Efficient syntheses of trans-(+)-laurediol from carbohydrate precursors

Article abstract of DOI:10.1016/S0957-4166(03)00078-8

Two routes for the synthesis of the marine natural product trans-laurediol 6 are described. In the first approach 6 is obtained in ten steps and 21% overall yield from monoacetone D-glucose. The second route provides the target in eleven steps and 13% yie

Full text of DOI:10.1016/S0957-4166(03)00078-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 737–742
Efficient syntheses of trans-(+)-laurediol from carbohydrate
precursors
Rajendrakumar Reddy Gadikota, Adam I. Keller, Christopher S. Callam and Todd L. Lowary*
Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA
Received 5 December 2002; accepted 8 January 2003
Abstract—Two routes for the synthesis of the marine natural product trans-laurediol 6 are described. In the first approach 6 is
obtained in ten steps and 21% overall yield from monoacetone
13% yield from
D-glucose. The second route provides the target in eleven steps and
-mannose. Both routes are more efficient, both in terms of number of steps and overall yield, than previously
D
reported syntheses. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
these linear diols represent useful starting materials for
the preparation of 1–5 and related compounds. Conse-
quently, the development of efficient routes for the
preparation of 6 and 7 have been the subject of a
number of investigations. The first synthesis of 6, by
Masamune and co-workers was accomplished in 21
steps from (2R,3R)-(+)-tartaric acid.4 Immediately fol-
lowing their report was another by Mart´ın and co-
workers who synthesized 6 and 7 from propargylic
alcohol in 28 steps.5 Later work by the Mart´ın group
led to a 12-step synthesis of 6 from 1,4-butanediol using
a Sharpless asymmetric dihydroxylation reaction as the
key step.6 We describe herein two alternative syntheses
of 6, which employ readily available carbohydrate
derivatives as the source of the chirality.
A rich variety of halogenated nonisoprenoid sesquiter-
penes have been isolated from the widely distributed
red algae of the genus Laurencia.1 The structures of
these natural products are diverse and include trans-
kumausyne 1, trans-deacetylkumausyne 2, srilankenyne
3, trans-obtusenyne 4, and obtusine 5. The biosynthesis
of these compounds has been proposed to occur via the
electrophilic cyclization of the linear glycols, trans-
laurediol 6 and cis-laurediol 7, which have been iso-
lated from Laurencia nipponica (Fig. 1).2
A recent synthesis3 of 2 involved, as the key step, a
bromonium ion-promoted cyclization of 7 and thus
Figure 1. Structures of trans-kumausyne 1, trans-deacetylkumausyne 2, srilankenyne 3, trans-obtusenyne 4, obtusine 5, trans-
laurediol 6 and cis-laurediol 7.
* Corresponding author. E-mail: lowary.2@osu.edu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00078-8

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R. R. Gadikota et al. / Tetrahedron: Asymmetry 14 (2003) 737–742
With 12 in hand, all that remained was the deoxygena-
2. Results and discussion
tion at C-2 and introduction of the enyne side chain at
C-1. To this end, the isopropylidene acetal was cleaved
with dry 0.1 M HCl in refluxing methanol to give a 1:1
a:b mixture of methyl furanosides 13 in 89% yield.
Deoxygenation at C-2 was accomplished via a two-step
protocol. Alcohol 13 was converted to the correspond-
ing 2-phenoxythiocarbonate 14 in 95% yield by treat-
ment with PhOC(S)Cl and pyridine and this product
was then deoxygenated upon reaction with n-Bu3SnH
and AIBN in refluxing toluene.9 Methyl glycoside 15
was obtained in 78% yield and subsequent hydrolysis
yielded 16 in 88% yield. This hemiacetal was then
reacted with the ylide obtained upon reaction of the
commercially available 3-(trimethylsilyl-2-propynyl)-
triphenyl phosphonium bromide with freshly sublimed
t-BuOK. The product of this Wittig reaction was not
purified;10 rather, following workup and concentration,
the reaction mixture was treated with NaOH in
methanol to yield 6 in 65% yield from 16. This route
provides 6 in ten steps from 8 in 21% overall yield.
The retrosynthetic analysis of our first approach to 6 is
provided in Fig. 2. We envisaged that this diol could be
obtained from 16 by reaction with the appropriate
Wittig reagent followed by debenzoylation. Lactol 16
could be prepared from 10 by a sequence of reactions
including a stereoselective Wittig olefination and deoxy-
genation at C-2. In turn, hemiacetal 10 could be synthe-
sized from the hydroxy alkene
regiocontrolled Pd(II) mediated Wacker oxidation.7
The synthesis of from commercially available
monoacetone glucose 8 has been previously reported.8
9
through
a
9
Thus, monoacetone- -glucose 8 was converted into 9 in
D
82% yield upon treatment8 with iodine, triphenylphos-
phine, and imidazole in refluxing THF (Scheme 1). This
alkene was subsequently reacted7 under standard
Wacker oxidation conditions to provide lactol 10 as a
2:1 diastereomeric mixture in 83% yield. Wittig reaction
of 10 with the ylide derived from (E)-CH3CH2-
CHꢀCHCH2CH2P+Ph3I− resulted in its stereoselective
conversion into diene 11, which was then protected as
the corresponding benzoate ester 12 in 81% yield over
the two steps.
We also explored another route to 6, which is illus-
trated in Scheme 2. This synthesis makes use of lactone
18, which can be prepared11 in two steps from
D-man-
Figure 2. Retrosynthetic analysis for the synthesis of 6 from monacetone glucose 8.
Scheme 1. Reagents and conditions: (a) I2, Ph3P, imidazole, THF, reflux, 3 h, 82%; (b) PdCl2 (cat), CuCl, O2, DMF:water (4:1),
rt, 4 h, 83%; (c) (E)-EtCHꢀCHCH2CH2PPh3I, KN(TMS)2, THF, −20°C, 2 h, 85%; (d) BzCl, pyridine, CH2Cl2, 0°C, 1 h, 95%;
(e) AcCl, CH3OH, reflux, 12 h, 89%; (f) PhOC(S)Cl, pyridine, DMAP, CH2Cl2, 0°C, 1 h, 95%; (g) n-Bu3SnH, AIBN (cat),
toluene, reflux, 2 h, 78%; (h) 30% aq. AcOH, 1N HCl, 60°C, 3 h, 88%; (i) TMSCCCH2PPh3Br, t-BuOK, Et2O, −10°C, 1 h;
(j) NaOH, CH3OH, rt, 2 h, 65% (two steps).

R. R. Gadikota et al. / Tetrahedron: Asymmetry 14 (2003) 737–742
739
Scheme 2. Reagents and conditions: (a) acetone, H2SO4, CuSO4, rt, 12 h, 82%; (b) PCC, CH2Cl2, reflux, 3 h, 81%; (c) SmI2, THF,
rt, 5 min, 91%; (d) TBDPSCl, imidazole, DMF, rt, 3 h, 88%; (e) HOAc:H2O, (3:2), rt, 8 h; (f) I2, Ph3P, imidazole, THF, reflux,
3 h, 66% (from 20); (g) PdCl2 (cat), CuCl, O2, DMF:water (8:2), rt, 5 h; (h) (E)-EtCHꢀCHCH2CH2PPh3I, KN(TMS)2, THF,
−20°C, 2 h, 67% (from 21); (i) DIBAL-H, toluene, −20°C, 1 h; (j) TMSCCCH2PPh3Br, t-BuOK Et2O, −10°C, 1 h; (k) n-Bu4NF,
THF, rt, 2 h, 55% (from 22).
nose 17. Treatment of 18 with samarium iodide12 gave,
in 91% yield, alcohol 20, which was then protected as
its t-butyldiphenylsilyl ether in 88% yield. Cleavage of
the 5,6-isopropylidene acetal and subsequent deoxy-
genation of the product diol with triphenylphosphine
and iodine afforded alkene 21 in 66% yield. Wacker
oxidation of 21 followed by Wittig reaction with (E)-
CH3CH2CHꢀCHCH2CHꢀPPh3 afforded the known lac-
tone 226b in 67% yield over two steps. Diol 6 was
obtained in three steps from 20 as previously
reported.6b The route illustrated in Scheme 2 afforded 6
in eleven steps from 17 in 13% overall yield.
between silica gel and crude product ranged from 100
to 50:1 (w/w). Optical rotations were measured at 21
1
2°C. Melting points are uncorrected. H NMR spectra
were recorded at 250, 400 or 500 MHz, and chemical
shifts are referenced to either TMS (0.0, CDCl3). 13C
NMR spectra were recorded at 62.5, 100, or 125 MHz,
and 13C chemical shifts are referenced to CDCl3 (77.00,
CDCl3). Electrospray mass spectra were recorded on
samples suspended in THF or CH3OH.
3.2. (2S,3S,4R,5R)-2,2-Dimethyl-hexahydrofuro[2%,3%:4,5]-
furo[2,3-d][1,3]dioxol-5-ol, 10
In summary, we have developed two efficient routes for
the synthesis of trans-laurediol 6, a marine natural
product that is proposed to be the biosynthetic precur-
To a solution of alkene 98 (0.70 g, 3.76 mmol) in 20%
aq. DMF (15 mL) was added PdCl2 (0.13 g, 0.73 mmol)
and CuCl (0.56 g, 5.6 mmol) in one portion. Air was
bubbled through the solution for 4 h at rt. The reaction
mixture was then diluted with CH2Cl2 (100 mL), and
the resulting mixture was filtered through Celite and
rinsed with CH2Cl2 (2×50 mL). The organic layers were
combined and washed with 1 M aq. HCl solution (100
mL) and water (2×100 mL). The organic phase was
separated, dried, filtered, and concentrated. Purification
of the resulting residue by chromatography (5:1, hex-
anes/EtOAc) afforded the title compound 10 (0.63 g,
83%) as a white solid as a 2:1 mixture of diastereomers:
Rf 0.41 (2:1, hexanes/EtOAc); 1H NMR (400 MHz,
CDCl3, lH) 6.03 (d, 0.43H, J=3.8 Hz), 5.88 (d, 0.56H,
J=3.8 Hz), 5.64 (ddd, 0.56H, J=5.3, 5.3, 3.9 Hz), 5.47
(dd, 0.43H, J=8.4, 5.5 Hz), 4.97–4.92 (m, 1H), 4.78 (d,
0.43H, J=3.8 Hz), 4.65–4.63 (m, 1.13H), 4.52 (d,
0.43H, J=3.7 Hz), 3.80 (d, 0.56H, J=3.9 Hz), 3.71 (d,
0.43H, J=8.5 Hz), 2.42 (dd, 0.56H, J=14.7, 5.4 Hz),
2.28 (d, 0.43H, J=14.5 Hz), 2.12–1.96 (m, 1.12H),
1.51–1.49 (m, 4.65H), 1.34 (s, 1.29H), 1.32 (s, 1.81H);
13C NMR (100 MHz, CDCl3, lC) 112.6, 112.2, 106.9
(2), 100.6, 100.4, 87.9, 85.8, 85.3, 84.0, 83.4, 83.1, 41.0,
40.7, 27.6, 27.5, 27.1, 27.0. HRMS (ESI) calcd for
[C9H14O5]Na+ 225.0733, found 225.0725.
sor of
a number of halogenated nonisoprenoid
sesquiterpene natural products. In one approach the
product is obtained in ten steps from monoacetone
glucose 8. In the other approach, 6 can be obtained in
eleven steps from
D
-mannose 17. Both routes give the
product in fewer number of steps and higher overall
yield than earlier syntheses.4–6
3. Experimental
3.1. General
Solvents were distilled from the appropriate drying
agents before use. Unless stated otherwise, all reactions
were carried out under a positive pressure of argon and
were monitored by TLC on silica gel 60 F254 (0.25 mm,
E. Merck). Spots were detected under UV light or by
charring with 10% H2SO4 in ethanol. Solvents were
evaporated under reduced pressure and below 40°C
(bath). Organic solutions of crude products were dried
over anhydrous Na2SO4. Column chromatography was
performed on silica gel 60 (40–60 mM). The ratio

740
R. R. Gadikota et al. / Tetrahedron: Asymmetry 14 (2003) 737–742
3.3. (2S,3S,4R,5R)-2,2-Dimethyl-5-[octa-2(Z),5(E)-
dienyl]-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol, 11
neutralized with pyridine (0.5 mL). The solution was
then concentrated to an oily residue, which was purified
via chromatography (6:1 hexanes/EtOAc) to yield 13
(0.53 g, 89%) as a colorless oil as a 1:1 a:b mixture: Rf
0.21 (1:1, hexanes/EtOAc); 1H NMR (400 MHz,
CDCl3, lH) 8.07–8.03 (m, 2.00H), 7.59 (dd, 1.17H,
J=7.4, 7.4 Hz), 7.45 (dd, 2.34H, J=7.9, 7.9 Hz),
5.54–5.28 (m, 4.99H), 5.19 (dd, 0.77H, J=5.3, 2.1 Hz),
5.05 (d, 0.41H, J=4.7 Hz), 4.90 (d, 0.72H, J=1.6 Hz),
4.49–4.27 (m, 2.34H), 2.74–2.42 (m, 4.85H), 1.97–1.92
(m, 2.59H), 0.95–0.90 (m, 3.44H); 13C NMR (100 MHz,
CDCl3, lC) 167.2, 166.6, 133.9, 133.8, 133.0, 131.1,
130.9, 130.2, 130.0, 129.9, 128.9 (2), 127.2, 127.1, 125.4,
125.0, 109.5, 101.8, 81.1, 80.4, 80.3, 80.1, 77.8 (2), 77.4,
77.1, 56.2, 56.1, 30.9, 28.9, 27.7, 25.9, 14.2. HRMS
(ESI) calcd for [C20H26O5]Na+ 369.1678, found
369.1661.
To a slurry of (E)-CH3CH2CHꢀCHCH2CH2PPh3I (3.50
,
g, 7.41 mmol), 4 A molecular sieves in dry THF (30
mL) at −20°C was added 0.5 M KN(TMS)2 solution
(14.8 mL, 7.41 mmol) in toluene. After stirring for 30
min, a solution of 10 (0.6 g, 2.97 mmol) in dry THF (10
mL) was added dropwise and the resulting mixture was
allowed to stir for 2 h. A satd. aq. solution of ammo-
nium chloride (50 mL) was added the resulting mixture
was subsequently extracted with CH2Cl2 (2×50 mL).
The combined organic layers were washed with water
(30 mL), dried, filtered, and concentrated to give an
oily residue, which was purified via column chromatog-
raphy (6:1 hexanes/EtOAc) to provide 11 (0.74 g, 85%)
as a colorless oil: Rf 10.50 (2:1, hexanes/EtOAc); [h]D
+29.3 (c 0.9, CHCl3); H NMR (250 MHz, CDCl3, lH)
5.91 (d, 1H, J=3.8 Hz), 5.62–5.34 (m, 4H), 4.51 (d, 1H,
J=3.8 Hz), 4.16 (ddd, 1H, J=8.3, 8.3, 2.4 Hz), 4.06 (br
s, 1H), 2.83–2.70 (m, 2H), 2.51–2.39 (m, 2H), 2.06–1.95
(m, 2H), 1.88 (br s, 1H), 1.50 (s, 3H), 1.31 (s, 3H), 0.96
(t, 3H, J=7.5 Hz); 13C NMR (62.5 MHz, CDCl3, lC)
133.1, 131.2, 127.3, 124.8, 111.9, 104.8, 85.6, 80.3, 75.4,
30.9, 27.0, 26.5, 26.2, 25.9, 14.2. HRMS (ESI) calcd for
[C15H24O5]Na+ 291.1566, found 291.1576.
3.6.(3S,4R,5R)-Benzoicacid5-methoxy-2-octa-[2(Z),5(E)-
dienyl]-4-phenoxythiocarbonyloxy-tetrahydro-furan-3-yl
ester, 14
To a solution of 13 (0.4 g, 1.16 mmol) in dry CH2Cl2 (5
mL) under an argon atmosphere was added pyridine (2
mL), followed by the subsequent addition of DMAP
(10 mg) and phenyl chlorothionoformate (0.19 mL, 1.4
mmol) at 0°C. The reaction was allowed to stir for 1 h
and then a satd. aq. NaHCO3 solution (2 mL) was
added. The resulting mixture was extracted with
CH2Cl2 (2×25 mL) and the combined organic phases
were dried, filtered, and concentrated to afford an oily
residue, which was purified by chromatography (12:1
hexanes/EtOAc) to provide 14 (0.5 g, 95%) as a pale
3.4. (2S,3S,4R,5R)-Benzoic acid 2,2-dimethyl-5-[octa-
2(Z),5(E)-dienyl]-tetrahydro-furo[2,3-d][1,3]dioxol-6-yl
ester, 12
To a solution of 11 (0.6 g, 2.24 mmol) in CH2Cl2 (10
mL) and pyridine (2 mL) at 0°C was added benzoyl
chloride (0.31 mL, 3.0 mmol) dropwise over 20 min.
The reaction mixture was subsequently warmed to rt
and stirred for 1 h before being diluted with CH2Cl2 (25
mL). This solution was washed successively with a 2%
aq. HCl solution (1×50 mL), a satd aq. NaHCO3
solution (1×50 mL), and water (1×50 mL). The organic
layer was dried, filtered, and concentrated to afford the
crude product, which was purified via chromatography
(10:1, hexanes/EtOAc) to give 12 (0.79 g, 95%) as a
colorless oil: Rf 10.43 (3:1, hexanes/EtOAc); [h]D +36.5
(c 1.0, CHCl3); H NMR (400 MHz, CDCl3, lH) 8.14
(d, 2H, J=7.1 Hz), 8.05 (d, 2H, J=7.1 Hz), 7.64 (dd,
2H, J=7.5, 7.5 Hz), 7.57 (dd, 1H, J=7.4, 7.4 Hz), 7.51
(dd, 2H, J=8.0, 7.6 Hz), 7.44 (dd, 2H, J=7.9, 7.5 Hz),
5.98 (d, 1H, J=3.8 Hz), 5.47–5.26 (m, 5H), 4.63 (d, 1H,
J=3.9 Hz), 4.39 (ddd, 1H, J=7.3, 7.3, 2.8 Hz), 2.68–
2.48 (m, 4H), 1.93–1.88 (m, 2H), 1.55 (s, 3H), 1.32 (s,
3H), 0.90 (t, 3H, J=7.5 Hz); 13C NMR (100 MHz,
CDCl3, lC) 165.8, 133.9, 133.0, 131.5, 130.2, 129.8,
128.9, 127.0, 124.4, 112.3, 105.0, 84.0, 79.5, 77.3, 30.8,
27.0, 26.6, 26.0, 25.9, 14.1. HRMS (ESI) calcd for
[C22H28O5]Na+ 395.1834, found 395.1821.
1
yellow oil: Rf 0.61 (2:1, hexanes/EtOAc); H NMR (500
MHz, CDCl3, lH) 8.15–8.13 (m, 2H), 7.54–7.46 (m,
5H), 7.35–7.31 (m, 2H), 7.19–7.18 (m, 2H), 5.90 (m,
0.37H), 5.75–5.72 (m, 1H), 5.56–5.42 (m, 3H), 5.35–
5.32 (m, 1H), 5.22 (s, 0.63H), 4.62 (ddd, 0.63H, J=5.8,
2.4, 2.4 Hz), 4.54 (dd, 0.37H, J=6.2, 6.2 Hz), 3.56–3.54
(m, 3H), 2.76–2.48 (m, 4H), 2.02–1.98 (m, 2H), 1.00–
0.96 (m, 3H); 13C NMR (125 MHz, CDCl3, lC) 195.1,
194.0, 166.2, 165.8, 154.0 (2), 153.9, 133.9, 133.1, 131.2,
130.2, 130.3, 130.1 (2), 130.0, 129.8, 129.0 (2), 127.2,
127.1, 127.0, 125.1, 124.8, 122.3, 122.2 (2), 106.9, 100.1,
89.3, 86.0, 82.1, 77.1, 76.6, 75.6, 56.2, 56.1, 31.0 (2),
28.9, 27.6, 25.9, 14.2. HRMS (ESI) calcd for
[C27H30O6]Na+ 489.1712, found 489.1701.
3.7. (4R,5R)-Benzoic acid 5-methoxy-2-octa-[2(Z),5(E)-
dienyl]-tetrahydro-furan-3-yl ester, 15
To a solution of 14 (0.4 g, 0.85 mmol) in toluene (5
mL) was added tri-n-butyltin hydride (0.29 g, 1.0
mmol) and AIBN (12 mg, 0.1 mmol) at rt. The result-
ing mixture was heated at reflux for 2 h, cooled, and the
solvent evaporated. The resulting residue was purified
by chromatography (10:1 hexanes/EtOAc) to yield 15
(0.31 g, 78%) as a colorless oil: Rf 0.53 (3:1, hexanes/
EtOAc); [h]D +59.1 (c 0.9, CHCl3); 1H NMR (250
MHz, CDCl3, lH) 8.07 (dd, 2H, J=8.2, 1.2 Hz), 7.53
(dd, 1H, J=7.9, 1.2 Hz), 7.43 (dd, 2H, J=6.4, 6.4 Hz),
3.5. (3S,4R,5R)-Benzoic acid 4-hydroxy-5-methoxy-2-
octa-[2(Z),5(E)-dienyl]-tetrahydro-furan-3-yl ester, 13
To a solution of dry methanol (10 mL) was added
acetyl chloride (0.1 mL) at 0°C followed by the addition
of 12 (0.7 g, 1.91 mmol). The resulting solution was
refluxed for 12 h under argon before being cooled and

R. R. Gadikota et al. / Tetrahedron: Asymmetry 14 (2003) 737–742
741
5.52–5.30 (m, 5H), 5.11 (dd, 1H, J=5.7, 1.2 Hz), 4.21
3.10. (5R,4R)-5-(2,2-Dimethyl-[1,3]dioxolan-4(R)-yl)-4-
hydroxy-dihydro-furan-2-one, 19
(ddd, 1H, J=5.8, 1.9, 1.9 Hz), 3.44 (s, 3H), 2.69 (dd,
2H, J=5.7, 5.2 Hz), 2.62–2.40 (m, 3H), 2.27–2.21 (m,
1H), 1.96–1.90 (m, 2H), 0.95–0.88 (m, 3H); 13C NMR
(62.5 MHz, CDCl3, lC) 167.1, 156.2, 133.8, 133.0,
131.1, 130.3, 130.1, 128.9, 127.2, 125.4, 121.0, 115.8,
104.8, 82.4, 73.7, 55.8, 40.0, 31.0, 29.0, 25.9, 18.0, 14.2.
HRMS (ESI) calcd for [C20H26O4]Na+ 353.1729, found
353.1705.
To a solution of 1811 (2.57 g, 10 mmol) in anhydrous
ethylene glycol (7.2 g, 120 mmol) and deoxygenated
anhydrous THF (10 mL) was added dropwise a solu-
tion of 0.1 M SmI2 in THF (30 mL, 30 mmol) at rt
under an argon atmosphere. After stirring for 5 min, a
satd. aq. NaHCO3 solution was added and then the
mixture was extracted with EtOAc. The organic layer
was washed with a sat. aq. Na2S2O3 solution, water,
and brine before being dried, filtered, and evaporated.
The product was purified by chromatography (8:1 hex-
anes/EtOAc) to yield 19 (1.83 g, 91%) as a white solid.
Rf 0.63 (2:1 hexanes/EtOAc); [h]D +39.9 (c 0.9, CHCl3),
3.8. (4R,5R)-Benzoic acid 5-hydroxy-2-octa-[2(Z),5(E)-
dienyl]-tetrahydro-furan-3-yl ester, 16
A solution of compound 15 (0.25 g, 0.76 mmol) in 30%
aqueous acetic acid (10 mL) and 1N HCl (2 mL) was
stirred for 3 h at 60°C. The reaction mixture was
subsequently neutralized with a satd aq. NaHCO3 solu-
tion (5 mL) and extracted into CH2Cl2 (2×50 mL). The
combined organic layers were washed with water (10
mL), dried, filtered, and concentrated. The crude
product was purified by chromatography (6:1, hexanes/
EtOAc) to yield the title compound 16 (0.21 g, 88%) as
1
mp=63–65°C; H NMR (500 MHz, CDCl3, lH) 4.70–
4.65 (m, 2H), 4.30–4.27 (m, 2H), 4.08 (dd, 1H, J=5.4,
10.9 Hz), 2.37 (dd, 1H, J=4.8, 17.3 Hz), 2.25 (br s,
1H), 2.22 (d, 1H, J=17.3 Hz), 1.48 (s, 3H), 1.43 (s,
3H); 13C NMR (125.7 MHz, CDCl3 lC) 110.1, 84.7,
72.3, 70.2, 67.6, 39.3, 27.2, 25.5. HRMS (EI) calcd for
(M+Na) C9H14O5 225.0739, found 225.0721.
1
a colorless oil: Rf 0.15 (1:1, hexanes/EtOAc); H NMR
(500 MHz, CDCl3, lH) 8.12–8.08 (m, 2.00H), 7.61 (dd,
1.01H, J=7.4, 7.4 Hz), 7.48 (dd, 2.02H, J=7.9, 7.9
Hz), 5.81 (br s, 0.75H), 5.64–5.59 (m, 1.26H), 5.54–5.39
(m, 3.05H), 5.33–5.29 (m, 0.96H), 4.40 (ddd, 0.76H,
J=7.0, 7.0, 3.6 Hz), 4.16 (ddd, 0.21H, J=7.1, 7.1, 4.0
Hz), 3.85 (br s, 0.72H), 3.61 (d, 0.19H, J=6.4 Hz),
2.74–2.48 (m, 4.29H), 2.43 (dd, 1.53H, J=4.0, 4.0 Hz),
2.01–1.94 (m, 2.02H), 0.94 (t, 3.00H, J=7.5 Hz); (125
MHz, CDCl3, lC) 166.3, 166.2, 133.7, 133.6, 133.0,
131.2 (2), 130.4, 130.3, 130.1 (2), 129.0, 128.9, 127.1,
125.1, 98.4, 97.8, 82.5, 80.0, 75.4, 74.0, 42.2, 41.3, 30.9
(2), 28.9, 27.4, 25.9, 14.2. HRMS (ESI) calcd for
[C19H24O4]Na+ 339.1572, found 339.1566.
3.11. (5R,4R)-4-(t-Butyldiphenylsilanyloxy)-5-(2,2-
dimethyl-[1,3]dioxolan-4(R)-yl)-dihydro-furan-2-one, 20
To a solution of 19 (1.0 g, 8.9 mmol) in DMF (10 mL)
was added imidazole (1.4 g, 24 mmol) followed by the
addition of t-butyldiphenylchlorosilane (1.4 mL, 16
mmol). The resulting solution was stirred at rt for 3 h.
The reaction mixture was subsequently partitioned
between H2O (10 mL) and ether (20 mL) and the
organic layer was washed with water (3×10 mL), dried,
filtered and concentrated. The crude product was
purified by chromatography (10:1 hexanes/EtOAc) to
give 20 (3.45 g, 88%) as a colorless oil. Rf 10.43 (4:1
hexanes/EtOAc); [h]D +49.1 (c 1.1, CHCl3); H NMR
(500 MHz, CDCl3, lH) 7.80–7.69 (m, 4H), 7.52–7.30
(m, 6H), 4.72–4.64 (m, 2H), 4.30–4.22 (m, 2H), 4.08
(dd, 1H, J=5.4, 10.9 Hz), 2.37 (dd, 1H, J=4.8, 17.3
Hz), 2.22 (d, 1H, J=17.3 Hz), 1.48 (s, 3H), 1.43 (s, 3H),
1.16 (s, 9H); 13C NMR (125.7 MHz, CDCl3 lC) 175.3,
136.5, 136.1, 135.2, 133.6, 132.6, 130.6, 130.5, 128.4,
128.1, 109.9, 84.9, 72.3, 70.2, 67.6, 39.3, 27.2, 25.6, 19.6.
HRMS (EI) calcd for (M+Na) C25H32O5Si 463.1917,
found 463.1901.
3.9. Synthesis of trans-laurediol 6 from 16
To a suspension of TMSCCCH2PPh3Br (0.37 g, 0.82
mmol) in anhydrous Et2O (5 mL) under an argon
atmosphere at −10°C was added potassium tert-butox-
ide (92 mg, 0.82 mmol) and the reaction mixture was
stirred for 30 min. A solution of lactol 16 (0.2 g, 0.63
mmol) in Et2O (5 mL) was added dropwise over the
course of 30 min, and the resulting mixture was allowed
to stir for 1 h. A satd. aq. solution of ammonium
chloride was added followed by Et2O (20 mL). The
organic layer was separated, dried, filtered, and concen-
trated to obtain the crude protected product. The crude
product was dissolved in CH3OH (10 mL), followed by
the addition of NaOH (0.1 g, 2.5 mmol) and the
mixture was allowed to stir for 2 h at rt. The reaction
mixture was then neutralized with acetic acid (0.2 mL)
and concentrated to an oily residue, which was purified
by chromatography (6:1 hexanes/EtOAc) to afford
target compound 6 (0.13 g, 65% over two steps) as a
colorless oil: [h]D23 +22.1 (c 1.0, CCl4); lit:6b [h]2D5 +19.8 (c
1.2, CCl4); lit:2 [h]D +27.2 (no concentration or temper-
3.12. (4R,5R)-4-(t-Butyldiphenylsilanoxy)-5-vinyl-dihy-
dro-furan-2-one, 21
A mixture of compound 20 (2.0 g, 4.5 mmol) and 60%
aq. acetic acid (50 mL) was stirred at rt for 8 h. The
resulting solution was azeotropically distilled with tolu-
ene in vacuo to obtain the crude product. The diol (4.5
mmol) was redissolved in THF (50 mL) containing
triphenylphosphine (4.7 g, 18 mmol) and imidazole (1.2
g, 18 mmol) and the solution was heated to 50°C. To
this mixture was added iodine (4.5 g, 18 mmol) and the
solution was heated at reflux for 3 h. The reaction
mixture was then cooled and evaporated and the result-
ing syrup was dissolved in EtOAc and successively
washed with 5% aq. NaOH, a sat. aq. Na2S2O3 solu-
tion, and water. The organic layer was dried, filtered
1
ature data reported). The H and 13C NMR spectral
data for this compound matched those previously
reported for 6.2,6b HRMS (ESI) calcd for
[C15H22O2]Na+ 257.1512, found 257.1535.

742
R. R. Gadikota et al. / Tetrahedron: Asymmetry 14 (2003) 737–742
and concentrated. The product was purified by chro-
matography (10:1 hexanes/EtOAc) to yield 21 (1.09 g,
66%, two steps). Rf 0.65 (3:1 hexanes/EtOAc); [h]D
TMSCCCH2PPh3Br (1.29 g, 3.0 mmol) in anhydrous
Et2O (5 mL) under an argon atmosphere at −10°C was
added potassium t-butoxide (335 mg, 3.0 mmol) and
the reaction was stirred for 30 min. A solution of the
lactol (1.0 g, 2.2 mmol) in Et2O (5 mL) was added
dropwise over the course of 30 min, and the resulting
mixture was allowed to stir for 1 h, before a satd. aq.
solution of ammonium chloride (10 mL) and Et2O (20
mL) were added. The organic layer was separated,
dried, filtered, and concentrated. This crude product
was dissolved in THF (10 mL) followed by addition of
n-Bu4NF (1 M solution in THF, 2.5 mL, 2.5 mmol)
and the mixture was allowed to stir for 2 h at rt. The
reaction mixture was then concentrated and the residue
purified by column chromatography (6:1, hexanes/
EtOAc) to provide 6 (0.28 g, 55% over three steps) as a
1
+36.2 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3, lH)
7.77–7.65 (m, 4H), 7.52–7.30 (m, 6H), 5.49–5.43 (m,
2H), 4.77 (dd, 1H, J=5.6, 5.6 Hz), 4.61 (dd, 1H,
J=4.8, 8.8 Hz), 2.45–2.43 (m, 1H), 1.12 (s, 9H); 13C
NMR (125.7 MHz, CDCl3 l) 175.2, 136.2, 136.1, 133.3,
132.9, 132.2, 130.6, 130.5, 128.3 (2), 120.4, 89.2, 717.7,
38.7, 27.3, 19.6. HRMS (EI) calcd for (M+Na)
C22H26O3Si 389.1549, found 389.1530.
3.13. (4R,5R)-4-(t-Butyldiphenylsilanoxy)-5-[octa-
2(Z),5(E)-dienyl]-dihydro-furan-2-one, 22
To a solution of 21 (1.40 g, 3.8 mmol) in 20% aq. DMF
(15 mL) was added PdCl2 (0.13 g, 0.73 mmol) and CuCl
(0.56 g, 5.6 mmol) in one portion. Air was bubbled
through the solution for 5 h at rt. The reaction mixture
was then diluted with CH2Cl2 (100 mL) and the result-
ing mixture was filtered through Celite and rinsed with
CH2Cl2 (2×50 mL). The organic layers were combined
and washed with 1 M aq. HCl solution (100 mL) and
water (2×100 mL). The organic phase was separated,
dried, filtered, and concentrated. This crude product
was used in the next step without further purification.
To a slurry of the (E)-CH3CH2CHꢀCHCH2CH2PPh3I
1
colorless oil: [h]D +21.4 (c 0.9, CCl4), The H and 13C
spectral data for this compound matched those previ-
ously reported for 6.2,6b HRMS (ESI) calcd for
[C15H22O2]Na+ 257.1512, found 257.1522.
Acknowledgements
This work was supported by the National Institutes of
Health and The Ohio State University Spectroscopy
Institute. C.S.C. is a recipient of an American Chemical
Society Organic Division Fellowship sponsored by
Aventis Pharmaceuticals.
,
(2.14 g, 4.6 mmol), 4 A molecular sieves in dry THF (30
mL) at −20°C was added 0.5 M KN(TMS)2 solution
(9.4 mL, 4.71 mmol) in toluene. After stirring for 30
min a solution of the crude aldehyde (1.45 g, 3.8 mmol)
in dry THF (10 mL) was added dropwise and the
resulting mixture was allowed to stir for 2 h. A sat. aq.
solution of ammonium chloride (50 mL) was added and
the resulting mixture was extracted with CH2Cl2 (2×50
mL). The combined organic extracts were washed with
water (30 mL) dried, filtered, and concentrated. The
product was purified by chromatography (8:1; hexanes/
EtOAc) to provide 22 (1.14 g, 67%) as a colorless oil. Rf
0.35 (4:1 hexanes/EtOAc); [h]D +76.1 (c 0.8, CHCl3); 1H
NMR (500 MHz, CDCl3, lH) 7.68–7.60 (m, 4H), 7.51–
.29 (m, 6H), 5.57–5.31 (m, 4H), 4.55 (ddd, 1H, J=4.3,
4.3, 4.6 Hz), 4.29 (ddd, 1H, J=4.3, 4.3, 8.4 Hz),
2.76–2.71 (m, 2H), 2.68–2.63 (m, 1H), 2.48–2.43 (m,
1H), 2.42 (d, 2H, J=4.3 Hz), 2.00–1.95 (m, 2H), 1.07
(s, 9H), 1.00 (dd, 3H, J=8.3 Hz); 13C NMR (125.7
MHz, CDCl3 lC) 174.1, 135.4, 132.7, 132.4, 131.8,
130.8, 129.9, 128.8, 127.4, 126.1, 124.0, 84.7, 70.1, 38.5,
30.8, 26.8, 25.8, 25.3, 18.9, 14.0. HRMS (EI) calcd for
(M+Na) C28H36O3Si 471.2331, found 471.2317.
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3.14. Synthesis of trans-Laurediol 6 From 22
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