The carbohydrate-sesquiterpene interface. A zirconocene-mediated synthesis of (+)-epiafricanol from D-glucose

Article abstract of DOI:10.1055/s-2002-34380

A total synthesis of (+)-epiafricanol (6) has been readily achieved from D-glucose. The tricyclic alcohol target was arrived at by first forming methyl 6-O-benzyl-2-deoxy-2-C-methyl-α-D-altropyranoside (12) and converting this intermediate into methyl 2-C-methyl-2,3,4-trideoxy-α-D-threo-hexopyranoside (14). There followed a series of steps resulting in extension of the side chain to give the isopropenyl pyranoside 9. This advanced intermediate was subjected to zirconocene-promoted ring contraction, which gave rise to 8 and set the stage for conversion to 7. This tertiary carbinol was transformed into 6 by sequential ring-closing metathesis and stereodirected Simmons-Smith cyclopropanation.

Full text of DOI:10.1055/s-2002-34380

PAPER
2105
The Carbohydrate-Sesquiterpene Interface. A Zirconocene-Mediated
Synthesis of (+)-Epiafricanol from D-Glucose
S
ynthesisof (+)
e
-Epiafrican
o
ol from
D
-GlucoseA. Paquette,* Ruslan M. Arbit, Jacques-Alexis Funel, Sergei Bolshakov
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA
Fax +1(614)2921685; E-mail: paquette.1@osu.edu
Received 7 June 2002
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday.
CH3
H
CH3
H
CH3
H
Abstract: A total synthesis of (+)-epiafricanol (6) has been readily
achieved from D-glucose. The tricyclic alcohol target was arrived at
by first forming methyl 6-O-benzyl-2-deoxy-2-C-methyl- -D-altro-
pyranoside (12) and converting this intermediate into methyl 2-C-
methyl-2,3,4-trideoxy- -D-threo-hexopyranoside (14). There fol-
lowed a series of steps resulting in extension of the side chain to
give the isopropenyl pyranoside 9. This advanced intermediate was
subjected to zirconocene-promoted ring contraction, which gave
rise to 8 and set the stage for conversion to 7. This tertiary carbinol
was transformed into 6 by sequential ring-closing metathesis and
stereodirected Simmons–Smith cyclopropanation.
H3C
H3C
H3C
OH
OH
OH
CH3
CH3
CH3
CH3
CH3
2
CH3
3
1
CH3
H
CH3
H
CH3
H
Key words: zirconocene, metathesis, ring contraction, glucose,
sesquiterpene
H3C
H3C
H3C
OH
OH
OH
CH3
CH3
CH3
CH3
4
CH3
5
CH3
6
The current perception of the field of hydroazulene ses-
quiterpene synthesis serves as an excellent testing ground
for new preparative methods. Among the many natural
products of this sub-type, africanol (1) has attracted con-
siderable attention as a consequence of its tricyclic struc-
ture that features five contiguous stereogenic centers and
three different ring sizes.1 This alcohol was first isolated
from the soft coral Lemnalia africana and later discovered
along with isoafricanol (2) in the ascomycete fungus Lep-
tographium lundbergii.2
Figure 1
The finding that the powerfully electrophilic zirconocene
equivalent known as ‘Cp2Zr’9 is capable of transforming
5-vinyl pyranosides cleanly and efficiently into enantio-
merically pure, highly functionalized cis-2-vinyl-
cyclopentanols10 is a recent discovery. Nevertheless, it is
already recognized to be a valuable process in practical
terms.11–13 Although most applications reported so far
have stopped at the immediate five-membered ring prod-
uct, we saw in this chemistry an opportunity to prepare in
highly enantioselective fashion an unknown stereoisomer
of africanol defined in absolute configurational terms as 6.
In our synthetic planning (Scheme 1), we were prepared
to evaluate the ease with which methyl -D-glucopyrano-
side (10) might be transformed into methyl glycoside 9.
The anticipation was that subsequent deoxygenative ring
contraction of 9 with ‘Cp2Zr’ would provide 8. Hopefully,
the ketone derived from 8 would lend itself to conversion
to 7 by an oxidation/1,2-addition sequence. The latter in-
These metabolites are believed to be derived biosyntheti-
cally from humulene and indeed the first synthetic inroads
to 1 were made successfully from this biomimetic direc-
tion.3 Subsequent approaches to this attractive target have
been based on suitable applications of the Claisen4 and an-
ionic oxy-Cope5 rearrangements, oxymercuration chemis-
try,6 and intramolecular cyclization reactions.7,8 These
protocols have also provided access to the africanol iso-
mers 3 5 (Figure 1).
CH3
CH3
CH3
O
H3C
6
HO
OMe
HO
CH3
CH3
7
8
9
Scheme 1
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,2105,2109,ftx,en;C02502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2106
L. A. Paquette et al.
PAPER
termediate held the promise of being receptive to ring- With 8 available in quantity, its conversion to ketone 17
closing metathesis and hydroxyl-directed Simmons- was pursued (Scheme 3). Although MM3-based calcula-
Smith cyclopropanation.
tions hinted that the cis-2,5-disubstituted cyclopentanone
(Esteric = 24.4 kcal/mol) was slightly less thermodynami-
cally stable than its trans counterpart (Esteric = 23.8 kcal/
mol) and its conjugated isomer (Esteric = 21.5 kcal/mol),24
possible complications related to these phenomena were
not encountered with periodinane as the oxidant in the
presence of sodium bicarbonate. Furthermore, the lithio
derivative of 4,4-dimethyl-5-iodo-1-pentene25 could be
added directly to 17 without the onset of extensive eno-
lization. The desired 1,2-addition was sterically con-
trolled as expected, giving rise to 7, the stereochemical
features of which were supported by NOESY studies. Cy-
clization of 7 by RCM with the Grubbs ruthenium
catalyst26 led to 18 in 93% yield after only 90 minutes at
room temperature in dichloromethane as solvent. The
identity of the 1H and 13C NMR spectra of (+)-18 prepared
in this manner with that of the known racemate5 served to
corroborate our stereochemical assignments. The cyclo-
propanation of 18 to produce 6 was almost as efficient
(87%) when performed with diethylzinc and di-
The present undertaking began with a short series of per-
tinent carbohydrate transformations (Scheme 2). Thus,
formation of the 4,6-O-benzylidene derivative14 was fol-
lowed by ditosylation15 and remarkable cyclization to ep-
oxide 11 according to precedent.14,16 Trans-diaxial
opening of the oxirane ring with the higher-order methyl
cuprate reagent17 set the stage for selective reductive
cleavage of the benzylidene acetal18 and arrival at diol 12.
The combination of triethylsilane and trifluoroacetic acid
was well suited to this objective, far superior to the classi-
cal sodium cyanoborohydride method.19 The availability
of intermediate 12 made possible generation of the dime-
sylate and reductive removal of the vicinal sulfonate ester
groups with zinc and sodium iodide in hot DMF in line
with the conventional Tipson Cohen protocol.20,21 Con-
current hydrogenolysis and saturation of the double bond
in 13 proceeded readily.
A four-step sequence was then required to secure vinyl
glycoside 9. Oxidation of 14 with Dess Martin
periodinane22,23 gave the sensitive aldehyde with no evi-
dence of epimerization. Controlled incorporation of a me-
thyl group was accomplished by way of
methylmagnesium bromide. The resulting alcohol 15 was
subjected to unbuffered oxidation without any configura-
tional complications, and 16 was subjected to Wittig ole-
fination. Experimental validation of the projected ring
contraction was immediately realized by treatment of 9
with ‘Cp2Zr’ in toluene at –78 °C and then warming to
room temperature followed by the introduction of boron
trifluoride etherate. This critical step afforded 8 in 63%
yield with 14% of a chromatographically separable dia-
stereomer that was not further investigated.
1
iodomethane.27 The H and 13C NMR spectra of 6 bear
close similarities to those of 1 and 2, but have features that
are specifically characteristic of this dextrorotatory end
product.
In summary, we have achieved a direct synthesis of the af-
ricanol diastereomer 6 by way of a three-component cou-
pling scheme. The first key operation is the zirconocene-
promoted ring contraction of 9 to cyclopentanol 8. Attach-
ment of the proper side chain as in 7 made possible effi-
cient cyclization to form the unsaturated seven-membered
ring. Hydroxyl-directed cyclopropanation resulted in in-
corporation of the final carbon atom. This approach holds
considerable flexibility in that different carbohydrate
starting materials are abundantly available and a great va-
1. PhCHO,
HO
BnO
HO
1. MeLi, CuCN,
ether, (76%)
ZnCl2 (70%)
2. TsCl, K2CO3,
CH3
O
O
Ph
O
O
O
HO
HO
2. Et3SiH,
CF3COOH,
CH2Cl2 (70%)
NaOH
3. NaOMe, MeOH
(76% for 2 steps)
O
HO
OMe
OMe
OH
OMe
10
11
12
1. Dess-Martin,
NaHCO3,
4Å MS, CH2Cl2
1. MsCl, py
DMAP
OH
H2
5% Pd/C
BnO
HO
CH3
O
CH3
O
H3C
CH3
O
2. Zn, NaI
DMF
2. CH3MgBr,
ether
MeOH
(99%)
OMe
OMe
OMe
(84% for 2 steps)
(95% for 2 steps)
13
14
15
O
Cp2ZrCl2,
H3C
CH3
O
Ph3P=CH2
n-BuLi,
Dess-Martin
9
8
THF
(81%)
CH2Cl2
(80%)
toluene;
BF3•OEt2
(63%)
OMe
16
Scheme 2
Synthesis 2002, No. 14, 2105–2109 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of (+)-Epiafricanol from D-Glucose
2107
orated to leave a residue that was dried under vacuum to remove
traces of pyridine. The resulting off-white solid (154.0 mg, quanti-
tative) was used without further purification.
IR (neat): 1454, 1359, 1279, 1179 cm–1.
1H NMR (300 MHz, CDCl3): = 7.36–7.16 (m, 5 H), 5.03 (dd,
J = 3.4, 8.4 Hz, 1 H), 4.95 (dd, J = 3.4, 4.6 Hz, 1 H), 4.61 (dd,
J = 11.7, 20.5 Hz, 2 H), 4.52 (d, J = 2.2 Hz, 1 H), 4.24 (dt, J = 8.4,
2.9 Hz, 1 H), 3.80–3.71 (m, 2 H), 3.38 (s, 3 H), 3.09 (s, 3 H), 3.04
(s, 3 H), 2.47–2.42 (m, 1 H), 1.16 (d, J = 7.4 Hz, 3 H).
PCy3
Ru
PCy3
Cl
Cl
CH3
O
Dess-Martin,
NaHCO3
I
Ph
8
7
CH2Cl2
CH2Cl2
(93%)
t-BuLi
THF/pentane
-50 ºC
(45% for 2 steps)
CH3
17
13C NMR (75 MHz, CDCl3): = 137.5, 128.4 (2 C), 127.9 (2 C),
127.7, 102.5, 79.2, 73.9, 71.7, 68.7, 67.0, 55.7, 38.7, 38.6, 38.4,
14.7.
CH3
CH3
Et2Zn,
CH2I2
HRMS (ES): m/z calcd for C17H26O9S2 Na (M + Na)+, 461.0910;
found, 461.0929.
CH2Cl2
(87%)
H3C
H3C
OH
OH
CH3
CH3
CH3
CH3
The above dimesylate (154.0 mg, 0.354 mmol) dissolved in DMF
(10 mL) was treated with sodium iodide (424 mg, 2.83 mmol) fol-
lowed by zinc dust (185 mg, 2.83 mmol, activated prior to use). The
system was flushed with argon and the mixture was stirred at the re-
flux temperature for 24 h before being cooled to r.t. and diluted with
hexane–Et2O, 1:1 (50 mL) and H2O (50 mL). The separated aq layer
was extracted with hexane–Et2O, 1:1 (3 50 mL). The combined
organic phases were washed with brine, dried, and evaporated.
Flash chromatography of the residue on silica gel (elution with 10%
EtOAc in hexane) gave 13 (83 mg, 95%) as a colorless oil.
18
6
Scheme 3
riety of unsaturated pendant groups may be introduced.
The implementation of this chemistry in the context of the
total synthesis of natural and nonnatural products is under
active investigation in this laboratory.
[ ]D18 +97.5 (c 1.13, CHCl3).
IR (neat): 1587, 1496, 1454, 1360 cm–1.
Solvents were reagent grade and in all cases dried before use. The
column chromatographic separations were performed with Woelm
silica gel (230–400 mesh). The purity of all compounds was shown
to be >95% by TLC and high field 1H and 13C NMR spectroscopy.
The drying agent used was Na2SO4.
1H NMR (300 MHz, CDCl3): = 7.37–7.25 (m, 5 H), 5.80–5.74 (m,
1 H), 5.68–5.64 (m, 1 H), 4.62–4.56 (m, 3 H), 4.40–4.35 (m, 1 H),
3.57 (dd, J = 10.1, 20.4 Hz, 1 H), 3.56 (dd, J = 10.1, 19.7 Hz, 1 H),
3.47 (s, 3 H), 2.19–2.14 (m, 1 H), 1.08 (d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 138.2, 129.0, 128.2 (2 C), 127.5 (2
C), 127.4, 124.7, 102.2, 73.3, 72.6, 67.6, 55.3, 34.0, 18.6.
Methyl 6-O-Benzyl-2-deoxy-2-C-methyl- -D-altropyranoside
(12)
To a cold (0 °C), vigorously stirred soln of methyl 4,6-O-ben-
zylidene-2-deoxy-2-C-methyl- -D-altropyranoside17 (3.05 g, 10.9
mmol) in CH2Cl2 (125 mL) under argon was added triethylsilane
(8.7 mL, 54.4 mmol) followed by TFA (4.2 mL, 54.4 mmol). After
the addition was complete, the mixture was kept at 0 °C for 1 h, al-
lowed to warm to r.t., stirred for an additional 2 h, carefully
quenched with sat. NaHCO3 soln, and extracted with CH2Cl2
(3 300 mL). The combined organic phases were washed with sat.
NaHCO3 soln, and brine, dried, and evaporated. The residue was
chromatographed on silica gel (gradient elution with hexane–
EtOAc, 2:1 1:1) to give 12 (2.17 g, 70%) as a colorless oil.
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.54; H,
8.21.
Methyl 2-C-Methyl-2,3,4-trideoxy- -D-threo-hexopyranoside
(14)
A soln of 13 (2.60 g, 10.47 mmol) in absolute MeOH (100 mL) con-
taining 5% Pd/C (0.26 g) was stirred for 5 h under 1 atm of hydro-
gen. Additional catalyst (0.15 g) was introduced and the process
was repeated for 3 h. The reaction mixture was filtered through a
short pad of celite and concentrated to give 14 (1.67 g, 99%) as a
colorless oil.
[ ]D 18 +91.3 (c 2.63, CHCl3).
[ ]D17 +111.4 (c 0.19, CHCl3).
IR (neat): 3472, 1453, 1420, 1384 cm–1.
IR (neat): 3423, 1454, 1383 cm–1.
1H NMR (300 MHz, CDCl3): = 7.38–7.24 (m, 5 H), 4.63 (s, 2 H),
4.56 (s, 1 H), 3.87–3.63 (m, 5 H), 3.40 (s, 3 H), 2.65 (br s, 2 H), 2.30
(qd, J = 7.5, 1.7 Hz, 1 H), 1.05 (d, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 138.3, 128.3 (2 C), 127.5 (2 C),
127.4, 102.6, 73.4, 72.1, 70.1, 68.5, 63.6, 55.3, 38.8, 14.4.
HRMS (ES): m/z calcd for C15H22O5 Na (M + Na)+, 305.1359;
found, 305.1389.
1H NMR (300 MHz, CDCl3): = 4.39 (s, 1 H), 3.84–3.76 (m, 1 H),
3.55 (dd, J = 11.4, 21.4 Hz, 1 H), 3.53 (dd, J = 11.4, 24.8 Hz, 1 H),
3.35 (s, 3 H), 2.14 (br s, 1 H), 2.07–1.95 (m, 1 H), 1.81–1.75 (m, 1
H), 1.57 (dq, J = 13.2, 4.3 Hz, 1 H), 1.42–1.30 (m, 1 H), 1.29–1.22
(m, 1 H), 1.03 (d, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 102.9, 69.1, 66.1, 54.5, 31.1, 23.5,
21.1, 16.1.
Anal. Calcd for C8H16O3: C, 59.97; H, 10.07. Found: C, 59.50; H,
10.11.
Methyl 6-O-Benzyl-2-C-methyl-2,3,4-trideoxy- -D-threo-hex-3-
enopyranoside(13)
A soln of 12 (100.0 mg, 0.354 mmol) in anhyd pyridine (5 mL) con-
taining DMAP (5.0 mg, 10 mol%) was cooled to –10 °C and treated
dropwise with freshly distilled methanesulfonyl chloride (0.110
mL, 1.42 mmol) under argon. The mixture was stirred for 1 h at –10
°C and allowed to warm slowly to r.t. After 6 h, the contents were
poured into ice H2O and extracted with CH2Cl2 (3 100 mL). The
combined organic layers were washed with brine, dried, and evap-
1-(6-Methoxy-5-methyltetrahydropyran-2-yl)ethanol (15)
Dess–Martin periodinane (2.57 g, 6.07 mmol) was added to a mix-
ture of 14 (810 mg, 5.06 mmol), NaHCO3 (4.28 g, 10 equiv), and
powdered 4 Å molecular sieves (3.5 g) in CH2Cl2 (12 mL). After 2
h of stirring at r.t., pentane (100 mL) was introduced and stirring
was maintained for another 30 min before filtration through a pad
of celite. The filtrate was stirred with pulverized anhyd K2CO3 (4 g)
Synthesis 2002, No. 14, 2105–2109 ISSN 0039-7881 © Thieme Stuttgart · New York

2108
L. A. Paquette et al.
PAPER
for an additional 30 min, filtered again, and concentrated to leave a
yellowish oil.
1H NMR (300 MHz, CDCl3): = 9.66 (s, 1 H), 4.48 (d, J = 1.7 Hz,
1 H), 4.20 (dd, J = 8.2, 6.4 Hz, 1 H), 3.41 (s, 3 H), 2.09–1.96 (m, 1
H), 1.86–1.74 (m, 1 H), 1.71–1.63 (m, 2 H), 1.48–1.35 (m, 1 H),
1.05 (d, J = 7.2 Hz, 3 H).
1H NMR (300 MHz, CDCl3): = 4.98–4.97 (m, 1 H), 4.84–4.83 (m,
1 H), 4.42 (s, 1 H), 4.11 (dd, J = 11.3, 2.2 Hz, 1 H), 3.37 (s, 3 H),
2.04 (tt, J = 8.5, 4.6 Hz, 1 H), 1.78 (s, 3 H), 1.77–1.62 (m, 2 H),
1.47–1.38 (m, 2 H), 1.06 (d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 146.0, 110.7, 103.3, 71.7, 54.6,
31.1, 24.4, 24.1, 18.8, 16.2.
13C NMR (75 MHz, CDCl3): = 201.8, 103.4, 74.1, 55.2, 31.5,
23.8, 20.4, 15.9.
HRMS (ES): m/z calcd for C10H18O2 Na (M + Na)+, 193.1199;
found, 193.1203.
The aldehyde was immediately dissolved in anhyd Et2O (25 mL),
cooled to 0 °C, and treated with ethereal methylmagnesium bromide
(5.35 mL of 2.65 M, 14.2 mmol). The reaction mixture was stirred
at r.t. for 30 min, quenched with sat. NH4Cl soln, and extracted with
Et2O (3 150 mL). The combined organic phases were washed
with brine, dried, and evaporated. Flash chromatography of the res-
idue on silica gel (gradient elution with 25 35% EtOAc in hexane)
gave 15 (743 mg, 84%) as a colorless oil.
[ ]D23 +112.6 (c 1.57, CHCl3).
IR (neat): 3448, 1452, 1383, 1370 cm–1.
1H NMR (300 MHz, CDCl3): = 4.38 (s, 1 H), 3.58 (quintet, J = 6.4
Hz, 1 H), 3.46–3.39 (m, 1 H), 3.34 (s, 3 H), 2.54 (br s, 1 H), 2.01–
1.93 (m, 1 H), 1.78–1.73 (m, 1 H), 1.55–1.28 (series of m, 3 H), 1.12
(d, J = 6.4 Hz, 3 H), 1.00 (d, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 102.9, 73.0, 70.4, 54.5, 31.0, 23.6,
21.5, 18.3, 16.1.
cis,cis-2-Isopropenyl-5-methylcyclopentanol (8)
A slurry of zirconocene dichloride (703 mg, 2.41 mmol) in anhyd
toluene (5 mL) was cooled to –78 °C under argon, treated with BuLi
(3.6 mL of 1.18 M, 4.21 mmol), and stirred in the cold for 1 h. A
soln of 9 (205 mg, 1.202 mmol) in anhyd toluene (4 mL) was intro-
duced and after 15 min at –78 °C, the mixture was gradually
warmed to r.t., where it was maintained for 3 h. During this period,
the color of the mixture gradually turned from bright yellow to dark
brown. At this point, the mixture was cooled to 0 °C, whereupon
BF3 OEt2 (0.300 mL, 2.405 mmol) was added. The mixture was al-
lowed to warm to r.t., stirred for 1 h, and quenched with 10% HCl
(10 mL). The separated aq phase was extracted with Et2O (3 50
mL) and the combined organic layers were washed with sat.
NaHCO3 soln and brine, dried, and evaporated. Flash chromatogra-
phy of the residue on silica gel (elution with 15% EtOAc in hexane)
gave 8 (104 mg, 63%) and an unknown diastereomer (23 mg, 14%).
Both were colorless oils.
HRMS (ES): m/z calcd for C9H18O3 Na (M + Na)+, 197.1148;
found, 197.1155.
8
[ ]D21 +5.2 (c 0.38, CHCl3).
IR (neat): 3448, 1645, 1454 cm–1.
1-(6-Methoxy-5-methyltetrahydropyran-2-yl)ethanone (16)
To a soln of 15 (1.05 g, 6.01 mmol) in CH2Cl2 (15 mL) was added
the Dess–Martin periodinane (3.06 g, 7.21 mmol) and the mixture
was stirred at r.t. for 3 h. Following dilution with pentane (30 mL),
stirring was maintained for an added 30 min. The solids were re-
moved by filtration through a pad of celite, the solvents were evap-
orated, and the residue was purified by bulb-to-bulb distillation to
give 16 (827 mg, 80%) as a colorless oil.
[ ]D22 +54.9 (c 0.86, CDCl3).
IR (neat): 1721, 1454, 1353 cm–1.
1H NMR (300 MHz, CDCl3): = 4.45 (s, 1 H), 4.18–4.13 (m, 1 H),
3.38 (s, 3 H), 2.21 (s, 3 H), 2.06–1.96 (m, 1 H), 1.80–1.75 (m, 1 H),
1.68–1.61 (m, 2 H), 1.41 (dq, J = 13.2, 3.6 Hz, 1 H), 1.04 (d, J = 7.3
Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 209.0, 103.3, 74.5, 55.0, 31.1,
25.8, 24.0, 21.8, 16.0.
1H NMR (300 MHz, CDCl3): = 5.01–4.99 (m, 1 H), 4.86 (s, 1 H),
3.92 (t, J = 3.4 Hz, 1 H), 2.58–2.49 (m, 1 H), 2.10–1.98 (m, 1 H),
1.93–1.78 (m, 2 H), 1.84–1.82 (m, 3 H), 1.76–1.64 (m, 1 H), 1.52–
1.38 (m, 1 H), 1.30 (br s, 1 H), 1.07 (d, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 144.5, 111.7, 75.2, 53.1, 39.7,
29.9, 25.2, 23.7, 14.6.
HRMS (ES): m/z calcd for C9H16O (M+), 141.1274; found,
141.1263.
Diastereomer
[ ]D 22 +14.0 (c 0.15, CHCl3).
IR (neat): 3440, 1644, 1456 cm–1.
1H NMR (300 MHz, CDCl3): = 5.03–5.00 (m, 1 H), 4.88–4.84 (m,
1 H), 3.74 (dd, J = 4.6, 1.3 Hz, 1 H), 2.55–2.45 (m, 1 H), 2.15–2.00
(m, 2 H), 1.83–1.81 (m, 3 H), 1.87–1.63 (series of m, 2 H), 1.51 (br
s, 1 H), 1.24–1.08 (m, 1 H), 1.01 (d, J = 7.1 Hz, 3 H).
HRMS (ES): m/z calcd for C9H16O3 Na (M + Na)+, 195.0992;
found, 195.0999.
cis,cis-1-(2,2-Dimethyl-4-pentenyl)-2-isopropenyl-5-methylcy-
clopentanol (7)
6-Isopropenyl-2-methoxy-3-methyltetrahydropyran (9)
A slurry of methyltriphenylphosphonium bromide (1.348 g, 3.77
mmol) in anhyd THF (5 mL) was treated with BuLi (2.7 mL of 1.40
M, 3.77 mmol) at –78 °C under an inert atmosphere. After 30 min
at this temperature and 2 h at 0 °C, a soln of 16 (500 mg, 2.90 mmol)
in anhyd THF (7 mL) was introduced and the temperature was al-
lowed to rise to 20 °C during another 3 h. The reaction mixture was
quenched with sat. NH4Cl soln, the aq phase was separated and ex-
tracted with Et2O (3 300 mL). The combined organic phases were
washed with brine, dried, and evaporated. The residue was purified
by bulb-to-bulb distillation to give 9 (402 mg, 81%) as a colorless
oil.
To a soln of 8 (34.0 mg, 0.242 mmol) in CH2Cl2 (2.8 mL) was added
NaHCO3 (203 mg, 10 equiv) followed by the Dess–Martin periodi-
nane (118.3 mg, 0.279 mmol). The mixture was stirred at r.t. for 2
h, diluted with pentane (30 mL), and after 15 min filtered through a
celite pad. After evaporation of the solvent, this procedure was re-
peated twice. Finally evaporation left a yellow oil, which was used
without further purification.
1H NMR (300 MHz, C6D6): = 4.84–4.81 (m, 1 H), 4.73–4.70 (m,
1 H), 2.51 (t, J = 7.8 Hz, 1 H), 1.84 (q, J = 7.3 Hz, 1 H), 1.67 (dd,
J = 1.3, 0.9 Hz, 3 H), 1.64–1.49 (m, 2 H), 1.39–1.15 (m, 2 H), 0.92
(d, J = 7.3 Hz, 3 H).
[ ]D21 +73.4 (c 0.37, CHCl3).
IR (neat): 1652, 1454, 1383 cm–1.
13C NMR (75 MHz, C6D6): = 217.2, 142.9, 112.3, 55.4, 42.8, 29.4,
26.3, 21.5, 15.3.
4,4-Dimethyl-5-iodo-1-pentene (62.5 mg, 0.279 mmol) was dis-
solved in anhyd pentane (2.0 mL), cooled to –60 °C, and treated
Synthesis 2002, No. 14, 2105–2109 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of (+)-Epiafricanol from D-Glucose
2109
dropwise under argon with tert-butyllithium (0.36 mL of 1.55 M,
0.558 mmol) while stirring. The mixture was stirred at –60 to –50
°C for 60 min, and the unpurified cyclopentanone from above dis-
solved in anhyd THF (2 mL) was introduced. After 2 h of stirring at
–60 to –40 °C, sat. NH4Cl soln was added and the aq phase was ex-
tracted with Et2O (3 50 mL). The combined organic phases were
washed with brine, dried, and evaporated. Purification of the resi-
due by chromatography on silica gel (elution with 1% EtOAc in
hexane) gave 7 (25.9 mg, 45%) as a colorless oil.
Acknowledgement
Financial support was obtained from the National Science Founda-
tion.
References
(1) (a) Tursch, B.; Braekman, J. C.; Daloze, D.; Fritz, P.;
Kelecom, A.; Karlsson, R.; Losman, D. Tetrahedron Lett.
1974, 747. (b) Karlsson, R. Acta Crystallogr., Sect. B 1976,
B32, 2609.
(2) (a) Abraham, W.-R.; Ernst, L.; Witte, L.; Hanssen, H.-P.;
Sprecher, E. Tetrahedron 1986, 42, 4475. (b) Abraham, W.-
R.; Sprecher, E.; Hanssen, H.-P. Flavour Fragrance J. 1987,
2, 175.
(3) Shirahama, H.; Hayano, K.; Kanemoto, Y.; Misumi, S.;
Ohtsuka, T.; Hashiba, N.; Furusaki, A.; Murata, S.; Noyori,
R.; Matsumoto, T. Tetrahedron Lett. 1980, 21, 4835.
(4) Paquette, L. A.; Ham, W. H. J. Am. Chem. Soc. 1987, 109,
3025.
(5) Fan, W.; White, J. B. J. Org. Chem. 1993, 58, 3557.
(6) Sugimura, T.; Futagawa, T.; Tai, A. Chem. Lett. 1990, 2295.
(7) Cossy, J.; BouzBouz, S.; Mouza, C. Synlett 1998, 621.
(8) Marques de, F. A.; Ferreira, J. T. B.; Piers, E. J. Braz. Chem.
Soc. 2000, 11, 502.
[ ]D21 +36.2 (c 0.07, CHCl3).
IR (neat): 3553, 1636, 1456, 1374 cm–1.
1H NMR (300 MHz, CDCl3): = 5.92–5.77 (m, 1 H), 5.06–4.95 (m,
3 H), 4.88–4.85 (m, 1 H), 2.45 (dd, J = 9.8, 8.3 Hz, 1 H), 2.16–2.01
(series of m, 3 H), 1.85 (dd, J = 1.4, 0.8 Hz, 3 H), 1.81–1.60 (m, 3
H), 1.53 (br s, 1 H), 1.44 (s, 2 H), 1.34–1.18 (m, 1 H), 1.01 (d,
J = 5.6 Hz, 6 H), 1.00 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 146.1, 135.9, 117.0, 113.3, 82.4,
57.8, 49.8, 49.6, 41.7, 34.0, 31.5, 28.4, 27.9, 27.6, 24.7, 15.0.
HRMS (ES): m/z calcd for C16H28O Na (M + Na)+, 259.2032;
found, 259.2021.
3,5,5,8-Tetramethyl-2,3,4,5,6,8a-hexahydro-1H-azulen-3a-ol
(18)
A soln of the Grubbs’ catalyst (15.8 mg, 19.2 mol) in CH2Cl2 (2
mL) was added under argon to a soln of 7 (15.1 mg, 63.9 mol) in
CH2Cl2 (18 mL). After 1.5 h of stirring at r.t., the reaction mixture
was concentrated and the residue was purified by flash chromatog-
raphy on silica gel (elution with 2% EtOAc in hexane) to give 18
(12.4 mg, 93%) as a colorless oil.
[ ]D 20 +37.5 (c 0.24, CHCl3).
IR (neat): 3602, 1452, 1364, 1241 cm–1.
1H NMR (300 MHz, CDCl3): = 5.71–5.63 (m, 1 H), 2.91 (t,
J = 9.5 Hz, 1 H), 2.20 (dd, J = 14.3, 4.9 Hz, 1 H), 2.02–1.11 (series
of m, 9 H), 1.78 (d, J = 1.3 Hz, 3 H), 1.03 (s, 3 H), 0.94 (s, J = 6.6
Hz, 1 H), 0.91 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 138.8, 125.5, 80.7, 53.7, 50.1,
46.2, 40.3, 34.9, 31.6, 30.2, 27.1, 24.6, 23.8, 12.9.
(9) (a) Negishi, E.; Cederbaum, F. E.; Takahashi, T.
Tetrahedron Lett. 1986, 27, 2829. (b) Swanson, D. R.;
Negishi, E. Organometallics 1991, 10, 825.
(10) Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem.
Soc. 1993, 115, 8835.
(11) Hanzawa, Y.; Ito, H.; Taguchi, T. Synlett 1995, 299.
(12) Jenkins, D. J.; Riley, A. M.; Potter, B. V. L. J. Org. Chem.
1996, 61, 7719.
(13) Paquette, L. A.; Cuniere, N. Org. Lett. 2002, 4, 1927.
(14) Richtmyer, N. K. Methods Carbohydr. Chem. 1962, 1, 107.
(15) Medgyes, A.; Farkas, E.; Liptak, A.; Pozsgay, V.
Tetrahedron 1997, 53, 4159.
(16) Rosenfeld, D. A.; Richtmyer, N. K.; Hudson, C. S. J. Am.
Chem. Soc. 1948, 70, 2201.
(17) Nicoll-Griffith, D. A.; Weiler, L. Tetrahedron 1991, 47,
2733.
(18) (a) DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C.
Tetrahedron Lett. 1995, 36, 669. (b) Arasappan, A.; Fraser-
Reid, B. J. Org. Chem. 1996, 61, 2401.
HRMS (ES): m/z calcd for C14H24O Na (M + Na)+, 231.1719;
found, 231.1727.
3,3,5,7b-Tetramethyldecahydrocyclopropa[e]azulen-4a-ol (6)
A soln of 18 (6.9 mg, 33.1 mol) in CH2Cl2 (2 mL) was treated with
diethylzinc in hexane (100 L of 1.0 M, 100 mol) at 0 °C under ar-
gon followed by diiodomethane (150 L). The reaction mixture was
stirred at 0 °C for 1.5 h, at r.t. for 30 min, quenched with sat. NH4Cl
soln, and extracted with CH2Cl2 (3 25 mL). The combined organic
phases were washed with brine, dried, and evaporated. The residue
was purified by flash chromatography on silica gel (gradient elution
with 0.5 2% EtOAc in hexane) to give 6 (6.4 mg, 87%) as a color-
less oil.
(19) Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93, C10.
(20) Tipson, R. S.; Cohen, A. Carbohydr. Res. 1965, 1, 338.
(21) Yamazaki, T.; Matsuda, K.; Sugiyama, H.; Seto, S.;
Yamaoka, N. J. Chem. Soc., Perkin Trans. 1 1977, 1981.
(22) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(23) Ireland, R. E.; Gleason, J. L.; Gegnas, L. D.; Highsmith, T.
K. J. Org. Chem. 1996, 61, 6856.
(24) The authors thank John Hofferberth for these calculations.
(25) Prepared in 3 steps: (a) Salomon, R. G.; Ghosh, S. Org.
Synth. 1984, 62, 125. (b) Anderson, R. J.; Ashwell, S.;
Garnett, I.; Golding, B. T. J. Chem. Soc., Perkin Trans 1
2000, 4488. (c) Ashby, E. C.; DePriest, R. N.; Goel, A. B.;
Wenderoth, B.; Pham, T. N. J. Org. Chem. 1984, 49, 3545.
(26) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413.
[ ]D21 +65.5 (c 0.16, CHCl3).
IR (neat): 3609, 1457, 1377, 1363 cm–1.
1H NMR (500 MHz, CDCl3): = 2.14–1.98 (m, 3 H), 1.80–1.57
(series of m, 4 H), 1.55 (s, 2 H), 1.33 (dd, J = 15.1, 0.9 Hz, 1 H),
1.30–1.21 (m, 1 H), 1.08 (s, 3 H), 0.99 (s, 3 H), 0.90 (s, 3 H), 0.79
(d, J = 6.8 Hz, 3 H), 0.72–0.66 (m, 1 H), 0.56 (br s, 1 H), 0.22 (dd,
J = 8.7, 3.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): = 80.8, 51.7, 49.7, 47.7, 38.8, 35.2,
31.9, 29.3, 29.1, 29.0, 27.4, 23.8, 21.6, 17.7, 12.3.
(27) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron
Lett. 1966, 3353. (b) Furukawa, J.; Kawabata, N.;
Nishimura, J. Tetrahedron 1968, 24, 53. (c) Furukawa, J.;
Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1968, 3495.
HRMS (ES): m/z calcd for C15H26O Na (M + Na)+, 245.1878;
found, 245.1889.
Synthesis 2002, No. 14, 2105–2109 ISSN 0039-7881 © Thieme Stuttgart · New York