factor
3.2 From a synthetic point of view, there has been only
one literature report on the total synthesis of 1 in which
asymmetric centers at C-4 and C-5 were elaborated from
dimethyl L-tartrate and the 6,8-diene moiety was intro-
duced via Stille coupling of (E)-prop-1-enyltributyltin
with a (Z)-vinylic iodide.2 As a part of our research
program aimed at developing enantioselective synthesis
of naturally occurring lactones4 and amino alcohols,5 we
have accomplished the stereoselective synthesis of sapi-
nofuranone B employing Sharpless asymmetric dihy-
droxylation as the source of chirality from the commer-
cially available starting material 1,4-butanediol.
An efficient enantioselective synthesis of sapinofuranone B
(1) using Sharpless asymmetric dihydroxylation, Sonogash-
ira coupling, and Wittig olefination as the key steps is
described.
During a screening program for inhibition of benzodi-
azepine binding to the GABAA receptor, xenovulene A
was isolated from submerged cultures of the fungus
Acremonium strictum.1 While optimizing the production
of xenovulene A in the preliminary fermentation work,
Simpson and co-workers isolated a novel metabolite from
fermentation extracts and named it (4S,5S,6Z,8E)-5-
hydroxydeca-6,8-dien-4-olide [(S,S)-sapinofuranone B] 1.2
At almost the same time, two closely related lactones,
sapinofuranones A (2) and B (ent-1), were isolated from
liquid cultures of Saphaeropsis sapinae, a phytopatho-
genic fungus causing a wide range of disease symptoms
on conifers.3 Both the structures and stereochemistry of
sapinofuranones were determined by spectroscopic meth-
ods. The optical rotations of sapinofuranones A (2) and
B (ent-1) were reported to be +65.9 and -18.9 and
stereochemistries at C-5 were designated as S and R,
respectively. Comparison of these data with those for the
A. strictum metabolite 1 indicated that sapinofuranones
A and B isolated from S. sapinae must be the (4R,5S)-
diastereomer (2) and (4R,5R)-enantiomer (ent-1), respec-
tively. The A. strictum lactone 1 was therefore described
as (4R,5S)-(+)-sapinofuranone B (Figure 1). The structure
of 1 was further established by spectroscopic studies and
chemical correlation with the known L-factor 3, which
is a reduced form of 1, isolated from Streptomyces
griseus.2 Definitive proof for the structures and stereo-
chemistry of 1 has been provided by a stereoselective total
synthesis from tartaric acid as a chiral pool material. The
absolute configuration at C-4 and C-5 in 1, isolated from
Results and Discussion
Our retrosynthetic strategy for the synthesis of sapi-
nofuranone B is outlined in Scheme 1. We envisioned that
the 1,3-diene system could be prepared by Wittig olefi-
nation of an aldehyde or partial hydrogenation of 1,3-
enyne 13, which in turn would be obtained from acetylene
12 by Sonogashira coupling. The acetylene 12 could be
obtained from the alcohol 9 through a Corey-Fuchs
protocol. In this strategy, both the stereogenic centers
could be obtained through Sharpless asymmetric dihy-
droxylation of an olefin 6.
The synthesis of sapinofuranone B 1 started from
commercially available 1,4-butanediol as illustrated in
Scheme 2. Selective monohydroxyl protection of 4 with
p-methoxybenzyl bromide in the presence of NaH gave
5 in 90% yield. Compound 5 was oxidized to the corre-
sponding aldehyde under standard Swern conditions6 and
(4) (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetrahedron 1999,
55, 13445. (b) Fernandes, R. A.; Kumar, P. Tetrahedron: Asymmetry
1999, 10, 4349. (c) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem.
2002, 2921. (d) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44,
6149. (e) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2004,
45, 849.
(5) (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000, 3447.
(b) Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2002,
43, 4425. (c) Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2000, 41,
10309. (d) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 1035.
(e) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 1957. (f)
Gupta, P.; Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44,
4231. (g) Kondekar, N. B.; Kandula, S. V.; Kumar, P. Tetrahedron Lett.
2004, 45, 5477. (h) Pandey, S. K.; Kandula, S. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5877.
* Corresponding author. Phone: +91-20-25893300 ext 2050. Fax:
+91-20-25893614.
(1) Ainsworth, A. M.; Chicarelli-Robinson, M. I.; Copp, B. R.; Fauth,
U.; Hylands, P. J.; Hollowwary, J. A.; Latif, M.; O’Beirne, G. B.; Porter,
N.; Renno, D. V.; Richards, M.; Robinson, N. J. Antibiot. 1995, 48, 568.
(2) Clough, S.; Raggatt, M. E.; Simpson, E. J.; Willis, C. L.; Whiting,
A.; Wrigley, S. K. J. Chem. Soc., Perkin Trans. 1 2000, 2475.
(3) Evidente, A.; Sparapano, L.; Fierro, O.; Bruno, G.; Motta, A. J.
Nat. Prod. 1999, 62, 253.
10.1021/jo048087k CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/26/2005
J. Org. Chem. 2005, 70, 2843-2846
2843

SCHEME 1. Retrosynthetic Analysis for Sapinofuranone B (1)
subsequently treated with (ethoxycarbonylmethylene)-
triphenylphosphorane in benzene under reflux conditions
to furnish the trans olefinic product 67 in 89% yield. The
olefin 6 was treated with osmium tetroxide and potas-
sium ferricyanide as co-oxidant in the presence of
(DHQ)2PHAL ligand under AD conditions8 to give the diol
7 in 96% yield with 97% ee.9 Treatment of diol 7 with
2,2-dimethoxypropane in the presence of p-TSA gave
compound 8, which on reduction with DIBAL-H fur-
nished the alcohol 9 in excellent yield. Subsequent
homologation to acetylene 12 was carried out using the
Corey-Fuchs protocol10 in a three-step sequence involv-
ing Swern oxidation, dibromomethylenation, of the al-
dehyde and dehalogenation. Thus, compound 9 was
oxidized to the aldehyde 10 using standard Swern
conditions followed by dibromomethylenation with CBr4
and PPh3 to furnish the dibromo olefin 11 in essentially
quantitative yield. Treatment of 11 with an excess of
n-BuLi in THF at -78 °C provided the acetylene 12 in
92% yield. The Sonogashira coupling11 of 12 with com-
mercially available trans-1-bromopropene 12a was suc-
cessfully carried out with Pd(PPh3)2Cl2 and CuI in
triethylamine to furnish the 1,3-enyne product 13 in
excellent yield. The partial hydrogenation of the triple
bond in 13 proved to be challenging. Irrespective of
whether catalytic quantities or several molar equivalents
of quinoline were present, a mixture of 14 and over-
hydrogenated product was formed. The use of 1-octene12
as a cosolvent along with EtOAc in the presence of
pyridine (EtOAc/pyridine/1-octene ) 10:1:1) furnished
the diene 14 as a single product (Scheme 3). Thus, the
use of the Corey-Fuchs protocol and Sonogashira cou-
pling followed by hydrogenation for the synthesis of the
1,3-diene system is an improvement over the first re-
ported synthesis.2 Alternatively, the diene 14 was also
obtained by the Wittig olefination (Scheme 4). Thus, the
aldehyde 10 was treated with the Wittig salt 15 in THF
at -80 °C in the presence of LiHMDS to furnish a
mixture of cis and trans Wittig products (Z:E ) 80:20).
The desired (Z)-isomer 14 was easily separated by silica
gel column chromatography. The subsequent deprotec-
tion of the p-methoxybenzyl group with DDQ furnished
the alcohol 16 in 94% yield. Oxidation of the resulting
alcohol to the corresponding aldehyde using Swern
conditions and further oxidation using sodium chlorite
in DMSO under buffer conditions afforded the acid 17.
Finally, the deprotection of acetonide as well as cycliza-
tion was achieved in one-pot by using catalytic concen-
trated HCl in methanol to furnish the target molecule 1
25
in 67% overall yield from alcohol 16, [R]D +19.6 (c 1.0,
CHCl3), [lit.2 [R]D +19.0 (c 0.77, CHCl3)]. The physical
20
and spectroscopic data of 1 were in accord with those
reported for the same compound obtained from a natural
source.2
(6) For reviews of the Swern oxidation, see: (a) Tidwell, T. T.
Synthesis 1990, 857. (b) Tidwell, T. T. Org. React. 1990, 39, 297.
(7) Chandrasekhar, S.; Mohapatra, S. Tetrahedron Lett 1998, 39,
6415.
(8) (a) Becker, H.; Sharpless, K. B.Angew Chem., Int. Ed. Engl. 1996,
35, 448. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (c) Torri, S.; Liu, P.; Bhuvaneswari, N.; Amatore,
C.; Jutand, A. J. Org. Chem. 1996, 61, 3055.
(9) For the measurement of enantiomeric excess, the diol 7 was
converted into its dibenzoate. The enantiomeric purity of the dibenzoate
was estimated to be 97% by chiral HPLC analysis using Lichocart 250-4
(4 mm i.d. x 25 cm) HPLC-Cartridge (R.R.-Whelk-01), 1% iPrOH in
hexane, 1 mL/min.
(10) (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(b) Critcher, D. J.; Connolly, S.; Wills, M. J. Org. Chem. 1997, 62, 6638.
(c) Horita, K.; Oikawa, Y.; Nagato, S.; Yonemitsu, O. Tetrahedron Lett.
1998, 29, 5143. (d) Mukai, C.; Kim, J. S.; Sonobe, H.; Hanaoka, M. J.
Org. Chem. 1999, 64, 6822. (e) Gonza´lez, I. S.; Forsyth, C. J. Org. Lett.
1999, 1, 319.
In conclusion, a practical and enantioselective total
synthesis of sapinofuranone B has been achieved using
Sharpless asymmetric dihydroxylation, Sonogashira cou-
pling, and Wittig olefination as the key steps. The obvious
advantages of our synthesis in terms of high overall
yields, ready access to the 1,3-diene system and stereo-
genic centers, high enantioselectivity, and various pos-
sibilities available for structural modifications are note-
worthy.
Experimental Section
2,3-Dihydroxy-6-(4-methoxybenzyloxy)-hexanoic Acid
Ethyl Ester (7). To a mixture of K3Fe(CN)6 (18.45 g, 56.0 mmol),
K2CO3 (7.74 g, 56.0 mmol), and (DHQ)2PHAL (145 mg, 1 mol
(11) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Yu, Q.; Wu, Y.; Ding, H.; Wu, Y.-L. J. Chem. Soc.,
Perkin Trans. 1 1999, 1183. (c) Madec, D.; Fe´re´zou, J.-P. Tetrahedron
Lett. 1997, 38, 6661. (d) Izzo, I.; Decaro, S.; De Riccardis, F.; Spinella,
A. Tetrahedron Lett. 2000, 41, 3975.
(12) (a) Nicolaou, K. C.; Ladduwahetty, T.; Taffer, I. M.; Zipkin, R.
E. Synthesis 1986, 344. (b) Overman, L. E.; Thompson, A. S. J. Am.
Chem. Soc. 1998, 110, 2248.
2844 J. Org. Chem., Vol. 70, No. 7, 2005

SCHEME 2a
a Reagents and conditions: (a) p-OCH3C6H5CH2Br, NaH, dry DMF, cat. TBAI, 0 °C to room temperature, 1 h, 90%; (b) (i) (COCl)2,
DMSO, Et3N, CH2Cl2, -78 to -60 °C, 95%; (ii) Ph3PdCHCO2Et, C6H6, reflux, 6 h, 89%; (c) (DHQ)2PHAL (1 mol %), 0.1 M OsO4 (0.4 mol
%), K2CO3, K3Fe(CN)6, MeSO2NH2, t-BuOH/H2O 1:1, 0 °C, 24 h, 96%; (d) p-TSA, 2,2-DMP, CH2Cl2, rt, overnight, 95%; (e) DIBAL-H,
CH2Cl2, 0 °C to room temperature, 2 h, 96%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to -60 °C, 94%.
SCHEME 3a
a Reagents and conditions: (a) CBr4, PPh3, CH2Cl2, -78 °C, 2 h, 98%; (b) n-BuLi, THF, -78 °C, 1 h, 92%; (c) Pd(PPh3)2Cl2, CuI, Et3N,
12a, 6 h, 85%; (d) H2, Lindlar’s catalyst, EtOAc/pyridine/1-octene (10:1:1), 6 h, 95%.
SCHEME 4a
5-[3-(4-Methoxybenzyloxy)-propyl]-2,2-dimethyl-[1,3]di-
oxolane-4-carboxylic Acid Ethyl Ester (8). To a solution of
the diol 7 (4.50 g, 14.41 mmol) and p-TSA (100 mg) in CH2Cl2
(100 mL) was added 2,2-dimethoxypropane (2.25 g, 21.60 mmol)
and reaction mixture stirred overnight at room temperature.
Solid NaHCO3 (1 g) was added and mixture again stirred for 30
min. The reaction mixture was filtered through a pad of neutral
alumina, and the filtrate was concentrated. Silica gel column
chromatography using petroleum ether/EtOAc (9:1) as an eluent
gave 8 (4.82 g, 95%) as a colorless liquid: [R]25 -26.2 (c 2.1,
D
CHCl3); IR (neat) νmax 2864, 1736, 1612, 1513, 1248, 1130, 1032
a Reagents and conditions: (a) CH3CHdCHCH2Ph3P+Br- (15),
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.26 (d, 2H, J ) 10.0 Hz),
LiHMDS, THF, -80 °C, 2 h, 76%; (b) DDQ, CH2Cl2/H2O (18:1),
6.91 (d, 2H, J ) 10.0 Hz), 4.52 (s, 2H), 4.22 (q, 2H, J ) 7.3 Hz),
rt, 1 h, 94%; (c) (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to -60 °C;
4.10-4.14 (m, 1H), 3.80 (s, 3H), 3.53 (t, 3H, J ) 5.8 Hz), 1.72-
1.93 (m, 4H), 1.47 (s, 3H), 1.44 (s, 3H), 1.29 (t, 3H, J ) 6.8 Hz);
13C NMR (125 MHz, CDCl3) δ 170.5, 158.9, 130.4, 128.8, 113.5,
110.4, 78.89, 78.71, 72.2, 69.2, 60.9, 54.9, 29.8, 26.9, 25.5, 25.4,
13.8. Anal. Calcd for C19H28O6 (352.42): C, 64.75; H, 8.01.
Found: C, 64.69; H, 8.24.
(ii) NaClO2, DMSO, NaH2PO4, rt, overnight; (d) HCl (cat.), MeOH,
rt, overnight, 67% from 16.
%), in t-BuOH-H2O (1:1, 100 mL) cooled at 0 °C, was added
OsO4 (0.79 mL, 0.1 M solution in toluene, 0.4 mol %) followed
by methanesulfonamide (1.78 g, 18.71 mmol). After stirring for
5 min at 0 °C, the olefin 6 (5.20 g, 18.68 mmol) was added in
one portion. The reaction mixture was stirred at 0 °C for 24 h
and then quenched with solid sodium sulfite (25 g). The stirring
was continued for 45 min, and the solution was extracted with
EtOAc (3 × 50 mL). The combined organic phases were washed
(10% KOH, then brine), dried (Na2SO4), and concentrated. Silica
gel column chromatography of the crude product using petro-
leum ether/EtOAc (3:2) as an eluent gave the diol 7 (5.63 g, 96%)
as a colorless, syrupy liquid: [R]25D -7.0 (c 1.6, CHCl3); IR (neat)
{5-[3-(4-Methoxybenzyloxy)-propyl]-2,2-dimethyl-[1,3]-
dioxolan-4-yl}-methanol (9). To a solution of 8 (4.0 g, 11.35
mmol) in dry CH2Cl2 (80 mL) at 0 °C was added dropwise
DIBAL-H (22.70 mL, 22.70 mmol, 1 M in toluene) through a
syringe. The reaction mixture was allowed to warm to room
temperature over 2 h and then recooled to 0 °C and treated with
saturated solution of sodium/potassium tartrate. The solid
material was filtered through a pad of Celite and concentrated.
Silica gel column chromatography of the crude product using
petroleum ether/EtOAc (7:3) as an eluent gave 9 (3.38 g, 96%)
as a colorless oil: [R]25D -11.7 (c 1.8, CHCl3); IR (neat) νmax 3440,
νmax 3440, 2938, 2864, 1736, 1612, 1513, 1248, 1130, 1032 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.25 (d, 2H, J ) 10.1 Hz), 6.87 (d,
2H, J ) 10.1 Hz), 4.44 (s, 2H), 4.26 (q, 2H, J ) 5.0 Hz), 4.06 (m,
1H), 3.91(d, 1H, J ) 5.3 Hz), 3.80 (s, 3H), 3.49 (t, 2H, J ) 6.1
Hz), 2.82 (brs, 2H), 1.73 (m, 4H), 0.88 (t, 3H, J ) 6.1 Hz); 13C
NMR (125 MHz, CDCl3) δ 173.2, 158.8, 130.1, 128.9, 113.4, 73.4,
72.1, 69.5, 61.2, 54.8, 42.5, 30.0, 25.6, 13.7. Anal. Calcd for
2938, 2860, 1361, 1204, 1126, 1038 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 7.25 (d, 2H, J ) 8.7 Hz), 6.89 (d, 2H, J ) 8.7 Hz), 4.44
(s, 2H), 3.90 (dt, J ) 7.6, 4.0 Hz, 1H), 3.81 (s, 3H), 3.76 (m, 2H),
3.60 (dd, 1H, J ) 7.5, 4.4 Hz), 3.46-3.53 (m, 2H), 2.18 (s, 1H),
1.62-1.84 (m, 4H), 1.41 (s, 3H), 1.40 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.1, 130.5, 129.1, 113.7, 108.5, 81.5, 76.7, 72.4, 69.6,
C
16H24O6 (312.36): C, 61.52; H, 7.74. Found: C, 61.66; H, 7.70.
J. Org. Chem, Vol. 70, No. 7, 2005 2845

62.1, 55.1, 29.7, 27.2, 26.9, 26.0. Anal. Calcd for C17H26O5
(310.39): C, 65.78; H, 8.44. Found: C, 65.71; H, 8.51.
raphy of the crude product using petroleum ether/EtOAc (6:4)
as an eluent afforded alcohol 16 (141 mg, 94%) as a pale yellow
oil: [R]25D +17.7 (c 0.7, CHCl3); IR (CHCl3) νmax 3460, 2941, 2858,
1612, 1300, 1204; 1H NMR (200 MHz, CDCl3) δ 6.36 (m, 2H),
5.81 (dq, J ) 15.2, 7 Hz, 1H), 5.26 (dd, J ) 10.9, 2 Hz, 1H),
4.43-4.60 (m, 1H), 3.80-3.86 (m, 1H), 3.67 (t, J ) 8.0 Hz, 2H),
2.64 (brs, 1H), 1.81 (ddd, J ) 6.9, 2.0, 1.0 Hz, 3H), 1.60-1.74
(m, 4H), 1.42 (s, 3H), 1.41 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 133.8, 132.9, 126.3, 124.3, 108.3, 80.7, 72.3, 67.9, 28.8, 27.2,
27.0, 26.1, 18.3. Anal. Calcd for C13H22O3 (226.31): C, 68.99; H,
9.80. Found: C, 68.42; H, 9.89.
To a solution of oxalyl chloride (0.118 g, 0.081 mL, 0.93 mmol)
in dry CH2Cl2 (20 mL) at -78 °C was added dropwise dry DMSO
(0.146 g, 0.132 mL, 1.87 mmol) in CH2Cl2 (5 mL). After 30 min,
alcohol 16 (141 mg, 0.62 mmol) in CH2Cl2 (5 mL) was added
over 10 min giving a copious white precipitate. After stirring
for 1 h at -78 °C, the reaction mixture was brought to -60 °C,
and Et3N (0.252 g, 0.347 mL, 2.49 mmol) was added slowly and
stirred for 30 min, allowing the reaction mixture to warm to
room temperature. The reaction mixture was poured into water
(50 mL), and the organic layer was separated. The aqueous layer
was extracted with CH2Cl2 (2 × 25 mL), and the combined
organic layers were washed with water (3 × 30 mL) and brine
(30 mL), dried (Na2SO4), and passed through a short pad of silica
gel. The filtrate was concentrated to give the aldehyde (140 mg)
as a pale yellow syrup, which was used as such for the next step
without purification.
A solution of 79% NaClO2 (91 mg, 1.00 mmol) in 1.0 mL of
water was added dropwise to a stirred solution of the above crude
aldehyde (140 mg, 0.62 mmol) in 0.5 mL of DMSO and NaH2-
PO4 (60 mg, 0.50 mmol) in 1.0 mL of water over 5 min at room
temperature. The mixture was left overnight at room temper-
ature, and then 5% aqueous solution of NaHCO3 was added. The
aqueous phase was extracted three times with CH2Cl2 and
washed with brine, dried (Na2SO4), and concentrated to give the
acid 17, which was used as such for the next step without
purification.
The above crude acid was dissolved in methanol (5 mL), and
a catalytic amount of concentrated HCl was added. The reaction
mixture was stirred at room temperature overnight and then
quenched with solid NaHCO3 and filtered, and the filtrate was
concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (6:4) as an eluent gave 1
(73 mg, 67% from 16) as an oil: [R]D25 +19.6 (c 1.0, CHCl3) [lit.2
[R]D20 +19.0 (c 0.77, CHCl3)]; IR (CHCl3) νmax 3450, 2811, 1772,
1641, 1513, 1239, 1130, 1032; 1H NMR (200 MHz, CDCl3) δ
6.12-6.37 (m, 2H), 5.82 (dq, 1H, J ) 14.8, 7.0), 5.26 (dd, 1H, J
) 10.8, 2.0 Hz), 4.65 (ddd, 1H, J ) 8.9, 5.0, 1.5 Hz), 4.52 (ddd,
1H, J ) 7.6, 6.9, 5.5 Hz), 2.48-2.72 (m, 3H), 2.10-2.35 (m, 2H),
1.82 (ddd, 3H, J ) 7.1, 1.7, 1.0 Hz); 13C NMR (125 MHz, CDCl3)
δ 180.1, 134.1, 133.1, 126.4, 125.8, 85.1, 69.8, 29.1, 24.6, 18.4.
4-Ethynyl-5-[3-(4-methoxybenzyloxy)-propyl]-2,2-dimeth-
yl-[1,3]dioxolane (12). To a cooled (-78 °C) and stirred solution
of 11 (5.8 g, 12.49 mmol) in THF (50 mL) was added n-BuLi
(1.6 M solution in hexane, 39.06 mL, 62.47 mmol) dropwise
under argon. After 1 h, the reaction mixture was quenched with
saturated aqueous NH4Cl solution and extracted with ethyl
acetate (3 × 50 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated. Silica gel column
chromatography of the crude product using petroleum ether/
EtOAc (8:2) as an eluent gave 12 (3.49 g, 92%) as a yellowish
oil: [R]25D -12.4 (c 1.4, CHCl3); IR (CHCl3) νmax 2943, 2859, 1615,
1518, 1244, 1132, 1030 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.29
(d, 2H, J ) 8.0 Hz), 6.90 (d, 2H, J ) 7.6 Hz), 4.46 (s, 2H), 4.23
(d, 1H, J ) 7.9 Hz), 4.06 (dt, J ) 7.9, 3.6 Hz, 1H), 3.82 (s, 3H),
3.48-3.54 (m, 2H), 2.53 (s, 1H), 1.71-1.82 (m, 4H), 1.47 (s, 3H),
1.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.0, 130.5, 129.0,
113.6, 109.8, 81.2, 80.7, 74.5, 72.4, 70.1, 69.4, 55.1, 28.9, 26.9,
26.0, 25.7. Anal. Calcd for C18H24O4 (304.38): C, 71.03; H, 7.95.
Found: C, 71.21; H, 8.01.
4-[3-(4-Methoxybenzyloxy)-propyl]-2,2-dimethyl-5-pent-
3-en-1-ynyl-[1,3]dioxolane (13) (Sonogashira Coupling). To
a stirred mixture of Pd(PPh3)2Cl2 (738 mg, 1.05 mmol) and CuI
(621 mg, 3.26 mmol) in Et3N (2 mL) were added solutions of
trans-1-bromopropene 12a (2.54 g, 21.0 mmol) in Et3N (2 mL)
and acetylene 12 (3.2 g, 10.51 mmol) in Et3N (2 mL) under argon.
After 6 h, the reaction mixture was filtered through Celite and
filtrate was concentrated. Silica gel column chromatography of
the crude product using petroleum ether/EtOAc (9:1) as an
eluent gave 13 (3.08 g, 85%) as a pale yellow oil: [R]25D -11.4 (c
0.4, CHCl3); IR (CHCl3) νmax 2952, 2854, 1615, 1514, 1232, 1132,
1030 cm-1 1H NMR (500 MHz, CDCl3) δ 7.29 (d, J ) 7.9 Hz,
;
2H), 6.89 (d, J ) 7.6 Hz, 2H), 6.21 (d, J ) 15.7 Hz, 1H), 5.69
(dq, J ) 14.9, 7.0 Hz, 1H), 4.45 (s, 2H), 4.2 (d, J ) 8.0 Hz, 1H),
4.01-4.08 (m, 1H), 3.82 (s, 3H), 3.50 (t, J ) 5.4 Hz, 2H), 1.84
(d, J ) 7.8 Hz, 3H), 1.54-1.79 (m, 4H), 1.46 (s, 3H), 1.42 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 159.1, 133.8, 132.5, 130.5,
129.0, 113.6, 109.8, 81.2, 82.1, 74.5, 72.4, 70.1, 69.4, 55.1, 28.9,
26.9, 26.0, 25.7. Anal. Calcd for C21H28O4 (344.45): C, 73.23; H,
8.19. Found: C, 73.42; H, 8.02.
4-[3-(4-Methoxybenzyloxy)-propyl]-2,2-dimethyl-5-penta-
1,3-dienyl-[1,3]dioxolane (14). To a solution of 13 (3.08 g, 8.94
mmol) in 5 mL of ethyl acetate/pyridine/1-octene (10:1:1) was
added Lindlar’s catalyst (6 mg). The reaction mixture was stirred
for 6 h under a balloon of H2 at room temperature and filtered
through a Celite pad. The filtrate was concentrated, and the
residue was purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1) as an eluent to give 14 (2.94 g, 95%)
as a pale yellow oil: [R]25D -16.7 (c 1.0, CHCl3); IR (CHCl3) νmax
2952, 2854, 1613, 1300, 1204, 1100, 1038 cm-1 1H NMR (200
;
MHz, CDCl3) δ 7.23 (d, J ) 8.1 Hz, 2H), 6.90 (d, J ) 10.0 Hz,
2H), 6.38 (m, 2H), 5.82 (dq, J ) 14.8, 7.1 Hz, 1H), 4.50-4.57
(m, 1H), 4.43 (s, 2H), 3.81 (s, 3H), 3.62-3.72 (m, 1H), 3.47 (t, J
) 6.1 Hz, 3H), 1.81 (ddd, J ) 6.8, 1.5, 1 Hz, 3H), 1.61-1.68 (m,
4H), 1.43 (s, 3H), 1.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0,
133.9, 132.9, 130.5, 129.1, 126.2, 124.3, 113.6, 108.3, 80.7, 76.8,
72.3, 69.6, 55.2, 28.2, 27.2, 27.0, 26.1, 18.3. Anal. Calcd for
C21H30O4 (346.46): C, 72.80; H, 8.73. Found: C, 72.61; H, 8.82.
3-(2,2-Dimethyl-5-penta-1,3-dienyl-[1,3]dioxolan-4-yl)-
propan-1-ol (16). To a solution of compound 14 (230 mg, 0.66
mmol) in CH2Cl2 (18 mL) and H2O (1 mL) at 0 °C was added
DDQ (180 mg, 0.79 mmol) in portions. The resultant mixture
was stirred at room temperature for 1 h, and then saturated
aqueous NaHCO3 (10 mL) was added. The phases were sepa-
rated, and the aqueous phase was extracted with CH2Cl2 (3 ×
50 mL). The combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated. Silica gel column chromatog-
Acknowledgment. S.V.N. and P.G. thank CSIR and
UGC New Delhi for a research fellowship, respectively.
Financial support from Department of Science and
Technology, New Delhi (Grant SR/S1/OC-40/2003), is
gratefully acknowledged. We are grateful to Dr. M. K.
Gurjar for his support and encouragement. This is NCL
Communication No. 6674.
Supporting Information Available: Spectroscopic data
and full experimental procedure for compounds 5, 6, 11, and
14. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO048087K
2846 J. Org. Chem., Vol. 70, No. 7, 2005