Synthesis of (+)-decarestrictine L

Article abstract of DOI:10.1016/S0957-4166(03)00126-5

A synthesis of (+)-decarestrictine L 1, a cholesterol biosynthesis inhibitory metabolite isolated from Penicillium simplicissimum, is described. Beginning from tri-O-acetyl-D-glucal, alkylation with trimethylaluminum introduced the axial methyl group at C-2 in a stereoselective fashion. Chain extension at the C-6 carbon was accomplished by generation of the primary tosylate, followed by displacement with cyanide anion. The synthesis of (+)-1 was completed in 13 steps and 6.3% overall yield.

Full text of DOI:10.1016/S0957-4166(03)00126-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 757–762
Synthesis of (+)-decarestrictine L
Julie M. Lukesh and William A. Donaldson*
Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, USA
Received 11 December 2002; accepted 19 December 2002
Abstract—A synthesis of (+)-decarestrictine L 1, a cholesterol biosynthesis inhibitory metabolite isolated from Penicillium
simplicissimum, is described. Beginning from tri-O-acetyl- -glucal, alkylation with trimethylaluminum introduced the axial methyl
D
group at C-2 in a stereoselective fashion. Chain extension at the C-6 carbon was accomplished by generation of the primary
tosylate, followed by displacement with cyanide anion. The synthesis of (+)-1 was completed in 13 steps and 6.3% overall yield.
© 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
been reported. We report herein a synthesis of (+)-1
using tri-O-acetyl- -glucal as starting material.
D
The decarestrictines consist of a family of thirteen new
metabolites isolated from Penicillium simplicissimum
and Penicillium corylophilum.1 The majority of the
decarestrictines contain a 10-membered lactone ring in
their structure. In contrast, decarestrictine L 1 possesses
a tetrahydropyranyl ring. These metabolites exhibit an
inhibitory effect on cholesterol biosynthesis. This
beneficial effect was corroborated by in vivo studies
with normolipidemic rats where it was found that
cholesterol biosynthesis in HEP-G2 liver cells was sig-
nificantly inhibited. Additionally, it appears that the
decarestrictines are highly selective in that they exhibit
no significant antibacterial, antifungal, anti-protozoal,
or antiviral activity.
2. Results and discussion
Under Lewis acidic conditions, the reaction of glycals
with a variety of weak C-nucleophiles generates the
corresponding C-glycosides.7 Suitable nucleophiles
include allyltrimethylsilane,8 trimethylsilylcyanide,9 and
trialkylaluminum reagents.10 Substituent factors con-
tributing to the stereoselectivity of this reaction have
been explored by Woerpel.11 Reaction of tri-O-acetyl-
D
-glucal 2 with trimethylaluminum in the presence of
boron trifluoride etherate gave a mixture of the
known12 cis-3a and trans-3b (94%, 17:83 ratio, Scheme
1). Complete separation of the two products was not
The structure of 1 was initially assigned on the basis of
its mass spectral data and extensive 2D NMR analy-
sis.1a The absolute configuration of 1 was established as
(2R,3S,6R) as a result of the first total synthesis by
Machinaga and Kibayashi [18 steps, 5%].2 The choles-
terol inhibitory activity of 1 along with its low abun-
dance continues to make it an appealing synthetic
target. Within the last decade, total syntheses by Clark
[9 steps, 6% (racemic)],3 Nokami [9 steps, 5%],4 Solladie
[19 steps, 13%],5 and Hatakeyama [17 steps, 14%]6 have
* Corresponding author. E-mail: william.donaldson@marquette.edu
Scheme 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00126-5

758
J. M. Lukesh, W. A. Donaldson / Tetrahedron: Asymmetry 14 (2003) 757–762
possible by column chromatography, however the lead-
ing and trailing fractions contained pure 3a and 3b,
respectively. The structural assignments are based on
NMR spectral data. In particular, the NOESY NMR
spectra of cis-3a evidences a cross peak due to a
nonbonding 1H–1H interaction between the C-2
methine proton (l 4.31 ppm) and the C-6 methine
proton (l 3.74 ppm), while the NOESY NMR spectra
of trans-3b shows an interaction between the methyl
group (l 1.28 ppm) and the C-6 methine proton (l 3.98
ppm). Catalytic hydrogenation of the mixture of 3a/b
(13:87 ratio) gave a readily separable mixture of cis-4a
and trans-4b (ca. 25:75 ratio, Scheme 1). The increase
in the ratio of 4a:4b compared to the starting ratio of
3a:3b is attributed to olefin isomerization of 3 prior to
reduction. The structural assignments of cis-4a and
trans-4b are based on their NMR spectral data. In
particular, the signal for the C-2 methine proton of
cis-4a appears at l 3.48 ppm, while the signal for the
corresponding proton of trans-4b appears at l 3.94
ppm. The chemical shift for an equatorial proton of a
rigid six-membered ring is generally found downfield by
0.1–0.7 ppm compared to that of an axial proton.13
Additionally, the 13C NMR signal for the methyl group
of cis-4a appears at l 21.7 ppm, while the correspond-
ing signal for trans-4b appears at l 19.9 ppm. It has
been observed that 13C NMR signals for axial methyl
groups in noninverting cyclohexane rings are shielded
by 5–7 ppm as compared to equatorial methyl groups.14
Scheme 3.
With nitrile 10 in hand, introduction of the methyl
ketone functionality was explored. Unfortunately, reac-
tion of 10 with methylmagnesium iodide, followed by
hydrolysis did not produce the methyl ketone 12b;
instead the product was tentatively assigned as an
unsaturated nitrile resulting from intramolecular elimi-
nation. Basic hydrolysis of 10 gave a mixture of two
isomeric carboxylic acids cis-11a and trans-11b (1:4
ratio, Scheme 3). Reaction of the crude mixture of
11a/11b with methyllithium in dry ether gave a mixture
of isomeric methyl ketones cis-12a and the known6
trans-12b (1:1 ratio). Presumably, epimerization of the
C-6 center is due to elimination with subsequent readdi-
tion. The increase in the ratio of 12a:12b (compared to
the starting ratio of 11a:11b) is attributed to epimeriza-
tion at C-6 via elimination/readdition. Due to this
epimerization, an alternative (albeit longer) route to
12b was explored.15 Hydrolysis of nitrile 10, followed
by LiAlH4 reduction and Swern oxidation gave an
inseparable mixture of aldehydes 13a and 13b (1:4
ratio). Addition of methylmagnesium bromide to 13a/b,
followed by oxidation then afforded a mixture of 12a/
12b (1:3 ratio), which were separable by preparative
TLC.
Hydrolysis of trans-4b gave the diol 5, which upon
reaction with benzaldehyde dimethyl acetal gave the
benzylidine acetal 6 (Scheme 2). Reductive cleavage of
the benzylidene acetal was accomplished using DIBAL-
H in toluene to afford a mixture of the primary alcohol
7 and the secondary alcohol 8 (7:1 ratio as determined
by 1H NMR spectroscopy). While chromatographic
separation of 7 and 8 was not possible, the following
step resulted in selective reaction at the primary
hydroxyl group, thus allowing purification. Reaction of
the mixture of 7/8 with tosyl chloride gave only the
corresponding primary tosylate 9 as a crystalline solid,
whilst tosylation of the secondary alcohol 8 is relatively
slow. Nucleophilic substitution of the tosylate 9 with
sodium cyanide (in the presence of NaI) then gave the
nitrile 10.
Structural assignments for cis-12a and trans-12b are
1
based on their H NMR spectral data. The signal for
the C-2 methine proton of cis-12a appears at l 3.96
ppm while that for trans-12b appears at l 3.51 ppm.
Additionally, the 13C NMR signal for the methyl group
of cis-12a appears l 22.5 ppm, while the corresponding
signal for trans-12b appears at l 18.9 ppm. The struc-
tural assignment of 12b was further corroborated by
reductive deprotection of the benzyl ether to give (+)-1.
1
The H and 13C NMR spectral data for 1 obtained by
the above route are consistent with the literature
values.1a,5
Scheme 2.

J. M. Lukesh, W. A. Donaldson / Tetrahedron: Asymmetry 14 (2003) 757–762
759
In summary, (+)-decarestrictine L was prepared in 13
trans-3b: [h]2D3 +71.2 (c 0.332, CHCl3); IR (neat, cm−1)
steps and 6.3% overall yield from commercially avail-
2977, 2935, 1739, 1448, 1371, 1232, 1194, 1049, 971,
1
able tri-O-acetyl-
D
-glucal. This route is competitive
907, 729; H NMR (CDCl3) l 5.86 (ddd, J=1.5, 2.4,
with the other reported syntheses of 1.
10.3 Hz, 1H), 5.72 (ddd, J=2.1, 2.9, 10.3 Hz, 1H), 5.08
(dddd, J=1.5, 2.1, 2.9, 6.1 Hz, 1H), 4.31–4.45 (m, 1H),
4.21 (dd, J=6.2, 11.7 Hz, 1H), 4.12 (dd, J=3.5, 11.7
Hz, 1H), 3.98 (dt, J=3.5, 6.2 Hz, 1H), 2.18 (s, 3H),
2.16 (s, 3H), 1.29 (d, J=6.8 Hz, 3H); 13C NMR
(CDCl3) l 170.7, 170.3, 134.5, 122.8, 69.5, 67.9, 64.9,
62.8, 21.2, 20.9, 19.2.
3. Experimental
3.1. General data
Spectrograde solvents were used without purification
with the exception of dry ether and dry THF which
were distilled from sodium benzophenone ketyl. Anhy-
drous methylene chloride, anhydrous N,N-dimethylfor-
mamide (DMF), anhydrous acetonitrile, and anhydrous
dimethyl sulfoxide (DMSO) were purchased from
Aldrich. Column chromatography was performed on
silica gel 60 (60–200 mesh, Aldrich). Melting points
were obtained on a Mel-Temp melting point apparatus
and are uncorrected. All 1H and 13C NMR spectra were
recorded at 300 and 75 MHz respectively. Elemental
analyses were obtained from Midwest Microlabs, Indi-
anapolis, IN and high resolution mass spectra were
obtained from the Washington University Resource for
Biomedical and Bioorganic Mass Spectrometry.
3.3. 2,6-Anhydro-1,3,4-trideoxy-D-ribo-heptitol diac-
etate, 4a and 2,6-anhydro-1,3,4-trideoxy-
heptitol diacetate, 4b
D-arabino-
In a Parr apparatus, a solution of the mixture of 3a/3b
(4.02 g, 17.6 mmol) in absolute ethanol (75 mL) con-
taining 10% Pd/C (60 mg) was stirred vigorously under
H2 (51 psi) for 4 h. The catalyst was removed via
filtration through a bed of Celite and the filter bed was
washed with CH2Cl2. The combined organic layers were
evaporated under reduced pressure to give a yellow oil,
which was purified by column chromatography (SiO2,
hexanes–ethyl acetate=4:1) to give the cis isomer 4a
(1.33 g, 26%) followed by the trans isomer 4b (2.39 g,
61%), both as colorless oils.
3.2. 2,6-Anhydro-1,3,4-trideoxy-D-ribo-hept-3-enitol
diacetate, 3a and 2,6-anhydro-1,3,4-trideoxy-
D
-arabino-
cis-4a: [h]2D3 +50 (c 0.29, CHCl3); IR (neat, cm−1) 2973,
2940, 2869, 1743, 1444, 1375, 1247, 1093, 1042, 998,
878; 1H NMR (CDCl3) l 4.67 (dt, J=5.0, 10.3 Hz, 1H),
4.21 (dd, J=5.3, 12.0 Hz, 1H), 4.14 (dd, J=2.4, 12.0
Hz, 1H), 3.56 (ddd, J=2.4, 5.3, 9.7 Hz, 1H), 3.56–3.48
(m, 1H), 2.28–2.16 (m, 1H), 2.11 (s, 3H), 2.06 (s, 3H),
1.78–1.67 (m, 1H), 1.65–1.55 (m, 1H), 1.55–1.37 (m,
1H), 1.24 (d, J=6.2, 3H); 13C NMR (CDCl3) l 170.4,
169.4, 77.4, 74.2, 68.4, 64.1, 32.7, 29.9, 22.0, 21.9, 21.7.
FAB-HRMS m/z 231.1230 (calcd for C11H18O5H [M+
H+] m/z 231.1233).
hept-3-enitol diacetate, 3b
Into a flame-dried flask under N2 at −40°C was added
a solution of tri-O-acetyl- -glucal (1.02 g, 3.75 mmol)
D
in anhydrous CH2Cl2 (25 mL), followed by a solution
of trimethylaluminum (2.0 M solution in hexanes, 3.64
mL, 7.5 mmol), and finally boron trifluoride diethyl
etherate (0.48 mL, 3.8 mmol). The reaction mixture was
stirred at −40°C for 1.5 h and at 0°C for 3.5 h. The
rose-colored reaction mixture was slowly quenched with
saturated aqueous NaHCO3 (50 mL), (CAUTION: vig-
orous effervescence) during which time the solution
became lime green in color. The layers were separated
and the organic layer was washed with water (2×25
mL) and brine (2×25 mL). The aqueous layers were
extracted with methylene chloride (4×25 mL), and the
combined organic layers were dried (MgSO4) and con-
centrated. The residue was purified by chromatography
(SiO2, hexanes–ethyl acetate=3:1) to give a nearly
inseparable mixture of the known12 cis-3a and trans-3b
(1:5.3 by GC) as a colorless oil (0.80 g, 94%). However,
the first eluting fraction from the column contained
only the cis isomer, whilst the trailing fraction con-
tained only the trans isomer.
trans-4b: [h]2D3 +32 (c 0.26, CHCl3); IR (neat, cm−1)
2966, 2940, 2875, 1747, 1448, 1371, 1244, 1120, 1040,
1
977, 861; H NMR (CDCl3) l 4.74 (ddd, J=3.8, 5.6,
6.5 Hz, 1H), 4.34 (dd, J=6.5, 11.5 Hz, 1H), 4.11 (dd,
J=4.4, 11.5 Hz, 1H), 4.00 (dpent, J=4.1, 6.5 Hz, 1H),
3.94 (dt, J=3.6, 6.2 Hz, 1H), 2.11 (s, 3H), 2.10 (s, 3H),
2.02–1.89 (m, 1H), 1.89–1.80 (m, 1H), 1.80–1.68 (m,
1H), 1.66–1.54 (m, 1H), 1.25 (d, J=6.5 Hz, 3H); 13C
NMR (C6D6) l 169.8, 169.3, 72.8, 68.2, 67.7, 63.0, 29.0,
25.3, 21.7, 21.4, 20.6. Anal. calcd for C11H18O5: C,
57.38; H, 7.88. Found: C, 57.09; H, 7.85%.
3.4. 2,6-Anhydro-1,3,4-trideoxy-D-arabino-heptitol, 5
cis-3a: [h]2D3 +109 (c 0.216, CHCl3); IR (neat, cm−1)
2977, 2935, 2874, 1748, 1455, 1372, 1239, 1103, 1050,
975, 908, 788, 722; 1H NMR (CDCl3) l 5.78 (td,
J=1.5, 10.3 Hz, 1H), 5.66 (td, J=2.1, 10.3 Hz, 1H),
5.26 (tdd, J=1.9, 2.7, 9.1 Hz, 1H), 4.36–4.27 (m, 1H),
4.24 (dd, J=2.6, 12.0 Hz, 1H), 4.15 (dd, J=5.9, 12.0
Hz, 1H), 3.74 (ddd, J=2.7, 6.2, 8.8 Hz, 1H), 2.12 (s,
3H), 2.10 (s, 3H), 1.28 (d, J=6.8 Hz, 3H); 13C NMR
(C6D6) l 169.9, 169.4, 134.2, 124.8, 75.5, 71.8, 66.3,
64.5, 22.1, 21.5, 21.3.
A solution of 4b (3.21 g, 14.1 mmol) in saturated
methanolic K2CO3 (20 mL) was stirred at room temper-
ature for 3 h. The reaction mixture was neutralized with
1% by volume aqueous HCl (ꢀ100 mL), and extracted
with ethyl acetate (6×40 mL). The combined organic
layers were dried (MgSO4) and concentrated. The
residue was purified by chromatography (SiO2,
CH2Cl2–MeOH=12:1) to give 5 as a colorless oil (1.45
g, 71%): 5: [h]2D3 +43 (c 0.26, CHCl3); IR (neat, cm−1)
3392, 2937, 1650, 1453, 1379, 1224, 1136, 1059, 1001,

760
J. M. Lukesh, W. A. Donaldson / Tetrahedron: Asymmetry 14 (2003) 757–762
1
939, 893; H NMR (CDCl3) l 4.07 (m, 1H), 3.82 (dd,
J=5.3, 11.2 Hz, 1H), 3.73 (dd, J=3.5, 11.2 Hz, 1H),
3.64–3.56 (m, 2H), 2.25–2.05 (m, 2H), 1.92–1.54 (m,
4H), 1.27 (d, J=6.8, 3H); 13C NMR (CDCl3) l 75.0,
68.1, 66.7, 62.6, 29.0, 27.4, 18.3. Anal. calcd for
C7H14O3·0.2H2O: C, 56.13; H, 9.69. Found: C, 56.29;
H, 9.69%.
C14H20O3·0.5H2O: C, 68.54; H, 8.63. Found: C, 68.25;
H, 8.31%.
3.7. 2,6-Anhydro-1,3,4-trideoxy-4-O-(phenylmethyl)-6-
methylbenzenesulfonate-D-arabino-heptitol, 9
To a solution of 7/8 (1.87 g, 7.93 mmol) in anhydrous
CH2Cl2 under N2 was added NEt3 (3.30 mL, 23.7
mmol), DMAP (0.26 g, 2.1 mmol), and p-toluenesul-
fonyl chloride (4.52 g, 23.8 mol). After addition was
complete, a condenser was attached and the reaction
mixture was heated at reflux for 40 h. The reaction
mixture was cooled to rt, washed with 1 M HCl (1×30
mL), followed by saturated aqueous NaHCO3 (1×30
mL), and brine (1×30 mL). The aqueous washings were
extracted with CH2Cl2 (3×50 mL). The combined
organic layers were dried (MgSO4) and concentrated.
The residue was purified by chromatography (SiO2,
hexanes–ethyl acetate=5:1) to afford recovered starting
material 8 (0.18 g) and 9 as a colorless crystalline solid
(2.70 g, 87%). 9: mp 45–46°C; [h]2D3 +45 (c 0.28, CHCl3);
IR (KBr, cm−1) 3031, 2938, 2872, 1598, 1453, 1360,
3.5. 2,6-Anhydro-1,3,4-trideoxy-4,6-O-(phenyl-
methylene)-D-arabino-heptitol, 6
To a solution of 5 (1.60 g, 11.0 mmol) dissolved in
anhydrous acetonitrile (40 mL), at room temperature
under N2, was added benzaldehyde dimethyl acetal
(16.4 mL, 0.110 mol) and p-toluenesulfonic acid (0.22
g, 10 mol%, as a solution in anhydrous acetonitrile ꢀ2
mL). The reaction mixture immediately turned bright
yellow and was stirred for 4 h. The mixture was neu-
tralized with triethylamine (ꢀ1 mL) and washed with
saturated aqueous NaHCO3 (2×50 mL), followed by
water (1×50 mL), and brine (2×50 mL). The aqueous
layers were extracted with ethyl acetate (4×50 mL) and
the combined organic layers were dried (MgSO4) and
concentrated. Purification of the residue by chromatog-
raphy (SiO2, hexanes–ethyl acetate=10:1) afforded 6 as
a colorless crystalline solid (2.40 g, 94%). 6: mp 67–
68°C; [h]2D3 +29 (c 0.20, CHCl3); IR (KBr, cm−1) 2974,
2951, 2927, 2876, 1458, 1386, 1332, 1291, 1214, 1144,
1
1178, 1097, 967, 814, 665; H NMR (CDCl3)l 7.79 (d,
J=8.5 Hz, 2H), 7.38–7.24 (m, 7H), 4.57 (d, J=11.5 Hz,
1H), 4.41 (d, J=11.5 Hz, 1H), 4.27 (dd, J=5.0, 10.3
Hz, 1H), 4.16 (dd, J=3.2, 10.3 Hz, 1H), 4.03–3.91 (m,
1H), 3.77 (ddd, J=3.3, 5.0, 7.6 Hz, 1H), 3.35 (dt,
J=4.4, 8.0 Hz, 1H), 2.44 (s, 3H), 2.03–1.90 (m, 1H),
1.80–1.65 (m, 2H), 1.65–1.52 (m, 1H), 1.19 (d, J=6.8
Hz, 3H); 13C NMR (CDCl3) l 144.2, 137.6, 132.7,
129.4, 128.1, 127.7, 127.5, 127.4, 72.5, 71.2, 70.8, 69.7,
68.4, 28.6, 24.4, 23.3, 18.2. Anal. calcd for C21H26O5S:
C, 64.59; H, 6.71. Found: C, 64.31; H, 6.69%.
1
1130, 1101, 1070, 1001, 769, 700; H NMR (CDCl3) l
7.52–7.32 (m, 5H), 5.57 (s, 1H), 4.26–4.16 (m, 2H),
3.76–3.62 (m, 2H), 3.62–3.48 (m, 1H), 2.14–1.81 (m,
3H), 1.68 (td, J=3.2, 13.2 Hz, 1H), 1.37 (d, J=6.8 Hz,
3H); 13C NMR (CDCl3) l 137.3, 128.7, 128.0, 125.8,
101.8, 79.5, 70.3, 69.4, 66.1, 29.7, 24.6, 17.6. Anal. calcd
for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.64; H,
7.80%.
3.8. 6-Methyl-3-(phenylmethoxy)-tetrahydro-2H-pyran-
2-acetonitrile, 10
To a solution of 9 (3.57 g, 9.15 mmol) in anhydrous
DMF (60 mL) under N2 was added NaI (4.14 g, 27.6
mmol) and NaCN (1.40 g, 28.6 mmol). After addition
was complete, a condenser was attached and the reac-
tion mixture was heated to 80°C for 14 h. The reaction
mixture was cooled to room temperature and was parti-
tioned between ethyl acetate (100 mL) and H2O (100
mL). The layers were separated and the organic layer
was washed with H2O (3×100 mL) and the aqueous
layers were extracted with ethyl acetate (6×100 mL).
The combined organic layers were dried (MgSO4) and
concentrated. The dark orange residue was purified by
chromatography (SiO2, hexanes–ethyl acetate=5:1) to
give 10 as a nearly colorless thin oil (1.89 g, 84%). 10:
[h]2D3 +91 (c 0.32, CHCl3); IR (neat, cm−1) 2974, 2939,
2876, 2252, 1497, 1454, 1378, 1226, 1097, 1029, 738,
3.6. 2,6-Anhydro-1,3,4-trideoxy-4-O-(phenylmethyl)-D-
arabino-heptitol, 7
To a solution of 6 (2.76 g, 11.8 mmol) in toluene (75
mL) at 0°C, was added dropwise a solution of DIBAL
(1.0 M in toluene, 30.0 mL, 30 mmol). After addition
was complete the ice bath was removed and the reac-
tion mixture was stirred at room temperature for 24 h.
Methanol (20 mL) was slowly added to destroy the
excess DIBAL and 10% aqueous NaOH (ꢀ5 ml) was
added to neutralize the reaction mixture. The mixture
was extracted with ethyl acetate (4×50 mL) and the
organic layers were washed with brine (3×20 mL), dried
(MgSO4), and concentrated. Purification of the residue
by chromatography (SiO2, hexanes–ethyl acetate=1:1)
afforded a colorless oil (2.43 g, 87%). The oil consisted
of a mixture of 7 and 8, in a 7:1 ratio as determined by
integration of the benzylic proton signals of each. 7: IR
(neat, cm−1) 3440, 3030, 2966, 2935, 2872, 1497, 1454,
1
700; H NMR (CDCl3) l 7.41–7.27 (m, 5H), 4.67 (d,
J=11.5 Hz, 1H), 4.48 (d, J=11.5 Hz, 1H), 4.14 (ddq,
J=2.3, 5.3, 6.8 Hz, 1H), 3.80 (ddd, J=4.4, 5.6, 8.2 Hz,
1H), 3.30 (ddd, J=4.1, 8.2, 9.1 Hz, 1H), 2.70 (dd,
J=4.4, 16.7 Hz, 1H), 2.65 (dd, J=5.9, 16.7 Hz, 1H),
2.15–2.04 (m, 1H), 1.94–1.80 (m, 1H), 1.78–1.68 (m,
1H), 1.67–1.58 (m, 1H), 1.29 (d, J=6.8 Hz, 3H); 13C
NMR (CDCl3) l 137.4, 128.2, 127.6, 127.5, 117.4, 76.0,
70.8, 68.9, 68.8, 28.7, 24.1, 22.1, 17.6. Anal. calcd for
C15H19O2N: C, 73.44; H, 7.81; N, 5.71%. Found: C,
73.28; H, 7.75; N, 5.78%.
1
1378, 1227, 1208, 1096, 736, 698; H NMR (CDCl3) l
7.40–7.28 (m, 5H), 4.65 (d, J=11.7 Hz, 1H), 4.50 (d,
J=11.7 Hz, 1H), 4.14–4.02 (m, 1H), 3.76–3.65 (m, 3H),
3.35 (m, 1H), 2.10 (br s, 1H), 2.04–1.95 (m, 1H),
1.81–1.59 (m, 3H), 1.28 (d, J=6.8 Hz, 3H); 13C NMR
(CDCl3) l 137.9, 128.2, 127.6, 127.5, 73.9, 73.1, 70.9,
68.2, 63.0, 29.0, 24.6, 18.4. Anal. calcd for

J. M. Lukesh, W. A. Donaldson / Tetrahedron: Asymmetry 14 (2003) 757–762
761
3.9. 1-[(3S,6R)-Tetrahydro-6-methyl-3-(phenylmethoxy)-
2H-pyran-2-yl]-2-propanone, 12a/12b
was cautiously added. The reaction mixture was stirred
at 0°C for 10 min, at room temperature for 20 min, and
at reflux for 1 h. The reaction mixture was then cooled
to room temperature and quenched by the slow drop-
wise addition of saturated aqueous sodium potassium
tartrate (50 mL). The layers were separated and the
aqueous layer was extracted with ether (4×30 mL). The
ethereal layers were dried (MgSO4) and concentrated to
give a yellow oil (163 mg, 86%) which was identified as
a mixture of alcohols (1:4) by NMR spectroscopy. 13C
NMR (CDCl3) l 137.8, 128.0, 127.3, 127.4, 76.1, 73.7,
70.6, 67.4, 61.5, 33.6, 28.7, 24.1, 19.2. To a flame-dried
flask cooled to −78°C under N2, was added oxalyl
chloride (0.13 mL, 1.50 mmol), anhydrous CH2Cl2 (8
mL) and anhydrous DMSO (0.20 mL, 2.7 mmol). The
reaction mixture was stirred for 1.5 h at −78°C and
then a solution of the crude alcohols (150 mg, 0.60
mmol) in anhydrous CH2Cl2 (6 mL) was added. After
stirring for 3 h at −78°C, NEt3 (0.55 mL, 3.9 mmol)
was added. The reaction mixture was warmed to room
temperature and quenched with saturated aqueous
NH4Cl (10 mL) and neutralized with 10% HCl (ꢀ2
mL). The layers were separated and the organic layer
was washed with brine (3×30 mL). The aqueous layers
were extracted with CH2Cl2 (3×40 mL). The combined
organic layers were dried (MgSO4) and concentrated.
The residue was purified by chromatography to give a
mixture of 13a/13b (1:4) as a yellow oil (141 mg, 95%).
A solution of 10 (0.21 g, 0.86 mmol) in aqueous KOH
(1.36 g, 25.8 mmol, in 10 mL H2O) was heated to reflux
for 4 h. The reaction mixture was cooled to rt, acidified
with 1 M HCl (ꢀ10 mL) and extracted with ether. The
ethereal layers were dried (MgSO4) and concentrated to
give a colorless oil (0.15 g, 65%). This oil consisted of a
mixture of isomeric carboxylic acids 11a and 11b (1:4)
as indicated by NMR spectroscopy. Separation of the
two isomers was not possible. 13C NMR (CDCl3) l
175.4, 137.7, 128.1, 127.9, 127.5, 75.9, 70.7, 70.1, 68.4,
37.8, 28.9, 24.3, 18.6. To a flame-dried flask under N2
at 0°C, was added a solution of 11a/11b (0.080 g, 0.30
mmol) in dry ether (ꢀ6 mL) followed by a solution of
methyllithium (1.6 M in ether, 0.40 mL, 0.66 mmol).
After addition was complete, the ice bath was removed
and the reaction mixture was allowed to stir at room
temperature for 2 h. Chlorotrimethylsilane (0.17 mL)
was added and the reaction was stirred for 30 min. The
reaction mixture was quenched by the addition of 1 M
HCl (4 mL), and after an additional 30 min of stirring,
the layers were separated. The aqueous layer was
extracted with ether (5×3 mL), the combined ethereal
layers were dried (MgSO4) and concentrated to give a
brown oil (0.073 g, 79%). This was determined to be a
mixture of 12a and 12b (1:1) by NMR spectroscopy.
Preparative thin-layer chromatography (SiO2, hexanes–
ethyl acetate=15:1) gave pure 12a and pure 12b.
13b: IR (neat, cm−1) 2919, 2853, 1726, 1448, 1368, 1255,
1
1202, 1090, 731, 698; H NMR (CDCl3) l 9.71 (dd,
Methyl ketone cis-12a: [h]2D3 +25.1 (c 0.432, CHCl3); IR
J=0.9, 2.1 Hz, 1H), 7.36–7.25 (m, 5H), 4.62 (d, J=11.5
Hz, 1H), 4.47 (d, J=11.5 Hz, 1H), 4.28–4.17 (m, 1H),
4.06–3.96 (m, 1H), 3.18 (dt, J=4.7, 7.6 Hz, 1H), 2.90–
1.50 (m, 6H), 1.27 (d, J=6.8 Hz, 3H); 13C NMR
(CDCl3) l 200.2, 137.6, 128.2, 127.6, 127.5, 76.3, 70.7,
68.9, 68.1, 46.8, 28.9, 24.4, 18.5. This product was used
in the next step without further characterization.
(neat, cm−1) 2925, 2855, 1716, 1455, 1374, 1208, 1081,
1
1028, 740, 697; H NMR (CDCl3) l 7.35–7.27 (m, 5H),
4.64 (d, J=12.0 Hz, 1H), 4.34 (d, J=12.0 Hz, 1H), 3.84
(ddd, J=1.5, 5.9, 7.1 Hz, 1H), 3.58–3.45 (m, 1H),
3.37–3.32 (m, 1H), 2.84 (dd, J=7.1, 16.4 Hz, 1H), 2.54
(dd, J=5.9, 16.4 Hz, 1H), 2.10 (s, 3H), 1.71–1.38 (m,
4H), 1.20 (d, J=6.2 Hz, 3H); 13C NMR (CDCl3) l
206.9, 138.0, 128.0, 127.9, 127.4, 75.8, 74.4, 71.6, 70.8,
46.2, 31.7, 28.2, 26.7, 22.5. FAB-HRMS m/z 269.1727
(calcd for C16H22O3Li [M+Li+] m/z 269.1729).
3.11. 1-[(3S,6R)-Tetrahydro-6-methyl-3-(phenyl-
methoxy)-2H-pyran-2-yl]-2-propanone, 12a/12b
To a flame-dried flask under N2 was added a solution
of 13a/13b (130 mg, 0.524 mmol) in dry THF (12 mL).
The reaction mixture was cooled to 0°C and a solution
of methylmagnesium bromide (3.0 M in Et2O, 0.35 mL,
1.0 mmol) was added. The ice bath was removed and
the reaction was stirred for 4 h at room temperature.
The reaction mixture was quenched by the addition of
saturated aqueous NH4Cl (10 mL). The layers were
separated and the aqueous layer was extracted with
CH2Cl2 (4×40 mL). The organic layers were dried
(MgSO4) and concentrated to give as a nearly colorless
solid (126 mg, 91%). To a solution of the solid (28.0
mg, 0.106 mmol) in DMF (10 mL) was added pyridium
dichromate (0.16 g, 0.42 mmol) and the reaction mix-
ture was stirred at room temperature for 4 h. The
reaction mixture was quenched by the addition of Et2O
(10 mL) and brine (10 mL). The layers were separated
and the aqueous layer was extracted with ether (4×20
mL). The combined ethereal layers were dried (MgSO4)
and concentrated to give a mixture of 12a and 12b (1:3)
by NMR spectroscopy. Purification of the crude
Methyl ketone trans-12b: [h]2D3 +43.3 (c 0.448, CHCl3);
IR (neat, cm−1) 2971, 2935, 2871, 1714, 1454, 1358,
1
1134, 1095, 1070, 1028, 738, 699; H NMR (CDCl3)l
7.38–7.27 (m, 5H), 4.63 (d, J=11.7 Hz, 1H), 4.49 (d,
J=11.7 Hz, 1H), 4.19 (ddd, J=4.7, 6.5, 8.5 Hz, 1H),
4.02–3.91 (m, 1H), 3.21–3.13 (m, 1H), 2.77 (dd, J=4.7,
15.3 Hz, 1H), 2.61 (dd, J=8.8, 15.3 Hz, 1H), 2.18 (s,
3H), 2.03–1.90 (m, 1H), 1.85–1.55 (m, 3H), 1.26 (d,
J=6.7 Hz, 3H); 13C NMR (CDCl3) l 206.2, 137.9,
128.1, 127.5, 127.4, 76.1, 70.7, 70.2, 67.9, 46.9, 30.9,
28.9, 24.4, 18.9. FAB-HRMS m/z 269.1726 (calcd for
C16H22O3Li [M+Li+] m/z 269.1729).
3.10. 6-Methyl-3-(phenylmethoxy)-tetrahydro-2H-pyran-
2-acetaldehyde
To a flame-dried flask, under N2, was added a solution
of the crude mixture of acids 11a/11b (200 mg, 0.758
mmol) in dry THF (15 mL). The reaction mixture was
cooled to 0°C and solid LiAlH4 (140 mg, 7.58 mmol)

762
J. M. Lukesh, W. A. Donaldson / Tetrahedron: Asymmetry 14 (2003) 757–762
product by preparative thin-layer chromatography
(SiO2, hexanes–ethyl acetate=10:1) gave pure 12a (5.4
mg, 19%) and pure 12b (16.0 mg, 57%).
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3.12. 1-[(2R,3S,6R)-Tetrahydro-3-hydroxy-6-methyl-
2H-pyran-2-yl]-2-propanone ((+)-decarestrictine L), 1
In a Parr apparatus, a solution of 12b (0.041 g, 0.16
mmol) and 10% Pd/C (60 mg) in CHCl3–MeOH (100:1,
12 mL) was stirred vigorously under a H2 (49.5–42.0
psi) for 5 h. The catalyst was removed via filtration
through a bed of Celite and the filter bed was washed
with CH2Cl2 (2×50 mL). The combined organic layers
were evaporated under reduced pressure to give (+)-1 as
a yellow oil (25.2 mg, 94%). (+)-1: [h]2D3 +21.1 (c 0.452,
CHCl3) [lit.2 [h]D23 +28.8 (c 0.49, CHCl3); 1H NMR
(CDCl3) l 4.01 (q, J=6.5 Hz, 1H), 3.95 (m, 1H), 3.40
(m, 1H), 2.76 (dd, J=5.6, 15.6 Hz, 1H), 2.70 (dd,
J=7.3, 15.6 Hz, 1H), 2.21 (s, 3H), 1.92–1.40 (m, 4H),
1.22 (d, J=6.5 Hz, 3H); 13C NMR (CDCl3) l 206.9,
72.2, 69.5, 67.7, 46.7, 31.2, 28.9, 27.7, 19.1. FAB-
HRMS m/z 179.1264 (calcd for C9H16O3Li [M+Li+]
m/z 179.1260).
Acknowledgements
12. The present route to 3a/b is higher yielding and gives
greater selectivity for the trans-isomer 3b than that previ-
ously reported: Brown, D. S.; Charreau, P.; Ley, S. V.
Synlett 1990, 749–750.
13. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectro-
metric Identification of Organic Compounds; John Wiley
and Sons: New York, 1991; p. 175.
Financial support for this work was provided by the
National Institutes of Health (GM-42641) and the
Department of Education (P200A000228). High resolu-
tion mass-spectral determinations were made at the
Washington University Mass Spectrometry Resource,
an NIH Research Resource (Grant No. P41RR0954).
14. Crews, P.; Rodriguez, J.; Jaspars, M. Organic Structure
Analysis; Oxford University Press: New York, 1998; pp.
78–79.
15. The latter steps of this route, Swern oxidation, methyl
Grignard addition, and PDC oxidation, follow those
reported by Hatakeyama.6
References
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